Isolation of bacteria with plant growth-promoting properties from microalgae-bacterial flocs produced in high-rate oxidation ponds.
Exploring plant growth-promoting (PGP) bacterial activity of microbial components aggregated by wastewater treatment can reduce dependence on fossil fuel-derived fertilisers. This study describes the isolation and identification of bacteria from microalgae-bacteria flocs (MaB-flocs) generated in high-rate algal oxidation ponds (HRAOP) of an integrated algal pond system (IAPS) remediating municipal wastewater. Amplified 16S rRNA gene sequence analysis determined the molecular identity of the individual strains. Genetic relatedness to known PGP rhizobacteria in the NCBI GenBank database was by metagenomics. Isolated strains were screened for the production of indoles (measured as indole-3-acetic acid; IAA) and an ability to mineralise NH4+, PO43-, and K + . Of the twelve bacterial strains isolated from HRAOP MaB-flocs, four produced indoles, nine mineralised NH4+, seven solubilised P, and one K. Potential of isolated strains for PGP activity according to one-way ANOVA on ranks was: ECCN 7b > ECCN 4b > ECCN 6b > ECCN 3b = ECCN 10b > ECCN 1b = ECCN 5b > ECCN 8b > ECCN 2b > ECCN 12b > ECCN 9b = ECCN 11b. Further study revealed that cell-free filtrate from indole-producing cultures of Aeromonas strain ECCN 4b, Enterobacter strain ECCN 7b, and Arthrobacter strain ECCN 6b promoted mung bean adventitious root formation suggestive of the presence of auxin-like biological activity.


Thyroid hormone-carbohydrate interaction at the hepatic nuclear level.
We have studied the interaction between triiodothyronine (T3) and carbohydrate (CHO) in the induction of hepatic lipogenic enzymes under both in vivo and in vitro conditions. Our studies demonstrate a synergistic relationship between T3 administration and CHO feeding in the induction of these enzymes. Likewise, in states characterized by CHO deprivation such as starvation and diabetes, the response to T3 is also inhibited. Studies in the aging animal have documented a diminished response both to CHO and to T3. Our studies suggest that T3 multiplies a primary CHO-generated signal by a constant factor, and that this signal declines with age. Additional studies with primary hepatocyte cultures provide evidence that glucose is the main factor responsible for the induction of hepatic malate dehydrogenase: decarboxylating (EC 126.96.36.199) (ME). Glucose induces ME in the absence of changes in extrahepatic hormones or metabolites and in the complete absence of T3. In the cultured hepatocyte system, T3 also acts as a constant multiplier of the primary glucose-derived signal. Our results provide further support for the thesis that the primary action of T3 at the molecular level is a multiplication of other nuclear signals. The complexity of response pattern to both T3 and CHO administration, however, is illustrated by recent studies in which we have analyzed the translated products of total poly(A+) RNA extracted from livers of rats subjected to various physiological stimuli.


Managing water resources for sustainable development: the case of integrated river basin management in China.
The emerging water crisis in China shows that the current institutional frameworks and policies with regard to water resources management are incapable of achieving an effective and satisfactory situation that includes Integrated River Basin Management (IRBM). This paper analyses this framework and related policies, examines their deficiencies in relation to all water stress problems and explores alternatives focusing on river basins. Water resources management reforms in modern China are reviewed and the main problems involved in transforming the current river management system into an IRBM-based system are analysed. The Huai River basin is used as an example of current river basin management, with quantitative data serving to show the scale and scope of the problems in the country as a whole. The institutional reforms required are discussed and a conceptual institutional framework is proposed to facilitate the implementation of IRBM in China. In particular, the roles, power and responsibilities of River Basin Commissions (RBCs) should be legally strengthened; the functions of supervising, decision-making and execution should be separated; and cross-sectoral legislation, institutional coordination and public participation at all levels should be promoted.


With(out) a little help from my friends: insecure attachment in adolescence, support-seeking, and adult negativity and hostility.
Attachment theory suggests that insecurely attached individuals will have more difficulty seeking and receiving support from others. Such struggles in adolescence may reinforce negative expectations of others and contribute to relationship difficulties into adulthood. Using a diverse community sample of 184 adolescents followed from age 13 to 27, along with friends and romantic partners, this study found that more insecure states of mind regarding attachment at age 14 predicted relative decreases in teens' abilities to seek and receive support from close friends from ages 14-18. In addition, greater attachment insecurity predicted greater observed negative interactions with romantic partners and relative increases in hostile attitudes from ages 14 to 27. The effect of attachment insecurity on observed negativity was mediated by difficulty seeking/receiving support in friendships during adolescence. Results suggest a type of self-fulfilling prophecy as insecure adolescents confirm their negative expectations of others through ongoing struggles to obtain support.


Protected hinge in the immunoglobulin G2-A2 disulfide isoform.
Human IgG2 consists of disulfide-mediated structural isoforms, classified by the number of Fab arms disulfide-linked to the heavy chain hinge. In the IgG2-B isoform, both Fab arms are linked to the hinge region, and in IgG2-A, neither Fab arm are linked to the hinge. IgG2-A/B is a hybrid between these two forms, with only one Fab arm disulfide-linked to the hinge. Within each of these isoform types are subtypes, with subtle disulfide-linkage differences. Here we explored the structural basis for the A1 and A2 isoform subtypes. Whereas A1 isoform converts into the A/B and B isoforms under mild redox conditions, A2 does not. Characterization of the disulfide connectivities of A2 isoform revealed a similar structure to A1 isoform, with parallel inter heavy chain disulfide linkages in the hinge region. However, the hinge disulfides in A2 isoform were resistant to reduction under conditions where A1 isoform hinge disulfides became reduced and they required thermal treatment (>55 °C) to obtain thiol-dependent disulfide reduction. Structural analysis of the hinge region indicated that the protected disulfides were restricted to cysteines 219 and 220 of the upper hinge. Disruption of the upper hinge through insertion mutagenesis eliminated A2 isoform behavior. (1)H NMR studies showed that the A1 isoform Fc glycan was more dynamic than that on A2 isoform and showed some other conformational differences. Results point to an IgG2-A2 upper hinge region that is more akin to the interior of a globular protein than the flexible hinge region expected on an IgG.


Induction by Bradyrhizobium diazoefficiens of Different Pathways for Growth in D-mannitol or L-arabinose Leading to Pronounced Differences in CO2 Fixation, O2 Consumption, and Lateral-Flagellum Production.
Bradyrhizobium diazoefficiens, a soybean N2-fixing symbiont, constitutes the basic input in one of the most prominent inoculant industries worldwide. This bacterium may be cultured with D-mannitol or L-arabinose as carbon-plus-energy source (C-source) with similar specific growth rates, but with higher biomass production with D-mannitol. To better understand the bacterium's carbon metabolism, we analyzed, by liquid chromatography and tandem mass spectrometry (MS), the whole set of proteins obtained from cells grown on each C-source. Among 3,334 proteins identified, 266 were overproduced in D-mannitol and 237 in L-arabinose, but among these, only 22% from D-mannitol cultures and 35% from L-arabinose cultures were annotated with well defined functions. In the D-mannitol-differential pool we found 19 enzymes of the pentose-phosphate and Calvin-Benson-Bassham pathways and accordingly observed increased extracellular-polysaccharide production by D-mannitol grown bacteria in a CO2-enriched atmosphere. Moreover, poly-3-hydroxybutyrate biosynthesis was increased, suggesting a surplus of reducing power. In contrast, the L-arabinose-differential pool contained 11 enzymes of the L-2-keto-3-deoxyarabonate pathway, 4 enzymes for the synthesis of nicotinamide-adenine dinucleotide from aspartate, with those cultures having a threefold higher O2-consumption rate than the D-mannitol cultures. The stoichiometric balances deduced from the modeled pathways, however, resulted in similar O2 consumptions and ATP productions per C-mole of substrate. These results suggested higher maintenance-energy demands in L-arabinose, which energy may be used partly for flagella-driven motility. Since B. diazoefficiens produces the lateral-flagella system in only L-arabinose, we calculated the O2-consumption rates of a lafR::Km mutant devoid of lateral flagella cultured in L-arabinose or D-mannitol. Contrary to that of the wild-type, the O2-consumption rate of this mutant was similar on both C-sources, and accordingly outcompeted the wild-type in coculture, suggesting that the lateral flagella behaved as parasitic structures under these conditions. Proteomic data are available via ProteomeXchange with identifier PXD008263.


Adult coeliac disease and cigarette smoking.
Genetic predisposition and gliadin exposure are known to be crucial factors in the development of coeliac disease. Circumstantial evidence suggests that other unidentified environmental factors may also be of pathogenetic importance. To define the relation between cigarette smoking and the risk of development of symptomatic adult onset coeliac disease. Eighty six recently diagnosed adult coeliac disease patients and 172 controls matched for age and sex. Matched case control study, using a simple questionnaire to determine smoking history, and in particular smoking status at the time of diagnosis of coeliac disease. At the time of diagnosis, the proportion of current smokers was 7% in the coeliac group, and 32.6% in the control group, giving a matched odds ratio of 0.15 (95% confidence intervals 0.06, 0.38). The difference could not be accounted for by social class, nor by coeliac patients giving up smoking after the onset of symptoms as most non-smokers in the coeliac group had never smoked. Cigarette smoking, or a factor closely linked to it, seems to exert a major protective effect against the development of symptomatic adult onset coeliac disease. The implication is that gliadin exposure is not the only important environmental factor involved in the pathogenesis of this condition.


[Effects of indomethacin and BCG vaccine on growth of transplanted tumors in mice].
Continuous administration of indomethacin (IM) in drinking water (20 micrograms/ml) causes moderate inhibition of the growth of transplantable tumors in control mice but significantly increases the antitumor effect of BCG vaccine inoculated in combination with transplanted tumor cells. Hepatoma 29, insensitive to the vaccine becomes highly sensitivity to it under IM administration.


A phase II trial of trebananib (AMG 386; IND#111071), a selective angiopoietin 1/2 neutralizing peptibody, in patients with persistent/recurrent carcinoma of the endometrium: An NRG/Gynecologic Oncology Group trial.
Ang1 & 2 (angiopoietin-1; -2) interact with Tie2 receptors on endothelial cells to mediate vascular remodeling in an angiogenesis signaling pathway distinct from the VEGF axis. Trebananib is a peptide Fc fusion protein that binds Ang1 and 2 and prevents interaction with Tie2. The efficacy of trebananib in recurrent/persistent endometrial cancer (EC) was studied. The primary objective was to determine the frequency of patients with objective tumor responses (ORR) and event-free survival for ≥6months (6-month EFS) and determine toxicity of trebananib at a dose and schedule of 15mg/kg, IV QW. Recurrent/persistent EC, measurable disease, and ≤2 prior chemotherapy lines were required. Thirty-two patients were eligible and treated. The most common histologies were G1/2 endometrioid (31%), G3 endometrioid (28%) and serous (31.3%). 78% of patients had 1 prior regimen. Patients received 1-9+ cycles of trebananib; 24 patients (75%) received ≤2cycles. One patient had a partial response (3.1%); 8 patients had stable disease (25%) and 5 patients (15.6%) had 6 month EFS. Median progression-free survival and overall-survival were 1.97 months (90% CI 1.77-2.1) and 6.6 months (90% CI 4.01-14.75), respectively. Most common adverse events (AEs) were fatigue, anemia, and GI issues. Grade 3 and 4 AEs were: GI 31 and 0%; vascular 22 and 0%; metabolism/nutrition 19 and 3%; and general (including edema) 16 and 0%. Trebananib has insufficient single agent activity in recurrent EC to warrant further investigation at this dose/schedule.


Evaluation of Cerebral Oxygenation in Neonates with Sepsis with Near-Infrared Spectroscopy.
Objective Neonates with sepsis have increased risk of cerebral injury. Our aim was to evaluate cerebral oxygenation in septic neonates using near-infrared spectroscopy. Study Design A prospective study was designed enrolling neonates with sepsis, as defined by the International Consensus Conference of Pediatric Sepsis criteria and matched controls. Three cerebral half-hourly measurements were performed during the first, third, and seventh day of the episode and the values of tissue oxygenation index (TOI) and fractional tissue oxygen extraction (FTOE) were compared between the two groups. Result The study population consisted of 50 septic and 44 control neonates with similar characteristics. No differences on TOI and FTOE were recorded in the first and third day. However, on the seventh day, septic neonates had significantly decreased oxygenation (62.7 ± 7 vs. 71.4 ± 4.4%, p < 0.001) and increased oxygen extraction (0.35 ± 0.07 vs. 0.27 ± 0.05, p < 0.001), irrespectively of the severity of the infection. Conclusion Although septic neonates have normal cerebral oxygenation in the first and third day of the sepsis, they present decreased cerebral oxygenation in the seventh day independently of the infection severity.


Multiple mutualist effects: conflict and synergy in multispecies mutualisms.
Most organisms interact with multiple mutualistic species that confer different functional benefits, yet current conceptual frameworks do not fully address this complexity. A network approach considers multiple mutualistic interactions within a functional type and has been largely nonmechanistic, with little attention to the fitness consequences of specific interactions. Alternatively, consumer-resource approaches have explicitly characterized the mechanisms and fitness consequences of resource exchange, but have not been extended to functionally divergent partners. First, we merge these approaches using graphical models to define the multiple mutualist effects (MMEs) that occur when a focal species has multiple partner mutualists. This approach mirrors food web research that has been advanced by studies of multiple predator effects as well as by detailed investigations of modules nested within larger networks. Second, we define the pathways through which a focal mutualist and two or more partner species could interact, reviewing examples of MMEs that span a range from positive to negative fitness effects. Third, given the potential for nonadditivity demonstrated by the existing literature, we pose new hypotheses for species-interaction outcomes by examining factors such as the extent of overlap in rewards exchanged among partners and their resulting network topologies. Our synthesis illustrates how the consideration of MMEs can improve the ability to predict the outcomes of losses or gains of mutualisms from ecosystems.


Diagnosing congenital malaria in a high-transmission setting: clinical relevance and usefulness of P. falciparum HRP2-based testing.
Congenital malaria diagnosis is challenging due to frequently observed low parasite density infections, while their clinical relevance during early infancy is not well characterized. In Nanoro health district (Burkina Faso), we determined the prevalence of congenital malaria by real-time quantitative PCR and we assessed the performance of rapid diagnosis test (RDT) and light microscopy (LM) to detect Plasmodium falciparum infections in cord-blood samples. In addition, we examined the usefulness of P. falciparum Histidine Rich Protein2 (PfHRP2) as surrogate biomarker of infection and explored association between congenital malaria and clinical outcomes. A prevalence of congenital malaria by qPCR of 4% (16/400) was found, which increased to 10% among newborns from mothers infected at delivery. RDT and LM showed poor performances indicating limited utility for congenital malaria screening in cord blood. Because PfHRP2 detection in cord blood could be affected by transplacental passage of parasite antigens, PfHRP2 might not be used as a surrogate biomarker of congenital malaria infections. There was no evidence of a significant clinical impact of congenital malaria on infant's health from birth to 59 days of life. Case control studies including long-term follow up may provide additional understanding on the relevance of neonatal malaria infections.


Levodopa/Carbidopa to Augment the Treatment of Amblyopia: A Report by the American Academy of Ophthalmology.
To review the published literature on the use of levodopa/carbidopa to augment the treatment of amblyopia. Literature searches for English language studies were last conducted in October 2022 in the PubMed database with no date restrictions. The combined searches yielded 55 articles, of which 23 were reviewed in full text. Twelve of these were considered appropriate for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist. Nine studies were rated level I, and 3 studies were rated level II; there were no level III studies. The duration of treatment was limited to 3 to 16 weeks because of concern about long-term adverse effects such as tardive dyskinesia. This complication was not reported in any of the study participants. The dose of levodopa ranged from 1.5 to 8.3 mg/kg/day, generally divided into 3 daily doses. The carbidopa dose was approximately 25% of the levodopa dose in all treatments. Evidence from these studies indicates that augmenting traditional patch occlusion therapy with the oral administration of levodopa/carbidopa can improve the vision of amblyopic children, but the effect was small (0.17-0.3 logarithm of the minimum angle of resolution [logMAR] units) and only statistically significant when compared with patching alone in 2 of the 12 studies cited. Regression of vision was reported in the majority of studies (9 of 12 reported; range, 0-0.17 logMAR unit regression) after discontinuation of therapy. Short-term side effects of the medications were not consistently reported but were most frequently mild and included headache and nausea. The best available evidence is currently insufficient to show that augmenting amblyopia therapy using up to 16 weeks of levodopa/carbidopa will result in meaningful improvement in visual acuity. Given the potential for significant side effects such as tardive dyskinesia with long-term therapy, levodopa/carbidopa does not appear to be a viable option for amblyopia therapy FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Adhesive foot pads: an adaptation to climbing? An ecological survey in hunting spiders.
Hairy pads relying on dry adhesion are fascinating structures that convergently evolved among spiders and lizards. Numerous studies underline the functional aspects leading to their strong adhesion to smooth surfaces, but rarely has their role been studied in the context of natural habitats and surfaces that animals are faced with. In hunting spiders, the hairy foot pads (claw tufts) underneath the paired claws are assumed to be an adaptation to a climbing lifestyle, particularly on smooth plant surfaces. However, surfaces that are too smooth for claws to generate a sufficient grip are rather rare in natural habitats and above-ground habitats are occupied by hunting spiders both with and without claw tufts. In this study we estimated the proportion of claw tuft-bearing hunting spiders (ct+ ratio) among microhabitat-specific assemblages by conducting both a field study and a meta-analysis approach. The effect of surface characteristics, structure fragmentation and altitude of the microhabitat niche on the ct+ ratio was analyzed. We hypothesized that the ct+ ratio will be higher in (i) hunting spider assemblages obtained from microhabitats above the ground than from those at the ground and (ii) in hunting spider assemblages obtained from microhabitats with smoother surfaces (tree foliage) than those with rougher surfaces (barks, stones), and lower in (iii) hunting spider assemblages obtained from microhabitats with more fragmented structures (small leaves) than in those with comparable but less fragmented structures (large leaves). We found the ct+ ratio to be significantly affected by the microhabitat's distance from the ground, whereas surface characteristics and fragmentation of the substrates were of minor importance. This suggests that claw tufts are highly beneficial when the microhabitat's height exceeds a value where the additional pad-related costs are exceeded by the costs of dropping. We assume the benefit to be mainly due to gaining a high safety factor at a lower energy demand if compared to alternative attachment devices (claws, silk). The previously presumed enhanced access to new microhabitat sites may play only a minor role as hunting spiders without claw tufts are present in most microhabitats.


RDS/peripherin gene mutations are frequent causes of central retinal dystrophies.
Patients from 76 independent families with various forms of mostly central retinal dystrophies were screened for mutations in the RDS/peripherin gene by means of SSCP analysis and direct DNA sequencing. Two nonsense mutations (Gln239ter, Tyr285ter), five missense mutations (Arg172Trp, Lys197Glu, Gly208Asp, Trp246Arg, Ser289Leu), and one single base insertion (Gly208insG), heterozygous in all cases, were detected. Only one of these mutations, Arg172Trp, has been reported previously. Cosegregation of the mutation with the disease phenotype could be established in selected families. Other missense mutations were excluded from a panel of 55-75 control subjects. The patients showed remarkable variation in phenotype and disease expression not only between cases with different mutations but also between affected members of the same family. This study indicates that RDS/peripherin mutations are a frequent cause of various types of central retinal dystrophies and that the RDS/peripherin gene exhibits a broad spectrum of allelic mutations. Comparative analysis of known mutations allowed us to hypothesise that the deleterious effect of RDS/peripherin gene mutations is the result of different molecular mechanisms.


Patterns of protein synthesis during the cell cycle of the fission yeast Schizosaccharomyces pombe.
The rate of protein synthesis through the cell cycle of Schizosaccharomyces pombe has been determined from the incorporation of pulses of [3H]tryptophan in synchronous cultures prepared by selection in an elutriating rotor. This selection procedure caused minimal perturbations as judged by asynchronous control cultures, which had also been put through the rotor. The rate of synthesis showed a periodic pattern rather than a smooth exponential increase. There was a sharp increase in the rate at an 'acceleration point' at about 0.9 of the cycle. Model-fitting by a novel procedure suggests that the average single cell has an increasing rate of protein synthesis for the first 60% of the cycle and a constant rate for the remaining 40%. The same pattern was shown in less extensive experiments with [3H]leucine and [3H]phenylalanine. It was also shown in a series of size mutants, which indicates that the pattern is not size-related, in contrast to earlier work on the rates of synthesis of messenger RNA. However, one large mutant (cdc 2.M35r20) had a significantly earlier acceleration point. Care was taken to justify the assumption that the rate of incorporation of tryptophan was a valid measure of the rate of protein synthesis. A tryptophan auxotroph was used to eliminate the problem of endogenous supply and the size of the metabolic pool was measured through the cycle. This pool did not show cell-cycle related fluctuations. An operational model of the pools is presented.


The crucible of COVID-19: what the pandemic is teaching us about health research systems.
The global health crisis created by COVID-19 is providing valuable insights into the strengths of our health research system and, perhaps even more clearly, displaying its weaknesses. Much of what is being shown so plainly in the current context is not truly new. We are being reminded that health research systems are slow and noisy as well as that there is a desire for research to inform decision-making, that researchers are great collaborators, and that the walls we are so quick to erect between health research and health practice are unhelpful facades. It is our hope that the clarity with which these issues are being demonstrated by COVID-19 might provide the impetus to address these challenges and seize these opportunities to improve our health research system, for the benefit for communities facing COVID-19 now, and for the benefit of us all in facing the further health challenges that are sure to come.


Lumbar spine stability can be augmented with an abdominal belt and/or increased intra-abdominal pressure.
The increased intra-abdominal pressure (IAP) commonly observed when the spine is loaded during physical activities is hypothesized to increase lumbar spine stability. The mechanical stability of the lumbar spine is an important consideration in low back injury prevention and rehabilitation strategies. This study examined the effects of raised IAP and an abdominal belt on lumbar spine stability. Two hypotheses were tested: (1) An increase in IAP leads to increased lumbar spine stability, (2) Wearing an abdominal belt increases spine stability. Ten volunteers were placed in a semi-seated position in a jig that restricted hip motion leaving the upper torso free to move in any direction. The determination of lumbar spine stability was accomplished by measuring the instantaneous trunk stiffness in response to a sudden load release. The quick release method was applied in isometric trunk flexion, extension, and lateral bending. Activity of 12 major trunk muscles was monitored with electromyography and the IAP was measured with an intra-gastric pressure transducer. A two-factor repeated measures design was used (P < 0.05), in which the spine stability was evaluated under combinations of the following two factors: belt or no belt and three levels of IAP (0, 40, and 80% of maximum). The belt and raised IAP increased trunk stiffness in all directions, but the results in extension lacked statistical significance. In flexion, trunk stiffness increased by 21% and 42% due to 40% and 80% IAP levels respectively; in lateral bending, trunk stiffness increased by 16% and 30%. The belt added between 9% and 57% to the trunk stiffness depending on the IAP level and the direction of exertion. In all three directions, the EMG activity of all 12 trunk muscles increased significantly due to the elevated IAP. The belt had no effect on the activity of any of the muscles with the exception of the thoracic erector spinae in extension and the lumbar erector spinae in flexion, whose activities decreased. The results indicate that both wearing an abdominal belt and raised IAP can each independently, or in combination, increase lumbar spine stability. However, the benefits of the belt must be interpreted with caution in the context of the decreased activation of a few trunk extensor muscles.


Development of a conceptual framework for a Virtual Reality-based Seizure Management Education Program for Parents (VR-ESMEPP).
Parents of children with epilepsy need support when managing epileptic seizures outside medical-care-center-settings. Previously developed training programs only provide information-based support. Therefore, within the scope of the VR-ESMEPP, a conceptual framework was developed in this study with the aim of developing parents' skills and motivation as well as providing them information regarding seizure management. The conceptual framework of the VR-ESMEPP was developed in four steps. In step 1, a scenario was developed wherein a pediatric patient with epilepsy is having a seizure. The selected seizure type was "Focal to bilateral tonic-clonic" seizure, which is the most common and most skill-intensive type of tonic-clonic-seizure. In step 2, data collection tools related to epileptic seizure management were developed for parents. These tools included Child and Parent Introductory Form, Parental Information Assessment Form for Epileptic Seizure Management, and Parental Skills Assessment Form for Epileptic Seizure Management. In step 3, the conceptual framework and data collection tools developed were confirmed by a group of 10 specialists consisting of physicians and pediatric nurses working in the field of pediatric neurology. In step 4, the epileptic-pediatric-patient-scenario and data collection tools confirmed by experts were programmed into an application by a software company and integrated into virtual reality headsets. VR-ESMEPP with the conceptual framework described in the present study is a valid virtual reality-based program, which can be carried out under nurses' supervision and used to provide epilepsy-related education to parents. VR-ESMEPP helped parents increase their knowledge and skills of epileptic seizure.


Delay in initiation of treatment after diagnosis of pulmonary tuberculosis in primary health care setting: eight year cohort analysis from district Faridabad, Haryana, North India.
Delay in initiation of tuberculosis (TB) treatment may have a tremendous impact on disease transmission, development of drug resistance, poor outcome and overall survival of TB patients. The delay can occur at various levels. Delay in initiation of treatment after diagnosis is mostly due to health system failure and has immense programmatic implications. It has not been studied extensively in the Indian setting. The authors did a cohort analysis of all TB patients initiated on treatment from two primary health centres (PHCs) at Ballabgarh Health and Demographic Surveillance System between January 2007 and December 2014. Diagnosis and treatment of TB in the study area was done as per the protocol envisaged in the national program. Information related to demography, details of diagnosis and treatment of TB and outcome of treatment were extracted from the TB register. Delay in initiation of treatment after diagnosis was considered if the gap between diagnosis and treatment was greater than 7 days. Bivariate and multivariate analyses were done to find the association of various factors with delay in initiation of treatment after diagnosis. Out of 885 patients, 662 patients started treatment for pulmonary TB. Mean time interval between diagnosis and initiation of treatment was 8.95 days. Only 57.7% of pulmonary TB patients were started on treatment within 7 days of diagnosis, and an additional 24.5% were started on treatment 8-14 days after diagnosis. Patients on retreatment regimens and those residing in villages without a PHC were more likely to have delayed initiation of treatment (odds ratio (OR)=1.82 (1.3-2.7, p=0.001) and OR=1.62 (1.1-2.5, p=0.01) respectively). Delay in initiation of treatment was also associated with unfavourable treatment outcome such as default, failure or death. There is a need to have healthcare changes related to TB care to enable initiation of treatment as early as possible. Pretreatment counselling especially for retreatment patients is of utmost importance.


Two regimes of wide angle acousto-optic interaction in tellurium dioxide single crystals.
The paper presents results of investigation of wide angle acousto-optic (AO) diffraction based on light beams propagating in birefringent crystals far away from optical axes and also close to the optical axes. A comparison of the two cases of wide angle interaction in tellurium dioxide crystal is carried out. Advantages and drawbacks of the far-off axis (FOA) diffraction are examined in the paper. Possibility of application of the FOA diffraction in imaging AO filters is discussed. Results of theoretical consideration of the problem are experimentally confirmed in a paratellurite filter using a slow shear acoustic wave propagating in the (11¯0) plane of the crystal at the angle α=10° relative to the axis [110].


Cushing, Cutler and the mitral valve.
Because of the over-all excellent results in the correction of many cardiac disorders which have accrued during the past several years, it is easy to take for granted the long and often painful evolution of surgery of the heart. Experimental work on the creation of valvular lesions and attempts at their repair stem back for a century, although it took until the 1920's before a few intrepid surgeons considered such procedures for clinical use. It is of interest that early attempts on repair of mitral stenosis, both in laboratory animals and in patients, were undertaken by Cushing and Cutler, two surgical innovators who succeeded each other as Moseley Professors of Surgery at the Peter Bent Brigham Hospital. Such early efforts in surgical manipulation of the heart opened the way for the refinements of modern cardiac surgery that have become routine.


[Inhibition of growth of E. coli cells by anolites of sodium and potassium chloride after processing solutions in a diaphragmatic electrolyzer].
The relationship between the inhibitory effect of sodium chloride and potassium anolites, obtained in a diaphragm electrolyser, and the physicochemical parameters of solutions was compared with that between the inhibitory effect and physicochemical properties of hypochlorites obtained after treating the solutions in an electrolyser having no diaphragm was compared. The biological activity of solutions containing molecular chlorine, hypochlorous acid, and hypochlorite ions was determined by their effect on the growth of E. coli cells. After a 5-min incubation of cells with each of the oxidizers, the bacterial growth stopped and was not restored during one day. The conclusion is made that the oxidizers irreversibly disturb the barrier properties of cell membranes and, in some cases, destroy cells. In model solutions, as well as in solutions treated after heating on a water bath or after the addition of sodium thiosulfate, a delay in the start of E. coli growth occurs. After the lag-phase, the repair of cells sets on, and after a day the optical density of cells increases and approaches the control.


Safety and efficacy of two starting doses of vandetanib in advanced medullary thyroid cancer.
Vandetanib is an oral tyrosine kinase inhibitor approved for treatment of advanced symptomatic or progressive medullary thyroid cancer (MTC). The current study (Nbib1496313) evaluated the benefit-risk of two starting doses of vandetanib in patients with symptomatic or progressive MTC. Patients were randomized 1:1 to receive vandetanib 150 or 300 mg daily and followed for a maximum of 14 months (Part A), with the option to then enter an open-label phase (Part B) investigating vandetanib 100, 150, 200 and 300 mg daily doses. Efficacy was assessed in Part A, and safety and tolerability during Parts A and B up to 2 years post randomization. Eighty-one patients were randomized in Part A and 61 patients entered Part B, of whom 37 (60.7%) received 2 years of treatment. Overall, 25% of patients experienced an objective response (OR) at 14 months (OR rate, 0.29 (95% CI, 0.176-0.445) for 300 mg, and 0.20 (95% CI, 0.105-0.348) for 150 mg; one-sided P value approximately 0.43). The most common adverse events (AEs) included diarrhea, hypocalcemia, asthenia, QTc prolongation, hypokalemia and keratopathy, all at generally higher incidence with 300 vs 150 mg (Part A). Part B safety and tolerability was consistent with Part A. OR was observed with both vandetanib doses; the 300 mg dose showed a more favorable trend vs 150 mg as initial dose. Thus, for most patients, 300 mg vandetanib is the most appropriate starting dose; dose reductions to manage AEs and lower initial doses for patients with particular comorbidities can be considered.


Chemokine receptor CXCR4 interacts with nuclear receptor Nur77 and promote glioma invasion and progression.
Glioma is the most common primary brain tumor. It is prone to progress and have high rate of mortality regardless of radiation or chemotherapy due to its invasive growth features. Chemokine and its receptor CXCL12 and CXCR4 play important roles in cancer metastasis. In this study, we investigate the role of CXCR4 in the progression of glioma by various molecular technologies, including qRT-PCR, Western blotting, wound closure assay, transwell assay et al. RESULTS: It was found that CXCR4 was overexpressed in glioma tissues. The expression of CXCR4 was correlated with patients' overall survival. Wound closure assay and transwell invasion assay showed that inhibition of CXCR4 significantly reduced the expression of biomarkers related to the formation of invadopodium, leading to decrease the invasion and migration of glioma tumor cells. Knocking down the nuclear receptor Nur77 remarkably decreased CXCR4 expression and reduced glioma cell invasion and migration. The reduction of glioma cell invasion and migration were observed after Nur77 inhibitor treatment. Taken together, these results indicated that CXCR4 is critical in promoting glioma migration and invasion. Inhibition of Nur77 reduces CXCR4 related cancer progression.


Evaluation of metal toxicity by a modified method based on the fungus Gerronema viridilucens bioluminescence in agar medium.
Metal cation toxicity to basidiomycete fungi is poorly understood, despite its well-known importance in terrestrial ecosystems. Moreover, there is no reported methodology for the routine evaluation of metal toxicity to basidiomycetes. In the present study, we describe the development of a procedure to assess the acute toxicity of metal cations (Na(+), K(+), Li(+), Ca(2+),Mg(2+), Co(2+), Zn(2+), Ni(2+), Mn(2+), Cd(2+), and Cu(2+)) to the bioluminescent basidiomycete fungus Gerronema viridilucens. The method is based on the decrease in the intensity of bioluminescence resulting from injuries sustained by the fungus mycelium exposed to either essential or nonessential metal toxicants. The assay described herein enables us to propose a metal toxicity series to Gerronema viridilucens based on data obtained from the bioluminescence intensity (median effective concentration [EC50] values) versus metal concentration: Cd(2+) > Cu(2+) > Mn(2+) approximately Ni(2+) approximately Co(2+) > Zn(2+) > Mg(2+) > Li(+) > K(+) approximately Na(+) > Ca(2+), and to shed some light on the mechanism of toxic action of metal cations to basidiomycete fungi.


Metabolism of macromolecular heparin in mouse neoplastic mast cells.
1. Polysaccharide in a heparin-producing mouse mastocytoma was pulse-labelled in vivo with [35S] sulphate, and after various periods of time was isolated from subcellular fractions. Such fractions were recovered from tissue homogenates by consecutive centrifugations at 1000g for 10min, 20000g for 20min and 100000g for 1h. Initially the 35S-labelled polysaccharide formed occurred principally in the second centrifugal fraction (20000g precipitate), with small amounts in the first (granular) and third (microsomal) fractions. Analysis for glycosyltransferase activity confirmed that glycosaminoglycans were formed chiefly in particles sedimenting at 20000g. Molecules of this newly synthesized polysaccharide were considerably larger than those of commercially available heparin, as judged from gel chromatography. 2. Within the first hour after injection of [35S]sulphate, most of the labelled polysaccharide was redistributed from the second to the first centrifugal fraction. During, and possibly also after, this shift, the macromolecular polysaccharide was degraded, ultimately to the size of commercial heparin. The degradation process appeared complete 6h after injection of [35S]sulphate. 3. Particulate subcellular fractions were incubated with macromolecular [35S]heparin and the products were analysed by gel chromatography. Significant degradation of the substrate occurred only with the second centrifugal fraction. Further characterization of this fraction, by density-gradient centrifugation in iso-osmotic colloidal silica, revealed a single visible band of particles, at approximately the same density at lysosomes. This band contained all the beta-glucuronidase, 35S-labelled endogenous polysacchride and heparin-degrading enzyme present in the second fraction.


Growth of Campylobacter jejuni supported by respiration of fumarate, nitrate, nitrite, trimethylamine-N-oxide, or dimethyl sulfoxide requires oxygen.
The human gastrointestinal pathogen Campylobacter jejuni is a microaerophilic bacterium with a respiratory metabolism. The genome sequence of C. jejuni strain 11168 reveals the presence of genes that encode terminal reductases that are predicted to allow the use of a wide range of alternative electron acceptors to oxygen, including fumarate, nitrate, nitrite, and N- or S-oxides. All of these reductase activities were present in cells of strain 11168, and the molybdoenzyme encoded by Cj0264c was shown by mutagenesis to be responsible for both trimethylamine-N-oxide (TMAO) and dimethyl sulfoxide (DMSO) reduction. Nevertheless, growth of C. jejuni under strictly anaerobic conditions (with hydrogen or formate as electron donor) in the presence of any of the electron acceptors tested was insignificant. However, when fumarate, nitrate, nitrite, TMAO, or DMSO was added to microaerobic cultures in which the rate of oxygen transfer was severely restricted, clear increases in both the growth rate and final cell density compared to what was seen with the control were obtained, indicative of electron acceptor-dependent energy conservation. The C. jejuni genome encodes a single class I-type ribonucleotide reductase (RNR) which requires oxygen to generate a tyrosyl radical for catalysis. Electron microscopy of cells that had been incubated under strictly anaerobic conditions with an electron acceptor showed filamentation due to an inhibition of cell division similar to that induced by the RNR inhibitor hydroxyurea. An oxygen requirement for DNA synthesis can thus explain the lack of anaerobic growth of C. jejuni. The results indicate that strict anaerobiosis is a stress condition for C. jejuni but that alternative respiratory pathways can contribute significantly to energy conservation under oxygen-limited conditions, as might be found in vivo.


Evaluating the gene-expression profiles of HeLa cancer cells treated with activated and nonactivated poly(amidoamine) dendrimers, and their DNA complexes.
Using dendrimers in cancer therapy as nonviral vectors for gene delivery seems promising. The biological performance of a dendrimer-based gene delivery system depends heavily on its molecular architecture. The transfection activity of dendrimers is significantly improved by processes activated in the heat degradation treatment of solvolysis. However, very little is known about the molecular mechanisms that dendrimers produce in cancer cells. We studied the changes in global gene-expression profiles in human cervical cancer HeLa cells exposed to nonactivated and activated poly(amidoamine) (PAMAM) dendrimers, alone or in complexes with plasmid DNA (dendriplexes). Real-time quantitative reverse transcriptase-polymerase chain reaction was used to confirm four regulated genes (PHF5A, ARNTL2, CHD4, and P2RX7) affected by activated dendrimers and dendriplexes. Activated and nonactivated dendrimers and dendriplexes alike induced multiple gene expression changes, some of which overlapped with their dendriplexes. Dendrimer activation improved transfection efficiency and induced additional gene expression changes in HeLa cells. Dendrimers and dendriplexes principally affect genes with the molecular functions of nucleic acid binding and transcription activity, metal-ion binding, enzyme activity, receptor activity, and protein binding. Our findings provide a deeper insight into the changes in gene expression patterns caused by the molecular structure of PAMAM dendrimers for gene-based cancer therapy.


Induced interleukin-33 expression enhances the tumorigenic activity of rat glioma cells.
Glioma development is a multistep process associated with progressive genetic alterations but also regulated by cellular and noncellular components in a tumor-associated niche. Using 2 rat C6 glioma cell clones with different tumorigenesis, named C6-1 and C6-2, this study characterized genes associated with enhanced tumorigenic features of glioma cells by comparative cDNA microarray analysis combined with Q-PCR. Neurospehere formation and clonogenicity were examined to determine the growth of tumorigenic C6 glioma cells. The lentivirus-mediated gene knockdown approach was conducted to determine the role of interleukin-33 (IL-33) in glioma cell proliferation and migration. Transwell cell invasion assay was used to examine microglia migration induced by tumorigenic C6 cells. The functional analysis of gene ontology (GO) biological processes shows that the upregulated genes found in tumorigenic C6 (C6-1) cells are closely related to cell proliferation. Tumorigenic C6 cells expressed cytokines and chemokines abundantly. Among these genes, IL-33 was profoundly induced in tumorigenic C6 cells with the expression of IL-33 receptor ST2. Furthermore, the growth rate and colony formation of tumorigenic C6 cells were attenuated by the inhibition of IL-33 and ST2 gene expression. Moreover, IL-33 was involved in tumorigenic glioma cell migration and regulation of the expression of several glioma-associated growth factors and chemokines in tumorigenic C6 cells. Accordingly, we concluded that glioma cells with abundant production of IL-33 grow rapidly; moreover, the interactions of multiple cytokines/chemokines induced by glioma cells may develop a microenvironment that facilitates microglia/macrophage infiltration and fosters glioma growth in the brain.


Role of the vascular wall in sodium homeostasis and salt sensitivity.
Excessive sodium intake is associated with both hypertension and an increased risk of cardiovascular events, presumably because of an increase in extracellular volume. The extent to which sodium intake affects extracellular volume and BP varies considerably among individuals, discriminating subjects who are salt-sensitive from those who are salt-resistant. Recent experiments have shown that, other than regulation by the kidney, sodium homeostasis is also regulated by negatively charged glycosaminoglycans in the skin interstitium, where sodium is bound to glycosaminoglycans without commensurate effects on extracellular volume. The endothelial surface layer is a dynamic layer on the luminal side of the endothelium that is in continuous exchange with flowing blood. Because negatively charged glycosaminoglycans are abundantly present in this layer, it may act as an intravascular buffer compartment that allows sodium to be transiently stored. This review focuses on the putative role of the endothelial surface layer as a contributor to salt sensitivity, the consequences of a perturbed endothelial surface layer on sodium homeostasis, and the endothelial surface layer as a possible target for the treatment of hypertension and an expanded extracellular volume.


Overexpression of the gene encoding alternative oxidase for enhanced glucose consumption in oxalic acid producing Aspergillus niger expressing oxaloacetate hydrolase gene.
The filamentous fungus Aspergillus niger is a well-known hyper-producer of organic acids such as citric acid and oxalic acid. This fungus possesses the cyanide (CN)-insensitive respiration pathway consisting of alternative oxidase (EC 18.104.22.168; AOX), in addition to the cytochrome pathway. Since this CN-insensitive respiration pathway reoxidizes NADH without ATP production, it contributes to continuous glycolysis in A. niger. In this study, to show the availability of aoxA gene encoding AOX as a tool for metabolic engineering, we generated efficient oxalic acid (OA)-producers by genetic engineering of A. niger using aoxA gene. The OA-producing strain EOAH-1, generated by overexpression of the oxaloacetate hydrolase (EC 188.8.131.52; OAH) gene oahA in A. niger WU-2223L, produced 28 g/L OA from 30 g/L glucose during the 9-day cultivation period. Moreover, the strain EAOXOAH-1, generated by overexpression of both aoxA and oahA genes in strain WU-2223L, produced 28 g/L OA during the 7-day cultivation period. Strain EAOXOAH-1 showed higher glucose consumption rate than EOAH-1 did, indicating that overexpression of aoxA contributed to the acceleration of glucose consumption, and that the OA production period was shortened by 2 days. Thus, we clearly show that AOX gene must be an effective tool in metabolic engineering for efficient organic acids production from carbohydrates.


Children's views of their adaptation to type 1 diabetes mellitus.
When a family learns their child has insulin-dependent type 1 diabetes mellitus, or type 1 diabetes, shock and anxiety are quickly followed by the reality of the demands of managing the condition. Demands include injections or continuous insulin infusion, blood glucose monitoring 2 to 4 times a day, regimented meal planning, and intensive planning of daily activities. Like many chronic illnesses, type 1 diabetes can have long-term effects on the child and family. Health providers must offer support in a number of ways. To determine the best way to approach children with diabetes mellitus, this study examined children's perceptions of their adaptation to type 1 diabetes. Recognizing children's own perceptions is critical for long-term understanding and management. The children in this study had overall positive self-perceptions and good attitudes toward illness. Even though many adults perceive diabetes mellitus in children as an overwhelming experience, the children's attitudes in this study were very positive.


Functional Connectivity Dynamics show Resting-State Instability and Rightward Parietal Dysfunction in ADHD.
Attention Deficit/Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders in children and is characterised by inattention, impulsiveness and hyperactivity. While several studies have analysed the static functional connectivity in the resting-state functional MRI (rs-fMRI) of ADHD patients, detailed investigations are required to characterize the connectivity dynamics in the brain. In an attempt to establish a link between attention instability and the dynamic properties of Functional Connectivity (FC), we investigated the differences in temporal variability of FC between 40 children with ADHD and 40 Typically Developing (TD) children. Using a sliding-window method to segment the rs-fMRI scans in time, we employed seed-to-voxel correlation analysis for each window to obtain time-evolving seed connectivity maps for seeds placed in the posterior cingulate cortex (PCC) and the medial prefrontal cortex (mPFC). For each subject, the standard deviation of the voxel connectivity time series was used as a measure of the temporal variability of FC. Results showed that ADHD patients exhibited significantly higher variability in dFC than TD children in the cingulo-temporal, cingulo-parietal, fronto-temporal, and fronto-parietal networks ( pFW E < 0.05). Atypical temporal variability was observed in the left and right temporal gyri, the anterior cingulate cortex, and lateral regions of the right parietal cortex. The observations are consistent with visual attention issues, executive control deficit, and rightward parietal dysfunction reported in ADHD, respectively. These results help in understanding the disorder with a fresh perspective linking behavioural inattention with instability in FC in the brain.


Multicenter, International Assessment of the Eighth Edition of the American Joint Committee on Cancer Cancer Staging Manual for Conjunctival Melanoma.
Eye cancer staging systems used for standardizing patient care and research need to be validated. To evaluate the accuracy of the eighth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual in estimating metastatis and mortality rates of conjunctival melanoma. This international, multicenter, registry-based case series pooled data from 10 ophthalmic oncology centers from 9 countries on 4 continents. A total of 288 patients diagnosed with conjunctival melanoma from January 1, 2001, to December 31, 2013, were studied. Data analysis was performed from July 7, 2018, to September 11, 2018. Treatments included excision biopsy, cryotherapy, topical chemotherapy, radiation therapy, enucleation, and exenteration. Metastasis rates and 5-year and 10-year Kaplan-Meier mortality rates according to the clinical T categories and subcategories of the eighth edition of the AJCC Cancer Staging Manual. A total of 288 eyes from 288 patients (mean [SD] age, 59.7 [16.8] years; 147 [51.0%] male) with conjunctival melanoma were studied. Clinical primary tumors (cT) were staged at presentation as cT1 in 218 patients (75.7%), cT2 in 34 (11.8%), cT3 in 15 (5.2%), and cTx in 21 (7.3%). There were no T4 tumors. Pathological T categories (pT) were pTis in 43 patients (14.9%), pT1 in 169 (58.7%), pT2 in 33 (11.5%), pT3 in 12 (4.2%), and pTx in 31 (10.8%). Metastasis at presentation was seen in 5 patients (1.7%). Metastasis during follow-up developed in 24 patients (8.5%) after a median time of 4.3 years (interquartile range, 2.9-6.0 years). Of the 288 patients, 29 died (melanoma-related mortality, 10.1%) at a median time of 5.3 years (interquartile range, 1.8-7.0 years). The cumulative rates of mortality among patients with cT1 tumors were 0% at 1 year, 2.5% (95% CI, 0.7%-7.7%) at 5 years, and 15.2% (95% CI, 8.1%-27.4%) at 10 years of follow-up; among patients with cT2 tumors, 0% at 1 year, 28.6% (95% CI, 12.9%-58.4%) at 5 years, and 43.6% (95% CI, 19.6%-77.9%) at 10 years of follow-up; and among patients with cT3 tumors, 21.1% (95% CI, 8.1%-52.7%) at 1 year of follow-up and 31.6% (95% CI, 13.5%-64.9%) at 5 years of follow-up. Patients with cT2 and cT3 tumors had a significantly higher cumulative mortality rate compared with those presenting with cT1 tumors (log-rank P < .001). Patients with ulcerated melanomas had significantly higher risk of mortality (hazard ratio, 7.58; 95% CI, 1.02-56.32; P = .04). This multicenter, international, collaborative study yielded evidence that the conjunctival melanoma staging system in the eighth edition of the AJCC Cancer Staging Manual can be used to accurately estimate metastasis and mortality rates. These findings appear to support the use of AJCC staging as a tool for patient care and research.


Sternal cancellous bone graft harvest for anterior cervical discectomy and fusion with interbody cage devices.
Retrospective chart review, technical note, cohort study. To describe the clinical outcome of a modified method of obtaining cancellous autograft from the manubrium of the sternum for use in interbody cages during anterior cervical fusions. Harvest of structural grafts from the anterior iliac crest (AIC) for anterior cervical fusion has well-established morbidities. In an effort to minimize morbidity and maximize fusion, we utilized interbody cages filled with autologous cancellous bone. In cases needing corpectomy, local bone graft from the corpectomy is used to fill the cage. In cases needing discectomy alone, no local bone is resected and therefore alternative donor sources must be used if autograft is to be used and the complications of AIC harvest are to be avoided. This technique is especially useful in countries where allograft is either not available or available in limited quantity. We have developed a modified technique for the harvest of autologous cancellous graft from the sternum which can be used as a fusion substrate with cervical interbody cages. This technique incorporates either a small incision just above the sternal notch or subcutaneous tunneling from the discectomy incision and use of a bone graft harvester. We retrospectively analyze the clinical outcome and fusion rates. Using the described technique, one-hundred sternal graft harvests (n=100) have resulted in three minor complications: one wound hematoma which resolved with observation, and two superficial wound infections which required treatment with oral antibiotics. All the patients were satisfied by the cosmetic appearance of the incision. Spinal fusion was achieved in all patients at the end of 12 months. We describe a modified technique of harvesting the sternal graft and also for the first time describe the long-term clinical outcome of using sternal autograft for ACDF. The sternal manubrium provides a viable alternative to AIC grafting. It confers the advantages of autograft fusion without the complications associated with AIC graft harvesting.


[Health care labor market in Brazil: nursing employment in the last 3 decades].
The present study shows the dynamics of employment for the nursing profession in Brazil from 1970 up to 1990. It outlines the main characteristics and trends of this labor market before and after the implantation of the Sistema Unico de Saúde-SUS (Federal Health Care System). The main source of information for this investigation was data published in the research Medical-Sanitary Assistance carried out by IBGE (Brazilian Geography and Statistics Institute).


Clinical Practice Guidelines for the Management of Atopic Dermatitis 2016.
Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. Most patients have an atopic predisposition. The definitive diagnosis of AD requires the presence of all three features: (i) pruritus; (ii) typical morphology and distribution of the eczema; and (iii) chronic and chronically relapsing course. The current strategies to treat AD in Japan from the perspective of evidence-based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.


Novel Guidewire Design and Coating for Continuous Delivery of Adenosine During Interventional Procedures.
Background The "no-reflow phenomenon" compromises percutaneous coronary intervention outcomes. There is an unmet need for a device that prevents no-reflow phenomenon. Our goal was to develop a guidewire platform comprising a nondisruptive hydrophilic coating that allows continuous delivery of adenosine throughout a percutaneous coronary intervention. Methods and Results We developed a guidewire with spaced coils to increase surface area for drug loading. Guidewires were plasma treated to attach hydroxyl groups to metal surfaces, and a methoxy-polyethylene glycol-silanol primer layer was covalently linked to hydroxyl groups. Using polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl acetate, a drug layer containing jet-milled adenosine was hydrogen-bonded to the polyethylene glycol-silanol layer and coated with an outer diffusive barrier layer. Coatings were processed with a freeze/thaw curing method. In vitro release studies were conducted followed by in vivo evaluation in pigs. Coating quality, performance, and stability with sterilization were also evaluated. Antiplatelet properties of the guidewire were also determined. Elution studies with adenosine-containing guidewires showed curvilinear and complete release of adenosine over 60 minutes. Porcine studies demonstrated that upon insertion into a coronary artery, adenosine-releasing guidewires induced immediate and robust increases (2.6-fold) in coronary blood flow velocity, which were sustained for ≈30 minutes without systemic hemodynamic effects or arrhythmias. Adenosine-loaded wires prevented and reversed coronary vasoconstriction induced by acetylcholine. The wires significantly inhibited platelet aggregation by >80% in vitro. Guidewires passed bench testing for lubricity, adherence, integrity, and tracking. Conclusions Our novel drug-releasing guidewire platform represents a unique approach to prevent/treat no-reflow phenomenon during percutaneous coronary intervention.


A longitudinal study on language acquisition in monozygotic twins concordant for autism and hyperlexia.
Hyperlexia, a strong orientation towards written materials, along with a discrepancy between the precocious acquisition of decoding skills and weaker comprehension abilities, characterizes up to 20% of autistic children. Sometimes perceived as an obstacle to oral language acquisition, hyperlexia may alternatively be the first step in a non-social pathway of language acquisition in autism. We describe two monozygotic twin brothers, both autistic and hyperlexic, from the ages of 4 to 8 years old. Following an in-depth diagnostic assessment, we investigated cross-sectionally and longitudinally their verbal and non-verbal cognitive abilities, language, reading and writing skills, interests, and strengths. The twins' features, including their high non-verbal level of intelligence, their special interests, and their skills in various domains, were highly similar. Their language consisted exclusively of letters and numbers until their fourth year. After that, their vocabulary broadened until they developed full sentences, and their perception-related interests expanded and merged over time to serve the development of other skills. Our results show that hyperlexic skills can be harnessed to favor oral language development. Given the strong concordance between the twins' cognitive and behavioral phenotypes, we discuss the environmental and genetic influence that could explain their abilities.


Oral Administration of Prunella vulgaris L Improves the Effect of Taxane on Preventing the Progression of Breast Cancer and Reduces Its Side Effects.
We aimed to explore the efficacy and safety of Prunella vulgaris L (PVL) combined with taxane for treatment of patients with breast cancer (BC). The main ingredients of PVL were analyzed by high-performance liquid chromatography (HPLC). In the experiment, 424 patients with BC were evenly assigned into two groups: experimental group (EG, oral administration of PVL and taxane) and control group (CG, oral administration of placebo and taxane). The primary endpoint was pathologic complete response (pCR), which was evaluated using Miller and Payne system. The secondary endpoints included adverse events (AE) and overall survival (OS), which were evaluated by Common Terminology Criteria for Adverse Event version and Kaplan-Meier curves, respectively. Response Evaluation Criteria in Solid Tumors was used to evaluate the clinical efficacy of PVL. Estrogen receptor (ER) status was also measured. The main side effects were compared between the two groups. The main ingredients of PVL were caffeic acid and rosmarinic acid, which both exert anti-tumor properties. The average follow-up time was 41 months. Eighteen and 31 patients dropped out from EG and CG, respectively. Overall, pCRs were detected in 94 cases (25.1%), comprising 61 cases (31.4%) from EG and 33 cases (18.2%) from CG (P < 0.05). PVL treatment improved the pCR rate and OS time compared with those in CG (P < 0.05). The 3-year OS rates were 86.5 and 77.2% in patients from EG and CG, respectively (P < 0.05). Moreover, ER status was associated with pCR rate and could be an independent prognostic factor in BC. Moreover, treatment with PVL prevented side effects, namely, neutrophil-reduced fever and anemia caused by chemotherapy. Hence, chemotherapy using PVL and taxane could be a safe and effective treatment for patients with BC. PVL may be a potential adjuvant medicine for BC treatment.


A follow up study of myocardial involvement in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).
To investigate cardiac function in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and clarify the clinical features of cardiomyopathy in MELAS. 11 consecutive patients with MELAS (mean age at initial examination 11.3 years, range 4 to 16 years) were enrolled in the study. Six were followed for more than five years. On echocardiographic examination, three patients showed increased left ventricular end diastolic posterior wall thickness (LVPWTd), exceeding 140% of the normal value. Four patients, including these three, had an ejection fraction of less than 50%, and two also had increased left ventricular end diastolic volume (LVEDV) exceeding 140% of the normal value (%N). The LVPWTd%N was correlated positively with the LVEDV%N (R = 0.669, p < 0.05) and negatively with the ejection fraction (R = -0.6701, p < 0.05). One patient died of heart failure aged 22 years. The cardiomyopathy in MELAS is characterised by an abnormally thick left ventricular wall with progressive dilatation and poor left ventricular contraction developing over several years, indicating hypertrophic cardiomyopathy advancing to dilated cardiomyopathy.


RAS signalling genes can be used as host-induced gene silencing targets to control fungal diseases caused by Sclerotinia sclerotiorum and Botrytis cinerea.
Sclerotinia sclerotiorum causes white mold (also called stem rot, Sclerotinia blight, etc.) in many economically important plants. It is a notorious soilborne fungal pathogen due to its wide host range and ability to survive in soil for long periods of time as sclerotia. Although host-induced gene silencing (HIGS) was recently demonstrated to be an effective method for controlling white mold, limited gene targets are available. Here, using a forward genetics approach, we identified a RAS-GTPase activating protein, SsGAP1, which plays essential roles in sclerotia formation, compound appressoria production and virulence. In parallel, as revealed by our knockout analysis, the SsGAP1 ortholog in Botrytis cinerea, BcGAP1, plays similar roles in fungal development and virulence. By knocking down SsRAS1 and SsRAS2, we also revealed that both SsRAS1 and SsRAS2 are required for vegetative growth, sclerotia development, compound appressoria production and virulence in S. sclerotiorum. Due to the major roles these RAS signalling components play in Sclerotiniaceae biology, they can be used as HIGS targets to control diseases caused by both S. sclerotiorum and B. cinerea. Indeed, when we introduced HIGS constructs targeting SsGAP1, SsRAS1 and SsRAS2 in Nicotiana benthamiana and Arabidopsis thaliana, we observed reduced virulence. Taken together, our forward genetics gene discovery pipeline in S. sclerotiorum is highly effective in identifying novel HIGS targets to control S. sclerotiorum and B. cinerea.


Insight into the thermal decomposition of ammonium hexahalogenoiridates(IV) and hexachloroiridate(III).
Thermal decomposition of (NH4)3[IrCl6]·H2O, (NH4)2[IrCl6] and (NH4)2[IrBr6] in reductive and inert atmospheres has been investigated in situ using quick-EXAFS and temperature-resolved powder X-ray diffraction. For the first time, (NH4)2[Ir(NH3)Cl5] and (NH4)2[Ir(NH3)Br5] have been proven as intermediates of thermal decomposition of (NH4)3[IrCl6]·H2O, (NH4)2[IrCl6] and (NH4)2[IrBr6]. Thermal degradation of (NH4)2[IrCl6] and (NH4)2[IrBr6] is a more complex process as suggested previously and includes simultaneous formation of (NH4)2[Ir(NH3)Cl5] and (NH4)2[Ir(NH3)Br5] intermediates mixed with metallic iridium. In the inert atmosphere, complexes (NH4)[Ir(NH3)2Cl4] and (NH4)[Ir(NH3)2Br4] as well as [Ir(NH3)3Br3] were proposed as possible intermediates before formation of metallic iridium particles.


Enhanced nasopharyngeal colonization of rats by piliated Haemophilus influenzae type b.
Piliated Haemophilus influenzae type b strains display an enhanced adherence to human epithelial cells in vitro. However, clinical isolates, even from mucosal sites, are seldom piliated, although piliated populations can be selected from them. Experiments with rats have led some authors to suggest that piliation does not implement colonization by H. influenzae type b. Piliated populations were obtained from 35 strains by selection for adherence to human erythrocytes. One strain, H. influenzae H305, simultaneously acquired an increased adherence to rat erythrocytes and buccal epithelial cells. In contrast to other strains, H. influenzae H305 in piliated form was more effective than in nonpiliated form in the colonization of rats by intranasal inoculation. After the piliated inoculum, however, the colonies cultured from the nasal washes were negative for erythrocyte adherence. Thus, piliated H. influenzae type b strains have an apparent advantage to initiating colonization in the rat model but may give rise to nonpiliated progeny that are more readily cultivable from the mucosal surface.


Maternal short-chain fructo-oligosaccharide supplementation increases intestinal cytokine secretion, goblet cell number, butyrate concentration and Lawsonia intracellularis humoral vaccine response in weaned pigs.
Prebiotic supplementation modulates immune system development and function. However, less is known about the effects of maternal prebiotic consumption on offspring intestinal defences and immune system responsiveness. We investigated the effects of maternal short-chain fructo-oligosaccharide (scFOS) supplementation on mucin-secreting cells, ileal secretory IgA and cytokine secretion of weaned offspring and their humoral response to an oral vaccine against obligate intracellular Lawsonia intracellularis. Sows were fed a control diet (CTRL) or scFOS-supplemented diet during the last third of gestation and throughout lactation. At weaning, each litter was divided into two groups receiving a post-weaning CTRL or scFOS diet for a month. Pigs from the four groups were either non-vaccinated (n 16) or vaccinated (n 117) at day 33. Biomarkers related to intestinal defences and immune parameters were analysed 3 weeks later. SCFA production was assessed over time in suckling and weaned pigs. Maternal scFOS supplementation improved ileal cytokine secretions (interferon (IFN)-γ, P<0·05; IL-4, P=0·07) and tended to increase caecal goblet cell number (P=0·06). It increased IgA vaccine response in the serum (P<0·01) and ileal mucosa (P=0·08). Higher bacterial fermentative activity was observed during lactation (total faecal SCFA, P<0·001) and after weaning (colonic butyrate, P=0·10) in pigs from scFOS-supplemented mothers. No synergistic effect between maternal and post-weaning scFOS supplementation was observed. Therefore, maternal scFOS supplementation has long-lasting consequences by strengthening gut defences and immune response to a vaccine against an intestinal obligate intracellular pathogen. Prebiotic consumption by gestating and lactating mothers is decisive in modulating offspring intestinal immunity.


Clinical significance of radiologic characterizations in COPD.
COPD is a heterogeneous disorder with clinical assessment becoming increasingly multidimensional. We hypothesized HRCT phenotype would strongly influence clinical outcomes including health status, exacerbation frequency, and BODE. COPD subjects were characterized via the SF-12, SGRQ, MMRC, physiologic testing, and standardized volumetric chest HRCT. Visual semi-quantitative estimation of bronchial wall thickness (VBT) and automated quantification of emphysema percent and bronchial wall thickness were generated. Multivariate modeling compared emphysema severity and airway abnormality with clinical outcome measures. Poisson models were used to analyze exacerbation frequency. SGRQ and SF-12 physical component scores were influenced by FEV(1)% predicted, emphysema percent, and VBT. VBT scores > 2 (scale 0-48) were associated with increased exacerbation frequency (p = 0.009) in the preceding year adjusting for age, gender, emphysema percent, smoking history and FEV(1)% predicted, although this effect was attenuated by age. Emphysema percent correlated with total BODE score in unadjusted (r = 0.73; p < 0.0001) and adjusted (p < 0.0001) analyses and with BODE individual components. HRCT provides unique COPD phenotyping information. Radiographic quantification of emphysema and bronchial thickness are independently associated with SGRQ and physical component score of the SF-12. Bronchial thickness but not emphysema is associated with exacerbation frequency, whereas emphysema is a stronger predictor of BODE and its systemic components MMRC, 6MWT, and BMI. Future research should clarify whether CT parameters complement BODE score in influencing survival.


Do reduced visual acuity and refractive error affect classroom performance?
The role of visual acuity and refractive errors in the academic performance of children is controversial due to the variable quality of the research in this area and the mixed findings reported. This review aims to provide clarity by reviewing and critiquing relevant peer-reviewed publications and also summarises what is known regarding the visual demands of modern classroom environments. The outcomes of this review suggest that while a number of studies have investigated the role of vision in relation to children's academic performances, the veracity of the evidence obtained from the majority of these studies is undermined by methodological limitations. Comparisons between studies are constrained by differences in experimental designs, instrumentation and sample characteristics. Despite these limitations, the weight of evidence suggests there is an association between academic performance and both visual acuity and refractive error in children. However, well-designed experimental studies are necessary to further understand the relationship between these parameters.


Diet-derived phytochemicals: from cancer chemoprevention to cardio-oncological prevention.
Cardiovascular diseases and cancer are the leading causes of death in most countries. These diseases share many common risk factors as well as pathogenetic determinants, and their incidence is related to age in an exponential manner. Furthermore, it has become apparent that several treatments used in therapy or even in prevention of cancer can impair the structural and functional integrity of the cardiovascular system, giving rise to an interdisciplinary field: cardio-oncology. However, tumors and cardiovascular diseases also share common protective factors: they can be prevented either by avoiding exposure to recognized risk factors, and/or by favoring the intake of protective compounds and by modulating the host defense machinery. These latter approaches are generally known as chemoprevention. A great variety of dietary and pharmacological agents have been shown to be potentially capable of preventing cancer in preclinical models, most of which are of plant origin. Phytochemicals, in particular diet-derived compounds, have therefore been proposed and applied in clinical trials as cancer chemopreventive agents. There is now increasing evidence that some phytochemicals can be also protective for the heart, having the potential to reduce cancer, cardiovascular disease and even anticancer drug-induced cardiotoxicity. We introduce the concept that these compounds induce pre-conditioning, a low level cellular stress that induces strong protective mechanisms conferring resistance to toxins such as cancer chemotherapeutics. Cancer cells and cardiomyocytes have fundamental differences in their metabolism and sensitivity to preconditioning, autophagy and apoptosis, so that dosage of the prevention compounds is important. Here we discuss the mechanisms responsible for the cardiotoxicity of anticancer drugs, the possibility to prevent them and provide examples of diet-derived phytochemicals and other biological substances that could be exploited for protecting the cardiovascular system according to a joint cardio-oncological preventative approach.


Unilateral hearing losses alter loud sound-induced temporary threshold shifts and efferent effects in the normal-hearing ear.
In animals with bilaterally normal hearing, olivocochlear pathways can protect the cochlea from the temporary shifts in hearing sensitivity (temporary threshold shifts; TTSs) caused by short-duration intense loud sounds. The crossed olivocochlear pathway provides protection during binaural loud sound, and uncrossed pathways protect when monaural or binaural loud sounds occur in noise backgrounds. Here I demonstrate that when there is a chronic unilateral hearing loss, effects of loud sounds, and efferent effects on loud sound, in the normal-hearing ear differ markedly from normal. Three categories of test animals with unilateral hearing loss were tested for effects at the normal-hearing ear. In all categories a monaural loud tone to the normal-hearing ear produced lower-than-normal TTSs, apparently because of a tonic re-setting of that ear's susceptibility to loud sound. Second, in the two test categories in which the hearing-loss ear was only partly damaged, binaural loud sound exacerbated TTSs in the normal-hearing ear because it caused threshold shifts that were a combination of "pure" TTSs and uncrossed efferent suppression of cochlear sensitivity. (In normal cats, this binaural tone results in crossed olivocochlear protection that reduces TTS.) Binaural loud sound did not produce such uncrossed efferent effects in the test category in which the nontest ear had suffered total hearing loss, suggesting that this uncrossed efferent effect required binaural input to the CNS. It is noteworthy that, in the absence of this uncrossed efferent suppression, the pure loud sound-alone induced TTSs after binaural exposure were low. Thus in the absence of any efferent effect, the normal-hearing cochlea had a reduced susceptibility to loud tone-induced damage. Finally, the results suggest that, with respect to cochlear actions at high sound levels, uncrossed and crossed efferent pathways may exert different effects at the one type of receptor cell.


Academic career progression in AANS/CNS Spine Section award recipients.
The American Association of Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) Joint Spine Section awards highlight outstanding abstracts submitted to the AANS/CNS Section on Disorders of the Spine and Peripheral Nerves by trainees interested in spine surgery, although the academic trajectory of awardees has not been studied. The aim of this study was to assess the academic career progression of prior recipients of the Journalistic and Academic Neurosurgical Excellence (JANE), Mayfield, and Kuntz research awards. Prior JANE, Mayfield, and Kuntz award recipients were identified using awardee records accrued between 1984 and February 2022. Awardee sex, country of residence, specialty, subspecialty focus, and current academic appointment status (if applicable) were searched online. Awardee h-indices and number of peer-reviewed publications were assessed via Google Scholar profiles (or Scopus if unavailable) and PubMed, respectively. Receipt of federal research funding as principal investigator (PI) was determined using the websites of the National Institutes of Health, the National Science Foundation, and the Department of Defense Congressionally Directed Medical Research Programs. The abstract-to-publication rate was assessed. A total of 7 JANE awards, 57 Mayfield awards, and 149 Kuntz awards were identified. Of the JANE awardees, all recipients were male. Of the 4 unique JANE awardees who completed training, 2 (50.0%) held academic appointments at the time of the study. All of the JANE abstracts were published in peer-reviewed journals. The mean h-index of all JANE awardees was 28 and the mean number of publications was 126. None of the awardees have received federal research funding. Of the Mayfield awards, 98.2% were awarded to males. Of the 43 unique Mayfield awardees who completed training, 20 (46.5%) held faculty appointments at academic medical centers. All of the Mayfield abstracts since 2011 were published in peer-reviewed journals. The mean h-index of all Mayfield awardees was 26 and the mean number of publications was 82. Five Mayfield awardees received National Institutes of Health funding as PI, and 7 awardees received Department of Defense funding as PI. Of the Kuntz awards, 95.3% were awarded to males. Most awards were given to current residents and fellows (46.3%). Of the 55 unique Kuntz awardees who completed training, 31 (56.4%) held faculty appointments at academic medical centers. The abstract-to-publication rate of the total Kuntz abstracts was 70.5%. The mean h-index of all Kuntz awardees was 15 and the mean number of publications was 58. Five Kuntz awardees (3.4%) received federal research funding as PI. Many recipients of the JANE, Mayfield, and Kuntz Joint Spine Section awards have successfully translated award abstracts into peer-reviewed publications. Furthermore, approximately one-third of the awardees are active in academic neurosurgery, with some having secured federal research funding.


Reduced regulatory effects of bone marrow-derived mesenchymal stem cells on activated T lymphocytes and Th1/Th2 cytokine secretion in children with aplastic anemia.
Acquired aplastic anemia (AA) is a recognized immune-mediated disorder and abnormally activated T lymphocyte-mediated bone marrow destruction is considered to be its main pathogenesis. Whether abnormal activation of T lymphocytes would also damage bone marrow-derived MSCs remains to be further studied. The aim of this study was to analyze the extent of T lymphocyte activation and the levels of Th1/Th2 cytokines of AA patients, and to explore the immunomodulatory effects of BM-MSCs on IL-2-stimulated T lymphocyte activation and cytokine production in vitro by means of transwell co-culture assay and flow cytometry measurement. The intermediate (CD25+) activated T cells were dominant in peripheral blood, while the early (CD69+) and late (HLA-DR+) activated T cells were predominant in bone marrow. Severe AA patients have an obviously higher proportion of CD3+CD8+CD69+ T cells than NSAA cases. The levels of IL-2 and IL-6 in AA patients were slightly elevated and INF-γ was mildly decreased in comparison with normal individuals. BM-MSCs derived from AA could not effectively inhibit the IL-2-induced activation of T cells with higher proportions of CD25+CD3+CD4+, CD69+CD3+CD4+ and CD25+CD3+CD8+ T cells after co-culture, and they showed a decreased ability to balance the Th1/Th2 cytokine production. Moreover, they had less robust osteogenic differentiation and more prone to adipogenic differentiation. We concluded that abnormally excessive T cell activation accompanied by abnormal cytokine secretion may impair the function of BM-MSCs in children with aplastic anemia.


Monitoring phases and phase transitions in phosphatidylethanolamine monolayers using active interfacial microrheology.
Active interfacial microrheology is a sensitive tool to detect phase transitions and headgroup order in phospholipid monolayers. The re-orientation of a magnetic nickel nanorod is used to explore changes in the surface rheology of 1,2-dilauroyl-sn-glycero-3-phosphoethanolamine (DLPE) and 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), which differ by two CH2 groups in their alkyl chains. Phosphatidylethanolamines such as DLPE and DMPE are a major component of cell membranes in bacteria and in the nervous system. At room temperature, DLPE has a liquid expanded (LE) phase for surface pressure, Π < ∼38 mN m(-1); DMPE has an LE phase for Π < ∼7 mN m(-1). In their respective LE phases, DLPE and DMPE show no measurable change in surface viscosity with Π, consistent with a surface viscosity <10(-9) N s m(-1), the resolution of our technique. However, there is a measurable, discontinuous change in the surface viscosity at the LE to liquid condensed (LC) transition for both DLPE and DMPE. This discontinuous change is correlated with a significant increase in the surface compressibility modulus (or isothermal two-dimensional bulk modulus). In the LC phase of DMPE there is an exponential increase in surface viscosity with Π consistent with a two-dimensional free area model. The second-order LC to solid (S) transition in DMPE is marked by an abrupt onset of surface elasticity; there is no measurable elasticity in the LC phase. A measurable surface elasticity in the S phase suggests a change in the molecular ordering or interactions of the DMPE headgroups that is not reflected in isotherms or in grazing incidence X-ray diffraction. This onset of measurable elasticity is also seen in DLPE, even though no indication of a LC-S transition is visible in the isotherms.


Molecular characterization of the 5' control region and of two lethal alleles affecting the hsp60 gene in Drosophila melanogaster.
The chaperonins are evolutionarily conserved essential cellular proteins that help folding newly synthesized or translocated proteins, spending ATP. We present here the molecular analysis of the hsp60 gene promoter region and of two Drosophila hsp60 ethyl methane sulfonate embryonic lethal alleles that have an identical phenotype. No heat shock element sequences were found in the 5' region, supporting previous data (Kozlova, T. et al., 1997) which suggests that mitochondrial Drosophila melanogaster HSP60.1 is not heat inducible. By sequencing the lethal allele's entire open reading frame (ORF), we found a C-T transition in the hsp60F409 allele that produces a serine to leucine change, apparently distorting the protein equatorial domain structure. No changes were found in the hsp60G93 ORF. However, an analysis of the heterogeneous nuclear RNA levels showed a reduction of the hsp60 transcript in hsp60G93 flies as compared to the wild-type. These data suggest that although the defects in the hsp60 gene produced by these alleles are at different levels, both behave as null mutations.


Cervical Spine Disability in Correlation with Subjective Voice Handicap in Patients With Voice Disorders: A Retrospective Analysis.
Neck muscle dysfunction has been considered as risk factor or consequence of voice disorders. This study investigates the correlation between neck and voice-related subjective symptoms in patients with voice disorders. Retrospective case-control study. 100 adult patients (59 female and 41 male) over 18 years with a mean age of 50.01 years (SD 16, range 24-87), of which 68 were under 60 years, were included. 50 patients had organic voice pathologies and 50 functional dysphonia. Outcome measures were the Voice Handicap Index 9 international (VHI-9i) and the Neck Disability Index (NDI-G). Spearman rank order coefficient was applied to determine the correlation between overall and single item VHI and NDI results. Subanalyses were done for functional vs. organic disorder, gender and age ± 60 years. Mean overall VHI-9i (13.93, SD = 7.81, range = 0-31) and mean NDI-G (6.07, SD = 7.71, range = 0-43) showed a significant mild correlation (rs = 0.220, P = 0.02). Split into subgroups the relation was stronger in patients with organic pathologies (rs = 0.297, P = 0.03), but not significant in functional disorders (r = 0.148, P = 0.30). There was a moderate relation in men (rs = 0.317, P = 0.04). Single item correlation was highest between VHI-9i item P4 (physiological) and NDI-G item reading (cognitive functioning) (rs = 0.480, P = 0.002). Specifically patients with organic voice disorders showed increased voice symptoms with the presence of neck dysfunction. This indicates a risk for a functional imbalance of the muscles surrounding the larynx, which in extreme cases may hinder functional voice rehabilitation even after phonosurgery. Therefore, neck dysfunction should be considered in voice diagnostics.


High-power, single-mode, linearly polarized, ytterbium-doped fiber superfluorescent source.
High-power operation of a single-mode, linearly polarized, broadband superfluorescent fiber source has been achieved by using a two-stage cladding-pumped fiber configuration comprising a low power, single-ended, ytterbium-doped superfluorescent fiber seed source and a high-power cladding-pumped, polarization-maintaining, large-mode-area, ytterbium-doped amplifier pumped by a high-power diode source at 976 nm. The source yielded a maximum linearly polarized output of 106 W with a slope efficiency of up to 67% with respect to the launched pump power and with a measured polarization extinction ratio of 13.5 dB. The wavelength spectrum of the superfluorescent source spanned the range continuously from ~1035 to 1100 nm, and the bandwidth (FWHM) of the emission spectrum was 21 nm. The minimum seed power required for an output power over 100 W was only 10 mW, corresponding to an effective power gain in the amplifier stage of 40 dB. Single-spatial-mode operation with a beam propagation factor (M(2))<1.1 was achieved by bending the amplifier fiber to a bend radius of ~8 cm, without a significant reduction in output power.


Hydrogen peroxide produced during gamma-glutamyl transpeptidase activity is involved in prevention of apoptosis and maintainance of proliferation in U937 cells.
It has been reported in several cell lines that exposure to low levels of reactive oxygen species can exert a stimulatory effect on their proliferation. We have previously shown that mild oxidative conditions can also counteract apoptotic stimuli. A constitutive cellular production of low levels of superoxide and hydrogen peroxide originates from various sources; among these, gamma-glutamyl transpeptidase (GGT), the plasma membrane-bound activity in charge of metabolizing extracellular reduced glutathione, has recently been included. Since the inhibition of GGT is a sufficient stimulus for the induction of apoptosis in selected cell lines, we investigated whether this effect might result from the suppression of the mentioned GGT-dependent prooxidant reactions, on the theory that the latter may represent a basal antiapoptotic and proliferative signal for the cell. Experiments showed that: 1) GGT activity in U937 monoblastoid cells is associated with the production of low levels of hydrogen peroxide, and two independent GGT inhibitors cause a dose-dependent decrease of such GGT-dependent production of H2O2; 2) GGT inhibition with acivicin results in cell growth arrest, and induces cell death and DNA fragmentation with the ladder appearance of apoptosis; 3) treatment of cells with catalase--and even more with Trolox C--is able to decrease their proliferative rate; 4) GGT inhibition (with suppression of H2O2 production) results in a down-regulation of poly(ADP-ribose) polimerase (PARP) activity, which precedes the proteolytic cleavage of PARP molecule, such as that typically induced by caspases. The reported data suggest that the low H2O2 levels originating as a by-product during GGT activity are able to act as sort of a 'life signal' in U937 cells, insofar as they can maintain cell proliferation and protect against apoptosis, possibly through an up-regulation of PARP activity.


ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up.
The European Society for Medical Oncology (ESMO) consensus conference on testicular cancer was held on 3-5 November 2016 in Paris, France. The conference included a multidisciplinary panel of 36 leading experts in the diagnosis and treatment of testicular cancer (34 panel members attended the conference; an additional two panel members [CB and K-PD] participated in all preparatory work and subsequent manuscript development). The aim of the conference was to develop detailed recommendations on topics relating to testicular cancer that are not covered in detail in the current ESMO Clinical Practice Guidelines (CPGs) and where the available level of evidence is insufficient. The main topics identified for discussion related to: (1) diagnostic work-up and patient assessment; (2) stage I disease; (3) stage II-III disease; (4) post-chemotherapy surgery, salvage chemotherapy, salvage and desperation surgery and special topics; and (5) survivorship and follow-up schemes. The experts addressed questions relating to one of the five topics within five working groups. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel. A consensus vote was obtained following whole-panel discussions, and the consensus recommendations were then further developed in post-meeting discussions in written form. This manuscript presents the results of the expert panel discussions, including the consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.


[Differences in ipsilateral afferent currents in rats with and without pain syndrome in trigeminal neuropathy].
Ipsilateral evoked potentials in the caudal trigeminal nucleus, ventrobasal thalamus, and cortex during electrical stimulation of the injured and opposite intact nerves were studied in rats with trigeminal neuropathy caused by partial compression of the infraorbital nerve. In spite of abnormally increased long latent evoked activity in the caudal nucleus ipsilaterally to compression, amplitude asymmetry of the ipsilateral thalamic and cortical evoked potentials in rats with pain syndrome was shown to be absent during nerve stimulation of the snout sides. In rats without pain-evoked potentials in the caudal nucleus during injured nerve stimulation had small differences as compared with the latter group. At that time, the increased magnitude of ipsilateral evoked potentials at uninjured nerve stimulation was recorded in all structures in rats without pain syndrome as compared with the pain syndrome group and sham-operated rats, and as compared with ipsilateral evoked potentials during injured nerve stimulation in rats without pain syndrome. The neuropathic pain syndrome is considered to result from the formation of the pathologic algic system with a generator of abnormality enhanced excitation which arises in the nonspecific nociceptive structures in response to specific structural injury. This alternative process is the compensative increase in the ipsilateral input of agents into the brain cortex from the intact nerve that prevents the development of its abnormal activities.


A mathematical model of the methionine cycle.
Building on the work of Martinov et al. (2000), a mathematical model is developed for the methionine cycle. A large amount of information is available about the enzymes that catalyse individual reaction steps in the cycle, from methionine to S-adenosylmethionine to S-adenosylhomocysteine to homocysteine, and the removal of mass from the cycle by the conversion of homocysteine to cystathionine. Nevertheless, the behavior of the cycle is very complicated since many substrates alter the activities of the enzymes in the reactions that produce them, and some can also alter the activities of other enzymes in the cycle. The model consists of four differential equations, based on known reaction kinetics, that can be solved to give the time course of the concentrations of the four main substrates in the cycle under various circumstances. We show that the behavior of the model in response to genetic abnormalities and dietary deficiencies is similar to the changes seen in a wide variety of experimental studies. We conduct computational "experiments" that give understanding of the regulatory behavior of the methionine cycle under normal conditions and the behavior in the presence of genetic variation and dietary deficiencies.


All advanced stage non-Hodgkin's lymphomas with a polymerase chain reaction amplifiable breakpoint of bcl-2 have residual cells containing the bcl-2 rearrangement at evaluation and after treatment.
Polymerase chain reaction (PCR) of bcl-2 provides an extremely sensitive method to detect minimal disease in approximately 50% of patients with non-Hodgkin's lymphomas (NHL). In an attempt to determine the clinical usefulness of this technique, we examined the bone marrow (BM) of 152 patients with advanced-stage NHL at the time of evaluation and after induction or salvage chemotherapy before autologous BM transplantation. The BM proved to be an accessible and reproducible tissue source to determine PCR positivity because all of the 102 patients examined had the same PCR-amplifiable breakpoint in their BM and lymph node. At the time of evaluation, PCR analysis in advanced-stage NHL patients added little additional information to morphologic analysis because each technique identified BM infiltration in approximately 70% of patients. PCR was significantly more useful in determining BM infiltration after induction or salvage therapy. At that time, approximately 50% of patients had morphologically normal BM, whereas PCR analysis remained positive in 100% of those with an amplifiable breakpoint. These observations were confirmed in a clinical trial attempting to induce remission in previously untreated low-grade advanced-stage NHL patients. In this series, PCR was positive in all patients after treatment although the BM was histologically uninvolved in 50% of cases, showing that conventional therapy did not eradicate bcl-2-positive cells.