Interfacial Microstructure in W/2024Al Composite and Inhibition of W-Al Direct Reaction by CeO₂ Doping: Formation and Crystallization of Al-Ce-Cu-W Amorphous Layers.
In this work, interfacial microstructure in W/2024Al composite and inhibition of the W-Al direct reaction by CeO₂ doping were investigated. The composites were prepared through powder sintering, and after preparation the composites were treated by annealing at 823 K. For the prepared W/2024Al composite, a multi-phase thin layer composed of WAl12 and WAl₅ compounds were formed at the interface due to the W-Al direct reaction. While doping CeO₂ in the composite, Al-Ce-Cu-W amorphous substituting of W-Al compounds were formed at the interfacial reaction layer. In an annealed state, the composite with CeO₂ doping shows a significant inhibitory effect on W-Al compounds, which was attributed to the crystallized layer that evolved from Al-Ce-Cu-W amorphous as an interfacial obstacle. The crystallization product for Al-Ce-Cu-W amorphous layer was identified as bcc-structure Al-Ce-Cu-W phase without any binary/ternary Ce-containing phases. Therefore, by doping CeO₂ in W/2024Al composite, W-Al direct reaction was markedly inhibited during both preparation and annealing.


Preventive skin care beliefs of people with spinal cord injury.
Although health beliefs have been correlated with self-care adherence in other chronic conditions, little is known about skin care beliefs after spinal cord injury (SCI). The purpose of this qualitative study was to identify the skin care beliefs of individuals with SCI. The conceptual framework was the Health Belief Model (HBM), which proposes that adherence to a health regimen is motivated by beliefs about susceptibility, severity, barriers, benefits, and self-efficacy. Purposive sampling was used to recruit 22 people with SCI. Content analysis of data collected using semistructured questions was used to identify domains of skin care beliefs, including HBM components. Themes that emerged about skin care beliefs included taking vigilant care, taking charge, maintaining health, and passing up care. Although most participants believed they were susceptible to pressure ulcers and preventive care was important, paradoxical statements about beliefs and preventive behaviors were common. These incongruent responses may reflect ambivalence about competing priorities or the efficacy of preventive practices. Further research is needed to understand this phenomenon. Increased understanding of skin care beliefs will assist in developing tailored teaching programs for people with SCI.


Sensitivity analysis in a multidimensional demographic projection model with a two-sex algorithm.
"Formulas are derived for the effect that a slight change in the occurrence/exposure rate of the multidimensional projection model has on the elements of the population vector. The projection model classifies the population by sex, age, and marital status. The model includes a two-sex algorithm in order to ensure consistency between numbers of male and female marriages, number of divorces for the two sexes, and new widows (widowers) and deceased spouses. The sensitivity functions and elasticities are applied to data from the Netherlands for the period 1980-1984. The results indicate that marriage market mechanisms, in particular competition and substitution effects, are reasonably well modelled."


Altered proportions of naïve, central memory and terminally differentiated central memory subsets among CD4+ and CD8 + T cells expressing CD26 in patients with type 1 diabetes.
Type 1 diabetes is an autoimmune process predominantly T-cell mediated. CD26 plays a role in T-cell costimulation, migration, memory development, thymic maturation and emigration patterns. In peripheral blood from 55 patients with type 1 diabetes and 20 healthy controls, CD4(+) and CD8(+) T cells expressing CD26 were differentiated into naïve (N, CD45RA(+)CCR7(+)), central memory (CM, CD45RA(-)CCR7(+)), effector memory (EM, CD45RA(-)CCR7(-)), and terminally differentiated effector memory (TEMRA, CD45RA(+)CCR7(-)). In type 1 diabetes, CD4(+) and CD8(+) T cells expressing CD26 showed a distinctive differentiation profile: percentages and absolute numbers of CM and N cells were reduced, whereas those of TEMRA cells were markedly increased. The indices of intermediate- and long-term glycaemic control were associated negatively with the number of CM and N cells while positively with the number of TEMRA cells. The considerable accumulation of TEMRA T cells in our patients suggests life-long stimulation by protracted antigen exposure (viruses, other agents or residual self-antigens?) or a homeostatic defect in the regulation/contraction of immune responses.


Two forms of the Na,K-ATPase catalytic subunit detected by their immunological and electrophoretic differences. Alpha and alpha+ in mammalian heart.
Differences in the expression of Na,K-ATPase isozymes in the heart make a significant contribution to the understanding of cardiac glycoside effects in this tissue. More explicit information is needed about the cardiac glycoside affinities of the different isozymes in various species, however, before a unified picture can emerge. Much more information is also needed on what controls the level of expression of the different isozymes, and why mammalian species differ in this respect. For the rat, at least, it appears that the relative abundance of two Na,K-ATPase isozymes is controlled by changes in gene expression during development. These changes correlate with large changes in other contractile and excitable membrane properties. Isoforms of myosin and other important cardiac proteins are known to change in hypertrophy. It may be of critical importance to understand how the isoforms of the cardiac glycoside receptor change as well.


24-Month follow-up of randomized controlled trial of guided-self-help for loss-of-control eating after bariatric surgery.
Loss-of-control (LOC)-eating postoperatively predicts suboptimal longer-term outcomes following bariatric surgery. This study examined longer-term effects through 24-month follow-ups after completing treatments in a randomized controlled trial testing guided-self-help treatments (cognitive-behavioral therapy [gshCBT] and behavioral weight-loss [gshBWL]) and control (CON) delivered postoperatively for LOC-eating. 140 patients with LOC-eating 6 months after bariatric surgery were randomized (5:5:2 ratio) to 3-months of gshCBT (n = 56), gshBWL (n = 60), or CON (n = 24) delivered by trained allied-health clinicians. Independent assessments were performed throughout/after treatments and at 6-, 12-, 18-, and 24-month follow-ups; 83% of patients were assessed at 24-month follow-up. Intention-to-treat analyses comparing the three groups (gshCBT vs. gshBWL vs. CON) in LOC-eating abstinence at posttreatment (30%, 27%, 38%), 12-month follow-up (34%, 32%, 42%), and 24-month follow-up (45%, 32%, 38%) revealed no significant differences. Mixed-models revealed significantly reduced LOC-eating frequency through posttreatment, no significant changes in LOC-eating frequency during follow-up, and no differences between the three groups. Weight reduced significantly, albeit modestly, through posttreatment but increased significantly and substantially during follow-ups, with no differences between groups. Overall, the 12-week scalable guided-self-help treatments did not differ from each other or control, were associated with significantly reduced frequency of LOC-eating and modest weight loss at posttreatment but were followed by significant weight gain during the 24-month follow-up. Weight gain was substantial and nearly universal whereas the frequency of LOC-eating did not change over time (i.e., LOC-eating reductions and abstinence rates were well maintained through 24-moth follow-ups). Patients with postoperative LOC-eating require more intensive adjunctive treatments. Loss-of-control (LOC) eating postoperatively predicts poorer bariatric surgery outcomes and the longer-term effects of postoperative adjunctive postoperative interventions for LOC eating are unknown. In this 24-month follow-up of a controlled study of scalable guided-self-help treatments and a control condition, improvements in LOC-eating frequency, eating-disorder psychopathology, and depression during treatment were maintained well, with no differences between the three groups. Proportion of patients achieving abstinence from LOC-eating at the 24-month follow-up ranged from 38% to 45% across the three groups. In contrast, weight increased significantly during the 24-month follow-ups, with no differences between the three groups. Findings suggest LOC-eating following bariatric surgery might represent a "marker" for a subgroup of patients that are at risk for substantial weight gains over time. LOC eating following bariatric surgery is challenging to treat with low-intensity scalable treatments and may require more intensive specialist treatments.


Branch migration and the international dispersal of families.
This paper discusses the dispersal of facilities where family members migrate to different destination countries. Terminology for internationally dispersed families is proposed, and the term branch migration is suggested for the migration of related people from the same source country to different destination countries. Data from two 1993 surveys of senior secondary students show that 22% of Sydney students and 20% of Hong Kong students have relatives in two or more other countries. The data suggest that many Asian migrant families have branched between the US, Canada, Australia and other migrant-receiving nations. The causes and implications of the international dispersal of families are discussed.


Sperm chemotaxis.
Communication between spermatozoa and egg before contact by chemotaxis appears to be prevalent throughout the animal kingdom. In non-mammalian species, sperm chemotaxis to factors secreted from the egg is well documented. In mammals, sperm chemotaxis to follicular factors in vitro has been established in humans and mice. The attractants of female origin in non-mammalian species are heat-stable peptides or proteins of various sizes, or other small molecules, depending on the species. Species specificity of the attractants in non-mammalian species may vary from high species specificity, through specificity to families with no specificity within a family, to absence of specificity. The mammalian sperm attractants have not been identified but they appear to be heat-stable peptides. The claim that progesterone is the attractant for human spermatozoa has failed to be substantiated, neither have claims for other mammalian sperm attractants been verified. The molecular mechanism of sperm chemotaxis is not known. Models involving modulation of the intracellular Ca2+ concentration have been proposed for both mammalian and non-mammalian sperm chemotaxis. The physiological role of sperm chemotaxis in non-mammalian species appears to differ from that in mammals. In non-mammalian species, sperm chemotaxis strives to bring as many spermatozoa as possible to the egg. However, in mammals, the role appears to be recruitment of a selective population of capacitated ('ripe') spermatozoa to fertilize the egg.


Arc Plasma-Based Dissociation Device: Fingerprinting Mass Spectrometric Analysis Realized at Atmospheric Condition.
Fingerprinting mass spectrometric analysis at atmospheric conditions has been realized using an arc plasma-based dissociation (APD) device. Because of its high energy, high temperature, and unique chemical reactivity, the thermal plasma can induce dissociation of neutral molecules or ions produced by atmospheric ion sources. Both even/odd electron (fragment) ions would be generated to provide fingerprinting structural information and molecular weight of the compounds simultaneously. Meanwhile, elimination and aromatization were observed as special dissociation patterns in this device, which can be applied in the differentiation of isomers. The good compatibility with atmospheric ion sources is demonstrated by coupling the device with nanoelectrospray ionization (nano-ESI) and zero volt paper spray ionization (PSI), respectively. With erythromycin as the tuning standard, informative dissociation spectra of various compounds can be reproducible, making it possible to establish an arc plasma-based dissociation spectra database. This device allows fingerprinting mass spectrometric analysis, with no need for harsh vacuum conditions and is promising for making a breakthrough in making up the deficiency of atmospheric ionization techniques.


Specialized metabolic functions of keystone taxa sustain soil microbiome stability.
The relationship between biodiversity and soil microbiome stability remains poorly understood. Here, we investigated the impacts of bacterial phylogenetic diversity on the functional traits and the stability of the soil microbiome. Communities differing in phylogenetic diversity were generated by inoculating serially diluted soil suspensions into sterilized soil, and the stability of the microbiome was assessed by detecting community variations under various pH levels. The taxonomic features and potential functional traits were detected by DNA sequencing. We found that bacterial communities with higher phylogenetic diversity tended to be more stable, implying that microbiomes with higher biodiversity are more resistant to perturbation. Functional gene co-occurrence network and machine learning classification analyses identified specialized metabolic functions, especially "nitrogen metabolism" and "phosphonate and phosphinate metabolism," as keystone functions. Further taxonomic annotation found that keystone functions are carried out by specific bacterial taxa, including Nitrospira and Gemmatimonas, among others. This study provides new insights into our understanding of the relationships between soil microbiome biodiversity and ecosystem stability and highlights specialized metabolic functions embedded in keystone taxa that may be essential for soil microbiome stability. Video abstract.


Primary tumors of the lung: should we consider thermal ablation as a valid therapeutic option?
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer death; percutaneous thermal ablation (TA) has proven feasibility, good local control and good tolerance in stage I tumors for patients with medical comorbidities and who are ineligible for surgery. In this context, stereotactic body radiotherapy (SBRT) has demonstrated high efficacy in treating T1 NSCLC and will need to be compared with percutaneous ablation. TA is also indicated in oligoprogressive disease; and can be proposed as a salvage treatment option for tumor recurrence after radiotherapy. Besides more advanced NSCLC could be also an indication of TA in combination with systemic treatments. A large majority of diagnosed NSCLC do not exhibit specific targetable genetic aberration. Those tumors present poorer prognosis and have been treated with standard chemotherapy regimen until the recent development of immune checkpoint inhibitors (ICIs) based immunotherapy. Combining TA with immunotherapy is promising and still needs to be explored.


Women endurance runners with menstrual dysfunction have prolonged interruption of training due to injury.
Strenuous exercise by women is associated with menstrual dysfunction, eating disorders and osteoporosis. Intensive training may also increase the susceptibility to infections. In this study, we investigated whether menstrual dysfunction was related to musculoskeletal injuries and/or upper respiratory tract infections in women middle/long-distance runners. A questionnaire was mailed to 127 Swedish female runners of whom 75% answered. This retrospective study showed a higher frequency of menstrual disorders (25%) in runners than in the general population. Furthermore, almost half of the athletes (46%) were classified as at risk of developing eating disorders. Women athletes with menstrual dysfunction were found to have had a longer interruption of training due to musculoskeletal injuries than those with regular cycles (34.1 +/- 3.0 vs. 9.0 +/- 9. 4 days, p < 0.05). However, no relation was found between susceptibility to infections and menstrual status.


Echocardiographic assessment of aortic stenosis.
Abnormal thickening and limited or eccentric mobility of the aortic leaflets were used as indicators of the aortic stenosis (AS). The magnitude of ventricular hypertrophy in response to afterloading was determined by wall stress, with wall thickness. Measures of the echocardiographic internal dimensions of the left ventricle, wall thickness and circumferential fiber shortening (Vcf), were able to characterize left ventricular function in 13 patients with AS. In moderate and severe AS with normal left ventricular function, left ventricular end-diastolic dimension (Dd) was normal, posterior wall thickness (Wt) increased and myocardial contraction (Vcf) was normal. In patients with left ventricular failure, Dd was increased and myocardial contraction markedly depressed. Echocardiography is a noninvasive method for estimating the severity of aortic stenosis and it appears to be more sensitive than other currently employed techniques.


In situ deletions reveal regulatory components for expression of an intracellular immune receptor gene and its co-expressed genes in Arabidopsis.
Intracellular immune receptor nucleotide-binding leucine-rich repeats (NLRs) are highly regulated transcriptionally and post-transcriptionally for balanced plant defense and growth. NLR genes often exist in gene clusters and are usually co-expressed under various conditions. Despite intensive studies of the regulation of NLR proteins, cis-acting elements for NLR gene induction, repression or co-expression are largely unknown due to a larger than usual cis-region for their expression regulation. Here we used the CRISPR/Cas9 genome editing technology to generate a series of in situ deletions at the endogenous location of an NLR gene SNC1 residing in the RPP5 gene cluster. These deletions that made in the wild type and the SNC1 constitutive expressing autoimmune mutant bon1 revealed both positive and negative cis-acting elements for SNC1 expression. Two transcription factors that could bind to these elements were found to have an impact on the expression of SNC1. In addition, co-expression of two genes with SNC1 in the same cluster is found to be mostly dependent on the SNC1 function. Therefore, SNC1 expression is under complex local regulation involving multiple cis-elements and SNC1 itself is a critical regulator of gene expression of other NLR genes in the same gene cluster.


Autoantibody to U3 nucleolar ribonucleoprotein (fibrillarin) in patients with systemic sclerosis.
To determine the clinical significance of serum antibodies to the U3 small nuclear ribonucleoprotein particle ([U3]snRNP), we studied sera from 416 patients with systemic sclerosis (SSc) and 264 controls, using immunofluorescence and immunoprecipitation assays. The presence of serum anti-(U3)snRNP was highly specific to SSc, was found more frequently in blacks, and was associated with skeletal muscle disease and primary pulmonary arterial hypertension. These antibodies may identify one or more unusual clinical subsets of SSc.


Early-onset childhood sarcoidosis with incidental multiple enchondromatosis.
The triad of rash, arthritis, and uveitis seems to be characteristic for early-onset childhood sarcoidosis. We describe an interesting case of early-onset childhood sarcoidosis coexisting enchondromatosis, which clinically masquerade as Langerhans cell histiocytosis. A 33 months old girl presented with skin rash, subcutaneous nodules with polyarthritis, and revealed the involvement of lymph nodes as well as spleen during work-up. She also presented with multiple osteolytic lesions which pathologically proven enchondromatosis. Oral prednisone was prescribed at 2 mg/kg/day for 2 months until when subcutaneous nodules and joint swellings almost disappeared, and then slowly tapered over a period of 5 months. We report an unusual case of early-onset childhood sarcoidosis presented with osteolytic bone lesions which were irrelevant to sarcoidosis.


Mutations of mtDNA in some Vascular and Metabolic Diseases.
The present review article considers some chronic diseases of vascular and metabolic genesis, the causes of which may be mitochondrial dysfunction. Very often, in the long course of the disease, complications may occur, leading to myocardial infarction or ischemic stroke and, as a result, death. In particular, a large percentage of human deaths nowadays belongs to cardiovascular diseases, such as coronary heart disease (CHD), arterial hypertension, cardiomyopathies, and type 2 diabetes mellitus. The aim of the present review was the analysis of literature sources, devoted to an investigation of a link of mitochondrial DNA mutations with chronic diseases of vascular and metabolic genesis. The analysis of literature indicates the association of the mitochondrial genome mutations with coronary heart disease, type 2 diabetes mellitus, hypertension, and various types of cardiomyopathies. The detected mutations can be used to analyze the predisposition to chronic diseases of vascular and metabolic genesis. They can also be used to create molecular-cell models necessary to evaluate the effectiveness of drugs developed for the treatment of these pathologies. MtDNA mutations associated with the absence of diseases of vascular and metabolic genesis could be potential candidates for gene therapy of the said diseases.


The 4-oxalocrotonate tautomerase family of enzymes: how nature makes new enzymes using a beta-alpha-beta structural motif.
4-Oxalocrotonate tautomerase (4-OT) catalyzes the isomerization of beta,gamma-unsaturated enones to their alpha,beta-isomers. The enzyme is part of a plasmid-encoded pathway, which enables bacteria harboring the plasmid to use various aromatic hydrocarbons as their sole sources of carbon and energy. Among isomerases and enzymes in general, 4-OT is unusual for two reasons: it has one of the smallest known monomer sizes (62 amino acids) and the amino-terminal proline functions as the catalytic base. In addition to Pro-1, three other residues (Arg-11, Arg-39, and Phe-50) have been identified as critical catalytic residues by kinetic analysis, site-directed mutagenesis, chemical synthesis, NMR, and crystallographic studies. Arginine-39 functions as the general acid catalyst (assisted by an ordered water molecule) in the reaction while Arg-11 plays a role in substrate binding and facilitates catalysis by acting as an electron sink. Finally, the hydrophobic nature of the active site, which lowers the pK(a) of Pro-1 to approximately 6.4 and provides a favorable environment for catalysis, is largely maintained by Phe-50. 4-OT is also the title enzyme of the 4-OT family of enzymes. The chromosomal homologues in this family are composed of monomers ranging in size from 61 to 79 amino acids, which code a beta-alpha-beta structural motif. The homologues all retain Pro-1 and generally have an aromatic or hydrophobic amino acid at the Phe-50 position. Characterization of representative members has uncovered mechanistic and structural diversity. A new activity, a trans-3-chloroacrylic acid dehalogenase, has been identified in addition to the previously known tautomerase and isomerase activities. Two new structures have also been found, along with the 4-OT hexamer. The dehalogenase functions as a heterohexamer while the Escherichia coli homologue, designated YdcE, functions as a dimer. Moreover, both 4-OT and the Bacillus subtilis homologue, designated YwhB, exhibit low-level dehalogenase activity. Amplification of this activity could have produced the full-fledged dehalogenase. The sum of these observations indicates that Nature uses the beta-alpha-beta structural motif as a building block in a variety of manners to create new enzymes.


Magnetic resonance imaging of normal meningeal enhancement at 1.5 T.
We examined patterns of intracranial meningeal enhancement on gadolinium chelate contrast media-enhanced 1.5-T spin-echo magnetic resonance (MR) imaging and developed criteria that might be useful for distinguishing between normal and abnormal meningeal enhancement. The convexity, falx cerebri, tentorium cerebelli, and suprasellar cistern regions of 204 patients were prospectively evaluated for contrast enhancement with a grading system ranging from 0 (no enhancement) to 5 (diffuse, irregular, thickened enhancement). Meningeal findings were correlated with other MR abnormalities and pertinent clinical histories that have been associated previously with meningeal enhancement. Short-segment convexity meningeal enhancement was commonly seen and most likely represents intravascular contrast material in normal meningeal vessels. Such enhancement did not correlate with the presence of other MR abnormalities. Long-segment (> 3 cm) or diffuse convexity meningeal enhancement did correlate with other significant MR abnormalities and pertinent clinical history. Fine linear falcine and tentorial meningeal enhancement, as an isolated finding, did not correlate with other MR or clinical abnormalities. The suprasellar cistern and ventricular walls were rarely enhanced. Short-segment convexity meningeal contrast enhancement is a normal finding representing normal vascular structures. More extensive convexity meningeal enhancement is abnormal and should prompt careful examination of the remainder of an MR image as well as the patient's clinical history for an etiology of the enhancement.


Theoretical versus empirical allometry: Facts behind theories and application to pharmacokinetics.
Although, no credible data are available, it is widely believed that the pharmacokinetic parameters such as clearance, volume of distribution, and elimination half-life can be scaled with a fixed exponent of 0.75, 1.0, and 0.25, respectively. However, logically it is difficult to perceive that the exponents of allometry for a given parameter will revolve around a fixed number. Over the last 80 years, theoretical biologists and physiologists are entangled in an argument whether the exponent of basal metabolic rate against body weight is 0.67 or 0.75. There are evidence for and against these two exponents. However, in-depth investigative works suggest that there is not really any universal exponent for any allometrically related parameter and the exponent of allometry depends on several factors. The main focus of this report is to show the readers that there is enough evidence from experimental data that negate the notion of fixed exponents in biology, physiology, and pharmacokinetics. In short, the notion of a fixed exponent is theoretical and there is no evidence that the exponent of a physiological or pharmacokinetic parameter revolves around a fixed number.


Ischemic postconditioning prevents renal ischemia reperfusion injury through the induction of heat shock proteins in rats.
Ischemic postconditioning (IPo) attenuates ischemia‑reperfusion injuries (IRI) in various organs, of both animals and humans. This study tested the hypothesis that IPo attenuates renal IRI through the upregulation of heat shock protein (HSP)70, HSP27 and heme oxygenase‑1 (HO‑1, also known as HSP 32) expression. Adult Sprague Dawley rats were subjected to bilateral renal ischemia for 45 min followed by reperfusion for up to 48 h. One group of rats received IPo prior to restoring full perfusion. Another group was administered 100 mg/kg HSP inhibitor quercetin, injected intraperitoneally 1 h prior to ischemia. Control rats received sham operations. Renal IR resulted in severe morphological and pathological changes, with increased serum creatinine and blood urea nitrogen concentrations. IR resulted in increased inflammation by inducing plasma tumor necrosis factor‑α and renal nuclear factor kappa‑light‑chain‑enhancer of activated B cells expression. IR also increased lipid peroxidation, as indicated by elevated malondialdehyde content, reduced superoxide dismutase activity and increased renal apoptosis. Renal HSP70, HSP27 and HO‑1 mRNA and protein levels were increased by IR and further elevated by IPo. IPo attenuated these changes observed in pathology, lipid peroxidation, apoptosis and inflammation. Quercetin treatment abolished all the protective effects of IPo. In conclusion, this study showed that IPo can attenuate lipid peroxidation, apoptosis and inflammation as well as renal IRI by upregulating the expression of HSP70, HSP27 and HO‑1.


Investigating Casual Associations Among Gut Microbiota, Metabolites, and Neurodegenerative Diseases: A Mendelian Randomization Study.
Recent studies had explored that gut microbiota was associated with neurodegenerative diseases (including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)) through the gut-brain axis, among which metabolic pathways played an important role. However, the underlying causality remained unclear. Our study aimed to evaluate potential causal relationships between gut microbiota, metabolites, and neurodegenerative diseases through Mendelian randomization (MR) approach. We selected genetic variants associated with gut microbiota traits (N = 18,340) and gut microbiota-derived metabolites (N = 7,824) from genome-wide association studies. Summary statistics of neurodegenerative diseases were obtained from IGAP (AD, 17,008 cases; 37,154 controls), IPDGC (PD, 37,688 cases; 141,779 controls), and IALSC (ALS, 20,806 cases; 59,804 controls) respectively. Greater abundance of Ruminococcus (OR, 1.245; 95% CI, 1.103-1.405; p = 0.0004) was found significantly related to higher risk of ALS. Besides, our study found suggestive associations of Actinobacteria, Lactobacillaceae, Faecalibacterium, Ruminiclostridium, and Lachnoclostridium with AD, of Lentisphaerae, Lentisphaeria, Oxalobacteraceae, Victivallales, Bacillales, Eubacteriumhalliigroup, Anaerostipes, and Clostridiumsensustricto1 with PD, and of Lachnospira, Fusicatenibacter, Catenibacterium, and Ruminococcusgnavusgroup with ALS. Our study also revealed suggestive associations between 12 gut microbiome-dependent metabolites and neurodegenerative diseases. Glutamine was related to lower risk of AD. For the serotonin pathway, serotonin was found as a protective factor of PD, while kynurenine as a risk factor for ALS. Our study firstly applied a two-sample MR approach to detect causal relationships among gut microbiota, gut metabolites, and neurodegenerative diseases. Our findings may provide new targets for treatments and may offer valuable insights for further studies on the underlying mechanisms.


[A methodological study on testing and evaluating of filtration efficiency of canister against microbial aerosol].
To establish a testing and evaluating method for filtration efficiency of the canister against microbial aerosol. Serratia marcescens aerosol served as model of bacterial aerosol, Bacillus subtilis var niger aerosol as model of spores aerosol, bacteriophage f(2) aerosol as model of viral aerosol. Employing the microbial aerosol testing platform was established in lab, models of microbial aerosol generated artificially were sampled quantitatively by air samplers before and after filtrating by canisters, respectively. Filtration efficiency was determined by the concentration of microbial aerosol in the air sample before and after filtrating. The four canisters of 1-1, 1-2, 1-3, 1-4 were tested for the filtration efficiency against Serratia marcescens, Bacillus subtilis var niger and phage f(2) aerosol. The two canisters of 543 and 544 canisters equipped with active carbon were tested for the filtration efficiencies against Serratia marcescens aerosol. The filtration efficiency of 1-1, 1-2, 1-3 canisters against Serratia marcescens, Bacillus subtilis var niger and phage f(2) aerosol was 100.000%. The filtration efficiency of 1-4 canister filtration efficiency against Bacillus subtilis var niger spores aerosol was 99.997% and efficiency of the other two aerosol was 100.000%. The filtration efficiency of the two canisters of 543 and 544 to those attached with active carbon against Serratia marcescens aerosol was 100.000%. The testing method might be used to evaluate the protective performance of the canister against microbiological aerosol. The effect of the canisters (including those equipped with active carbon) against microbiological aerosol should be reliable.


[Communication among physicians--impact, quality and requirements of discharge and referral letters].
Discharge and referral letters are essential for the communication among physicians. In contrast to Anglo-American research this issue has not received much attention in Germany, until now. For many years deficiencies in the quality of letters have been internationally reported in all medical specialist publications; these deficiencies relate in particular to the speed of delivery and the length of the discharge letters. Rapidly delivered, well-structured letters, one or two pages in length, with relevant information for outpatient care are preferred by physicians in private practice. The diagnosis, the results of examinations, lists of medications, and the suggestions made for treatment after discharge are essential items of information. The requirements mentioned with regard to discharge letters also apply to referral letters. From the point of view of clinicians, details about actual medications, suicidal tendency/aggression, current problems, the reason(s) for referral, drug intolerance and somatic disorders are felt to be indispensable. Details concerning guardianship, previous therapy, substance misuse, phone numbers of relatives, prior examinations, diagnoses, and previous examination findings are considered most important.


Preclinical evaluation of a novel drug-eluting balloon in an animal model of in-stent stenosis.
Despite advances in contemporary stent technology, in-stent restenosis (ISR) remains the major limitation following revascularization procedures. We developed a porcine model of ISR to specifically investigate the preclinical outcomes of a novel drug-eluting balloon (DEB) in this particular setting. Fifteen pigs received bare metal stents in each of the major coronary arteries for 28 days to induce neointimal growth. Following repeat angiography, animals were allocated to fourdifferent treatment groups. The control group consisted of a bare angioplasty catheter, while the Pantera Lux™ (3.0 µg/mm(2) paclitaxel) (30 s inflation) was compared to two consecutive deployments of the Pantera Lux™ (60 s inflation each) and the commercial SeQuent(®) Please balloon (60 s inflation). Twenty-eight days following balloon deployment, the animals underwent repeat angiography and were subsequently sacrificed for histopathologic assessment. There was a trend in reduction of percent diameter stenosis in the DEB group versus control (13.9% vs. 20.4%), while longer inflation duration or consecutive DEB deployment had no additional growth-limiting effect. Neointimal thickness was reduced from 0.38 ± 0.13 to 0.30 ± 0.09 mm in the control versus DEB group. All DEB groups showed delayed vascular healing characterized by dose-dependent increases in fibrin deposition and neointimal cell vacuity. Investigation of DEB in a porcine model of ISR is feasible and more accurately represents human disease conditions. The magnitude of neointima suppression is lower than that observed in non-diseased animal models and is accompanied by delayed vascular healing.


The Detroit Research on Cancer Survivors (ROCS) Pilot Study: A Focus on Outcomes after Cancer in a Racially Diverse Patient Population.
African Americans are often diagnosed with advanced stage cancer and experience higher mortality compared with whites in the United States. Contributing factors, like differences in access to medical care and the prevalence of comorbidities, do not entirely explain racial differences in outcomes. The Detroit Research on Cancer Survivors (ROCS) pilot study was conducted to investigate factors related to short- and long-term outcomes among patients with cancer. Participants completed web-based surveys, and mailed saliva specimens were collected for future genetic studies. We recruited 1,000 participants with an overall response rate of 68%. Thirty-one percent completed the survey without any interviewer support and the remaining participated in an interviewer-administered survey. Seventy-four percent provided a saliva specimen and 64% consented for tumor tissue retrieval. African American survivors required more interviewer support (P < 0.001); however, their response rate (69.6%) was higher than non-Hispanic whites (65.4%). African Americans reported poorer overall cancer-related quality of life compared with non-Hispanic whites, measured by FACT-G score (P < 0.001), however, this relationship was reversed after controlling for socioeconomic factors, marital status, and the presence of comorbidities. In this pilot study, we demonstrated that a web-based survey supplemented with telephone interviews and mailed saliva kits are cost-effective methods to collect patient-reported data and DNA for large studies of cancer survivors with a high proportion of minority patients. The preliminary data collected reinforces differences by race in factors affecting cancer outcomes. Our efforts continue as we expand this unique cohort to include more than 5,000 African American cancer survivors. Formal investigation of factors influencing adverse outcomes among African American cancer survivors will be critical in closing the racial gap in morbidity and mortality.


Dysbiosis index to evaluate the fecal microbiota in healthy cats and cats with chronic enteropathies.
Previous studies have identified various bacterial taxa that are altered in cats with chronic enteropathies (CE) vs healthy cats. Therefore, the aim of this study was to develop a targeted quantitative molecular method to evaluate the fecal microbiota of cats. Fecal samples from 80 client-owned healthy cats and 68 cats with CE were retrospectively evaluated. A panel of quantitative PCR (qPCR) assays was used to measure the fecal abundance of total bacteria and seven bacterial taxa: Bacteroides, Bifidobacterium, Clostridium hiranonis, Escherichia coli, Faecalibacterium, Streptococcus and Turicibacter. The nearest centroid classifier algorithm was used to calculate a dysbiosis index (DI) based on these qPCR abundances. The abundances of total bacteria, Bacteroides, Bifidobacterium, C hiranonis, Faecalibacterium and Turicibacter were significantly decreased, while those of E coli and Streptococcus were significantly increased in cats with CE (P <0.027 for all). The DI in cats with CE was significantly higher compared with healthy cats (P <0.001). When the cut-off value of the DI was set at 0, it provided 77% (95% confidence interval [CI] 66-85) sensitivity and 96% (95% CI 89-99) specificity to differentiate the microbiota of cats with CE from those of healthy cats. Fifty-two of 68 cats with CE had a DI >0. A qPCR-based DI for assessing the fecal microbiota of cats was established. The results showed that a large proportion of cats with CE had an altered fecal microbiota as evidenced by an increased DI. Prospective studies are warranted to evaluate the utility of this assay for clinical assessment of feline CE.


Population health data. Get a load of me.
UK Biobank has around 330,000 people signed up to provide personal data, including DNA. Large pharmaceutical companies and research organisations will have access to the material. UK Biobank insists access will be restricted to "bona fide" medical research. The project sees scope for international co-operation with other comparable databases.


The insanity defense: examination of the extent of congruence between psychiatric recommendation and adjudication.
The insanity plea is a known defense often utilized in courts of law. In such cases the accused may be referred for an outpatient psychiatric examination or for hospital observation. In this study, we examined the extent of the accord between the medical recommendations of the forensic unit of the Yehuda Abarbanel Mental Health Center and judicial decisions. It was found that in 99.4% of the cases, the court accepted the psychiatric recommendation. In only 2 cases the recommendations were not accepted. We discuss this issue and recommend improvements and strengthening of the relationship between the psychiatric and court systems.


Hydroclimatic contrasts over Asian monsoon areas and linkages to tropical Pacific SSTs.
Knowledge of spatial and temporal hydroclimatic differences is critical in understanding climatic mechanisms. Here we show striking hydroclimatic contrasts between northern and southern parts of the eastern margin of the Tibetan Plateau (ETP), and those between East Asian summer monsoon (EASM) and Indian summer monsoon (ISM) areas during the past ~2,000 years. During the Medieval Period, and the last 100 to 200 years, the southern ETP (S-ETP) area was generally dry (on average), while the northern ETP (N-ETP) area was wet. During the Little Ice Age (LIA), hydroclimate over S-ETP areas was wet, while that over N-ETP area was dry (on average). Such hydroclimatic contrasts can be broadly extended to ISM and EASM areas. We contend that changes in sea surface temperatures (SSTs) of the tropical Pacific Ocean could have played important roles in producing these hydroclimatic contrasts, by forcing the north-south movement of the Intertropical Convergence Zone (ITCZ) and intensification/slowdown of Walker circulation. The results of sensitivity experiments also support such a proposition.


A Novel Ratiometric Probe Based on Nitrogen-Doped Carbon Dots and Rhodamine B Isothiocyanate for Detection of Fe(3+) in Aqueous Solution.
A ratiometric probe for determining ferric ions (Fe(3+)) was developed based on nitrogen-doped carbon dots (CDs) and rhodamine B isothiocyanate (RhB), which was then applied to selective detection of Fe(3+) in PB buffer solution, lake water, and tap water. In the sensing system, FePO4 particles deposit on the surface of CDs, resulting in larger particles and surface passivation. The fluorescence (FL) intensity and the light scattering (LS) intensity of CDs can be gradually enhanced with the addition of Fe(3+), while the FL intensity of RhB remains constant. The ratiometric light intensity of CDs LS and RhB FL was quantitatively in response to Fe(3+) concentrations in a dynamic range of 0.01-1.2 μM, with a detection limit as low as 6 nM. Other metal ions, such as Fe(2+), Al(3+), K(+), Ca(2+), and Co(2+), had no significant interference on the determination of Fe(3+). Compared with traditional probes based on single-signal probe for Fe(3+) detection, this dual-signal-based ratiometric probe exhibits a more reliable and stable response on target concentration and is characterized by easy operation in a simple fluorescence spectrophotometer.


Enrolling, Retaining, and Benefiting Out-of-Treatment Drug Users in Intervention Research.
LONGITUDINAL RESEARCH ON street-recruited out-of-treatment drug users involves ethical issues concerning enrollment and retention of participants, remuneration and benefits. In contrast to practices of excluding such high-risk populations from research and assuming that they would not comply with a protocol requiring repeated measures over a 12-month period, this report presents examples from 15 years of community-based studies that have enrolled drug-using participants and achieved a 96% retention rate. We also examine ethical issues connected with cash remuneration, and describe methods to elucidate the kinds of benefits that are most meaningful to this population. Findings suggest that the research community must reconsider the ethics of blanket exclusions of such high-risk subjects, and make evidence-based decisions about recruitment, retention, remuneration, and benefits.


Heterotopic bone formation after joint replacement.
Bone formation outside the skeleton, heterotopic ossification (HO), is a common finding on radiographs from patients who have undergone arthroplasty of the hip, knee, shoulder, or elbow. Only a minority (5%-10%) of the patients with HO suffer from any consequence of the condition. However, because of the great number of joint replacements performed, the number of patients with decreased function that can be attributed to HO is significant. The risk for severe HO after total hip arthroplasty is increased in 1) patients who have developed HO after previous surgery, 2) men with hypertrophic osteoarthrosis and, 3) in patients with ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis. The same risk factors are probably valid for other joints as well. Two preventive treatments for HO after hip arthroplasty, nonsteroidal anti-inflammatory drugs and local radiation, are effective and reasonably well documented but are associated with potential side effects. Thus, a treatment protocol to prevent HO must identify the patients at risk for severe HO and recommend them treatment with one of these two modalities. Based on the current literature, we suggest that the patients at risk for severe HO be treated with 1) nonsteroidal anti-inflammatory drugs from the day of surgery for 7-10 days or 2) preoperative (or postoperative) radiation in a single dose.


Differential proteomic analysis of bronchoalveolar lavage fluid from lung transplant patients with and without chronic graft dysfunction.
Biomarkers are urgently needed for diagnosis, prognosis and monitoring of lung transplant chronic graft dysfunction. Bronchoalveolar lavage fluid (BAL) has been used in the past as proximal fluid for biomarker discovery in various lung diseases including chronic graft dysfunction (CGD). The current study describes the proteomic analysis of BAL fluids collected from 4 asymptomatic post-transplant patients and 3 patients with symptoms of CGD. BAL proteome was fractionated by size-exclusion chromatography at protein level and reverse-phase-chromatography at peptide level followed by Orbitrap mass spectrometry detection. Our in-depth proteomic analysis identified 531 proteins, the largest catalog of BAL proteins reported to date in the context of CGD. A total of 30 and 39 proteins detected exclusively in CGD and non-CGD samples, respectively, are potential candidates for verification phase. A new protocol was developed to enhance the sensitivity of detecting less abundant proteins in BAL.


MicroRNA-138 Overexpression Alters Aβ42 Levels and Behavior in Wildtype Mice.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by changes in cognitive and behavioral functions. With the exception or rare mutations in PSEN and APP genes causing early-onset autosomal dominant AD (EOADAD), little is known about the genetic factors that underlie the vast majority (>95%) of early onset AD (EOAD) cases. We have previously identified copy number variations (CNVs) in microRNA genes in patients with EOAD, including a duplication of the MIR-138-2 gene. Overexpression of miR-138 in cultured cells increased Aβ production and tau phosphorylation, similar to what is seen in AD brain. In this study, we sought to determine if miR-138 overexpression could recapitulate certain features of disease in vivo in non-transgenic mice. A mild overexpression of pre-miR-138 in the brain of C57BL/6J wildtype mice altered learning and memory in a novel object recognition test and in the Barnes Maze. Increased levels of anxiety were also observed in the open-field test. MiR-138 upregulation in vivo caused an increase in endogenous Aβ42 production as well as changes in synaptic and inflammation markers. Tau expression was significantly lower with no overt effects on phosphorylation. We finally observed that Sirt1, a direct target of miR-138 involved in Aβ production, learning and memory as well as anxiety, is decreased following miR-138 overexpression. In sum, this study further strengthens a role for increased gene dosage of MIR-138-2 gene in modulating AD risk, possibly by acting on different biological pathways. Further studies will be required to better understand the role of CNVs in microRNA genes in AD and related neurodegenerative disorders.


Effect of alcohols and their interaction with ethylene on the ripening of epidermal pericarp discs of tomato fruit.
Ethanol concentrations that were induced in pericarp discs of mature-green tomato fruit (Lycopersicon esculentum Mill, cv Castlemart) either by anaerobic metabolism or by exposure to ethanol vapor inhibited ripening without increasing the rate of ion leakage. Inhibition of ripening (i.e. lycopene synthesis) of excised tomato pericarp tissue by ethanol vapor was reversed by increasing concentrations of the plant hormone ethylene. A Lineweaver-Burk plot indicated noncompetitive interaction between ethanol and ethylene. Methanol and n-propanol also inhibited lycopene synthesis without significantly increasing ion leakage. The similar inhibitory effects of methanol, ethanol, and n-propanol at concentrations which did not stimulate ion leakage, and the relationship between activity and lipophilia of the alcohols suggest that their mode of action was through disruption of membranes associated with ethylene action.


Behavioral therapy in children and adolescents with obsessive-compulsive disorder: a pilot study.
Despite advances in pharmacotherapy for obsessive-compulsive disorder (OCD), medication treatments are not always effective. This pilot project examined the feasibility of a structured behavioral therapy program in the treatment of children and adolescents with OCD. Ten subjects with a primary diagnosis of OCD were invited to participate in the treatment program. Seven youngsters, 5 boys and 2 girls (age range 10.8-15.8, mean 13.0 years), participated and were treated for a mean of 14 sessions. These 7 subjects showed a broad range of OCD severity, as measured by the Children's Yale-Brown Obsessive Compulsive Scale (CYBOCS score range 12-29). Five subjects were also receiving antiobsessional medication (dose was not changed during the trial), and 2 subjects were treated without medication. All 7 youngsters showed a clinically significant reduction in the CYBOCS score at treatment endpoint (mean change 61%, range 30%-90%, effect size 2.04, p < 0.05), and the therapeutic gains were stable for at least 3 months after treatment. One of 5 children who had been receiving concurrent antiobsessional medication was able to tolerate a dose reduction following behavioral treatment. Two to three booster sessions within 6 months posttreatment were effective in preventing relapse in 4 of 6 subjects. The 3 children who declined behavioral treatment showed no improvement at 3-month and 6-month follow-up. Behavioral treatment appeared to be a useful adjunct to medication in children and adolescents with OCD. Further research could evaluate whether behavioral treatment would lower the dose requirements for children receiving antiobsessional medications. Randomized clinical trials are also needed to confirm the effectiveness of behavioral therapy alone or in combination with medication.


Medical management of AIDS patients. Gastrointestinal manifestations.
Gastrointestinal manifestations of AIDS are common. Opportunistic infections and tumors may affect any portion of the GI tract from oral cavity to anus. Esophageal involvement may result from Candida, CMV, HSV, HIV, and tumors. Biliary tract and pancreatic disease may cause abdominal pain. Diarrhea occurs in over 50% of AIDS patients and is multifactorial.


In situ templated synthesis of anatase single-crystal nanotube arrays.
Anatase single-crystal nanotubes were obtained using an in situ templated method. First, highly ordered titania arrays were formed through an anodization process in H(3)PO(4) electrolytes containing 0.5 wt% HF. Under optimized conditions titania nanotubes with a diameter of up to 100 nm and a length of up to 1.1 microm were prepared. Second, the crystallization and stability of the titania nanotubes were studied in air at elevated temperatures. Anatase single-crystal nanotubes were fabricated after annealing the sample in air at 450 degrees C. The anatase single-crystal structure was verified by selected area diffraction pattern and HRTEM images.


Response of Plasmodium falciparum to chloroquine and Fansidar in vivo and chloroquine and amodiaquine in vitro in Uganda.
The response of P. falciparum to chloroquine and pyrimethamine-sulfadoxine in vivo and chloroquine and amodiaquine in vitro was investigated in parasitaemic school children from six locations. Mean parasite sensitivity to chloroquine at day 7 was 74% (range 61-97) with parasite clearance rates between 2-3 days and complete defervescence in 85% of febrile children. Sensitivity declined in the four sites followed up to day 14 to 45% (range 37-53). Parasites were significantly more sensitive to pyrimethamine/sulfadoxine at 5/6 sites (100% day 7) but 5% of subjects became parasitaemic by day 14. In vitro isolates were significantly less sensitive to chloroquine than to amodiaquine with a mean 99% effective concentration of 348 mumol/L compared to 6.44 mumol/L. Clearly the role of chloroquine as the primary therapy for uncomplicated P. falciparum malaria should be reconsidered especially in the light of increasing disease severity and resurgence. Amodiaquine may be suitable alternative with pyrimethamine/sulfadoxine as second line and for more severe malaria prior to referral. The cost of alternative antimalarials and the dynamic and deteriorating pattern of resistance are powerful arguments for more objective slide diagnosis to minimise drug pressure and a regular drug sensitivity surveillance system. We believe that the latter should concentrate on measuring clinical drug efficacy in symptomatic outpatients rather than in asymptomatic children while the former needs more pragmatic and economical strategies possibly centred on seasonality and risk.


Vitamin D-influenced gene expression via a ligand-independent, receptor-DNA complex intermediate.
A lingering question regarding the regulation of target gene expression by 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] has been the delineation of vitamin D receptor (VDR)-DNA binding and transactivation. This report confirms that initial VDR-DNA interaction occurs in a ligand-independent fashion. An electrophoretic mobility-shift analysis demonstrated that VDR, derived from extracts of the small intestines of vitamin D-deficient rats, is capable of binding a vitamin D response element (DRE). Additional mobility-shift studies using either porcine-derived VDR or recombinant rat VDR from insect cells revealed DRE-binding capability in the absence of 1,25-(OH)2D3. The reactions were performed in various salt environments, with the maximum of porcine VDR-DRE and rat VDR-DRE binding detected at 100 mM and 150 mM KCl, respectively. The addition of 1,25-(OH)2D3 to an identical set of reaction mixtures resulted in increased DRE binding with greater affinities exhibited by both VDR types. These two phenomena were confirmed upon examination of an elution profile of VDR bound to DRE-linked Sepharose. When a linear KCl gradient was used for elution without the addition of 1,25-(OH)2D3, the peak of VDR was 205 mM KCl; the presence of exogenous hormone shifted the maximum VDR elution to a position corresponding to 265 mM KCl. Based on these data and previous reports on VDR-mediated transactivation, we propose a model for 1,25-(OH)2D3-influenced target gene expression.


Red meat intake, CYP2E1 and PPARγ polymorphisms, and colorectal cancer risk.
The association between red meat intake and colorectal cancer (CRC) may be modulated by genetic polymorphisms of cytochrome P450 2E1 (CYP2E1), a key enzyme in the metabolism of nitrosamines, and peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor involved in adipogenesis and lipid and glucose metabolism. We conducted a case-control study of 971 patients with CRC and 658 controls who were admitted to two university hospitals between 1995 and 2004 in Seoul, Korea. Participants were asked about red meat intake by using a validated food frequency questionnaire. Polymorphisms of CYP2E1 (rs3813867) and PPARγ (rs1801282 or rs3856806) were identified using the TaqMan assay. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression models. We found that the association between red meat and CRC varied by CYP2E1 polymorphisms; ORs (95% CIs) for at least five or more vs. less than one time/week of red meat intake were 2.77 (1.23-6.25) among individuals with C alleles of CYP2E1 and 0.89 (0.51-1.54) among individuals with the GG allele (Pinteraction=0.05). Compared with those individuals with the CC allele, increasing risk of CRC with increasing red meat intake was more pronounced among individuals with T alleles of PPARγC161T (rs3856806), but the association was not significant. Our data provide evidence that East Asians with the variant type of CYP2E1 may have high susceptibility to development of CRC risk.


Laxative management in ambulatory cancer patients on opioid therapy: a prospective, open-label investigation of polyethylene glycol, sodium picosulphate and lactulose.
Constipation and the laxatives polyethylene glycol (PEG), sodium picosulphate (SPS) and lactulose (L) were investigated in outpatients with cancer and on opioid therapy. Randomly selected patients were enrolled in a prospective, controlled, open-label trial. Endpoints were number of patients taking laxatives >28 days, number of patients with a stool-free interval >72 h (sfi72), dosage, numerical rating scale (NRS) for constipation, and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) questionnaire scores. The 348 patients had comparable demographic and medical data. In this ambulatory population, mobility scores remained unaffected. Constipation incidence was 5.7%, with sfi72 42, mean NRS 2.3557 and mean QoL 2.1. A total of 53.2% discontinued their laxative medication. Laxative use correlated with higher opioid usage (morphine-equivalent mg/day: no laxative 98.2, SPS 128.2, PEG 139.9, L 154.5). PEG was the most frequently prescribed laxative (PEG 27.3%, SPS 10.3%, L 9.2%). PEG (sfi72 12.6%, NRS 2.2, QoL 2.1) and SPS (sfi72 11.1%, NRS 2.7, QoL 2.2) proved more effective than L (sfi72 15.5%, NRS 3.8, QoL 2.5). In spite of opioid therapy, the incidence of constipation was low in these ambulatory cancer pain patients at an early disease stage. For prevention of constipation, PEG or SPS is recommended instead of L.


(Trifluoromethylselenyl)methylchalcogenyl as Emerging Fluorinated Groups: Synthesis under Photoredox Catalysis and Determination of the Lipophilicity.
The synthesis of molecules bearing (trifluoromethylselenyl)methylchalcogenyl groups is described via an efficient two-step strategy based on a metal-free photoredox catalyzed decarboxylative trifluoromethylselenolation with good yields up to 88 %, which raised to 98 % in flow chemistry conditions. The flow methods allowed also to scale up the reaction. The mechanism of this key reaction was studied. The physicochemical characterization of these emerging groups was performed by determining their Hansch-Leo lipophilicity parameters with high values up to 2.24. This reaction was also extended to perfluoroalkylselenolation with yields up to 95 %. Finally, this method was successfully applied to the functionalization of relevant bioactive molecules such as tocopherol or estrone derivatives.


Double thermoresponsive block copolymers featuring a biotin end group.
A poly(oligo(ethylene glycol) monomethyl ether methacrylate)-block-poly(N-isopropyl methacrylamide) (POEGMA-b-PNIPMAM) block copolymer with a biotin end group on the PNIPMAM block as a biotarget was synthesized as a model system for temperature-controlled polymer immobilization. The synthesis was based on RAFT polymerization followed by postpolymerization modification of an activated ester precursor block and an exchange of the dithioester end group within one step. NMR, differential scanning calorimetry (DSC), dynamic light scattering (DLS), and turbidimetry measurements were performed to investigate the stimulus-responsive properties. The double thermoresponsive POEGMA-b-PNIPMAM with biotin end group showed a temperature-dependent multistage assembly behavior as it was completely soluble in water at temperatures below the LCST of both blocks, formed micellar structures above the LCST of PNIPMAM but below the LCST of POEGMA, or precipitated from solution above the LCST of both blocks. At room temperature, the polymer could be immobilized onto a streptavidin surface via its biotin end group, as shown in surface plasmon resonance (SPR) experiments. At 50 °C, at which the block copolymer formed micelles trapping the biotin target within the PNIPMAM core, no immobilization was observed, showing that the biological binding ability of the model could be controlled via external stimuli.


Functionalizing titanium surface with PAMAM dendrimer and human BMP2 gene via layer-by-layer assembly for enhanced osteogenesis.
The study reports on the gene functionalization of titanium substrates with multilayered functional human BMP2 (hBMP2) gene plasmid and its effects on osteogenesis in vitro and in vivo. The multilayers comprising cationic poly(amidoamine) (PAMAM) dendrimer/EGFP-hBMP2 plasmid DNA complex (d-DNA) and anionic naked plasmid were deposited on titanium substrates via layer-by-layer (LbL) assembly technique, which was revealed by atomic force microscopy (AFM), water contact angle measurement, and release profiles. The expression of marker gene EGFP and functional gene hBMP2 were observed in osteoblasts. The assays of alkaline phosphatase activity, collagen secretion, ECM mineralization, and osteogenesis-related genes expression indicated that the multilayered structure improved the osteogenic differentiation in vitro. Moreover, the femur and subcutaneous transplantation of multilayered titanium implants were also investigated to reveal osteogenesis peri-implant by using histological examination and X-ray imaging. The in vivo histologic results showed that the BMP2 group (containing functional gene hBMP2) resulted in improved osteogenic proteins expression in subcutaneous and femur tissue, as well as high level of bone formation and % bone-implant contact (%BIC) peri-implant. The study offers an effective dendrimer and hBMP2 based strategy for surface functionalization of titanium implants in potential orthopedic applications. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 706-717, 2018.


Effects of dragon's blood resin and its component loureirin B on tetrodotoxin-sensitive voltage-gated sodium currents in rat dorsal root ganglion neurons.
Using whole-cell patch clamp technique on the membrane of freshly isolated dorsal root ganglion (DRG) neurons, the effects of dragon's blood resin and its important component loureirin B on tetrodotoxin-sensitive (TTX-S) voltage-gated sodium currents were observed. The results show that both blood resin and loureirin B could suppress TTX-S voltage-gated sodium currents in a dose-dependent way. The peak current amplitudes and the steady-state activation and inactivation curves are also made to shift by 0.05% blood resin and 0.2 mmol/L loureirin B. These results demonstrate that the effects of blood resin on TTX-S sodium current may contribute to loureirin B in blood resin. Perhaps the analgesic effect of blood resin is caused partly by loureirin B directly interfering with the nociceptive transmission of primary sensory neurons.


Intercellular adhesion molecule-2 (ICAM-2) in experimental trichinosis.
The estimation of the serum adhesion molecules (ICAM-2) levels in experimental trichinosis and evaluation of its impact on the course of infection as well as its possible role in the diagnosis of early trichinosis were studied. Serum levels of ICAM-2 correlated significantly with the inflammatory and course sequences of trichinosis in mice and had a similar relation with blood eosinophilia. So, estimation of ICAM-2 serum levels may prove useful in diagnosis of trichinosis recent infections, and in monitoring the prognosis and response to treatment. Investigations of the ICAM-2 role in human trichinosis and applying the findings to improve the diagnostic approaches are highly recommended.


[Neurilemmoma of the head and neck--report of 3 cases].
Neurilemmoma are benign tumors of the nerve-sheath, also known as schwannoma. Beside intracranial manifestation, neurilemmoma are found at other peripheral nerves of the head and neck. We present three cases of patients with seldom manifestation of neurilemmoma of the supraglottis, the retropharyngeal space and a neurilemmoma of the hypoglossal nerve. The histological examination showed two types of Antoni-A-neurilemmoma, whereas one tumor was found with mixed type A and B-neurilemmoma. Although extracranial neurilemmoma of retropharygeal space, neck or supraglottic larynx are rare tumors, neurilemmoma should be involved in differential diagnosis of tumors in these areas. The therapy of choice consists of complete surgical removal and histological examination.


Facilitation of signal onset and termination by adenylyl cyclase.
The alpha subunit (Gsalpha) of the stimulatory heterotrimeric guanosine triphosphate binding protein (G protein) Gs activates all isoforms of mammalian adenylyl cyclase. Adenylyl cyclase (Type V) and its subdomains, which interact with Gsalpha, promoted inactivation of the G protein by increasing its guanosine triphosphatase (GTPase) activity. Adenylyl cyclase and its subdomains also augmented the receptor-mediated activation of heterotrimeric Gs and thereby facilitated the rapid onset of signaling. These findings demonstrate that adenylyl cyclase functions as a GTPase activating protein (GAP) for the monomeric Gsalpha and enhances the GTP/GDP exchange factor (GEF) activity of receptors.


Ti(C,N) and WC-Based Cermets: A Review of Synthesis, Properties and Applications in Additive Manufacturing.
In recent years, the use of cermets has shown significant growth in the industry due to their interesting features that combine properties of metals and ceramics, and there are different possible types of cermets, depending on their composition. This review focuses on cemented tungsten carbides (WC), and tungsten carbonitrides (WCN), and it is intended to analyze the relationship between chemical composition and processing techniques of these materials, which results in their particular microstructural and mechanical properties. Moreover, the use of cermets as a printing material in additive manufacturing or 3D printing processes has recently emerged as one of the scenarios with the greatest projection, considering that they manufacture parts with greater versatility, lower manufacturing costs, lower raw material expenditure and with advanced designs. Therefore, this review compiled and analyzed scientific papers devoted to the synthesis, properties and uses of cermets of TiC and WC in additive manufacturing processes reported thus far.


Short leg cast versus orthotic removable support for the management of pseudo-Jones avulsion fracture: A systematic review and meta-analysis.
The fifth metatarsal base avulsion fracture (i.e., Pseudo-Jones fracture) is one of the most common foot fractures. The management of pseudo-Jones fractures could be carried out surgically or conservatively. This systematic review and meta-analysis aimed to provide an update about the efficacy of orthotic removable support compared to short-leg casting for individuals with pseudo-Jones fracture. We searched Embase, Medline, and Cochrane Central register of Controlled Trials (CENTRAL) for randomized controlled trials (RCTs) that compared the clinical outcomes of orthotic removable support and short-leg cast for adult individuals with a fifth metatarsal base avulsion fracture. We used 95% as a confidence level and P <0.05 as a threshold. The standardized mean difference (SMD) was used for the continuous outcomes, and the risk ratio (RR) was used for the dichotomous outcomes. A total of 6 RCTs incorporating 403 individuals out were deemed eligible. There was no significant difference between orthotic removable support and short-leg casting regarding AOFAS score (standardized mean difference (SMD)= 0.31, 95% CI -0.17 to 0.8), pain on VAS score (SMD= -0.08, 95% CI -0.39 to 0.22), VAS-FA score (SMD= 0.22, 95% CI -0.19 to 0.62) EQ-5D VAS score, and non-union rate (RR=0.37, 95% CI 0.05 to 2.74). The current meta-analysis reveals that there is no difference between orthotic removable support and short-leg casting for the conservative management of individuals sustaining pseudo-Jones fracture.


Cyanide-Bridged Polynuclear and One-Dimensional FeIII-MnIII/II Bimetallic Complexes Based-on Pentacyanoferrite(III) Building Block: Synthesis, Crystal Structures, and Magnetic Properties.
In this contribution, based-on the structurally confirmed pentacyanometallate (PPh4)2[Fe(CN)5(imidazole)]·(imidazole)·H2O (1) and the manganese compounds [Mn(L)(H2O)2]ClO4 (L = N,N-ethylenebis(3-methoxysalicylideneiminate) or [Mn(MAC)(H2O)Cl]ClO4 (MAC = 2,13-dimethyl-3,6,9,12,18-pentaazabicyclo-[12.3.1]octadeca-1(18),2,12,14,16-pentaene), two new cyanide-bridged bimetallic FeIII-MnIII/II complexes [Mn(L)(H2O)]3[Fe(CN)5(imidazole)](ClO4) (2) and [Mn(MAC)][Fe(CN)5(imidazole)]·CH3OHn (3) were successfully synthesized and characterized by elemental analysis, IR spectroscopy and X-ray structure determination. Single X-ray diffraction analysis reveals the cationic FeMn3 tetranuclear entity for complex 2, which can be further assembled into supramolecular 1D ladder-like double chain by the strong intermolecular hydrogen bond interactions. For complex 3, it can be structurally characterized as neutral one-dimensional linear single infinite chain. The magnetic investigations discover the ferromagnetic coupling between the FeIII-MnIII units in complex 2 and the antiferromagnetic coupling in complex 3 between the FeIII-MnII units through the bridging cyanide group, respectively.


[Performance of matrix assisted laser desorption ionization time of flight biotyper system in clinical bacteria identification].
Objective: To evaluate the performance of MALDI Biotyper system in identification of clinically isolated pathogens so as to provide a new rapid identification method. Methods: Total 21 270 pathogens strains, isolated from the First Affiliated Hospital of Fujian Medical Universityduring Nov. 2015 to Dec. 2016, were identified by VITEK-Ⅱ, API and MALDI Biotyper system, respectively.The isolated strains were confirmed by DNA sequencing. Results: The identification of common bacteria with MALDI Biotyper and phenotypic system is highly consistent (>95% and >90%). Among 43 strains of anaerobic bacteria, MALDI Biotyper could identify 90.7% bacteria to species level and 97.7% bacteria to genus level with the statistical significance(χ(2)=6.76, P<0.01), while phenotypic system only identified 65.1% bacteria to species and 69.8% bacteria to genus. Also, no statistical significance was shown for Trichosporon and Candida(P>0.05). MALDI Biotyper could identify 76% filamentous fungi and all of Actinomycetes, Nocardia, Mycobacterium and Legionella to genus level. Conclusions: MALDI Biotyper is an easy-performed, sensitive method for the identification of clinically isolated pathogens. Additionally, the pretreatment and reference database has the effect on identification.


Myocardial ischemia during percutaneous transluminal coronary angioplasty in patients with rich collateral circulation of the target lesion.
Although it is commonly believed that ischemia does not develop during coronary intervention in patients with rich collateral circulation to the target vessel, ST changes are often observed, the study group comprised 40 consecutive patients who underwent elective percutaneous coronary angioplasty and who had rich collateral vessels to the target lesions. None had side branches in the target vessel that would be occluded by the angioplasty balloon. During the intervention, the 12-lead electrocardiogram was monitored for any change in the ST-T segment and 13 (32.5%) showed significant ST changes. Of these, 3 had ST changes with every balloon inflation and the remaining 10 patients had ST changes with the second or subsequent inflations. Myocardial ischemia caused by balloon inflation is not uncommon during coronary angioplasty in patients with rich collaterals to the target vessel. The collateral circulation may stop functioning very early after improvement in the forward flow of the target vessel.


Catalytic reaction mechanism of homogentisate dioxygenase: a hybrid DFT study.
Human homogentisate dioxygenase is an Fe(II)-dependent enzyme responsible for aromatic ring cleavage. The mechanism of its catalytic reaction has been investigated with the hybrid density functional method B3LYP. A relatively big model of the active site was first used to determine the substrate binding mode. It was found that binding of the substrate dianion with a vacant position trans to Glu341 is most favorable. The model was then truncated to include only the most relevant parts of the active-site residues involved in iron coordination and substrate binding. Thus, methylimidazole was used to model His292, His335, His365, and His371, while propionate modeled Glu341. The computational results suggest that the catalytic reaction of homogentisate dioxygenases involves three major chemical steps: formation of the peroxo intermediate, homolytic cleavage of the O-O bond leading to an arene oxide radical, and finally, cleavage of the six-membered ring. Calculated barriers for alternative reaction paths are markedly higher than for the proposed mechanism, and thus the computational results successfully explain the product specificity of the enzyme. Interestingly, the results indicate that the type of ring scission, intra or extra with respect to the substituents coordinating to iron, is controlled by the barrier heights for the decay of the arene oxide radical intermediate.


[Fe(II) enhanced sonochemical degradation of azo dye Acid Red B (ARB)].
Sonochemical degradation of azo dye Acid Red B (ARB) was studied in this paper. The effect of pH and ferrous ion concentrations on the process was investigated. The results show that decolorization of ARB proceeds faster in acidic medium. The production of H2O2 is proportional to sonication time. The presence of Fe(II), which could react with H2O2 to produce *OH, enhances the sonochemical decolorizatio and degradation of the dye. The decolorization rates of ARB are 2.17 and 2.75 times faster, respectively, when Fe(II) concentrations are 1.43 mg/L and 2.85 mg/L. The UV absorptions at 322 nm and 254 nm also reduce ARB dramatically.


[Coronary angioplasty in the acute phase of a myocardial infarction on a myocardial bridge].
A myocardial bridge is usually asymptomatic but can cause myocardial ischemia, myocardial infarction or sudden death. Two occurrences of coronary angioplasty in the acute phase of an anterior myocardial infarction on a myocardial bridge are reported. The first case was first treated only with a balloon, and then with a stent 12 h later after a relapse of angina pectoris and the recurrence of a severe compression. The second case immediately benefited from a stent. A systematic control at six months has shown the absence of restenosis in the first case and an asymptomatic occlusion of the stent in the second case. Its deocclusion has revealed a myocardial bridge downstream of the stent. Myocardial stunning might have caused a decreased systolic compression by the bridge in the first case, and an underestimation of its actual length in the second case. Its regression is held responsible for these two relapses. A long active stent installed at high pressure could be used to treat myocardial bridges during myocardial infarctions.


An epidemiological investigation of Norwalk virus infection in South Africa.
A study was carried out to determine the incidence and seroprevalence of Norwalk virus (NV) in the Pretoria area, South Africa, using a recombinant NV (rNV) immunoassay for the detection of serum IgG antibodies. Maternal antibody was detectable in infants' sera up to approximately 6 months of age. Infection with NV was detected serologically in the second year of life and the seroprevalence of NV IgG rose from 37.1% at 7-11 months of age to 62.1% by the age of 40 years. No significant differences in seroprevalence of NV IgG antibody was evident between subjects of European or African ethnic origin, where overall seroprevalence rates were 56.4% and 53.9% respectively.


Difference in the lubrication efficiency of bovine and vegetable-derived magnesium stearate during tabletting.
The purpose of this work was to evaluate and compare the functionality of bovine fatty acids-derived (MgSt-B) and vegetable fatty acids-derived (MgSt-V) magnesium stearate powders when used for the lubrication of granules prepared by high-shear (HSG) and fluid bed (FBG) wet granulation methods. The work included evaluation of tablet compression and ejection forces during tabletting and dissolution testing of the compressed tablets. Granules prepared by both granulation methods required significantly lower ejection force (p < 0.01) when lubricated with the MgSt-V powder as compared to those lubricated with the MgSt-B powder. Granules prepared by the HSG method and lubricated with the MgSt-V powder also required significantly lower compression force (p < 0.01) to produce tablets of similar weight and hardness as compared to those lubricated with the MgSt-B powder. The dissolution profiles were not affected by these differences and were the same for tablets prepared by same granulation method and lubricated with either magnesium stearate powder. The results indicate significant differences (p < 0.01) between lubrication efficiency of the MgSt-B and the MgSt-V powders and emphasize the importance of functionality testing of the MgSt powders to understand the impact of these differences.


Mechanical Brain Injury Increases Cells' Production of Cystathionine β-Synthase and Glutamine Synthetase, but Reduces Pax2 Expression in the Telencephalon of Juvenile Chum Salmon, Oncorhynchus keta.
The considerable post-traumatic brain recovery in fishes makes them a useful model for studying the mechanisms that provide reparative neurogenesis, which is poorly represented in mammals. After a mechanical injury to the telencephalon in adult fish, lost neurons are actively replaced due to the proliferative activity of neuroepithelial cells and radial glia in the neurogenic periventricular zone. However, it is not enough clear which signaling mechanisms are involved in the activation of adult neural stem cells (aNSC) after the injury (reactive proliferation) and in the production of new neurons (regenerative neurogenesis) from progenitor cells (NPC). In juvenile Pacific salmon, the predominant type of NSCs in the telencephalon are neuroepithelial cells corresponding to embryonic NSCs. Expression of glutamine synthetase (GS), a NSC molecular marker, was detected in the neuroepithelial cells of the pallium and subpallium of juvenile chum salmon, Oncorhynchus keta. At 3 days after a traumatic brain injury (TBI) in juvenile chum salmon, the GS expression was detected in the radial glia corresponding to aNSC in the pallium and subpallium. The maximum density of distribution of GS+ radial glia was found in the dorsal pallial region. Hydrogen sulfide (H2S) is a proneurogenic factor that reduces oxidative stress and excitotoxicity effects, along with the increased GS production in the brain cells of juvenile chum salmon. In the fish brain, H2S producing by cystathionine β-synthase in neurogenic zones may be involved in maintaining the microenvironment that provides optimal conditions for the functioning of neurogenic niches during constitutive neurogenesis. After injury, H2S can determine cell survivability, providing a neuroprotective effect in the area of injury and reducing the process of glutamate excitotoxicity, acting as a signaling molecule involved in changing the neurogenic environment, which leads to the reactivation of neurogenic niches and cell regeneration programs. The results of studies on the control of the expression of regulatory Sonic Hedgehog genes (Shh) and the transcription factors Paired Box2 (Pax2) regulated by them are still insufficient. A comparative analysis of Pax2 expression in the telencephalon of intact chum salmon showed the presence of constitutive patterns of Pax2 expression in neurogenic areas and non-neurogenic parenchymal zones of the pallium and subpallium. After mechanical injury, the patterns of Pax2 expression changed, and the amount of Pax2+ decreased (p < 0.05) in lateral (Dl), medial (Dm) zones of the pallium, and the lateral zone (Vl) of the subpallium compared to the control. We believe that the decrease in the expression of Pax2 may be caused by the inhibitory effect of the Pax6 transcription factor, whose expression in the juvenile salmon brain increases upon injury.


Stereoselective synthesis and structure-affinity relationships of bicyclic kappa receptor agonists.
Reductive amination of the bicyclic ketone 4 led diastereoselectively to endo-configured amines, which were transformed into the amides 7-10. The synthesis of the diastereomers 25 with an exo-configured amino moiety at position 6 was only successful after deactivation of both N-atoms of the 1,4-diazabicyclo[3.3.1]nonane system. The N-1-oxide 19 with an N-4-tosyl moiety was the crucial intermediate, which allows SN2 substitution with NaN3 under inversion of the configuration at position 6. Whereas the endo-configured pyrrolidine 7a (WMS-1302) revealed a kappa receptor affinity of 73 nM, the exo-configured diastereomer 25a was almost inactive at the kappa receptor (Ki > 1 microM). Replacement of the 3,4-dichlorophenylacetyl residue by other acyl and sulfonyl residues showed that it is essential for high kappa affinity. The kappa receptor affinities of the conformationally constrained pyrrolidines 7a and 25a were correlated with the dihedral angle N(pyrrolidine)-C-C-N(acetamide). A systematic conformational analysis of the potent but flexible kappa agonist 2 showed that a dihedral angle of 168 degrees (as in 25a) is energetically more disfavored than a dihedral angle of 58 degrees (7a). However, even the conformation with a dihedral angle of 58 degrees does not represent an energy minimum, which might explain the reduced kappa affinity of 7a.


On the form of ROCs constructed from confidence ratings.
A classical question for memory researchers is whether memories vary in an all-or-nothing, discrete manner (e.g., stored vs. not stored, recalled vs. not recalled), or whether they vary along a continuous dimension (e.g., strength, similarity, or familiarity). For yes-no classification tasks, continuous- and discrete-state models predict nonlinear and linear receiver operating characteristics (ROCs), respectively (D. M. Green & J. A. Swets, 1966; N. A. Macmillan & C. D. Creelman, 1991). Recently, several authors have assumed that these predictions are generalizable to confidence ratings tasks (J. Qin, C. L. Raye, M. K. Johnson, & K. J. Mitchell, 2001; S. D. Slotnick, S. A. Klein, C. S. Dodson, & A. P. Shimamura, 2000, and A. P. Yonelinas, 1999). This assumption is shown to be unwarranted by showing that discrete-state ratings models predict both linear and nonlinear ROCs. The critical factor determining the form of the discrete-state ROC is the response strategy adopted by the classifier.


Association between objective clinical variables and patient-rated disability of the wrist.
Although the outcome of fractures of the distal radius is traditionally assessed using objective clinical variables such as grip strength and range of movement of the wrist, the extent to which they reflect function and outcomes of importance for the patient is uncertain. This may cause considerable inconsistencies in the assessment of outcome using current scoring systems. We prospectively studied 31 patients recovering from unstable fractures of the distal radius in order to investigate the association between objective variables and the level of post-traumatic disability of the wrist as measured by the patient-rated wrist evaluation (PRWE) score. Multiple regression showed considerable differences in the extent to which limitations in specific objective clinical variables reflected the level of disability of the wrist. Grip strength was shown to be a significant predictor of the PRWE score (regression coefficient -1.09, 95% confidence interval -1.76 to -0.42, p < 0.01) and thus appears to be a sensitive indicator of return of function of the wrist. Forearm rotation and flexion and extension of the wrist were not significantly associated with the PRWE score. These observations should be taken into account during the evaluation of methods of treatment and in constructing future clinical outcome scoring systems.


Role of the Skin Prick Test in Urticaria Patients.
Background Urticaria, a vascular reaction of the skin, is marked by the transient appearance of erythematous papules or plaques (wheals) of varying sizes that are blanchable and associated with severe pruritus which lasts from a few hours to days. The etiological factors for urticaria include food, drugs, bacterial foci, pollen, fungi, dust, worms, physical stimuli, stress, anxiety, insect stings, etc. Skin prick tests (SPTs) represent the cheapest and most effective method to diagnose immunoglobulin E-mediated type 1 allergic reactions such as urticaria. A history suggestive of clinical sensitivity supported by a positive test strongly implicates the allergen in the disease process. In this study, we aimed to detect the common allergens and correlate the findings of SPTs with various epidemiological characteristics of urticaria patients. Methodology A total of 100 patients with urticaria were included in this study. After receiving written and informed consent from patients, SPTs using a battery of 45 allergens were performed. Results In our study, SPT positivity was seen in 88 (88%) patients. The highest sensitization was noted toward Dermatophagoides pteronyssinus (house dust mite) (30%), followed by D. farinae, Cynodon dactylon, and peanuts (each comprising 24%), and Ailanthus excelsa (20%). Conclusions Finding the causative allergen in urticaria is often a difficult and long-drawn process, both for the physician and the patient. Our study identified an allergen in 88% of patients with urticaria, thereby showing that the SPT is a cost-effective, easy, and reliable tool for diagnosing and guiding treatments in urticaria patients.


The Origin of Abnormal Beta Oscillations in the Parkinsonian Corticobasal Ganglia Circuits.
Parkinson's disease (PD) is a neurodegenerative brain disorder associated with motor and nonmotor symptoms. Exaggerated beta band (15-30 Hz) neuronal oscillations are widely observed in corticobasal ganglia (BG) circuits during parkinsonism. Abnormal beta oscillations have been linked to motor symptoms of PD, but their exact relationship is poorly understood. Nevertheless, reduction of beta oscillations can induce therapeutic effects in PD patients. While it is widely believed that the external globus pallidus (GPe) and subthalamic nucleus (STN) are jointly responsible for abnormal rhythmogenesis in the parkinsonian BG, the role of other cortico-BG circuits cannot be ignored. To shed light on the origin of abnormal beta oscillations in PD, here we review changes of neuronal activity observed in experimental PD models and discuss how the cortex and different BG nuclei cooperate to generate and stabilize abnormal beta oscillations during parkinsonism. This may provide further insights into the complex relationship between abnormal beta oscillations and motor dysfunction in PD, which is crucial for potential target-specific therapeutic interventions in PD patients.


Low larval vector survival explains unstable malaria in the western Kenya highlands.
Several highland areas in eastern Africa have recently suffered from serious malaria epidemics. Some models predict that, in the short term, these areas will experience more epidemics as a result of global warming. However, the various processes underlying these changes are poorly understood. We therefore investigated malaria prevalence, malaria vector densities and malaria vector survival in a highland area in western Kenya, ranging from approximately 1,550-1,650 m altitude. Although only five adult malaria vectors were collected during 180 light traps and 180 resting collections over a 23-month study period, malaria was prevalent among school children (average parasite prevalence: 10%). During an extensive survey of potential larval habitats, we identified only seven habitats containing Anopheles gambiae Giles s.l. larvae. Their limited number and low larval densities suggested that their contribution to the adult vector population was small. Experiments on adult and larval survival showed that at this altitude, adult mosquitoes survived inside local houses, but that larval development was severely retarded: only 2 of 500 A. gambiae s.l. larvae developed to the pupal stage, whereas all other larvae died prior to pupation. At present, high vector densities are unlikely because of unfavourable abiotic conditions in the area. However, temporary favourable conditions, such as during El Niño years, may increase larval vector survival and may lead to malaria epidemics.


Small cell lung cancer: current therapy and promising new regimens.
In this review, we cover current therapy and promising new regimens and highlight areas where improvement is needed in the management of small cell lung cancer.


Potentiation of carbon tetrachloride hepatotoxicity by beta-phenethyl alcohol.
Carbon tetrachloride (CCl4)-induced hepatotoxicity was potentiated by pretreatment with beta-phenethyl alcohol, abundantly present in sake. The injury was determined by serum GPT levels and histological examination. Similar results were observed in ethanol- and phenobarbital-pretreated rats. Acetaminophen-induced hepatotoxicity was not accentuated by beta-phenethyl alcohol or ethanol pretreatment. The activities of liver microsomal enzymes, such as cytochrome P-450, cytochrome b5 reductase, aniline hydroxylase and aminopyrine demethylase, were not altered in beta-phenethyl alcohol-pretreated rats. Thus, CCl4-induced hepatotoxicity potentiation by beta-phenethyl alcohol administration is postulated to be due to a mechanism other than increased free radical generation.


Blocking IDO activity to enhance anti-tumor immunity.
Tumors express potentially immunogenic antigens, yet the immune response to these antigens is typically profoundly suppressed. Patients with established tumors behave as if they were functionally tolerant to any antigens associated with the tumor. This tolerance reflects a process of active immune suppression elicited by the tumor, and represents a critical barrier to successful anti-tumor immunotherapy. Indoleamine 2,3-dioxygenase (IDO) is a natural immunoregulatory mechanism contributes to immune suppression and tolerance in a variety of settings. In tumor-bearing hosts, animal models suggest that tumor-induced IDO helps create a tolerogenic milieu within the tumor and the associated tumor-draining lymph nodes. IDO directly suppresses the proliferation and differentiation of effector T cells, and markedly enhances the suppressor activity of regulatory T cells (Tregs). Together, these effects contribute to the inability of the immune system to respond effectively to tumor antigens. Treatment of tumor-bearing animals with IDO-inhibitor drugs enhances anti-tumor immune responses, and IDO-inhibitors are synergistic with a variety of chemotherapeutic drugs, anti-tumor vaccines and other immunotherapy. Strategies to pharmacologically inhibit IDO may thus enhance immune-mediated responses following conventional chemotherapy, and may be synergistic with other forms of immunotherapy.


Evolution of a chordate-specific mechanism for myoblast fusion.
Vertebrate myoblast fusion allows for multinucleated muscle fibers to compound the size and strength of mononucleated cells, but the evolution of this important process is unknown. We investigated the evolutionary origins and function of membrane-coalescing agents Myomaker and Myomixer in various groups of chordates. Here, we report that Myomaker likely arose through gene duplication in the last common ancestor of tunicates and vertebrates, while Myomixer appears to have evolved de novo in early vertebrates. Functional tests revealed a complex evolutionary history of myoblast fusion. A prevertebrate phase of muscle multinucleation driven by Myomaker was followed by the later emergence of Myomixer that enables the highly efficient fusion system of vertebrates. Evolutionary comparisons between vertebrate and nonvertebrate Myomaker revealed key structural and mechanistic insights into myoblast fusion. Thus, our findings suggest an evolutionary model of chordate fusogens and illustrate how new genes shape the emergence of novel morphogenetic traits and mechanisms.


Nod factor induces soybean resistance to powdery mildew.
Plants possess highly sensitive perception systems by which microbial signal molecules are recognized. In the Bradyrhizobium-soybean (Glycine max (L.) Merr.) symbiosis, recognition is initiated through exchange of signal molecules, generally flavonoids from soybean and lipo-chitooligosaccharides (Nod factors) from the microsymbiont. Application of the Nod factor Nod Bj-V (C18:1, MeFuc) induced soybean resistance to powdery mildew caused by Microsphaera diffusa. Addition of Nod factor (concentrations ranging from 10(-6) to 10(-10) M) to soybean root systems led to reductions in disease incidence. The lowest disease incidence was caused by Nod factor treatment at 10(-6) M. The effect of Nod factor application on fungal growth and development was measured at 4, 12, 48, and 96 h after inoculation. Colony diameter and number of germ tubes per conidium were decreased by 10(-6) M Nod factor. Phenylalanine ammonia lyase (PAL, EC.184.108.40.206.) is the first enzyme of the phenyl propanoid pathway, and is commonly activated as part of plant responses to disease. Treatment of soybean seedlings with Nod factor, through stem wounds, induced PAL activity; the most rapid increase followed treatment with 10(-6) M Nod factor. These data show that soybean plants are able to detect root applied LCO and respond by increased disease resistance.


Probable trigeminal autonomic cephalgia in a 3-month-old male infant.
To my knowledge trigeminal autonomic cephalgias (TACs) have not previously been reported in infancy. The diagnosis is dependent on an accurate history, including parents noting any physical signs at the time of the episode. Obtaining a clear history can be challenging when such symptoms occur in preverbal children. Similarly, physical signs, being transient, may have resolved by the time the parents take the child to a doctor. In addition, the investigations may also be normal. In such circumstances, taking a photograph during an episode can confirm the diagnosis. I describe a case of probable trigeminal autonomic cephalgia starting in a 3-month-old male infant who presented with screaming episodes associated with characteristic changes seen on his face. Investigations, including cranial magnetic resonance imaging, electroencephalography, and urinary catecholamines, were normal. The diagnosis was confirmed from a photograph taken by the parents at the time of the attack. As the condition is very rare in young children, there is little information available in the literature on using treatment for prophylaxis or for aborting acute episodes in this age group.


Parvovirus initiator protein NS1 and RPA coordinate replication fork progression in a reconstituted DNA replication system.
We show here that the DNA helicase activity of the parvoviral initiator protein NS1 is highly directional, binding to the single strand at a recessed 5' end and displacing the other strand while progressing in a 3'-to-5' direction on the bound strand. NS1 and a cellular site-specific DNA binding factor, PIF, also known as glucocorticoid modulating element binding protein, bind to the left-end minimal replication origin of minute virus of mice, forming a ternary complex. In this complex, NS1 is activated to nick one DNA strand, becoming covalently attached to the 5' end of the nick in the process and providing a 3' OH for priming DNA synthesis. In this situation, the helicase activity of NS1 did not displace the nicked strand, but the origin duplex was distorted by the NS1-PIF complex, as assayed by its sensitivity to KMnO(4) oxidation, and a stretch of about 14 nucleotides on both strands of the nicked origin underwent limited unwinding. Addition of Escherichia coli single-stranded DNA binding protein (SSB) did not lead to further unwinding. However, addition of recombinant human single-stranded DNA binding protein (RPA) to the initiation reaction catalyzed extensive unwinding of the nicked origin, suggesting that RPA may be required to form a functional replication fork. Accordingly, the unwinding mediated by NS1 and RPA promoted processive leading-strand synthesis catalyzed by recombinant human DNA polymerase delta, PCNA, and RFC, using the minimal left-end origin cloned in a plasmid as a template. The requirement for RPA, rather than SSB, in the unwinding reaction indicated that specific NS1-RPA protein interactions were formed. NS1 was tested by enzyme-linked immunosorbent assay for binding to two- or three-subunit RPA complexes expressed from recombinant baculoviruses. NS1 efficiently bound each of the baculovirus-expressed complexes, indicating that the small subunit of RPA is not involved in specific NS1 binding. No NS1 interactions were observed with E. coli SSB or other proteins included as controls.