Can health and health equity be advanced by urban planning strategies designed to advance global competitiveness? Lessons from two Australian case studies.
The purpose of this article is to investigate whether the neo-liberal goal of global economic competitiveness when included alongside image-inspired social goals such as liveability and environmental goals such as sustainability can lead to policies that impact positively on health and health equity. The paper presents an analysis of the content and intent of strategic planning and transport plans from two Australian state governments. The analysis was undertaken using a thematic document analysis of each plan and interviews with agents (n = 21) directly involved in the preparation of each document. Key strategic documents formulated under a neo-liberal hegemony simultaneously provided and reduced opportunities to promote and advance health. The policies viewed goals like liveability and sustainability as means of enhancing their cities' image in global competition for exogenous capital flows. Although liveability has many definitions, one definition was able to be used in one jurisdiction as an avenue to include a broad array of social determinants of health into urban planning policy. However, a productivity or a narrowly focussed image narrative can undermine the social determinants of health credentials of liveability. Overemphasising immediate city problems like road congestion as mechanisms to enhance global competitiveness can undermine necessary long-term strategies for city planning that are known to improve liveability and human health. Even where liveability is at the fore, there is a high risk of exacerbating spatial inequities through liveability investments for competitive advantage because they tend to flow to parts of cities with the greatest connections to the global economy, not those with the greatest social need. A neo-liberal-inspired competitive city paradigm provides opportunities for the advancement of health in urban development. However, when driven by the goals of productivity and/or liveability as image enhancement it can potentially exacerbate health inequities.


Three sibling species within Contracaecum osculatum (Nematoda, Ascaridida, Ascaridoidea) from the Atlantic Arctic-Boreal region: reproductive isolation and host preferences.
Genetic variation within and between population samples from 22 locations of the Atlantic Arctic-Boreal region, including 1657 specimens morphologically assigned to Contracaecum osculatum, was electrophoretically analysed at 17 loci. Highly significant deviations from the Hardy-Weinberg equilibrium were found at various loci in several samples, owing to the existence of three distinct gene pools within C. osculatum (sensu lato) from the study area. These gene pools correspond to three biological species (provisionally designated A, B and C), characterized by distinct genotypes at several diagnostic loci. Reproductive isolation between C.osculatum A, B and C is confirmed by the lack of F1, recombinant, or backcross genotypes in sympatric areas, despite the occurrence of multiple infections. Mean heterozygosity per locus is on average 0.11 in species A, 0.10 in B and 0.07 in C. High levels of gene flow were found within each of the three species, the values of Nm (number of migrant individuals) ranging from 3.41 (C. osculatum C) to 5.77 (C. osculatum A). Average Nei's genetic distance is 0.46 between A and B, 0.50 between A and C and 0.77 between B and C. From these values, times of evolutionary divergence from 2 to 4 million years can be estimated. Genetic relationships among populations and species of the C. osculatum complex are illustrated by principal component analysis. The role of both geographical isolation and host preferences in the speciation of C. osculatum (sensu lato) is discussed. A morphological distinction of the three species has not yet been possible (sibling species). However, there is evidence that the name C. osculatum (sensu stricto) should be used for species C, which shows a geographical distribution and definitive host corresponding to the neotype of C. osculatum (sensu stricto). Finally, a comparison is made between the members of the C. osculatum complex from the Atlantic Arctic-Boreal region and those of the Pseudoterranova decipiens complex from the same area, as to: (i) times of evolutionary divergence, (ii) geographical distribution, and (iii) host preferences.


A cohort study on second malignancies in gastrectomized patients with gastric cancer. II. Second malignancies in the gastric remnant.
In a retrospective cohort study, a total of 22 (0.22 per cent) carcinomas of the gastric remnant were clinically observed, as second malignancies, in 7,672 patients during the average of a 9.4-year follow-up period. All had undergone distal subtotal gastrectomy for gastric cancer from 1960-1975 in seven different institutions. Of 22 carcinomas of the gastric remnant, 5 were at the anastomotic site, 14 distant from the anastomosis; the location was unknown in three. All five carcinomas of the anastomotic site occurred after Billroth II operation. Time intervals between the first operation and the occurrence of second cancer varied from two to 21 years. With regard to the administration of adjuvant chemotherapeutic agents such as mitomycin-C (MMC), 5-fluorouracil (5FU) or its derivative Tegafur, no significant differences in the rate of second malignancies were obtained between the chemotherapy and non-chemotherapy groups. The occurrence rate of cancer of the gastric remnant between Billroth I and Billroth II groups showed no statistically significant difference, although it did tend to be slightly higher in the latter.


Comorbid impulsivity after one year of epilepsy surgery.
Psychiatric comorbidities in patients with drug-resistant epilepsy (DRE) are frequently observed before and after epilepsy surgery. Impulsivity, defined as behaviors that are poorly conceived, are also frequent among patients with epilepsy. The aim of this study was to determine the presence of comorbid impulsivity in patients with DRE after one year of epilepsy surgery. Patients who underwent epilepsy surgery for DRE and completed the postsurgical assessment protocol one year after surgery were included. All patients underwent a presurgical protocol comprising of neurological, psychiatric, neuropsychological, video-EEG and MRI assessments. The psychiatric evaluation was performed before and one year after surgery using SCID-I, SCID-II, GAF scale of DSM IV, and Beck Depression Inventory II. One year after surgery, Barratt Impulsiveness Scale 11, and Engel classification of seizures, were administered. A total of 38 patients were included in this study, 21 women (55.3%) and 17 men (44.7%), mean age 36 years (SD = 9.4). Higher impulsivity was associated with a worse epilepsy seizure outcome (p < 0.05), one year after surgery. According to the multiple linear regression analysis, a worse epilepsy seizure outcome was associated with higher levels of nonplanning impulsivity (p < 0.05) (p < 0.05, β -0.5, r2 0.25). The GAF score was negatively associated with motor score (p < 0.05, β -0.584, r2 0.42) and with the total BIS-11 score (p < 0.05, β -0.557, r2 0.39). Impulsivity has been associated with a worse post-surgical seizure outcome. Larger studies about impulsivity might confirm these preliminary findings.


Meta-analysis of randomized trials comparing off-pump with on-pump coronary artery bypass graft patency.
Off-pump coronary artery bypass graft surgery (OPCAB) is increasingly becoming a widely used technique and challenges conventional on-pump coronary artery bypass grafting as the standard surgical therapy for coronary artery disease. Little information, however, is available concerning postoperative performance of bypass grafts done with this new technique. The aim of this study is to assess differences in graft patency between OPCAB and coronary artery bypass grafting by meta-analysis of data published in randomized trials. A literature search for the period beginning January 1990 until December 2004 supplemented with manual bibliographic review was performed for all peer-reviewed English-language publications. A systematic overview (meta-analysis) of randomized trials was conducted to assess differences between OPCAB and coronary artery bypass grafting in graft occlusion rates. Literature search yielded five comparable randomized studies, for a total of 872 and 998 grafts performed during OPCAB and coronary artery bypass grafting procedures, respectively. Meta-analysis of these studies showed an increased risk of graft occlusion in the OPCAB group of patients, both when all the studies were analyzed together (odds ratio, 1.51; 95% confidence intervals, 1.15 to 1.99; p = 0.003), and when low-quality (odds ratio, 1.46; 95% confidence intervals, 1.05 to 2.03; p = 0.02) and high-quality (odds ratio, 1.65; 95% confidence intervals, 0.99 to 2.75; p = 0.05) studies were analyzed separately. Cumulative analysis of the few prospective randomized studies currently available in the literature documents a reduction in postoperative patency of coronary artery bypass grafts performed during OPCAB procedures. The risk of reduced graft patency needs to be considered when choosing OPCAB as tailored strategy for selected patients.


Development and Pilot-Testing of a Cognitive Behavioral Coping Skills Group Intervention for Patients with Chronic Hepatitis C.
Psychosocial interventions for patients with chronic hepatitis C viral (HCV) infection are needed to attenuate the impact of extrahepatic symptoms, comorbid conditions, and treatment side effects on HCV health outcomes. We adapted empirically-supported interventions for similar patient populations to develop a Cognitive Behavioral Coping Skills group intervention for HCV patients (CBCS-HCV) undergoing treatment. The objectives of this paper are to describe the research activities associated with CBCS-HCV development and pilot testing, including: (1) formative work leading to intervention development; (2) preliminary study protocol; and (3) pilot feasibility testing of the intervention and study design. Formative work included a literature review, qualitative interviews, and adaption, development, and review of study materials. A preliminary study protocol is described. We evaluate the feasibility of conducting a randomized controlled trial (RCT) of the CBCS-HCV with 12 study participants in Wave 1 testing to examine: (a) feasibility of intervention delivery; (b) patient acceptability; (c) recruitment, enrollment, retention; (d) feasibility of conducting a RCT; (d) therapist protocol fidelity; and (e) feasibility of data collection. Numerous lessons were learned. We found very high rates of data collection, participant attendance, engagement, retention and acceptability, and therapist protocol fidelity. We conclude that many aspects of the CBCS-HCV intervention and study protocol were highly feasible. The greatest challenge during this Wave 1 pilot study was efficiency of participant enrollment due to changes in standard of care treatment. These findings informed two additional waves of pilot testing to examine effect sizes and potential improvements in clinical outcomes, with results forthcoming.


Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1.
ERAP1 trims antigen precursors to fit into MHC class I proteins. To fulfill this function, ERAP1 has unique substrate preferences, trimming long peptides but sparing shorter ones. To identify the structural basis for ERAP1's unusual properties, we determined the X-ray crystal structure of human ERAP1 bound to bestatin. The structure reveals an open conformation with a large interior compartment. An extended groove originating from the enzyme's catalytic center can accommodate long peptides and has features that explain ERAP1's broad specificity for antigenic peptide precursors. Structural and biochemical analyses suggest a mechanism for ERAP1's length-dependent trimming activity, whereby binding of long rather than short substrates induces a conformational change with reorientation of a key catalytic residue toward the active site. ERAP1's unique structural elements suggest how a generic aminopeptidase structure has been adapted for the specialized function of trimming antigenic precursors.


Differential effects of scopolamine on working and reference memory depend upon level of training.
Controversy exists whether the cholinergic system in the brain is involved in working memory (WM) selectively or in both WM and reference memory (RM). Rats were trained to obtain food from four baited arms of an eight-arm radial maze. The remaining arms were never baited. Three types of errors were recorded: entry into unbaited arms (RM errors), reentry into baited arms (WM errors), and reentry into unbaited arms (WRM errors). There were no differences among three control conditions: methyl scopolamine, physiological saline, and uninjected. Scopolamine increased WM but not RM errors. When rats were trained to a higher criterion of learning, however, both WM and RM were impaired. It appears that when baseline error rate is sufficiently low RM errors under scopolamine become observable. The results suggest that the cholinergic system is involved in both WM and RM, and the selective involvement of WM is the result of insufficient training. The controversy in the literature over the involvement of the cholinergic system in WM and RM was addressed.


"Just be respectful of the primary doc": teaching mutual respect as a dimension of teamwork in general pediatrics.
Although others have reported on teamwork training, little is known about what pediatric residents in inpatient settings learn implicitly about respectful working relationships with community-based general pediatricians. The purpose of this brief report is to examine how pediatric residents on an inpatient general pediatric rotation regard "the other" (community-based general pediatricians), and how academic, hospital-based general pediatric attending physicians respond. We conducted a case study on one general pediatrics floor, which entailed 143 hours of observation over 8 months (January to August 2006), as well as in-depth interviews with 25 residents and 14 general pediatric attending physicians whom we observed as they worked on the floor. Data were derived from >1000 pages of field notes and interview transcripts. We systematically reviewed the data and inductively derived codes related to explicit and implicit education. In this brief report, we focused our analysis on data relevant to the concept of boundary crossing: when members of the group talk about members of another group in the process of inquiring about or negotiating patient care. Residents' comments tended to reveal a neutral or somewhat negative regard for their general pediatric community counterparts, whom they typically referred to as PMDs (primary medical doctors). Attending physicians' responses to these comments varied, but often explicitly taught residents about dimensions of teamwork, including mutual respect. Explicit teamwork training in pediatric education should not be limited to partnering with other disciplines or other specialties, but expanded to enhance positive regard and mutual respect for general pediatricians in hospital- and community-based settings alike. Attending physicians in general pediatrics are ideally positioned to implicitly teach respectful working relationships within the specialty.


The length of the interdomain region of the L7/L12 protein is important for its function.
Several mutated L7/L12 proteins with changed interdomain regions were obtained. The results showed that the flexible region comprising the 39-52 amino acid residues is functionally important. Its length, but not its amino acid composition, is crucial for the function.


Deficits in face perception in the amnestic form of mild cognitive impairment.
The fusiform gyrus is involved pathologically at an early stage of the amnestic form of mild cognitive impairment (aMCI), and is also known to be involved in the perceptual stage of face processing. We assessed face perception in patients with aMCI to determine if this cognitive skill was impaired. We compared 12 individuals (4 men) with aMCI and 12 age- and education-matched healthy controls on the ability to discriminate changes in the spatial configuration or color of the eyes or the mouth in faces. Patients with aMCI performed less quickly and accurately for all changes on trials with limited viewing duration. With unlimited duration, they could achieve normal perceptual accuracy for configural changes to the mouth, but remained impaired for changes to eye color or configuration. Patients with aMCI show deficits in face perception that are more pronounced for the highly salient ocular region, a pattern similar to that seen in acquired prosopagnosia. This form of perceptual impairment may be an early marker of additional cognitive deficits beyond memory in aMCI.


Percutaneous treatment of aortic stenosis and mitral regurgitation in the same patient: first human cases description.
Transcatheter valve therapy is becoming an established treatment for aortic stenosis (AS) and it is very promising for mitral regurgitation (MR). There are no formal reports of percutaneous treatment of both AS and MR in the same patient. Here, we report on the first human cases of successful totally percutaneous management of combined severe AS and MR as a planned staged approach and using MitraClip(®) implantation as a procedure necessitated by an unpredictable complication of self-expanding CoreValve device, respectively.


The influence of interferon alpha and gamma, singly or in combination on human natural cell mediated cytotoxicity.
The influence of interferon alpha and gamma alone or in combination on the augmentation of human natural cytotoxicity was studied. Treatment of peripheral blood lymphocytes with IFN- alpha led to a rapid augmentation of NK activity, in contrast to IFN-gamma where target cell killing was observed only following 18 hrs exposure of lymphocytes to IFN-gamma. The results of the single cell assay paralleled those obtained using the Chromium release test, but neither interferon type caused an increase in the number of target binding lymphocytes. The combined effect of IFN-alpha and IFN-gamma in stimulating human natural cytotoxicity demonstrated individual lymphocyte responses to be variable. Exposure of lymphocytes to IFN-alpha and IFN-gamma for 18 hrs prior to assay for cytotoxicity usually decreased the level of cytotoxicity compared with control values, whereas other treatment regimes gave an additive and sometimes synergistic effect. Only treatment with IFN-alpha for 18 hrs and IFN-gamma for one hr produced a synergistic response in the majority of individuals tested. We conclude from this study that individual responses to IFN-alpha and IFN-gamma alone or in combination are variable and dependent upon timing of exposure of lymphocytes to individual interferon types, and possibly reflects the donor status at the time of sampling.


Liquid chromatographic assay for the antiviral nucleotide analogue tenofovir in plasma using derivatization with chloroacetaldehyde.
A sensitive and selective reversed-phase liquid chromatographic assay for tenofovir in human plasma has been developed and validated. Tenofovir was isolated from a 200 microl plasma sample using protein precipitation with trichloroacetic acid. The fluorescent 1,N(6)-etheno derivative is formed at 98 degrees C in the buffered extract with chloroacetaldehyde. This derivative was analysed using gradient ion-pair liquid chromatography and fluorescence detection at 254 nm for excitation and 425 nm for emission. In the evaluated concentration range (20-1000 ng/ml), the intra-day precision was 4% and the inter-day precision was 5-6%. An accuracy of between 97 and 110% was determined. The lower limit of quantification was 20 ng/ml with an inter-day precision of 11%, an intra-day precision of 12% and an accuracy of 103%. The assay is subject to interference from co-administered abacavir. The usefulness of the assay was demonstrated for samples obtained from an HIV-infected patient treated with tenofovir.


Lethal and mutagenic effects of nitrosoguanidine on synchronized Chlamydomonas.
The lethal and mutagenic effects of 5 mug/ml N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were maximal during the nuclear S-period of synchronously grown Chlamydomonas reinhardtii. This was revealed by a 50% drop in survival and a 50- to 100-fold increase in the recovery of slow-growth mutants (up to 40% of the survivors) which were first recognized as small colonies on agar medium. Partial characterization of these isolates revealed about 50% to be stable on subculture, and several were demonstrated to be either acetate-dependent, dark-lethal (light-dependent), or acetate-sensitive mutants. There was no significant increase of lethality or of slow-growth mutants correlated with treatment during the chloroplast DNA replication phase of the cell-cycle. The results of genetic analysis with 13 mutants induced during the nuclear S-period were consistent with their nuclear origin. These analyses were hampered by the high proportion of lethality among the progeny of most crosses. It is concluded that the enhanced mutant induction among nuclear S-phase cells may indicate preferential mutagenesis of replication fork DNA and induction of multiple-closely-linked mutations, as in some bacteria. Consequently, for C. reinhardtii, caution should be exercised in drawing relationships between abnormal behavioral and biochemical phenotypes in MNNG-induced mutants.


Clinical characteristics of children and adolescents with ADHD with or without methylphenidate prescription at their first diagnostic assessment.
Attention Deficit/Hyperactivity Disorder (ADHD) is the most prevalent neurodevelopmental disorder diagnosed in the scholar age. It is associated with significant impairment in global functioning, and in moderate/severe presentations the outcome is critically dependent on pharmacological optimization of the multi-modal treatment. Methylphenidate (MPH) is the first-choice pharmacological treatment in children and adolescents with ADHD, with substantial evidence of significant efficacy and effectiveness on global functioning and symptoms' severity. There is some evidence supporting a few clinical and socio-demographic variables as predictors of pharmacological treatment prescription in children with ADHD independently of ADHD symptoms severity. However, it is warranted to investigate clinical and general psychopathological characteristics potentially associated with negative outcomes and the need for pharmacological treatment to inform appropriate prescription strategies. In this context, we compared 268 children and adolescents who were prescribed MPH (ADHD/MPH) for the first time after their first diagnostic assessment at our center, and 444 children and adolescents with ADHD (ADHD/noMPH) who were recommended non-pharmacological evidence-based interventions alone. ADHD/MPH group had higher severity of non-ADHD psychopathological symptoms compared to the ADHD/noMPH group, as documented by higher scores on the Child Behavior Checklist (CBCL) subscales, higher severity of ADHD symptoms, lower average IQ and lower adaptive levels independently of IQ. More specifically, beside externalizing symptoms, also internalizing symptoms were significantly higher in the ADHD/MPH group. The presence of significant non-ADHD psychopathology should be considered as a clinical factor associated with the need for MPH prescription in children and adolescents with ADHD.


Pharmacophore modeling and applications in drug discovery: challenges and recent advances.
Pharmacophore approaches have become one of the major tools in drug discovery after the past century's development. Various ligand-based and structure-based methods have been developed for improved pharmacophore modeling and have been successfully and extensively applied in virtual screening, de novo design and lead optimization. Despite these successes, pharmacophore approaches have not reached their expected full capacity, particularly in facing the demand for reducing the current expensive overall cost associated with drug discovery and development. Here, the challenges of pharmacophore modeling and applications in drug discovery are discussed and recent advances and latest developments are described, which provide useful clues to the further development and application of pharmacophore approaches.


Abelson transformed fibroblasts lacking the EGF receptor are not tumourigenic in nude mice.
Cells transformed by the v-abl-oncogene produce large amounts of the tumour growth factor alpha TGF. alpha TGF is homologous to the epidermal growth factor (EGF) and stimulates cell growth via the EGF receptor pathway. To separate metabolic events in the v-abl-transformed cells mediated by alpha TGF as opposed to the v-abl-encoded protein-tyrosine kinase, we have employed the Swiss 3T3 variant cell line NR6 which lacks a functional EGF receptor. v-abl was found to transform efficiently NR6 cells in vitro. These transformed NR6 cells displayed a variety of in vitro properties which were indistinguishable from transformed wild-type fibroblast lines. However, in contrast to the wild-type lines, v-abl-transformed NR6 cells failed to form tumours when injected into athymic nude mice. These results imply an important function for alpha TGF and the EGF receptor in the establishment of the v-abl-induced fibrosarcomas.


Biological activities of N6,C8-disubstituted adenosine derivatives as partial agonists at rat brain adenosine A1 receptors.
C8-substituted derivatives of the adenosine A1 receptor-selective agonist N6-cyclopentyladenosine (CPA) were evaluated as potential partial adenosine A1 receptor agonists in rat brain. Potencies and efficacies of 8-alkylamino-CPA derivatives were determined in G protein activation assays by their ability to stimulate binding of [35S]guanosine-5'-(gamma-thio)triphosphate ([35S]GTPgammaS) to rat forebrain membranes, by their ability to inhibit forskolin-stimulated adenylate cyclase, and by inhibition of evoked field excitatory postsynaptic potentials (field EPSPs) in hippocampal slices. EC50 values around 1 microM were determined for all C8-substituted CPA derivatives. Increase in chain length of the substituent gradually reduced agonist efficacy in [35S]GTPgammaS binding studies. Only C8-methylamino-, C8-ethylamino- and C8-propylamino-CPA inhibited forskolin-stimulated adenylate cyclase. In contrast, 8-methylamino- and 8-butylamino-CPA were the compounds of highest intrinsic activity in inhibition of field EPSPs in the hippocampus, followed by 8-ethylamino-CPA. 8-Cyclopentylamino-CPA was without effect in this tissue, and the propylamino derivative, when applied cumulatively, caused an inhibition which was smaller the higher the concentration used and the longer the application, which is suggestive of drug-induced desensitization. These data indicate that 8-aminoalkyl-substituted CPA derivatives act as partial agonists on the brain and may serve as valuable tools to dissect adenosine A1 receptor mediated signal trafficking in various organs.


Comparison of graphical procedures for estimating the intrinsic molar fluorescence of protein-bound drugs for drug-binding studies. A reevaluation of existing plots and introduction of two inverse hyperbolic plots.
A theoretical evaluation of existing and new graphical procedures for estimating the intrinsic molar fluorescence (psi B) of a protein-bound drug has been undertaken. The results do not concord with a recent proposition that psi B should be obtained by direct reading from a graph of emitted fluorescence intensity (I) against the logarithm of the binding protein concentration ([P]) rather than by extrapolation of a double reciprocal plot. The calculated errors in estimates of psi B obtained by direct reading or by extrapolation of standard plots and of three new inverse hyperbolic plots showed that, independently of binding affinity: 1. Direct reading from the logarithmic plot gave the least accurate estimates. 2. The single reciprocal plot gave more accurate estimates than the double reciprocal plot providing the (constant) drug concentration was similar to or greater than its dissociation constant in the binding system. At lower drug concentrations the double reciprocal plot gave more accurate estimates. 3. Extrapolation of an inverse hyperbolic sine plot (sinh-1 (1/I) against 1/[P]) did not give more accurate estimates than the standard reciprocal plots. 4. If the drug concentration was close to its dissociation constant the most accurate estimates were obtained with an inverse hyperbolic cosine plot of cosh-1 (I + 1) against 1/[P]. For a low affinity binding system in which non-specific binding is significant an inverse hyperbolic sine plot of 1/sinh-1I against 1/[P] gave the most accurate estimates at low drug concentrations. An experimental and theoretical procedure for optimizing the estimation of psi B is proposed on this basis.


Spectrofluorimetric study and detection of ketoconazole in the presence of beta-cyclodextrin.
The formation of a complex between ketoconazole and beta-cyclodextrin was followed by spectrofluorimetry. The inclusion of ketoconazole in beta-cyclodextrin cavity enhanced the native fluorescence of the drug. The stoichiometry of the complex was 1:1 beta-cyclodextrin to ketoconazole and the stability constant of the complex (log K(f)) was determined to be 4.3+/-0.01 at pH=7.9 and 3.7+/-0.04 at pH=2.6. A sensitive spectrofluorimetric method for the detection of ketoconazole is presented. At optimized experimental conditions, a linear relationship between the fluorescence intensity of the solution and concentration of ketoconazole is observed in the range of 0.01-10 microg ml(-1) (5 x 10(-8) M-1.88 x 10(-5) M). The method was applied to the detection of ketoconazole in pharmaceutical products and the results were satisfactory in comparison to the official method (relative error=2.8% and standard deviation=0.06 for tablets of ketoconazole). The recovery of ketoconazole from a blood serum sample, determined by the proposed method, was 97.1+/-2.4%.


Effectiveness of kukui nut oil as a topical treatment for psoriasis.
No cure for psoriasis exists for the 1-3% of the American population who suffer from it; however, anecdotal reports from patients with psoriasis visiting Hawaii who purchased kukui nut oil, claim it helped reduce the severity of their lesions. This pilot study was a double-blind, placebo-controlled clinical trial to determine the effectiveness of kukui nut oil as a topical treatment for psoriasis. Thirty adult subjects (18-78 year) were recruited from the community for a 12-week randomized, double-blind, placebo-controlled pilot study. Subjects were previously diagnosed with mild, stable plaque psoriasis (less than 15% of total body surface area [TBSA]) and agreed to abstain from other treatments during the course of the study. Following a 4-week washout period the subjects were randomized into a treatment group (15 subjects applying kukui nut oil) or a control group (15 applying the mineral oil placebo). Patients were seen every 2 weeks (seven visits at 0, 2, 4, 6, 8, 10, and 12 weeks) by a dermatological nurse practitioner under the general supervision of a board certified dermatologist. Measurable outcomes included evaluation of one targeted lesion and of the overall severity of their psoriasis using clinical evaluation, Psoriasis Area and Sensitivity Index (PASI), Global Severity of Psoriasis Scale, and photographs. Each patient also evaluated their own lesions daily using the Global Severity of Psoriasis Scale, and noted any side-effects or other treatments used. Although both groups improved, we found no significant difference between the treatment (kukui nut oil) and the placebo (mineral oil) among the 24 out of 30 subjects (80%) who completed the study. No side-effects or adverse events were reported. Kukui nut oil did not significantly reduce symptoms of psoriasis; however, this was a small pilot study, and the use of this oil cannot be dismissed without using a larger study population of patients with psoriasis.


Comparison of mesh fixation and non-fixation in transabdominal preperitoneal (TAPP) inguinal hernia repair: a randomized control trial.
Mesh fixation in inguinal hernia repair, has been a controversial subject for many years. Therefore, in this study, we evaluated and compared fixation and non-fixation of mesh in Transabdominal Preperitoneal (TAPP) Inguinal hernia repair. In this randomized control trial, 100 patients diagnosed with unilateral inguinal hernia were included. We divided the study population into two groups of fifty. For both groups, a 15 × 13 cm Prolene(polypropylene) mesh was used for repair. In the fixation group, mesh was fixed to the abdominal wall by endoscopic tacks, while in the non-fixation group, mesh was secured at the proper place without any fixation. Postoperative outcomes were complications, recurrence, and pain intensity after 1-, 3- and 6-months. Postoperative pain intensity in the 1st month [Median of 2 and 0, (P < 0.001)], and 3rd month [Median of 0.5 and 0, (P < 0.001)], in the fixation group were significantly higher than the non-fixation group. However, 6 months after surgery, pain intensity was almost similar for both groups. In the 6th postoperative month, only one patient experienced recurrence who was in the fixation group. The rate of recurrence and urinary retention between the groups was not significant. It was observed that until 6 months after surgery patients who received the non-fixating method of TAPP repair experienced lower levels of pain in comparison to the fixation group while other complications did not differ between the two groups. This trail was registered at www.irct.ir with Trial Registration Number of IRCT20210224050491N1.


Mortality Correlates in Patients With Takotsubo Syndrome During the COVID-19 Pandemic.
We completed a systematic review of Takotsubo syndrome (TTS) cases reported during the coronavirus disease 2019 (COVID-19) pandemic and performed clustering and feature importance analysis and statistical testing for independence on the demographic, clinical, and imaging parameters. Compared with the data before the COVID-19 pandemic, TTS was increasingly diagnosed in physical stress (mostly COVID-19 pneumonia)-triggered male patients without psychiatric/neurologic disorders, warranting further investigation to establish new reference criteria to improve diagnostic specificity. In clustering analysis, sex and inpatient mortality primarily contributed to the automated classification of the TTS. Both sex and inpatient mortality had essential correlations with COVID-19 infection/pneumonia. There is effect modification of sex on outcomes in patients with COVID-19 infection and TTS, with male patients having significantly worse inpatient mortality. Meanwhile, significantly more male patients with TTS were classified as high risk according to International Takotsubo Registry prognostic scores, suggesting that male COVID-19/TTS survivors will likely have worse long-term outcome.


Isolation of unsaturated diols after oxidation of conjugated linoleic acid with peroxygenase.
Oat seeds are a rich source of peroxygenase, an iron heme enzyme that participates in oxylipin metabolism in plants. An isomer of CLA, 9(Z),11 (E)-octadecadienoic acid (1), believed to have anticarcinogenic activity, was used as a substrate for peroxygenase in an aqueous medium using t-butyl hydroperoxide as the oxidant. After acidification of the reaction medium, the products were extracted with ethyl ether, converted to their methyl esters, and characterized using HPLC. Major products after reaction for 24 h showed resonances from 1H NMR spectroscopy that were further downfield than the expected epoxides and were thought to be diol hydrolysis products. However, analyses by HPLC with atmospheric pressure chemical ionization MS (APCI-MS) of the putative allylic diols or their bis-trimethylsilyl ether derivatives gave incorrect M.W. The M.W. of the diols could be obtained by APCI-MS after removal of unsaturation by hydrogenation or by EI-MS after conversion of the allylic 1,2-diols to cyclic methyl boronic esters. Data from MS in conjunction with analyses using 1H and 13C NMR showed that the methylated products from 1 were methyl 9,10(threo)-dihydroxy-11 (E)-octadecenoate, methyl 9,10(erythro)-dihydroxy-11(E)-octadecenoate, methyl 9,12(erythro)-dihydroxy-10(E)-octadecenoate, and methyl 9,12(threo)-dihydroxy-10(E)-octadecenoate. Solid-phase extraction without prior acidification and conversion of the products to methyl esters allowed identification of the following epoxides: methyl 9,10(Z)-epoxy-11 (E)-octadecenoate (6M), methyl 9,10(E)-epoxy-11 (E)-octadecenoate, and methyl 11,12(E)-epoxy-9(Z)-octadecenoate. At times of up to at least 6 h, 6M accounted for approximately 90% of the epoxide product. Product analysis after the hydrolysis of isolated epoxide 6M showed that hydrolysis of epoxide 6 could largely account for the diol products obtained from the acidified reaction mixtures.


The Impact of Health and Social Services on the Quality of Life in Families of Adults with Autism Spectrum Disorder (ASD): A Focus Group Study.
Autism spectrum disorder (ASD) is a complex developmental condition that affects the whole family. The gap between childrens' needs and their satisfaction, especially regarding what concerns the presence of social and healthcare services, is still a source of burden, particularly after the transition to adulthood. Our study aimed to gather a comprehensive view on how parents of adults with ASD perceive (and interact with) health and social services, and how the provision of care impacts family quality of life with the aim to advise ASD intervention programs. The goal is to identify specific areas of change useful to influence autism intervention strategies so that they more effectively meet the needs of young people with autism and their families. We conducted two focus groups with parents of young adults with ASD. A semi-structured focus group methodology was adopted. The QoL conceptual framework guided data collection and analysis as part of a directed theory-driven content analysis approach. The lack of structured care pathways and the low level of integration of different services were the main limits reported by parents during the focus group, while a shared positive perception of the experience conducted together as caring families emerged. The experience here reported claims for a greater role of the institutions in order to facilitate the building of networks that are really inclusive for persons with autism in society and to support the implementation of innovative solutions for the welfare system. Furthermore, parents stressed the need for the provision of support to the family.


Sonazoid-enhanced ultrasonography for the diagnosis of an intrapancreatic accessory spleen: a case report.
We report a case of an intrapancreatic accessory spleen in 59-year-old man, in which contrast-enhanced sonography (US) using Sonazoid, a second-generation contrast agent, was useful for the diagnosis. Sonazoid-enhanced US could prove both hypervascularity and the existence of reticuloendothelial cell systems in the mass, which is the key to the diagnosis of an accessory spleen. Sonazoid-enhanced US might become a standard imaging technique for the diagnosis of an accessory spleen.


Evaluation of bone health in patients with mucopolysaccharidosis.
This study aimed to evaluate the relationship between clinical findings, height and weight standard deviation scores, 25-hydroxyvitamin D3 (25(OH)D3) level, and dual-energy X-ray absorptiometry (DXA) results in patients diagnosed with mucopolysaccharidosis (MPS), where effective current treatments such as enzyme replacement therapy (ERT) can be accessed. 25(OH)D3 level was measured in 126 patients with MPS (17 with MPS I, 14 with MPS II, 18 with MPS III, 33 with MPS IVA, and 44 with MPS VI; 24-524 months). DXA was performed in 45 of these patients (8 with MPS I, 4 with MPS II, 4 with MPS III, 12 with MPS IVA, and 17 with MPS VI; 62-197 months; all patients were under 18 when DXA was performed) to assess bone mineral density (BMD) of the lumbar spine. In total, 67.5% patients had a short stature, and 50% of them were underweight for their age. Of the patients, 13.5% were immobile, 28.6% had 25(OH)D3 deficiency, and 30.2% had an insufficient level of 25(OH)D3. BMD z score of 45 patients was - 2.5 ± 1.7. In 40% patients, it was < - 2. However, after correction for height-for-age z score (HAZ), HAZ-adjusted BMD z score was - 0.1 ± 0.9. In 2.2% patients, it was < - 2. The low BMD z score prevalence reported with DXA was misleadingly higher in children with MPS and short stature. To prevent exposure to unnecessary antiresorptive treatments in these children, the effect of severe short stature and bone geometry on DXA measurements should be considered; further studies on bone health are warranted.


Cost-Effectiveness of Pit and Fissure Sealing at Schools for Caries Prevention in China: A Markov Modeling Analysis.
The World Health Organization states that the application of pit and fissure sealants (PFSs) is an effective way to prevent dental caries. Estimates of potential health and economic impacts of PFS upon school-age children provide crucial evidence to support the extension of PFS coverage to all target populations. The China Children's Oral Disease Comprehensive Intervention Project was launched in 2009 to provide free oral health examinations, PFS application, and oral health education for children aged 7 to 9 years. However, the national-level health and economic impacts of the program are unclear. To provide higher quality evidence at the national level in China, we developed a multi-perspective, multistate Markov model to estimate the cost and effect of PFS application to prevent dental caries. The total cost of the PFS project was 2.087 billion CNY, which can prevent 16.06 million PFMs from caries lesions. Compared with no intervention, PFS application was cost-effective from payer and society perspectives (BCR = 1.22 from the payer's perspective, BCR = 1.91 from the societal perspective). The incremental cost-effectiveness ratio from both perspectives was negative (-61.46 CNY from the payer's perspective, and -125.75 CNY from the societal perspective), indicating that PFS was cost-effective and cost-saving. Expanding the coverage of PFS application in school can be a more cost-effective strategy for caries prevention in China.


The role of the rhinostomy ostium size on functional success in dacryocystorhinostomy.
Endonasal and external dacryocystorhinostomy procedures have both been used for the treatment of post-saccular obstruction of the lacrimal system. Functional success of these surgeries depends on several factors. To evaluate the status of the rhinostomy ostium with endonasal and external approaches in dacryocystorhinostomy operations and to determine the effect of ostium size on postoperative functional success. The charts of the patients operated in our hospital between May 2017 and January 2019 were analyzed retrospectively (ethical approval number: 2018-12.04). The patients that were operated in the ophthalmology and otolaryngology departments were included in the study. Endoscopic rhinostomy ostium measurements, punctum lavage findings and complications were recorded at 8 weeks postoperative at the earliest. When the 64 patient charts were reviewed (76 operations), the mean ostium width was 1.85±1.11mm in the endonasal approach group and 3.60±2.24mm in the external approach group. The mean ostium areas in endonasal and external group were 14.61±16.66mm2 and 56.05±60.41mm2, respectively. The ostium was anatomically patent and punctum lavages were negative in 11 patients (6 patients in the endonasal approach group and 5 patients in the external approach group) and these cases were considered as functional failures. The rhinostomy ostium was significantly wider in the external approach group, but this was considered ineffective on functional outcomes. Lacrimal duct stenosis can be successfully treated with endonasal and external methods. Tear drainage may be insufficient even in the presence of a patent ostium. Therefore, functional success should also be considered when evaluating the overall success of dacryocystorhinostomy. An anatomically patent ostium is definitely required, while it is believed that ostium size does not affect functional surgical success.


Western diet leads to aging-related tumorigenesis via activation of the inflammatory, UPR, and EMT pathways.
Among the principal causative factors for the development of complications related to aging is a diet rich in fats and sugars, also known as the Western diet. This diet advocates numerous changes that might increase the susceptibility to initiate cancer and/or to create a tissue microenvironment more conducive to the growth of malignant cells, thus favoring the progression of cancer and metastasis. Hypercaloric diets in general lead to oxidative stress generating reactive oxygen species and induce endoplasmic reticulum stress. Our results demonstrate that mice bearing tumors fed with a Western diet presented bigger tumor mass with increased insulin sensitivity in these tissues. Several markers of insulin signaling, such as AKT phosphorylation and mTOR pathway, are promoted in tumors of Western diet-fed animals. This process is associated with increased macrophage infiltration, activation of unfolded protein response pathway, and initiation of epithelial-mesenchymal transition (EMT) process in these tumor tissues. Summing up, we propose that the Western diet accelerates the aging-related processes favoring tumor development.


Genotype dependence of monoamine oxidase in inbred strains of mice.
MAO activity was found to be influenced by the genotype or strain of mouse up to 20 days of age. The strain differences observed may derive from different rates of brain development. A number of neurological mutations comprizing three pathological classes had no effect on MAO.


Analysis of bovine leukemia virus integration sites in cattle under 3 years old with enzootic bovine leukosis.
In the present study, we analyzed bovine leukemia virus (BLV) integration sites in under 3 years old with enzootic bovine leukosis (EBL) cattle and compared these to 30 cattle over 3 years old with EBL. BLV proviruses were integrated near CpG islands and into long interspersed nuclear elements more frequently in EBL cattle under 3 years old than in those over 3 years old. These results suggest that cattle under 3 years old with EBL have different BLV provirus integration sites from those of cattle over 3 years old with EBL, and the BLV provirus integration site may represent one factor contributing to early onset of EBL.


Salmonella resistant to extended-spectrum cephalosporins: prevalence and epidemiology.
Salmonella resistant to extended-spectrum cephalosporins (ESCs) have emerged worldwide since 1988. By 2004, 43 countries had reported this public health problem. Resistance was mediated by classical extended-spectrum beta-lactamases, plasmid-mediated cephalosporinases, and recently a class A carbapenemase. Of these, CMY-2 is the most widely disseminated enzyme. Salmonella enterica serotype Typhimurium and S. enterica serotype Enteritidis are the most common serovars associated with ESC resistance in human infections. Many outbreaks in humans have been reported, most often among children and neonates. ESC-resistant Salmonella is frequently recovered from animals and food, with poultry as primary food source, suggesting that humans are often infected by these routes.


YAP1 contributes to NSCLC invasion and migration by promoting Slug transcription via the transcription co-factor TEAD.
Yes-associated protein 1 (YAP1) contributes to the development of multiple tumors, but the mechanism underlying YAP1 deregulation in non-small cell lung cancer (NSCLC) remains unclear. By performing immunohistochemistry (IHC) assays, we found that YAP1 was significantly upregulated in NSCLC compared with adjacent tissues; therefore, we sought to elucidate whether the upregulation of YAP1 contributes to NSCLC progression. MTT and transwell assays showed that YAP1 overexpression promoted proliferation, migration, and invasion in the NSCLC cell lines A549 and H460; YAP1 overexpression also promoted the significant differential expression of epithelial-mesenchymal transition (EMT)-related markers. Nevertheless, YAP1 knockdown alleviated TGF-β1-induced EMT and proliferation, migration, and invasion in NSCLC. Furthermore, western blotting showed that the co-transcription complex YAP1/TEAD was impaired by YAPS94A (a YAP1 mutant without the TEAD binding site), and verteporfin (a small molecular inhibitor of YAP1) inhibited A549 and H460 cell metastasis and EMT-related markers expression, indicating that TEAD mediated the NSCLC aggressiveness induced by YAP1. Moreover, sequence analysis and ChIP and luciferase assays confirmed that YAP1 transcriptionally activated Slug expression by binding to TEAD. Importantly, silencing YAP1 inhibited A549 cell tumorigenesis and EMT and downregulated Slug expression in vivo. Overall, our findings revealed that YAP1 is a driver of NSCLC metastasis because YAP1 promoted the EMT program by inducing Slug transcription.


Effect of glucagon on cyclic AMP, albumin metabolism and incorporation of 14C-leucine into proteins in isolated parenchymal rat liver cells.
Parenchymal rat liver cells were isolated by the collagenase method and incubated in Krebs-Henseleit buffer containing 0.5% gelatin. The basal level of cyclic AMP in isolated cells was 0.52 nmol per g liver wet wt. Glucagon (10(-10)-10(-6) M) caused a significant increase in the level of cyclic AMP. Maximum levels were obtained 2-15 min after addition of glucagon. Repeated administration of glucagon caused a new increase in cyclic AMP, but the response was lesser than after the first addition of glucagon, indicating refractoriness to glucagon. The rate of albumin secretion was 4.6 mug/min per g liver wet wt. This is about the rate found in the perfused liver, Glucagon (10(-8-10(-6) M) inhibited albumin secretion and the incorporation of 14C-leucine into albumin, into total proteins in the medium and into total proteins in the cell suspension. The effect of glucagon on albumin secretion is compatible with an effect on the rate of synthesis. A positive correlation existed between the maximal level of cyclic AMP after glucagon administration and the inhibition of both albumin secretion and the incorporation of 149leucine.


Potential health risks of toxic heavy metals and nitrate via commonly consumed bivalve and vegetable species in Ho Chi Minh City, Vietnam.
This study aimed to evaluate the health risks of cadmium (Cd), lead (Pb), inorganic arsenic (As), and nitrate exposure through the consumption of bivalves and vegetables collected from local markets in Ho Chi Minh City. The present study analyzed four favorite bivalve species (Meretrix lyrate; Perna viridis; Anadara subcrenata; Anadara granosa) for concentrations of Cd, Pb, and inorganic As and 9 vegetable species (Brassica juncea; Brassica integrifolia; Brassica rapa chinensis; Nasturtium officinale; Lactuca sativa; Ipomoea aquatica; Amaranthus gangeticus; Ipomoea batatas; Spinacia oleracea) for concentrations of Pb and nitrate. The target hazard quotient (THQ) and target cancer risk (TR) were calculated to estimate non-carcinogenic and carcinogenic health risks, respectively. For bivalves, Cd and inorganic As were present at relatively lower concentrations, whereas a relatively higher accumulation of Pb was recorded. The THQ for Cd, Pb, or inorganic As was below the threshold of 1, suggesting no potential health risks. In the case of vegetables, Pb was present at relatively low concentrations, while nitrate accumulation was at relatively high concentrations. The THQ for nitrate was higher than the threshold of 1, suggesting a potential health risk. The combined effects are estimated according to the hazard index (HI), which shows the health risks associated with the consumption of these bivalves and vegetable species. Therefore, continuous and excess consumption for a lifetime of more than 70 years has a probability of target cancer risk.


Purification of cAMP-specific phosphodiesterase from rat heart by affinity chromatography on immobilized rolipram.
Affinity chromatography on a cAMP-specific phosphodiesterase inhibitor related to Rolipram, immobilized to AH Sepharose allowed to perform an efficient purification of the cAMP-specific phosphodiesterase isoenzyme from rat heart cytosol (102-fold purification with a 35% yield in a single step). This affinity chromatography involved a biospecific interaction since a 2 mM cAMP elution step at 30 degrees C was necessary for releasing the cAMP specific form tightly bound on the affinity gel. The cAMP eluate fraction exhibited a high specificity towards cAMP (cAMP/cGMP hydrolysis ratio 5-10), a marked sensitivity to Rolipram inhibition and could be resolved in two cAMP-specific, highly Rolipram-sensitive peaks of pI 6.7 and 4.8 by IEF on polyacrylamide gel plates. Protein stain of the IEF gel revealed a single band at pI 6.7.


Simple and convenient radiolabeling of proteins using a prelabeling-approach with thiol-DOTA.
Commonly applied methods for radiometal-labeling of proteins require complex and protracted derivatization reactions of the protein and the subsequent radiolabeling is time-consuming due to the low reaction temperatures applicable. Therefore, a convenient and efficient prelabeling technique for proteins using the DOTA derivative 2,2',2''-(10-(2-(2-mercaptoethylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (thiol-DOTA) containing a thiol moiety for rapid and selective introduction into maleimide-derivatized proteins was developed. Thiol-DOTA was labeled with (68)Ga, (90)Y and (177)Lu and subsequently introduced into bovine serum albumin and a human IgG with maximum radiochemical yields of 66%. The entire radiolabeling procedure was completed after only 30 min making this a favorable new labeling technique for proteins.


Few-Layer Graphdiyne Nanosheets Applied for Multiplexed Real-Time DNA Detection.
Despite recent progress in 2D nanomaterials-based biosensing, it remains challenging to achieve sensitive and high selective detection. This study develops few-layer graphdiyne (GD) nanosheets (NSs) that are used as novel sensing platforms for a variety of fluorophores real-time detection of DNA with low background and high signal-to-noise ratio, which show a distinguished fluorescence quenching ability and different affinities toward single-stranded DNA and double-stranded DNA. Importantly, for the first time, a few-layer GD NSs-based multiplexed DNA sensor is developed.


Prevention of nutritionally induced diabetes by rosiglitazone in the gerbil Psammomys obesus.
Psammomys obesus is a desert gerbil developing hyperglycaemia, hyperinsulinaemia and insulin resistance when placed for 2 weeks on a high-energy (HE) diet. The mechanism underlying the antidiabetic effect of rosiglitazone (RG) treatment (20 mg/kg per day for 2 weeks) was studied. The antidiabetogenic effect of RG treatment on serum insulin and metabolic parameters in serum and target tissues of insulin action was investigated in vivo and compared with the pancreatic beta cell protective effects of RG. Almost all RG-treated animals remained normoglycaemic compared to controls, but, at the same time, they were hyperinsulinaemic. RG had no effect on serum free fatty acid and serum and muscle triglyceride concentrations and did not appreciably affect body weight and fat depots. RG prevented a HE diet-induced reduction of GLUT 4 glucose transporter content in epididymal adipose tissue, but not in gastrocnemius muscle. The normoglycaemic effect was not associated with a suppression of liver PEPCK activity. Muscle PKCepsilon expression, known to be elevated in diabetic Psammomys and to inhibit insulin signalling, was only marginally decreased. However, RG treatment prevented the marked decrease in insulin immunostaining as well as the vacuolization of the beta cells and accelerated beta cell proliferation. These data indicate that the skeletal muscle is not the primary target of RG action, whereas the preservation of the insulin secretory capacity and the prevention of degenerative beta cell vacuolization in spite of persisting insulin resistance appear to be the basis for the anti-hyperglycaemic effect of RG in Psammomys.


Adipocytes promote ovarian cancer chemoresistance.
Ovarian cancer (OvCa), while accounting for only 3% of all women's cancer, is the fifth leading cause of cancer death among women. One of the most significant obstacles to successful OvCa treatment is chemoresistance. The current lack of understanding of the driving mechanisms underlying chemoresistance hinders the development of effective therapeutics against this obstacle. Adipocytes are key components of the OvCa microenvironment and have been shown to be involved in OvCa cell proliferation, however, little is known about their impact on OvCa chemoresistance. In the current study, we found that adipocytes, of both subcutaneous and visceral origin, secrete factors that enhance the resistance of OvCa cells against chemotherapeutic drugs by activating the Akt pathway. Importantly, we have demonstrated that secreted lipids mediate adipocyte-induced chemoresistance. Through a comprehensive lipidomic analysis, we have identified this chemo-protective lipid mediator as arachidonic acid (AA). AA acts on OvCa cells directly, not through its downstream derivatives such as prostaglandins, to activate Akt and inhibit cisplatin-induced apoptosis. Taken together, our study has identified adipocytes and their secreted AA as important mediators of OvCa chemoresistance. Strategies that block the production of AA from adipocytes or block its anti-apoptotic function may potentially inhibit chemoresistance in OvCa patients.


[Arthroscopic superior capsule reconstruction using a 6 mm thick acellular dermal allograft for irreparable posterosuperior rotator cuff tears].
Implantation of an acellular dermal allograft between glenoid and humerus to restore a stable glenohumeral center of rotation in cases of irreparable posterosuperior rotator cuff tears. Irreparable posterosuperior rotator cuff tears with low-grade cuff tear arthropathy (Hamada grade 1 and 2) and isolated pseudoparesis for flexion. Absolute: Infection, nerve lesions (brachial plexus, axillary nerve), concomitant irreparable subscapularis tendon tear, anterosuperior subluxation of the humeral head ("anterosuperior escape"). Relative: Cuff tear arthropathy ≥ Hamada grade 3, fatty infiltration of the infraspinatus muscle ≥ Goutallier grade 2, deficiency of the deltoid muscle, inability to adhere to the rehabilitation program, poor compliance. Arthroscopic fixation of a 6 mm thick acellular dermal allograft with three suture anchors at the superior glenoid rim and a double-row construct at the greater tuberosity. Dorsal and ventral interval closure with side-to-side sutures. Abduction brace for 6 weeks with passive mobilization. Active motion exercises are commenced at 6 weeks with progression to strengthening exercises after 12 weeks. Between April 2019 and September 2020, 15 patients (5 women and 10 men) underwent arthroscopic superior capsule reconstruction using a 6 mm thick acellular dermal allograft for treatment of irreparable posterosuperior rotator cuff tears. After a mean follow-up of 15.4 ± 5.5 months, there was a significant improvement in active flexion (102° ± 37°preop vs. 143° ± 24°postop; P = 0.001; 95% CI 19.6-63.7), ASES score (45.5 ± 16.1preop vs. 68.2 ± 17.4postop; P < 0.001; 95% CI; 12.9-33.7) and DASH score (57.2 ± 18.6preop vs. 22.0 ± 17.4postop; P < 0.001; 95% CI; -46.0 to 24.7), along with significant pain reduction (4.5 ± 2.0preop vs. 2.5 ± 2.1postop; P = 0.001; 95% CI; -3.2 to 1.1). There were no complications requiring revision surgery.


Molstack: A platform for interactive presentations of electron density and cryo-EM maps and their interpretations.
In the Special Issue on Tools for Protein Science in 2018, we presented Molstack: a concept of a cloud-based platform for sharing electron density maps and their interpretations. Molstack is a web platform that allows the interactive visualization of density maps through the simultaneous presentation of multiple datasets and models in a way that allows for easy pairwise comparison. We anticipated that the users of this conceptually simple platform would find many different uses for their projects, and we were not mistaken. We have observed researchers use Molstack to present experimental evidence for their models in the form of electron density maps, omit maps, and anomalous difference density maps. Users also employed Molstack to present alternative interpretations of densities, including rerefinements and speculative interpretations. While we anticipated these types of projects to be the main use cases, we were pleased to see Molstack used to display superpositions of different models, as a tool for story-driven presentations, and for collaboration as well. Here, we present developments in the platform that were driven by user feedback, highlight several cases that used Molstack to enhance the publication, and discuss possible directions for the platform.


The axis of local cardiac endogenous Klotho-TGF-β1-Wnt signaling mediates cardiac fibrosis in human.
Cardiovascular fibrosis is a major contributor to cardiovascular disease, the primary cause of death in patients with chronic kidney disease (CKD). We previously reported expression of endogenous Klotho in human arteries, and that CKD is a state of Klotho deficiency, resulting in vascular calcification, but myocardial expression of Klotho is poorly understood. This study aimed to further clarify endogenous Klotho's functional roles in cardiac fibrosis in patients with underlying CKD. Human atrial appendage specimens were collected during cardiac surgery from individuals with or without CKD. Cardiac fibrosis was quantified using trichrome staining. For endogenous Klotho functional studies, primary human cardiomyocytes (HCMs) were treated with uremic serum from CKD patients or recombinant human TGF-β1. The effects of endogenous Klotho in HCMs were studied using Klotho-siRNA and Klotho-plasmid transfection. Both gene and protein expression of endogenous Klotho are found in human heart, but decreased Klotho expression is clearly associated with the degree of cardiac fibrosis in CKD patients. Moreover, we show that endogenous Klotho is expressed by HCMs and cardiac fibroblasts (HCFs) but that HCM expression is suppressed by uremic serum or TGF-β1. Klotho knockdown or overexpression aggravates or mitigates TGF-β1-induced fibrosis and canonical Wnt signaling in HCMs, respectively. Furthermore, co-culture of HCMs with HCFs increases TGF-β1-induced fibrogenic proteins in HCFs, but overexpression of endogenous Klotho in HCMs mitigates this effect, suggesting functional crosstalk between HCMs and HCFs. Our data from analysis of human hearts as well as functional in vitro studies strongly suggests that the loss of cardiac endogenous Klotho in CKD patients, specifically in cardiomyocytes, facilitates intensified TGF-β1 signaling which enables more vigorous cardiac fibrosis through upregulated Wnt signaling. Upregulation of endogenous Klotho inhibits pathogenic Wnt/β-catenin signaling and may offer a novel strategy for prevention and treatment of cardiac fibrosis in CKD patients.


Progress at protein structure prediction, as seen in CASP15.
In Dec 2020, the results of AlphaFold version 2 were presented at CASP14, sparking a revolution in the field of protein structure predictions. For the first time, a purely computational method could challenge experimental accuracy for structure prediction of single protein domains. The code of AlphaFold v2 was released in the summer of 2021, and since then, it has been shown that it can be used to accurately predict the structure of most ordered proteins and many protein-protein interactions. It has also sparked an explosion of development in the field, improving AI-based methods to predict protein complexes, disordered regions, and protein design. Here I will review some of the inventions sparked by the release of AlphaFold.


Assessment and validation of groundwater vulnerability to nitrate and TDS using based on a modified DRASTIC model: a case study in the Erbil Central Sub-Basin, Iraq.
In recent years, groundwater vulnerability assessment has become a crucial step in effectively protecting groundwater resources against increasing groundwater pollution in recent years. Sustainable effectual management of groundwater sources in terms of quality has become a critical factor in the development of unplanned urbanization areas, especially in regions with intensive agricultural and industrial activities in the land use/land cover (LULC) models. In this study, the GIS-based DRASTIC model was used by modified to estimate the groundwater vulnerability of porous aquifers to nitrate and total dissolved solids (TDS). The DRASTIC and the modified DRASTIC models generate four different groundwater vulnerability zones: high (33.6, 37.8%), moderate (45.9, 42.3%), low (18.7, 18.3%), and very low (1.8,1.6%). DRASTIC_LULC index map provides four different vulnerability zones: low, moderate, high, and very high, covering 0.1%, 7.6%, 83.6%, and 8.7% of the Erbil Central Sub-Basin, respectively. The most important hydrogeological factors determining the DRASTIC vulnerability obtained from sensitivity analyses are depth to the water table and impact of vadose zone parameters with average effective weight values of 23.7% and 22.6%. For validating the DRASTIC_LULC model, the water quality parameters, nitrate and TDS, have been used with an accuracy of 68% and 79%, which indicates that the validation accuracy for this model is quite high. Maps obtained as a result of this study can be used to create a baseline map for the sustainable management of groundwater quality in vulnerable areas of the Erbil Central Sub-Basin and its planning.


Ganciclovir-resistant cytomegalovirus retinitis in a 4-month-old infant.
We present a case of ganciclovir-resistant cytomegalovirus retinitis (CMV) in a 4-month-old boy with congenital CMV infection. This case highlights the potential utility of a combination of intermittent viral load monitoring and retinal examinations in cases of congenital CMV with retinitis.


Human breast microbiome correlates with prognostic features and immunological signatures in breast cancer.
Currently, over half of breast cancer cases are unrelated to known risk factors, highlighting the importance of discovering other cancer-promoting factors. Since crosstalk between gut microbes and host immunity contributes to many diseases, we hypothesized that similar interactions could occur between the recently described breast microbiome and local immune responses to influence breast cancer pathogenesis. Using 16S rRNA gene sequencing, we characterized the microbiome of human breast tissue in a total of 221 patients with breast cancer, 18 individuals predisposed to breast cancer, and 69 controls. We performed bioinformatic analyses using a DADA2-based pipeline and applied linear models with White's t or Kruskal-Wallis H-tests with Benjamini-Hochberg multiple testing correction to identify taxonomic groups associated with prognostic clinicopathologic features. We then used network analysis based on Spearman coefficients to correlate specific bacterial taxa with immunological data from NanoString gene expression and 65-plex cytokine assays. Multiple bacterial genera exhibited significant differences in relative abundance when stratifying by breast tissue type (tumor, tumor adjacent normal, high-risk, healthy control), cancer stage, grade, histologic subtype, receptor status, lymphovascular invasion, or node-positive status, even after adjusting for confounding variables. Microbiome-immune networks within the breast tended to be bacteria-centric, with sparse structure in tumors and more interconnected structure in benign tissues. Notably, Anaerococcus, Caulobacter, and Streptococcus, which were major bacterial hubs in benign tissue networks, were absent from cancer-associated tissue networks. In addition, Propionibacterium and Staphylococcus, which were depleted in tumors, showed negative associations with oncogenic immune features; Streptococcus and Propionibacterium also correlated positively with T-cell activation-related genes. This study, the largest to date comparing healthy versus cancer-associated breast microbiomes using fresh-frozen surgical specimens and immune correlates, provides insight into microbial profiles that correspond with prognostic clinicopathologic features in breast cancer. It additionally presents evidence for local microbial-immune interplay in breast cancer that merits further investigation and has preventative, diagnostic, and therapeutic potential.


Possible Mechanisms of Hypnosis from an Interactional Perspective.
In this paper, utilizing the interactional research paradigm developed by Éva Bányai, we discuss the hypnotic relationship from the viewpoint of interactional synchrony. Based on our three decades of empirical studies of an interactional paradigm, we propose the analogy between hypnosis and mother-child interaction. Hypnosis is considered as a potential corrective/reparative possibility when the real childhood experiences appear to be unfavourable. Possible neuroanatomical and neurochemical mechanisms are also suggested in the right hemispheric orbitofrontal cortex and central oxytocin system.


How do horses (Equus caballus) learn from observing human action?
A previous study demonstrated that horses can learn socially from observing humans, but could not draw any conclusions about the social learning mechanisms. Here we develop this by showing horses four different human action sequences as demonstrations of how to press a button to open a feed box. We tested 68 horses aged between 3 and 12 years. 63 horses passed the habituation phase and were assigned either to the group Hand Demo (N = 13) for which a kneeling person used a hand to press the button, Head Demo (N = 13) for which a kneeling person used the head, Mixed Demo (N = 12) for which a squatting person used both head and hand, Foot Demo (N = 12) in which a standing person used a foot, or No Demo (N = 13) in which horses did not receive a demonstration. 44 horses reached the learning criterion of opening the feeder twenty times consecutively, 40 of these were 75% of the Demo group horses and four horses were 31% of the No Demo group horses. Horses not reaching the learning criterion approached the human experimenters more often than those who did. Significantly more horses used their head to press the button no matter which demonstration they received. However, in the Foot Demo group four horses consistently preferred to use a hoof and two switched between hoof and head use. After the Mixed Demo the horses' actions were more diverse. The results indicate that only a few horses copy behaviours when learning socially from humans. A few may learn through observational conditioning, as some appeared to adapt to demonstrated actions in the course of reaching the learning criterion. Most horses learn socially through enhancement, using humans to learn where, and which aspect of a mechanism has to be manipulated, and by applying individual trial and error learning to reach their goal.


JAK2 V617F-positive essential thrombocythemia in a patient with Klinefelter syndrome: a case report.
Klinefelter syndrome (KS) is the most commonly diagnosed X chromosome aneuploid syndrome among males. The association between hematologic malignancies such as non-Hodgkin lymphoma and leukemia and KS has been established recently on the basis of numerous case reports and a large cohort study. The risk of chronic myeloproliferative disease (MPD) as a hematologic malignancy in KS, however, has not been evaluated to date. Moreover, to our knowledge, there is only one case report that observed MPD in a patient with KS. Even though the Janus kinase 2 (JAK2) mutation was considered the primary cause in the pathogenesis of MPD, the mutation status was not described in that report. We found JAK2 V617F mutation-positive essential thromobocythemia (ET) in a patient with KS. To the best of our knowledge, this case represents the first case report of JAK2 V617F mutation in a patient with KS. Furthermore, we also suggest the hypothesis that X chromosome aneuploidy as a "pre-JAK2" cytogenetic change may be associated with the development of clonal hematopoiesis and carcinogenesis, because of the finding of higher oncogenic potential of extra X chromosome. In this study, we present the first report of JAK2 V617F-positive ET in a patient with KS, as well as a review of the relevant literature.


An old but still burning problem: Inter-rater reliability in clinical trials with antidepressant medication.
Antidepressant trials are criticized due to potential methodological flaws. Root causes of failing methodology can be found in insufficient inter-rater reliability (IRR) and training practices, leading to higher placebo response and reduced study-power. However, it is unknown to what extent reliability estimates or training procedures are currently included in antidepressant reports. Therefore, we aimed to determine the proportion of publications concerning double-blind randomized controlled antidepressant trials that report on IRR coefficients and training procedures. We extracted all double-blind randomized clinical trials (RCTs) from the meta-analysis of Cipriani et al. (2018) concerning the period from 2000 until January 2016. Further, we conducted a Medline-search for double-blind RCTs from January 2016 until January 2020 for additional reports. We identified IRR coefficients and training procedures in these publications. In total we identified 179 double-blind RCTs. Only 4.5% reported an IRR coefficient whereas 27.9% reported training procedures. We did not contact individual authors for additional information regarding implementation of training procedures or inter-rater reliability assessment. There is a substantial lack of reporting IRR coefficients and training procedures in RCTs with antidepressant medication. Considering the large implications of insufficient reliability, we urge researchers to conduct and report training procedures and reliability estimations.


Virological and molecular characterization of Kaposi's sarcoma-associated herpesvirus strains from Xinjiang, China.
Kaposi's sarcoma (KS) is a highly and abnormally vascularized tumor-like lesion affecting the skin. KS-associated herpesvirus (KSHV/HHV-8) is etiologically linked to all epidemiological forms of KS. However, clinical phenotypes show considerable discrepancy, indicating the presence of virological and molecular characteristics of KSHV that influence its pathogenesis. We investigated the molecular virological features of KSHV strains from Xinjiang, where KSHV infection is endemic and there is a high incidence of KS. Phylogenetic characterization based on the VR1 region of the KSHV K1 gene for 21 classical and AIDS-KS specimens revealed the Eurasian KSHV genotypes C (n = 18) and A (n = 3), with subtypes A5, C6, and C7 identified for the first time in China. The distribution was closely associated with their unique ethnic origin and evolution. The KSHV viral load in AIDS-KS was substantially lower than in classic KS (p = 0.05), as quantified by real-time fluorescent quantitative polymerase chain reaction (PCR). The results reveal the general consistency of the biological and pathological properties of local KS with others, but characteristics associated with unique ethnicity evolution still remain.


Chronic instability of the thumb metacarpo-phalangeal joint: Seven-year outcomes of three surgical techniques.
Severe sprain of the thumb metacarpo-phalangeal joint (TMCPJ) is a common injury whose functional outcome is good when repair is performed at the acute stage. The diagnosis is often missed, however, leading to chronic instability. The optimal treatment of chronic TMCPJ instability is controversial. The objective of this study was to compare the clinical outcomes of the three main surgical techniques used to treat chronic TMCPJ instability. Arthrodesis is the best surgical option when ligament repair is not feasible. This single-centre retrospective study included all patients managed surgically between 2000 and 2012 for chronic post-traumatic TMCPJ instability using any of the three following techniques: primary repair, ligament reconstruction, and arthrodesis. Subjective and objective outcomes and complication rates at last follow-up were compared across these three techniques. Of 67 included patients, 55 were re-evaluated, after a mean follow-up of 84 months (range: 24-164 months). Among them, 48 (87.3%) were satisfied or very satisfied with the outcome. Pain relief was significantly better in the arthrodesis group. Mean Quick-DASH scores were 17.4 (range: 0.0-89.5) with primary repair, 25.7 (range: 0.0-58.3) with ligament reconstruction, and 17.8 (range: 0.0-50.0) with arthrodesis. Mean pinch-test strength compared to the normal side was 89% with primary repair, 84% with ligament reconstruction, and 94% with arthrodesis. In the ligament reconstruction group, 6 of the 10 patients had instability at last follow-up and the proportion of patients describing themselves as fully recovered was significantly smaller than in the other groups. Four failures were recorded at last follow-up. Surgery to treat chronic TMCPJ instability produces good outcomes. Primary repair deserves preference whenever possible. In contrast to previous reports, outcomes after ligament reconstruction were not better compared to arthrodesis. IV, retrospective study.


Interorganelle communication, aging, and neurodegeneration.
Our cells are comprised of billions of proteins, lipids, and other small molecules packed into their respective subcellular organelles, with the daunting task of maintaining cellular homeostasis over a lifetime. However, it is becoming increasingly evident that organelles do not act as autonomous discrete units but rather as interconnected hubs that engage in extensive communication through membrane contacts. In the last few years, our understanding of how these contacts coordinate organelle function has redefined our view of the cell. This review aims to present novel findings on the cellular interorganelle communication network and how its dysfunction may contribute to aging and neurodegeneration. The consequences of disturbed interorganellar communication are intimately linked with age-related pathologies. Given that both aging and neurodegenerative diseases are characterized by the concomitant failure of multiple cellular pathways, coordination of organelle communication and function could represent an emerging regulatory mechanism critical for long-term cellular homeostasis. We anticipate that defining the relationships between interorganelle communication, aging, and neurodegeneration will open new avenues for therapeutics.


Antibiotic prophylaxis in colorectal surgery: are oral, intravenous or both best and is mechanical bowel preparation necessary?
The benefit of adding oral antibiotic prophylaxis (OA) to intravenous prophylaxis (IV) in elective colorectal surgery to prevent surgical site infection (SSI) and whether the benefit of OA requires a mechanical bowel cleansing (MBP) are assessed in a systematic review. Meta-analyses compare randomized trials of IV versus IV plus OA, both with MBP; OA versus IV plus OA, both again with MBP; OA plus IV in studies randomizing patients to MBP or no MBP; and IV versus IV plus OA in patients with no MBP. MEDLINE, EMBASE, and the Cochrane Library were searched for eligible studies from 1965 to April 1, 2020. The outcome assessed was SSI, superficial and deep, but not organ space. For each included study, risk of bias was assessed using the Cochrane Risk of Bias tool version 1. For each comparison, meta-analysis was performed from data from eligible studies to obtain a summary effect and heterogeneity using RevMan. Sensitivity analyses were performed excluding studies of poor quality. Certainty of evidence was assessed using GRADE for each comparison. Sixty-one studies published in 1971-2020 from 55 publications reporting 12,297 patients were eligible for inclusion. A total of 36 studies compared IV to OA plus IV with MBP. The risk ratio (RR) and 95% confidence interval (CI) for SSI with oral and IV vs. IV alone are 0.47, 0.40-0.56. The RR in 19 studies for IV plus OA versus OA alone is 0.48, 0.38-0.62. The RR for OA plus IV with MBP versus without MBP in 5 studies is 1.17, 0.84-1.64. The RR for OA plus IV versus IV alone when no bowel prep was used in two studies is 0.36, 0.18-0.72. RRs were similar in sensitivity analyses. The GRADE is high for the first two comparisons, moderate for the 3rd, and low for the 4th due to imprecision and heterogeneity. Combined OA and IV is superior to either alone in preventing SSI. The certainty of evidence is such that further research is unlikely to alter this relationship when MBP is used. In randomized trials of MBP, OA plus IV shows no benefit from MBP versus no MBP. The last comparison shows in just two studies that as in the first meta-analysis, but in the absence of MBP, combined OA plus IV is also superior to IV alone.


Axillary response rates to neoadjuvant chemotherapy in breast cancer patients with advanced nodal disease.
Utilization of sentinel lymph node biopsy (SLNB) in breast cancer patients with positive nodes after neoadjuvant chemotherapy (NAC) has increased. We examine axillary response rates after NAC in patients with clinical N2-3 disease to determine whether SLNB should be considered. Breast cancer patients with clinical N2-3 (AJCC 7th Edition) disease who received NAC followed by surgery were selected from our institutional tumor registry (2009-2018). Axillary response rates were assessed. Ninety-nine patients with 100 breast cancers were identified: 59 N2 (59.0%) and 41 (41.0%) N3 disease; 82 (82.0%) treated with axillary lymph node dissection (ALND) and 18 (18.0%) SLNB. The majority (99.0%) received multiagent NAC. In patients undergoing ALND, cCR was observed in 20/82 patients (24.4%), pathologic complete response (pCR) in 15 patients (18.3%), and axillary pCR in 17 patients (20.7%). In patients with a cCR, pCR was identified in 60.0% and was most common in HER2+ patients (34.6%). In this analysis of patients with clinical N2-3 disease receiving NAC, 79.3% of patients had residual nodal disease at surgery. However, 60.0% of patients with a cCR also had a pCR. This provides the foundation to consider evaluating SLNB and less extensive axillary surgery in this select group.


Production of three phenylethanoids, tyrosol, hydroxytyrosol, and salidroside, using plant genes expressing in Escherichia coli.
Polyphenols, which include phenolic acids, flavonoids, stilbenes, and phenylethanoids, are generally known as useful antioxidants. Tyrosol, hydroxytyrosol, and salidroside are typical phenylethanoids. Phenylethanoids are found in plants such as olive, green tea, and Rhodiola and have various biological activities, including the prevention of cardiovascular diseases, cancer, and brain damage. We used Escherichia coli to synthesize three phenylethanoids, tyrosol, hydroxytyrosol, and salidroside. To synthesize tyrosol, the aromatic aldehyde synthase (AAS) was expressed in E. coli. Hydroxytyrosol was synthesized using E. coli harboring AAS and HpaBC, which encodes hydroxylase. In order to synthesize salidroside, 12 uridine diphosphate-dependent glycosyltransferases (UGTs) were screened and UGT85A1 was found to convert tyrosol to salidroside. Using E. coli harboring AAS and UGT85A1, salidroside was synthesized. Through the optimization of these three E. coli strains, we were able to synthesize 531 mg/L tyrosol, 208 mg/L hydroxytyrosol, and 288 mg/L salidroside, respectively.


Application of response surface methodology to optimize the adsorption performance of a magnetic graphene oxide nanocomposite adsorbent for removal of methadone from the environment.
Magnetic graphene oxide (MGO) nanocomposites have been synthesized by the co-precipitation route. The surface structure of MGO nanocomposites were analyzed by XRD, TEM, SEM, VSM and nitrogen adsorption-desorption instrumental technique. Response surface methodology was used to optimize the removal of methadone by MGO nanocomposites in aqueous solution. Experiments were conducted based on Box-Behnken design (BBD). The influence of three parameters on the removal of methadone was examined using the response surface methodological approach. The significance of independent variables and their interactions were tested by analysis of variance (ANOVA). The optimum pH, adsorbent dose and temperature were found to be 6.2, 0.0098g and 295.7K, respectively. Under these conditions, removal efficiency of methadone was found to be 87.20mg/g.


Alarmingly high prevalence of obesity in Curaçao: data from an interview survey stratified for socioeconomic status.
The aim of the article is to report the prevalence of obesity, abdominal fatness and waist circumference in different socioeconomic classes in Curaçao. In 1993/1994 a health interview survey (the Curaçao Health Study) was carried out among a random sample (n = 2248, response rate = 85%) of the adult non-institutionalized population of Curaçao. We analyzed the association between obesity (BMI > or = 30), abdominal fatness (waist hip ratio (WHR) > or = 0.95 for men, WHR > or = 0.80 for women) waist circumference (WC > or = 100 cm for men, WC > or = 91 cm for women) and socioeconomic status (SES) by age adjusted logistic regressions, for men and women separately. The prevalence of obesity was about 27%: 36% of the women and 19% of the men were obese. An at risk WHR was reported among 62.2% of the women and among 20.4% of the men. A WC above the cut-off point was reported for 44.3% women and 25.3% men. Compared to women of higher SES, the lower SES women have a two to three times higher risk of a BMI, WHR or WC exceeding the cut-off points. Among men, no statistically significant difference between an increased BMI, WHR or WC and SES factors was found. The overlap between the three measures is large, about 56% of the women scored similarly on all three measurements. Among men the overlap is even greater (73%). The prevalence of obesity in Curaçao is alarming. Low SES women are at the greatest risk of an increased BMI, WHR or WC. The obesity figures can be placed between industrialized societies and less modernized cultures. Action and additional research on the prevention of obesity in Curaçao are deemed necessary. The cut-off points in our study for WC in the non-white population are preliminary and need to be elucidated further.


Neural bases of sensorimotor adaptation in the vocal motor system.
The present study used event-related potential (ERP) recordings to investigate the neural mechanisms of sensorimotor adaptation in response to altered auditory feedback (AAF) during vocal production. 12 healthy speakers were tested under a vocal motor adaptation paradigm in which the fundamental frequency (F0) of their voice auditory feedback was pitch-shifted downward by one semi-tone (- 100 cents) during vowel vocalizations. Behavioral results revealed that subjects adapted to AAF by producing opposing (upward) responses to pitch-shift stimuli, and this adaptive behavior persisted after feedback alteration was removed (washout). We found that adaptation to AAF was accompanied by a significant increase in the amplitude of a parietal ERP activity elicited after the onset of vocalization. However, no such effect was observed for pre-motor ERPs elicited before vocalization onset. Moreover, we found that adaptive vocal responses were negatively correlated with ERPs over the parietal and positively correlated with those over the fronto-central areas after vocalization onset. These findings suggest that vocal motor adaptation is mediated by sensorimotor reprogramming of feedforward motor commands through incorporating auditory feedback, which is indexed by modulation of behavioral and ERP responses to AAF. We suggest that modulation of neural activities in the parietal cortex highlights its significance as a neural interface for sensorimotor integration and indicates its critical role in vocal motor adaptation. Our findings support the notion that the parietal mechanisms are involved in driving adaptive motor behavior to cope with unexpected changes in the sensory environment to accomplish communication goals during vocal production and motor control.


An individual differences analysis of the self-teaching hypothesis.
The self-teaching hypothesis suggests that children learn orthographic structure of words through the experience of phonologically recoding them. The current study is an individual differences analysis of the self-teaching hypothesis. A total of 40 children in Grades 2 and 3 (7-9 years of age) completed tests of phonological recoding, word identification, and orthographic knowledge. The relation of phonological recoding and word identification was significantly mediated by orthographic knowledge. Furthermore, two aspects of orthographic knowledge (perhaps word-specific and general orthographic knowledge) mediated different variance shared between phonological recoding and word identification. Results support an individual differences version of the self-teaching hypothesis and emphasize the importance of phonological recoding in the primary curriculum.


Acquired von Willebrand disease associated with an inhibitor to factor VIII antigen and gastrointestinal telangiectasia.
A patient with acquired von Willebrand disease and gastrointestinal telangiectasia is described. He presented with the recent onset of spontaneous hemorrhage and demonstrated a prolonged bleeding time, reduced factor VIII coagulant (FVIII:C), and undetectable factor VIII-related antigen (FVIIIR:AG) and ristocetin cofactor (FVIIIR:WF). Following transfusion of cryoprecipitate, there was a smaller than expected immediate increase in FVIII:C, FVIIIR:WF and FVIIIR:AG, with a rapid return to baseline levels and no secondary increase in FVIII:C. An inhibitor could be demonstrated in the patient's plasma which markedly decreased the level of FVIIIR:AG in normal plasma whereas it only weakly decreased the activity of FVIIIR:WF and FVIII:C. The inhibitor was contained in the immunoglobulin G(IgG) fraction of plasma and lacked precipitating properties. This inhibitor demonstrates a specificity not previously seen in spontaneous antifactor VIII antibodies. Our report also demonstrates that ristocetin-induced agglutination of platelets is not always the most sensitive method for detecting an inhibitor in acquired von Willebrand disease.


[Ocular complications after renal transplantation].
Seventy-two post-renal transplant patients were studied for ocular complications. Of 72 patients, 56 (77.8%) showed some ocular abnormality. Steroid cataract was the most common complication, occurring in 45 patients (62.5%). Eleven patients (18 eyes) had undergone operations for cataract. The average of their ages was 39.7 years and the period from renal transplantation to cataract operation was 3.3 years. Postoperative visual acuity was over 20/20 in most cases. Increased intraocular pressure was encountered in 9 patients (12.5%), cytomegalovirus ocular infection in 2 (2.8%), hypertensive retinopathy in 2 (2.8%), branch retinal vein occlusion in 1 (1.4%), and subconjunctival hemorrhage in 15 (20.8%). A new immunosuppressant, cyclosporine, increased renal graft survival more than azathioprine. However, ocular complications such as steroid cataract occurred frequently in spite of the use of cyclosporine, as in the azathioprine era. In conclusion, it is necessary for renal transplant patients to receive a periodical ophthalmological check-up.


Gene expression profiling of mantle cell lymphoma cells reveals aberrant expression of genes from the PI3K-AKT, WNT and TGFbeta signalling pathways.
Microarray studies have revealed the differential expression of several genes in mantle cell lymphoma (MCL), but it is unknown which of these differences are dependent on the transformed MCL cell itself or on the tumour microenvironment. To investigate which genes and signalling pathways are aberrantly expressed in MCL cells we used oligonucleotide microarrays to perform gene expression profiling of both purified leukaemic MCL cells and their normal counterparts, the naive B cells. A total of 106 genes were differentially expressed at least threefold in MCL cells compared with naive B cells; 63 upregulated and 43 downregulated. To validate the microarray results in a larger set of samples, we selected 10 differentially expressed genes and quantified their expression by real-time polymerase chain reaction in peripheral blood of MCL patients (n=21), purified MCL cells (n=6) and naive B cells (n=4), obtaining fully concordant results. A computer-assisted approach was used to procure specific molecular signalling pathways that were aberrantly expressed in MCL cells. Several genes related to apoptosis and to the PI3K/AKT, WNT and tumour growth factor beta signalling pathways were altered in MCL cells when compared with naive B cells. These pathways may play a significant role in the pathogenesis of MCL and deserve further investigation as candidates for new therapeutic targets.


A simple explanation for declining temperature sensitivity with warming.
Recently, multiple studies have reported declining phenological sensitivities (∆ days per ℃) with higher temperatures. Such observations have been used to suggest climate change is reshaping biological processes, with major implications for forecasts of future change. Here, we show that these results may simply be the outcome of using linear models to estimate nonlinear temperature responses, specifically for events that occur after a cumulative thermal threshold is met-a common model for many biological events. Corrections for the nonlinearity of temperature responses consistently remove the apparent decline. Our results show that rising temperatures combined with linear estimates based on calendar time produce the observations of declining sensitivity-without any shift in the underlying biology. Current methods may thus undermine efforts to identify when and how warming will reshape biological processes.


Toxic and mutagenic effects of formaldehyde in Salmonella typhimurium.
Toxic and mutagenic activities of formaldehyde were studied in Salmonella typhimurium strain TM677, using forward mutation to 8-azaguanine (8-AG) resistance both in the absence and in the presence of Aroclor-induced rat-liver postmitochondrial supernatant (PMS). The results showed that formaldehyde was toxic and mutagenic to the bacteria in both systems, but toxicity and mutagenicity were reduced in the presence of PMS. The minimum concentration required to induce toxicity and mutagenicity was 0.17 mM in the absence of PMS and 0.33 mM in the presence of PMS.


Emerging Roles of the Nervous System in Gastrointestinal Cancer Development.
Our understanding of the fascinating connection between nervous system and gastrointestinal (GI) tumorigenesis has expanded greatly in recent years. Recent studies revealed that neurogenesis plays an active part in GI tumor initiation and progression. Tumor-driven neurogenesis, as well as neurite outgrowth of the pre-existing peripheral nervous system (PNS), may fuel GI tumor progression via facilitating cancer cell proliferation, chemoresistance, invasion and immune escape. Neurotransmitters and neuropeptides drive the activation of various oncogenic pathways downstream of neural receptors within cancer cells, underscoring the importance of neural signaling pathways in GI tumor malignancy. In addition, neural infiltration also plays an integral role in tumor microenvironments, and contributes to an environment in favor of tumor angiogenesis, immune evasion and invasion. Blockade of tumor innervation via denervation or pharmacological agents may serve as a promising therapeutic strategy against GI tumors. In this review, we summarize recent findings linking the nervous system to GI tumor progression, set the spotlight on the molecular mechanisms by which neural signaling fuels cancer aggressiveness, and highlight the importance of targeting neural mechanisms in GI tumor therapy.


Deoxyribonucleic acid flow cytometric analysis of cervical adenocarcinoma: prognostic significance of deoxyribonucleic acid ploidy and S-phase fraction.
Paraffin-embedded tumor samples from 125 patients with cervical adenocarcinoma were analyzed by deoxyribonucleic acid flow cytometry. Thirty-one percent of the tumors were aneuploid. Triploid deoxyribonucleic acid content predominated (51.3%) and one third of the deoxyribonucleic acid aneuploid tumors were tetraploid, whereas near-diploid deoxyribonucleic acid aneuploidy was seen infrequently. Deoxyribonucleic acid aneuploidy was associated with tumor size, histologic grade, clinical stage, and high S-phase fraction. Deoxyribonucleic acid ploidy and S-phase fraction value were independent prognostic parameters, together with the presence of lymph node metastases and tumor size. In conclusion, our results indicate that flow cytometric deoxyribonucleic acid analysis helps to predict the prognosis and may thus influence the choice of treatment.