Outcomes of eating disorders: a systematic review of the literature.
The RTI International-University of North Carolina at Chapel Hill Evidence-based Practice Center systematically reviewed evidence on factors associated with outcomes among individuals with anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED) and whether outcomes differed by sociodemographic characteristics. We searched electronic databases including MEDLINE and reviewed studies published from 1980 to September, 2005, in all languages against a priori inclusion/exclusion criteria and focused on eating, psychiatric or psychological, or biomarker outcomes. At followup, individuals with AN were more likely than comparisons to be depressed, have Asperger's syndrome and autism spectrum disorders, and suffer from anxiety disorders including obsessive-compulsive disorders. Mortality risk was significantly higher than what would be expected in the population and the risk of suicide was particularly pronounced. The only consistent factor across studies relating to worse BN outcomes was depression. A substantial proportion of individuals continue to suffer from eating disorders over time but BN was not associated with increased mortality risk. Data were insufficient to draw conclusions concerning factors associated with BED outcomes. Across disorders, little to no data were available to compare results based on sociodemographic characteristics. The strength of the bodies of literature was moderate for factors associated with AN and BN outcomes and weak for BED.


Altered E-C coupling in triads isolated from malignant hyperthermia-susceptible porcine muscle.
Triad vesicles were isolated from normal (N) and homozygous malignant hyperthermia-susceptible (MHS) porcine skeletal muscle, and two types of sarcoplasmic reticulum Ca2+ release were investigated: 1) polylysine-induced Ca2+ release (direct stimulation of the junctional foot protein), and 2) depolarization-induced Ca2+ release (stimulation of the junctional foot protein via the dihydropyridine receptor). At submaximal concentrations of polylysine, the rates of induced Ca2+ release from the MHS triads were greater than from normal triads. The T tubules of polarized triads were depolarized by the K(+)-to-Na+ ionic replacement protocol. Higher grades of T-tubule depolarization resulted in higher rates of Ca2+ release from both MHS and normal triads but, when compared at a given grade of T-tubule depolarization, the release rate was always greater from the MHS than from normal triads. Thus the activity of the SR Ca2+ release channel is always higher in MHS than in normal muscle at a given submaximal dose of release trigger. This difference is observed when the channel is stimulated directly by polylysine or indirectly via a depolarization-induced activation of the T-tubule dihydropyridine receptor.


Clinical applications of somatostatin.
Because of its wide distribution in the organism, natural somatostatin (SRIF) demonstrates an ample spectrum of actions, involving mainly the central neuroendocrine system and the enteropancreatic area. In the former, this peptide may find its field of application in conditions characterized by excessive GH, TSH or ACTH secretion, depending on the central or peripheral cause of the inappropriate hormone control. The inhibitory effect of SRIF on gastrointestinal and pancreatic hormones may be useful in the management of tumors originating in this system and also in the treatment of inflammatory processes such as pancreatitis, in malignant diarrhea, and in gastrointestinal bleeding. A complex action of SRIF and its derivative on insulin release and glucose homeostasis may offer some advantages in the control of unstable diabetes. Dampening of organic functions in the upper digestive tract may also render SRIF and its analogues useful in the exploration of the gallbladder, gastric and pancreatic functions. The effect of such peptides on tissue growth and on the regulation of blood pressure are the subject of present investigations. Cytoprotection, an interesting aspect of SRIF application, is discussed elsewhere in this compendium. Finally, some comments on the possible use of SRIF as an additive to the conventional treatment of burns and sepsis close this review.


The Seventh K Prathap Memorial Lecture. The pathogenesis of autoimmune immune complex disease.
It has been proposed that autoimmune immune complex disease, of which SLE is the type example, is caused essentially by a failure to properly metabolise immune complexes and that this allows the establishment of feedback cycles which cause more immune complexes to be formed. The essential genetic predisposition to this disease is complement deficiency of the components of the early classical pathway and some degree of genetic complement deficiency, particularly of C4a, is found in more than half the patients. It seems likely that acquired complement deficiencies, possibly present at the time of initiation of the disease, may be important in many of the other cases.


Efficient neutralization of antibody-resistant forms of anthrax toxin by a soluble receptor decoy inhibitor.
A soluble receptor decoy inhibitor (RDI), comprised of the extracellular I domain of ANTXR2, is a candidate anthrax therapeutic. Here we show that RDI can effectively neutralize altered forms of the protective antigen toxin subunit that are resistant to 14B7 monoclonal antibody neutralization. These data highlight the potential of RDI to act as an adjunct to existing antibody-based therapies and indicate that inhibitors based on RDI might be useful as a stand-alone treatment against specifically engineered strains of Bacillus anthracis.


Shaping X-ray spectra with filters in X-ray diagnostics.
The influence on image contrast, tube load and patient mean absorbed dose of different ways of shaping diagnostic X-ray spectra by placing filters in the beam is derived fro two radiographic models (abdominal screen-film radiography and intra-oral, dental radiography) using a computational model. The filters are compared at either equal tube load (keeping tube potential constant) or equal contrast (adjusting the tube potential with the different filters), but always at equal energy imparted per unit area to the image receptor. Compared at equal tube load and relative to standard aluminum filtration, reductions in the mean absorbed dose in the patient of 15-25% can be achieved using filters of Cu, Ti, W and Au (increasing the tube load by 30-40% compared with standard aluminium filtration). However, contrast is also reduced by 7%. Compared at equal contrast, the dose reductions are smaller, about 10%. Filters of copper are generally recommended, as are filters of aluminium. The use of bandpass filters (K-edge filters) should be restricted to examinations where the need for substantial variation in tube potential from patient to patient is small. The benefit of using thicker filters than those commonly used today (increasing tube load by factors of 1.4-2.0 compared with no added filter) is small as the dose reduction is most rapid for small initial values of added filters, and the increase in tube load increases steadily with increasing filter thickness.


Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study.
This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = -8.4, 95% CI -11.4--5.4, p = 3.9 × 10-8) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3-6.7, p = 7.4 × 10-7) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = -1.5, 95% CI -5.3-2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8-3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.


Streptomyces harbinensis sp. nov., an endophytic, ikarugamycin-producing actinomycete isolated from soybean root [Glycine max (L.) Merr].
A novel ikarugamycin-producing actinomycete, designated strain NEAU-Da3(T), was isolated from soybean root [Glycine max (L.) Merr.] and characterized using a polyphasic approach. 16S rRNA gene sequence similarity studies showed that strain NEAU-Da3(T) belonged to the genus Streptomyces, and was most closely related to Streptomyces carpaticus NRRL B-16359(T) (99.5 %), Streptomyces cheonanensis VC-A46(T) (99.3 %) and Streptomyces xiamenensis MCCC 1A01550(T) (97.2 %); similarities to other type strains of species of the genus Streptomyces were lower than 97.1 %. The maximum-likelihood phylogenetic tree based on 16S rRNA gene sequences showed that the isolate formed a distinct phyletic line with S. carpaticus NRRL B-16359(T), S. cheonanensis VC-A46(T) and S. xiamenensis MCCC 1A01550(T). This branching pattern was also supported by the tree reconstructed with the neighbour-joining method. A comparative study between strain NEAU-Da3(T) and the type strains of the closest related species of the genus Streptomyces revealed that it differed from them in morphological, physiological and biochemical characteristics. Therefore, it is proposed that strain NEAU-Da3(T) represents a novel species of the genus Streptomyces, for which the name Streptomyces harbinensis sp. nov. is proposed. The type strain is NEAU-Da3(T) ( = CGMCC 4.7047(T) = DSM 42076(T)).


Remote Monitoring of the Performance Status and Burden of Symptoms of Patients With Gastrointestinal Cancer Via a Consumer-Based Activity Tracker: Quantitative Cohort Study.
The number of older patients with gastrointestinal cancer is increasing due to an aging global population. Minimizing reliance on an in-clinic patient performance status test to determine a patient's prognosis and course of treatment can improve resource utilization. Further, current performance status measurements cannot capture patients' constant changes. These measurements also rely on self-reports, which are subjective and subject to bias. Real-time monitoring of patients' activities may allow for a more accurate assessment of patients' performance status while minimizing resource utilization. This study investigates the validity of consumer-based activity trackers for monitoring the performance status of patients with gastrointestinal cancer. A total of 27 consenting patients (63% male, median age 58 years) wore a consumer-based activity tracker 7 days before chemotherapy and 14 days after receiving their first treatment. The provider assessed patients using the Eastern Cooperative Oncology Group Performance Status (ECOG-PS) scale and Memorial Symptom Assessment Scale-Short Form (MSAS-SF) before and after chemotherapy visits. The statistical correlations between ECOG-PS and MSAS-SF scores and patients' daily step counts were assessed. The daily step counts yielded the highest correlation with the patients' ECOG-PS scores after chemotherapy (P<.001). The patients with higher ECOG-PS scores experienced a higher fluctuation in their step counts. The patients who walked more prechemotherapy (mean 6071 steps per day) and postchemotherapy (mean 5930 steps per day) had a lower MSAS-SF score (lower burden of symptoms) compared to patients who walked less prechemotherapy (mean 5205 steps per day) and postchemotherapy (mean 4437 steps per day). This study demonstrates the feasibility of using inexpensive, consumer-based activity trackers for the remote monitoring of performance status in the gastrointestinal cancer population. The findings need to be validated in a larger population for generalizability.


In Vitro Skin Permeation of Idebenone from Lipid Nanoparticles Containing Chemical Penetration Enhancers.
Lipid nanoparticles (LNPs) have been proposed as carriers for drug skin delivery and targeting. As LNPs effectiveness could be increased by the addition of chemical penetration enhancers (PE), in this work, the feasibility of incorporating PE into LNPs to improve idebenone (IDE) targeting to the skin was investigated. LNPs loading IDE 0.7% w/w were prepared using hydrophilic (propylene glycol, PG, 10% w/w or N-methylpyrrolidone, NMP, 10% w/w) and/or lipophilic PE (oleic acid, OA, 1% w/w; isopropyl myristate, IPM, 3.5% w/w; a mixture of 0.5% w/w OA and 2.5% w/w IPM). All LNPs showed small sizes (<60 nm), low polydispersity index and good stability. According to the obtained results, IDE release from LNPs was not the rate-limiting step in IDE skin penetration. No IDE permeation was observed through excised pigskin from all LNPs, while the greatest increase of IDE penetration into the different skin layers was obtained using the mixture OA/IPM. The antioxidant activity of IDE-loaded LNPs, determined by the oxygen radical absorbance capacity assay, was greater than that of free IDE. These results suggest that the use of suitable PE as LNPs components could be regarded as a promising strategy to improve drug targeting to the skin.


Complex de novo chromosomal rearrangement at 15q11-q13 involving an intrachromosomal triplication in a patient with a severe neuropsychological phenotype: clinical report and review of the literature.
Interstitial triplications of 15q11-q13, leading to tetrasomy of the involved region, are very rare, with only 11 cases reported to date. Their pathogenicity is independent of the parental origin of the rearranged chromosome. The associated phenotype resembles, but is less severe, than that of patients bearing inv dup(15) marker chromosomes. Here, we describe a boy of 3 years and 9 months of age who exhibited very mild craniofacial dysmorphism (arched eyebrows, hypertelorism, and a wide mouth), developmental delay, generalized hypotonia, ataxic gait, severe intellectual disability, and autism. Array comparative genomic hybridization (CGH) analysis identified a heterozygous duplication of 1.1 Mb at 15q11.2 (between low-copy repeats BP1 and BP2), and a heterozygous triplication of 6.8 Mb at 15q11.2-q13.1 (BP2-BP4). Both acquisitions were de novo and contiguous. Microsatellite polymorphism analysis revealed the maternal origin of the triplication and the involvement of both maternal chromosomes 15. Furthermore, fluorescence in situ hybridization (FISH) analysis using BAC clones revealed that the rearrangement was complex, containing three differently sized tandem repeats of which the middle one was inverted. Our study confirms and extends the model proposed to explain the formation of intrachromosomal triplications through recombination events between non-allelic duplicons. The comparison of the proband's clinical presentation with those of previously described cases attests the existence of endophenotypes due to the parental origin of the 15q11-q13 triplicated segment and suggests a timetable for achievement of developmental milestones, thereby contributing to improved genotype-phenotype correlations.


Serological responses triggered by different SARS-CoV-2 vaccines against SARS-CoV-2 variants in Taiwan.
Broadly neutralizing ability is critical for developing the next-generation SARS-CoV-2 vaccine. We collected sera samples between December 2021-January 2022 from 113 Taiwan naïve participants after their second dose of homologous vaccine (AZD1222, mRNA-1273, BNT162-b2, and MVC-COV1901) and compared the differences in serological responses of various SARS-CoV-2 vaccines. Compared to AZD1222, the two mRNA vaccines could elicit a higher level of anti-S1-RBD binding antibodies with higher broadly neutralizing ability evaluated using pseudoviruses of various SARS-CoV-2 lineages. The antigenic maps produced from the neutralization data implied that Omicron represents very different antigenic characteristics from the ancestral lineage. These results suggested that constantly administering the vaccine with ancestral Wuhan spike is insufficient for the Omicron outbreak. In addition, we found that anti-ACE2 autoantibodies were significantly increased in all four vaccinated groups compared to the unvaccinated pre-pandemic group, which needed to be investigated in the future.


Telokin (kinase-related protein) modulates the oligomeric state of smooth-muscle myosin light-chain kinase and its interaction with myosin filaments.
Telokin, an abundant gizzard protein, inhibited phosphorylation of regulatory light chain when filamentous myosin was used as the substrate but no inhibition was observed with myosin subfragment 1. At physiological telokin-to-myosin molar ratio (1:1), the inhibition amounted to a 3.5-fold reduction in the initial phosphorylation rate whereas at high molar excess of telokin over myosin, we observed an up to 20-fold decrease in this rate. In agreement with previous observations [Shirinsky, Vorotnikow, Birukov, Nanaev, Collinge, Lukas, Sellers and Watterson (1993) J. Biol. Chem. 268, 16578-16583], telokin did not inhibit phosphorylation of the isolated regulatory light chain of myosin and only moderately (35%) inhibited that of heavy meromyosin. To gain a better understanding of the mechanism of this inhibition, we investigated the effects of telokin on the recently described [Babiychuk, Babiychuk and Sobieszek (1995) Biochemistry 34, 6366-6372] oligomeric properties of smooth-muscle myosin light-chain kinase (MLCK). We showed, on the one hand, that telokin rapidly solubilized the large kinase oligomers formed at low ionic strength. With soluble kinase, on the other hand, telokin acted to increase the relative concentration of MLCK dimers and to decrease that of the hexamers and octamers. This, in turn, resulted in a reduction in the amount of MLCK bound to myosin because filamentous myosin appeared to exhibit a higher affinity for the hexamers than for the dimers. Telokin by itself was also shown to dimerize and oligomerize in solution and this oligomerization was greatly enhanced in the presence of MLCK. We suggest that telokin affects myosin phosphorylation by modulation of the oligomeric state of MLCK and its interaction with myosin filaments.


A comparison of signal processing techniques for Intrinsic Optical Signal imaging in mice.
Intrinsic Optical Signal imaging is a technique which allows the visualisation and mapping of activity related changes within the brain with excellent spatial and temporal resolution. We analysed a variety of signal and image processing techniques applied to real mouse imaging data. The results were compared in an attempt to overcome the unique issues faced when performing the technique on mice and improve the understanding of post processing options available.


No disadvantage in outcome of using matched unrelated donors as compared with matched sibling donors for bone marrow transplantation in children with acute lymphoblastic leukemia in second remission.
We evaluated the outcome of children with acute lymphoblastic leukemia (ALL) in second remission (2CR), comparing bone marrow transplantation (BMT) using either matched sibling donors or unrelated donors (URDs). A total of 65 patients, aged 2 months to 20 years at BMT, with ALL in 2CR underwent allogeneic BMT at seven Nordic centers during 1990 to 1997. Of the first relapses, 85% were in bone marrow; 46% occurred on therapy, and 54%, off therapy. The preparative regimens were cyclophosphamide plus total-body irradiation +/- antithymocyte/antilymphocyte globulin, busulfan plus cyclophosphamide +/- antithymocyte/antilymphocyte globulin, or cytarabine plus total-body irradiation. Of the allografts, 37 were from HLA-matched siblings and 28 were from URDs. In the sibling versus URD graft recipient groups, the posttransplantation 5-year event-free survival was 39% versus 54% (P =.4), the estimated posttransplantation relapse rate was 76% versus 40% (P = not significant [NS]), and the toxic death rate was 19% versus 11% (P = NS). The incidence of significant (grade 2 to 4) acute graft-versus-host disease (GVHD) was 38% versus 64% (P <.05) and was 14% versus 32% (P <.10) for severe (grade 3 to 4) acute GVHD; the incidence of chronic GVHD was 26% versus 57% (P <.05) and was 13% versus 22% (P = NS) for extensive chronic GVHD in the sibling and URD groups. BMT with matched URD allografts offers at least equal survival for children with ALL in 2CR, as compared with allografts from matched sibling donors. URD allografts were not associated with a higher toxic mortality rate, although both acute and chronic GVHD were more frequent with URD. Indications for using matched URD allografts in ALL 2CR can be considered the same as for using matched sibling donors.


Retrieving information on clinical methodology.
Evidence derived from several simple searchers of the literature suggests that one interested in identifying papers which discuss the methodologies of clinical trials will have reasonable success. However, the retrieval of a meaningful methodologic duscussion of any actual trial is unlikely because very little of this information has been published. Some suggestions to remedy this deficiency are given.


The immunoexpression of EGFR and Her2/neu in oral squamous carcinoma.
In this study, we have analyzed the EGFR and Her2/neu expression in oral squamous carcinoma and adjacent dysplastic areas. The lesions were diagnosed especially in the sixth decade of life, in male patients, localized on the lips, especially as well and poorly differentiated carcinomas (34%). The EGFR immunostain has been intense in over 50% of the tumors cells in well-differentiated carcinomas, expression diminished in the moderately and poorly differentiated carcinomas. Her2/neu marker recorded a score of 3+ in moderately and poorly differentiated carcinomas, the reaction turning out positive in 25% of the cases.


Septic arthritis in young infants: clinical and microbiologic correlations and therapeutic implications.
In order to assess and correlate the bacteriology of neonatal septic arthritis with its clinical presentation, the records of nine infants with this disease that were diagnosed at Edmonton hospitals between 1964 and 1981 were reviewed and 92 other cases reported in the English-language literature since 1960 were evaluated. All Edmonton cases developed outside of the hospital in previously healthy infants. A Streptococcus species was isolated in four of six patients from whom joint fluid was obtained before antibiotic therapy. Analysis of cases from the literature revealed a more variable bacteriology that seemed dependent on whether the case was hospital or community acquired. In 52 hospital-acquired cases, staphylococci were the predominant isolates (62%); next in frequency were Candida species (17%) and gram-negative enteric bacilli (15%). Community-acquired neonatal septic arthritis was most often caused by streptococci (52% of cases), staphylococci (26%), and gonococci (17%). Since 1970 the relative imbalance between staphylococcal (5%) and streptococcal (75%) isolates in community-acquired neonatal septic arthritis is even more pronounced. This pattern emphasizes the importance of ensuring optimal coverage against penicillin-sensitive organisms in community-acquired neonatal septic arthritis; this is in contrast to the situation with hospital-acquired arthritis, where wider-spectrum coverage against staphylococci and gram-negative enteric bacilli remains mandatory.


Optical backaction-evading measurement of a mechanical oscillator.
Quantum mechanics imposes a limit on the precision of a continuous position measurement of a harmonic oscillator, due to backaction arising from quantum fluctuations in the measurement field. This standard quantum limit can be surpassed by monitoring only one of the two non-commuting quadratures of the motion, known as backaction-evading measurement. This technique has not been implemented using optical interferometers to date. Here we demonstrate, in a cavity optomechanical system operating in the optical domain, a continuous two-tone backaction-evading measurement of a localized gigahertz-frequency mechanical mode of a photonic-crystal nanobeam cryogenically and optomechanically cooled close to the ground state. Employing quantum-limited optical heterodyne detection, we explicitly show the transition from conventional to backaction-evading measurement. We observe up to 0.67 dB (14%) reduction of total measurement noise, thereby demonstrating the viability of backaction-evading measurements in nanomechanical resonators for optical ultrasensitive measurements of motion and force.


Mediterranean Diet and the Association Between Air Pollution and Cardiovascular Disease Mortality Risk.
Recent experimental evidence suggests that nutritional supplementation can blunt adverse cardiopulmonary effects induced by acute air pollution exposure. However, whether usual individual dietary patterns can modify the association between long-term air pollution exposure and health outcomes has not been previously investigated. We assessed, in a large cohort with detailed diet information at the individual level, whether a Mediterranean diet modifies the association between long-term exposure to ambient air pollution and cardiovascular disease mortality risk. The National Institutes of Health-American Association for Retired Persons Diet and Health Study, a prospective cohort (N=548 845) across 6 states and 2 cities in the United States and with a follow-up period of 17 years (1995-2011), was linked to estimates of annual average exposures to fine particulate matter and nitrogen dioxide at the residential census-tract level. The alternative Mediterranean Diet Index, which uses a 9-point scale to assess conformity with a Mediterranean-style diet, was constructed for each participant from information in cohort baseline dietary questionnaires. We evaluated mortality risks for cardiovascular disease, ischemic heart disease, cerebrovascular disease, or cardiac arrest associated with long-term air pollution exposure. Effect modification of the associations between exposure and the mortality outcomes by alternative Mediterranean Diet Index was examined via interaction terms. For fine particulate matter, we observed elevated and significant associations with cardiovascular disease (hazard ratio [HR] per 10 μg/m3, 1.13; 95% CI, 1.08-1.18), ischemic heart disease (HR, 1.16; 95% CI, 1.10-1.23), and cerebrovascular disease (HR, 1.15; 95% CI, 1.03-1.28). For nitrogen dioxide, we found significant associations with cardiovascular disease (HR per 10 ppb, 1.06; 95% CI, 1.04-1.08) and ischemic heart disease (HR, 1.08; 95% CI, 1.05-1.11). Analyses indicated that Mediterranean diet modified these relationships, as those with a higher alternative Mediterranean Diet Index score had significantly lower rates of cardiovascular disease mortality associated with long-term air pollution exposure ( P-interaction<0.05). A Mediterranean diet reduced cardiovascular disease mortality risk related to long-term exposure to air pollutants in a large prospective US cohort. Increased consumption of foods rich in antioxidant compounds may aid in reducing the considerable disease burden associated with ambient air pollution.


Toll-Like Receptors in the Progression of Autosomal Dominant Polycystic Kidney Disease.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of chronic kidney disease. The intriguing role of innate immune system and inflammation become a target for potential therapeutic approach to slow progression. When toll-like receptors (TLRs) signaling and their receptors activate, they start a cascade of intracellular signaling that induces the production of the inflammatory cytokines and chemokines. Thus, we aim to investigate the association of TLRs between progression of ADPKD. Ninety ADPKD patients and ninety matched controls were enrolled this prospective study and were followed during 3 years. TLR-2 and TLR-4 gene polymorphisms and expressions were measured. Hypertension was diagnosed with ambulatory blood pressure monitoring. Rapid progression was defined as sustained decline in estimated glomerular filtration rate (eGFR) of more than 5 mL/min per 1.73 m2 per year. TLR-4Asp299Gly polymorphisms were significantly different between patient and control group (P < 0.05). Also, TLR-2 and TLR-4 gene expressions were significantly different between the ADPKD patients and the control subjects (P < 0.05). The expression levels of both TLR-2 and TLR-4 were found to be higher in the rapid progression groups comparing the slow progression group (P < 0.05). TLR-2 gene expression, hypertension and uric acid were found to be independent risk factors in identifying rapid progression in ADPKD patients. TLR-2 and TLR-4 gene expressions are associated with rapid progression in ADPKD patients. TLRs may play a role in the progression of ADPKD.


Thermal phase transition behaviours of the blue phase of bent-core nematogen and chiral dopant mixtures under different boundary conditions.
We have investigated dramatic changes in the thermal phase transition of a liquid-crystalline (LC) blue phase (BP) consisting of bent-core nematogen and chiral dopants under various boundary conditions during cooling from the isotropic phase. Blue phase III, which has arbitrary morphological characteristics, between two glass plates goes to blue phase I, which has a body-centred cubic structure, when the sample is placed on the glass as a droplet form. These two distinctive phase transition behaviours were directly observed by polarized optical microscopy as well as selective reflection spectroscopy, in which the phase transition between BPs started from the air/LC interface. We determined that this transition resulted from the ordered double-twisted cylinders near the air-boundary by confocal laser-scanning microscopy.


Oral combination therapy: repaglinide plus metformin for treatment of type 2 diabetes.
Type 2 diabetes is characterized by decreases in insulin secretion and insulin sensitivity. Several classes of oral antidiabetic medications are currently approved for the treatment of type 2 diabetes. A stepwise treatment approach from monotherapy to combination therapy is traditionally used; however, the frequency of treatment failure with monotherapy has resulted in a move towards earlier treatment with combination therapies that target the two principal defects in glycaemic control. One such combination regimen is repaglinide (a prandial glucose regulator that increases insulin release) plus metformin (an insulin sensitizer that inhibits hepatic glucose output, increases peripheral glucose uptake and utilization and minimizes weight gain). Findings from several clinical trials have shown that combination therapy with repaglinide plus metformin is well tolerated and results in greater reductions of haemoglobin A(1c) and fasting plasma glucose values compared with either monotherapy. Repaglinide may also provide a more suitable alternative to combination therapy with sulphonylureas and metformin because of its reduced propensity for hypoglycaemia. The combination regimen of repaglinide plus metformin should therefore be considered as a valuable option in the management of patients with type 2 diabetes when monotherapy is no longer adequate.


Data linkage: a powerful research tool with potential problems.
Policy makers, clinicians and researchers are demonstrating increasing interest in using data linked from multiple sources to support measurement of clinical performance and patient health outcomes. However, the utility of data linkage may be compromised by sub-optimal or incomplete linkage, leading to systematic bias. In this study, we synthesize the evidence identifying participant or population characteristics that can influence the validity and completeness of data linkage and may be associated with systematic bias in reported outcomes. A narrative review, using structured search methods was undertaken. Key words "data linkage" and Mesh term "medical record linkage" were applied to Medline, EMBASE and CINAHL databases between 1991 and 2007. Abstract inclusion criteria were; the article attempted an empirical evaluation of methodological issues relating to data linkage and reported on patient characteristics, the study design included analysis of matched versus unmatched records, and the report was in English. Included articles were grouped thematically according to patient characteristics that were compared between matched and unmatched records. The search identified 1810 articles of which 33 (1.8%) met inclusion criteria. There was marked heterogeneity in study methods and factors investigated. Characteristics that were unevenly distributed among matched and unmatched records were; age (72% of studies), sex (50% of studies), race (64% of studies), geographical/hospital site (93% of studies), socio-economic status (82% of studies) and health status (72% of studies). A number of relevant patient or population factors may be associated with incomplete data linkage resulting in systematic bias in reported clinical outcomes. Readers should consider these factors in interpreting the reported results of data linkage studies.


Fluorescence in situ hybridization detection of chromosomal aberrations in human lymphocytes: applicability to biological dosimetry.
Human lymphocytes in G0 have been irradiated with X-ray doses from 0 to 4.0 Gy. Metaphase chromosomes 2, 3 and 5 and all centromeres were painted using fluorescence in situ hybridization (FISH) probe libraries. Dicentrics, centric rings and acentrics in the whole genome as well as translocations involving the painted chromosomes were recorded. The translocations were subdivided as complete or incomplete. Interstitial insertions and inversions were also noted. The observations were also recorded according to the Protocol for Aberration Identification and Nomenclature Terminology (PAINT) system of scoring. Given that the painted chromosomes comprise 20.4% of the genome it was found that the yield of bicoloured dicentrics was consistent with the yield of dicentrics in the whole genome. The yield of radiation-induced translocations was not significantly higher than that of bicoloured dicentrics. Of the translocations, 60% were complete and it was concluded that the majority of dicentrics and translocations are complete exchanges. Chromosome 5 took part in exchanges marginally more commonly than its length suggests, but it is not known if this is a property of the chromosome or whether it is a donor-dependent observation. The PAINT system of recording rearrangements was examined and the suggested numerical interpretation of this nomenclature was considered to be unsuitable for use in the estimation of dose for cases of accidental overexposure.


Seed Predation on Oil-Polluted and Unpolluted Vachellia (Acacia) Trees in a Hyper-Arid Desert Ecosystem.
Acacia trees are keystone species in many arid environments, supporting high levels of plant and animal diversity. In Israel, the populations of Vachellia (formerly Acacia) tortilis (Forssk.) and V. raddiana (Savi) are declining at an alarming rate. Severe infestations by bruchid beetles (Coleoptera, Chrysomelidae) are among the major causes of seed mortality, but additional environmental stressors can reduce the defence level of the seeds, exacerbating their susceptibility to predators. In a hyper-arid desert ecosystem affected by two major oil spills (in 1975 and 2014), we quantified seed predation rates caused by insect granivores before and after the pods dropped to the ground. We recorded predation rates of up to 84% for both tree species, and higher predation rates at the ground level than in the canopy, suggesting that repeated infestations occur. These results reinforce the call to protect the populations of large ungulates such as gazelles, which kill the bruchids by feeding upon the pods, and promote seed germination and dispersion. We found no clear evidence of a negative effect of the oil spill on seed predation, indicating that oil pollution did not increase the vulnerability of the seeds to granivores even in trees affected by the recent oil spill.


A randomized controlled trial of a therapeutic relational agent for reducing substance misuse during the COVID-19 pandemic.
The COVID-19 pandemic disrupted access to treatment for substance use disorders (SUDs), while alcohol and cannabis retail sales increased. During the pandemic, we tested a tailored digital health solution, Woebot-SUDs (W-SUDs), for reducing substance misuse. In a randomized controlled trial, we compared W-SUDs for 8 weeks to a waitlist control. U.S. adults (N = 180) who screened positive for substance misuse (CAGE-AID>1) were enrolled June-August 2020. The primary outcome was the change in past-month substance use occasions from baseline to end-of-treatment (EOT). Study retention was 84%. General linear models tested group differences in baseline-to-EOT change scores, adjusting for baseline differences and attrition. At baseline, the sample (age M = 40, SD = 12, 65% female, 68% non-Hispanic white) averaged 30.2 (SD = 18.6) substance occasions in the past month. Most (77%) reported alcohol problems, 28% cannabis, and 45% multiple substances; 46% reported moderate-to-severe depressive symptoms. Treatment participants averaged 920 in-app text messages (SD = 892, Median = 701); 96% of completed lessons were rated positively; and 88% would recommend W-SUDs. Relative to waitlist, W-SUDs participants significantly reduced past-month substance use occasions (M = -9.1, SE = 2.0 vs. M = -3.3, SE = 1.8; p = .039). Secondary substance use and mood outcomes did not change significantly by group; however, reductions in substance use occasions correlated significantly with increased confidence and fewer substance use problems, cravings, depression and anxiety symptoms, and pandemic-related mental health effects (p-value<.05). W-SUDs was associated with significant reductions in substance use occasions. Reduction in substance use occasions was associated with better outcomes, including improved mental health. W-SUDs satisfaction was high.


Comparison of clinical efficacy of inhaled glucocorticoids.
Ratios of clinical efficacy of inhaled steroids are determined by re-evaluation of 29 clinical studies including 6538 patients. The method is based on the calculation of the areas under the curves (AUCs) describing the increase of morning peak flow over baseline during the period of treatment with inhaled glucocorticoids. Dividing the AUC by the applied dose results in a normalized AUC for a dose of 1 mg. Effects of treatments are compared for pairs of glucocorticoids tested in carefully matched groups using the normalized AUCs. Additionally, the effect of the drug delivery system is taken into account according to the literature because of its influence on the effective dose deposed in the lung. Thus, ratios of treatment success are determined: fluticasone propionate (FP, CAS 80474-14-2) versus budesonide (Bud, CAS 51333-22-3) 1:0.309, FP versus beclomethasone dipropionate (BDP, CAS 5534-09-8)1:0.561, FP versus flunisolide (CAS 3385-03-3) 1:0.339, FP versus triamcinolone acetonide (TAAC, CAS 76-25-5) 1:0.206, BDP versus Bud 1:0.609. Ratios for clinical efficacy correspond with the ratios of relative receptor affinities of these pairs of glucocorticoids. Besides the dominant influence of the receptor mediated effect the influence of local metabolisation in case of BDP is discussed as well as the effect of tissue binding in case of FP.


A second mechanism of increase of cerebellar hypermetria in humans.
So far, there is only one procedure known to increase hypermetria in cerebellar patients. Facing an increased inertia of the moving limb, patients presenting a lesion of the lateral cerebellum are able to increase appropriately the intensity of the agonist electromyographic (EMG) activity (the launching force), but are unable to adapt the intensity of the antagonist activity (the braking force). As a result, hypermetria is larger when the inertial load is artificially increased. Recent studies have demonstrated that hyperventilation increases hypermetria in patients presenting a spinocerebellar ataxia type 6 (SCA 6), a disorder associated with polyglutamine expansions in the alpha1A-voltage-dependent calcium channel. The mechanism of this increase of hypermetria has not been identified so far. In the present work, we combined kinematic, EMG and transcranial Doppler studies to understand the effects of hyperventilation on fast goal-directed movements in patients presenting a SCA 6. Both in the normal mechanical state and after increasing the inertial load of the moving hand, hyperventilation induced an increase of hypermetria. Hyperventilation increased the delay of the onset latency of the antagonist EMG activity and decreased the rate of rise of both the agonist and the antagonist EMG activities. Hyperventilation induced a marked decrease in cerebral blood flow velocities. The mechanism of this provocative test is original and is distinct from the mechanism of the load-induced increase of hypermetria.


Circulating CD4+ TEMRA and CD4+ CD28- T cells and incident diabetes among persons with and without HIV.
A higher proportion of circulating memory CD4+ T cells is associated with prevalent diabetes mellitus in persons with HIV (PWH) and HIV-negative persons. We assessed whether circulating T-cell subsets could also identify individuals who will subsequently develop diabetes. This is a longitudinal follow-up study of PWH and similar HIV-negative individuals from the Veterans Aging Cohort Study who provided peripheral mononuclear blood cells between 2005 and 2007. We quantified T-cell subsets using flow cytometry and functional assays to identify CD4+ and CD8+ naive, activated, senescent, memory (central, effector, and effector RA+), and TH1, TH2, and TH17-phenotype cells. The occurrence of an incident diabetes diagnosis (i.e. after baseline blood draw) was adjudicated by a two-physician chart review. Cox proportional hazards models adjusted for traditional risk factors, cytomegalovirus serostatus, and plasma inflammatory biomarkers assessed the relationship between T-cell subsets and incident diabetes. One thousand, eight hundred and thirty-seven participants (1259 PWH) without diabetes at baseline were included; 69% were black, 95% were men, and median follow-up was 8.6 years. Higher baseline frequencies of CD4+ T effector memory RA+ (TEMRA) cells defined as CD45RA+ CD27- (P = 0.04) and senescent T cells defined as CD4+ CD28- (P = 0.04) were associated with incident diabetes in PWH only. Higher frequencies of CD4+ TEMRA and CD4+ CD28- T cells were associated with incident diabetes in PWH only after adjustment for other factors. Additional studies are necessary to assess whether these cells act in blood via inflammatory mediators or reflect T-cell populations in metabolically active tissues.


Patient satisfaction in home health care.
To assess the current use of patient satisfaction measures in home health care and to examine the reliability and validity of current measures of patient satisfaction in home health care. Patient satisfaction has been one of the widely used measures in home health care as an indicator of quality of care. A few efforts have been made to develop psychometrically sound patient satisfaction scales for use in home health care. A critical review of the literature. Electronic databases were systematically searched to identify the studies or publications that measured and addressed patient satisfaction and its measurement in home health care. The review of the literature showed that patient satisfaction measures have been used in the evaluation of care programmes including rehabilitation programmes, discharge and home follow-up programmes, care process and management practices. Also, patient satisfaction measures were used to evaluate new care protocols and treatments. Home healthcare agencies need valid and reliable patient satisfaction scales. Frameworks of patient satisfaction are still in their early developmental stage. Only some of the variables related to patient satisfaction are explained by many frameworks. Home healthcare mangers and researchers need to take in consideration the reliability and validity of measures and tools of patient satisfaction.


Regulation of immune responses by mTOR.
mTOR is an evolutionarily conserved serine/threonine kinase that plays a central role in integrating environmental cues in the form of growth factors, amino acids, and energy. In the study of the immune system, mTOR is emerging as a critical regulator of immune function because of its role in sensing and integrating cues from the immune microenvironment. With the greater appreciation of cellular metabolism as an important regulator of immune cell function, mTOR is proving to be a vital link between immune function and metabolism. In this review, we discuss the ability of mTOR to direct the adaptive immune response. Specifically, we focus on the role of mTOR in promoting differentiation, activation, and function in T cells, B cells, and antigen-presenting cells.


Survey of nine abortifacient infectious agents in aborted bovine fetuses from dairy farms in Beijing, China, by PCR.
Abortion in dairy cattle causes considerable economic losses to the dairy industry. Aborted fetuses and samples from the corresponding aborting dams from 12 dairy herds in Beijing were tested for 9 abortifacient infectious pathogens by PCR between 2008 and 2010. From a total of 80 abortion cases collected during this period, infectious agents were detected in 45 (56.3%) cases, 22 (48.9%) of which represented co-infections with two or three infectious agents. The detected pathogens included infectious bovine rhinotracheitis virus (36.3%) and Neospora caninum (31.3%), followed by bovine viral diarrhoea virus (7.5%), Brucella abortus (6.3%), Tritrichomonas foetus (5%) and Toxoplasma gondii (1.3%). Campylobacter fetus, Coxiella burnetii and Chlamydophila psittaci were not detected in any abortion case. Findings from this study indicated that infectious bovine rhinotracheitis virus and Neospora caninum were the main potential causes of abortions in Beijing dairy herds, whereas the bacterial pathogens were not, in contrast to reports from other countries. This is the first study to test nine abortifacient infectious agents by PCR at the same time, and it is also the first time to report the involvement of a variety of infectious agents in bovine abortion cases in China.


Can the neutrophil count from hepatic fine-needle aspirate cytology be used to diagnose hepatitis in dogs? A pilot study.
The cytologic diagnosis of inflammation on canine hepatic aspirates can be confounded by neutrophilic infiltrates in the liver of dogs with nodular regeneration, by extramedullary hematopoiesis, and by marked blood contamination. We aimed to assess the association between neutrophil counts on hepatic cytology and the histopathologic diagnosis in dogs with hepatitis and non-inflammatory hepatopathy. We also sought to determine a cut-off value for the cytologic diagnosis of hepatitis. In a retrospective blinded pilot study, three observers independently reviewed hepatic aspirates that had corresponding histopathologic examinations performed within 2 days. The number of neutrophils per 200 hepatocytes was determined and averaged among observers. Only neutrophils within or directly in contact with a cluster of ≥5 hepatocytes were counted, and only intact hepatocytes within an approximate monolayer were included. Data are presented as the median (range), and the Mann-Whitney U test is used to make comparisons between groups. Eighteen cases were included (13 hepatitis and five vacuolar hepatopathy). Aspirates with a histopathologic diagnosis of hepatitis had increased numbers of neutrophils compared with those of vacuolar hepatopathy (7.7 [0.3-18.3] vs 3.0 [1.0-5.3]; P = .038). Receiver operating characteristic curve analysis indicated that ≥6 neutrophils were 61.5% (CI 31.6%-86.1%) sensitive and 100% (CI 47.8%-100%) specific for identifying hepatitis. Liver aspirates from hepatitis cases have a higher number of neutrophils on cytology compared with those from vacuolar hepatopathy; however, larger studies, including those with dogs with other liver pathologies, are required. Identification of six or more neutrophils per 200 hepatocytes is highly suggestive of hepatitis.


Emotional information-processing correlates of positive mental health in adolescence: a network analysis approach.
The combined cognitive bias hypothesis proposes that emotional information-processing biases may conjointly influence mental health. Yet, little is known about the interrelationships amongst cognitive biases, particularly in adolescence. We used data from the CogBIAS longitudinal study (Booth et al., 2017), including 450 adolescents who completed measures of interpretation bias, memory bias, and a validated measure of general mental health in a typically developing population. We used a moderated network modelling approach to examine positive mental health-related moderation of the cognitive bias network. We found that mental health was directly associated with positive and negative memory biases, and positive interpretation biases, but not negative interpretation biases. Further, we observed some mental health-related moderation of the network structure. Network connectivity decreased with higher positive mental health scores. Network approaches allow us to model complex relationships amongst cognitive biases and develop novel hypotheses for future research.


In vitro and in vivo protein synthesis inhibition by methylated derivatives of 4-oxypiperidine-1-oxyl.
A new Soviet experimental antioxidant, nitroxyl-2 (2,2,6,6-tetramethyl 4-oxypiperidine 1-oxyl), is a potent inhibitor of protein synthesis in vivo (mouse liver) and in vitro (reticulocyte lysate). Demethylated derivatives of this agent demonstrate a significantly lower inhibitory activity. The HPLC estimation of ATP/ADP ratio in a mouse liver tissue homogenate shows that nitroxyl-2 and its demethylated derivatives possess a similar antioxidant effect. In cell-free translation, the drugs have no effect on the ATP/ADP ratio. The acute drug toxicity (LD50 and the protein synthesis inhibitory activity in vivo (ID50) and in vitro (IC50) were determined and were shown to be highly correlated with the number of methyl groups of the drug molecule. These results are discussed.


Determination of Sorbic Acid in Cheese Samples by Rapid HPLC-DAD Method.
The sorbic acid and its salts have been widely used in the food industries for many years as important food preservatives in order to inhibit the growth of various bacteria, yeasts, and fungi in acidic media. The health effects have led to limitation on the concentrations that can be used in food. Because of that, the analytical determination of these preservatives is important for consumer interest and protection. The purpose of this study is to determine the concentration of sorbic acid in cheese samples by using HPLC. For HPLC analysis, an X-Terra RP-18 (150 × 4.60 mm i.d. × 5 μm) column was selected as the stationary phase at 25°C. Analysis time is about 3 minutes. The developed method was applied to 10 different cheese samples collected from the Turkish market. The levels of sorbic acid in the analyzed samples were between 21.3 mg/kg and 511.3 mg/kg.


The Regulatory Framework Across International Jurisdictions for Risks Associated with Consumption of Botanical Food Supplements.
Dietary supplements, including those containing botanical ingredients and botanical-derived compounds, have been marketed to consumers globally for many decades. However, the legislative framework for such products remains inconsistent across jurisdictions internationally. This study aims to compare the regulatory framework of botanical food supplements in the EU, USA, Canada, Australia, New Zealand, India, Japan, and China. The study also aims to investigate and describe safety assessment criteria for botanical food supplements where they are present in the above said jurisdictions, and attempts to analyze whether these criteria are suitable for addressing the toxicological risks associated with the use of botanical food supplement products, based on the evaluation of reported adverse effects related to botanical food supplement use as examples. Finally, this study discusses some future issues that need further attention, such as the consideration of less than lifetime exposures, potential for misidentification, and adulteration of botanical supplements by pharmacologically active substances. It is concluded that the regulatory approaches towards botanical food supplements differ significantly across jurisdictions. In addition, national authorities are increasingly considering having more regulatory oversight for such products. Further consideration of the actual impact of adverse events arising from botanical food supplement usage will be helpful in guiding such decisions.


Effects of consanguinity, exposure to pregnant females, and stimulation from young on male gerbils' responses to pups.
In three experiments investigating variables affecting responses of male Mongolian gerbils to conspecific young, we compared the behavior directed towards pups of natural fathers, virgin foster fathers, and sexually experienced foster fathers (Experiment 1); males either previously exposed or not exposed to pregnant females (Experiment 2); and males provided or not provided with extra opportunities to huddle over pups (Experiment 3). We found no difference in responses to pups among natural fathers, virgin foster fathers, and foster fathers that had fathered litters. On the other hand, both a week of exposure to a pregnant female and opportunity to huddle over pups for an extra 15 min/day had significant effects on males' subsequent responses to conspecific young. We speculate on the reasons why a male's response to pups might be affected by his exposure to a pregnant female and stimuli from pups, but not by the probability that the pups were his own offspring.


Non-aqueous microgel particles: synthesis, properties and applications.
Microgels are cross-linked polymer latex particles that can form stable colloidal dispersions. Their typical sizes range from 10 to 1000 nm and they can swell in response to their external environment (pH, temperature and solvency). This swelling behaviour is central to many potential applications for microgels. The existing literature is dominated by studies of the properties of aqueous microgel dispersions. In contrast, this review focusses on the development of microgel particles in non-aqueous systems, looking at the challenges of studying these particles as well as their swelling behaviour. The five main mechanisms of producing microgel particles will be discussed and examples of materials used for microgels that swell in non-aqueous solvents will be given. Finally some examples of applications for non-aqueous microgels are given.


Identification of ILK as a novel therapeutic target for acute and chronic myeloid leukemia.
Current treatment options as well as clinical efficacy are limited for chronic myelogenous leukemia (CML), Ph+ acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). In response to the pressing need for more efficacious treatment approaches and strategies to override drug resistance in advanced stage CML, Ph+ ALL, and AML, we investigated the effects of inhibition of ILK as a potentially novel and effective approach to treatment of these challenging malignancies. Using the small molecule ILK inhibitor, Cpd22, and ILK knockdown, we investigated the importance of ILK in the growth and viability of leukemia. Our results suggest that the ILK inhibition may be an effective treatment for CML, Ph+ ALL, and AML as a single therapy, with ILK expression levels positively correlating with the efficacy of ILK inhibition. The identification of ILK as a novel target for leukemia therapy warrants further investigation as a therapeutic approach that could be of potential clinical benefit in both acute and chronic myeloid leukemias.


Mismatch Negativity in Children: Reference Values.
Introduction The Mismatch Negativity (MMN) auditory evoked potential evaluation is a promising procedure to assess objectively the ability of auditory discrimination. Objective To characterize the latency and amplitude values of MMN in children with normal auditory thresholds and without auditory complaints. Methods Children between 5 and 11 years old participated in the present study. All participants underwent acoustic immittance measurements and tonal and vocal audiometry. The MMN was recorded with the MASBE ATC Plus system (Contronic, Pelotas, RS, Brazil). The electrodes were fixed in Fz (active electrode), Fpz (ground electrode) and in M2 and M1 (references electrodes). The intensity used was 80 dBHL, the frequent stimulus was 1,000 Hz and the rare stimulus was 2,000 Hz. The stimuli were presented in both ears separately. Results For the female group, the mean latencies and amplitude of MMN were 177.3 ms and 5.01 μV in the right ear (RE) and 182.4 ms and 5.39 μV in the left ear (LE). In the male group, the mean latencies were 194.4 ms in the RE and 183.6 ms in the LE, with an amplitude of 5.11 μV in the RE and 5.83 μV in the LE. There was no statistically significant difference between ears ( p = 0.867 - latency and p = 0.178 - amplitude), age ( p > 0.20) and the gender of the participants ( p > 0.05). Conclusion Using the described protocol, the mean latency value of MMN was 184.0 ms for RE and 182.9 ms for LE, and the amplitude was 5.05 μV and 5.56 μV for the left and right ears, respective.


Expression of the Xanthomonas campestris pv. vesicatoria hrp gene cluster, which determines pathogenicity and hypersensitivity on pepper and tomato, is plant inducible.
The hrp gene cluster from Xanthomonas campestris pv. vesicatoria determines functions necessary not only for pathogenicity on the host plants pepper and tomato but also for the elicitation of the hypersensitive reaction on resistant host and nonhost plants. Transcriptional orientation and expression of the hrp loci were determined with hrp::Tn3-gus fusions. In addition, expression of the hrp loci was studied by RNA hybridization experiments. Expression of the hrp genes was not detectable after growth of the bacteria in complex medium or in minimal medium. However, high levels of induction of hrp gene expression were measured during growth of the bacteria in the plant. To search for a plant molecule responsible for this induction, we examined a variety of materials of plant origin for their ability to induce hrp gene expression. Filtrates from plant suspension cultures induced hrp genes to levels comparable to those induced in the plant. The inducing molecule(s) was found to be heat stable and hydrophilic and to have a molecular mass of less than 1,000 daltons.


State-of-the-art lasers and light treatments for vascular lesions: from red faces to vascular malformations.
Notable milestones in the treatment of vascular lesions have been achieved over the past century. Many cutaneous vascular lesions can be successfully treated with lightbased devices. In this review, we will discuss the treatment of port-wine birthmarks, lymphatic malformations, infantile hemangiomas, rosacea, venous lakes, pyogenic granulomas, cherry angiomas, and angiofibromas using lasers, total reflection amplification of spontaneous emission of radiation, intense pulsed light, and photodynamic therapy. In addition, for several of these diagnoses, we will review medical therapies that can be combined with light-based devices to provide enhanced results.


Vicinal cysteines in the prosequence play a role in von Willebrand factor multimer assembly.
von Willebrand factor (vWf) is synthesized as a large precursor that dimerizes in the endoplasmic reticulum and forms multimers in the trans- and post-Golgi compartments of megakaryocytes and endothelial cells. The disulfide-bonded multimers are stored in alpha granules of platelets and Weibel-Palade bodies of endothelial cells. The prosequence, composed of two homologous D domains, is required for vWf multimerization and storage. Each D domain contains vicinal cysteines (159Cys-Gly-Leu-162Cys and 521Cys-Gly-Leu-524Cys) that are similar to those at the active site of disulfide isomerases that catalyze thiol protein disulfide interchange. As in disulfide isomerases, a positively charged amino acid (lysine) is also found in close proximity to the vicinal cysteines. Although conserved, the lysine present in thioredoxin was shown not to be essential for its redox activity. We investigated the role of the vicinal cysteines and the lysine residue in the vWf propolypeptide by site-directed mutagenesis and expression of the resulting constructs in mammalian cells. Insertion of an extra glycine between the vicinal cysteines in either D domain inhibited multimerization of dimers, whereas alteration of lysine to glycine in both domains (residues 157 and 519) had no effect. This suggests the importance of the vicinal cysteines but not the lysines in vWf multimerization. Expression of the mutant with an additional glycine in the D1 domain in AtT-20 cells, a mouse pituitary cell line that can store vWf, led to the storage of the resulting dimers. This demonstrates that the mutation did not effect the capacity of the propolypeptide to direct vWf storage while its ability to promote interchain disulfide bonding was eliminated.


[Water and ionic variations in dog kidneys during hypothermic plasma perfusion(author's transl)].
Dog kidneys have been perfused with homologous plasma at plus 6 degrees-C for 24 and 48 h and the water, K+ and Na+ variations in the cortex and medulla have been studied. After 24 h perfusion Na+-gain and K+-loss in the cortex are found while water content shows no changes. After 48 h perfusion additional increase of Na+ and gain of water are observed while the K+ content remains unchanged as compared with the cortex after 24 h perfusion time. In the medulla after 24 h perfusion K+ loss and water gain are registered while the Na+ content remains unchanged. In the following 24 h no additional changes of the K+, Na+ or water contents are observed.


Preliminary findings of the minimally-invasive surgery plus rtPA for intracerebral hemorrhage evacuation (MISTIE) clinical trial.
Compared to ischemic stroke, intracerebral hemorrhage (ICH) is easily and rapidly identified, occurs in younger patients, and produces relatively small initial injury to cerebral tissues--all factors suggesting that interventional amelioration is possible. Investigations from the last decade established that extent of ICH-mediated brain injury relates directly to blood clot volume and duration of blood exposure to brain tissue. Using minimally-invasive surgery plus recombinant tissue plasminogen activator (rtPA), MISTIE investigators explored aggressive avenues to treat ICH. We investigated the difference between surgical intervention plus rtPA and standard medical management for ICH. Subjects in both groups were medically managed according to standard ICU protocols. Subjects randomized to surgery underwent stereotactic catheter placement and clot aspiration. Injections of rtPA were then given through hematoma catheter every 8 h, up to 9 doses, or until a clot-reduction endpoint. After each injection the system was flushed with sterile saline and closed for 60 min before opening to spontaneous drainage. Average aspiration of clots for all patients randomized to surgery plus rtPA was 20% of mean initial clot size. After acute treatment phase (aspiration plus rtPA), clot was reduced an average of 46%. Recorded adverse events were within safety limits, including 30-day mortality, 8%; symptomatic re-bleeding, 8%; and bacterial ventriculitis, 0%. Patients randomized to medical management showed 4% clot resolution in a similar time window. Preliminary analysis indicates that clot resolution rates are greatly dependent on catheter placement. Location of ICH also affects efficacy of aggressive treatment of ICH. There is tentative indication that minimally-invasive surgery plus rtPA shows greater clot resolution than traditional medical management.


The metabolic interactions between tumor cells and tumor-associated stroma (TAS) in prostatic cancer.
Tumor-associated stroma (TAS) is not simply a supporting element for cancer cells, but plays an important role in tumor growth, invasion and metastasis. Changes on the level of stromal constituents, such as loss of Caveolin-1 and increased thymidine phosphorylase (TP) expression, have been associated with tumor aggressiveness. The mutual cooperation between stromal fibroblasts and cancer cells is another distinguishing feature, which has recently emerged. In this investigation, both the loss of Caveolin-1 and the increased TP expression in the prostatic TAS was associated with high Gleason score (p = 0.0002 and 0.003, respectively); the two proteins were acting both independently and synergistically. In addition, TP was significantly associated with high stromal Ki-67 (MIB1) proliferation index (p = 0.03). Analysis of the metabolic interactions between stromal and epithelial elements showed that, while prostatic cancer cells express principally (> 91%) lactate dehydrogenase-5 (LDH-5) (anaerobic metabolism), the tumor-associated fibroblasts/myofibroblasts (TAFs) express largely (67.8%) LDH-1 (aerobic metabolism)-the terms TAFs and TAS are used interchangeably. These two isoenzyme pathways act complementary; the LDH-5 pathway converts pyruvate to lactate, whereas the LDH-1 enzyme system utilizes the secreted metabolite lactate to produce pyruvate, essential for continuous energy supply to tumor cells. Monocarboxylate transporter-1 (MCT-1)-the main facilitator of lactate uptake in tumor cells, was expressed exclusively in prostate cancer cells and related directly to LDH-5 overexpression. These findings support and extend our previous studies on energy recycling between the aerobic stroma and the anaerobic cancer cells within the framework of Warburg effect.


Altered localization and cytoplasmic domain-binding properties of tyrosine-phosphorylated beta 1 integrin.
We describe a novel approach to study tyrosine-phosphorylated (PY) integrins in cells transformed by virally encoded tyrosine kinases. We have synthesized a peptide (PY beta 1 peptide) that represents a portion of the cytoplasmic domain of the beta 1 integrin subunit and is phosphorylated on the tyrosine residue known to be the target of oncogenic tyrosine kinases. Antibodies prepared against the PY beta 1 peptide, after removal of cross-reacting antibodies by absorption and affinity purification, recognized the PY beta 1 peptide and the tyrosine-phosphorylated form of the intact beta 1 subunit, but did not bind the nonphosphorylated beta 1 peptide, the nonphosphorylated beta 1 subunit or other unrelated tyrosine-phosphorylated proteins. The anti-PY beta 1 antibodies labeled the podosomes of Rous sarcoma virus-transformed fibroblasts, but did not detectably stain nontransformed fibroblasts. The localization of the tyrosine phosphorylated beta 1 subunits appeared distinct from that of the beta 1 subunit. Adhesion plaques were stained by the anti-beta 1 subunit antibodies in Rous sarcoma virus-transformed fibroblasts plated on fibronectin, whereas neither podosomes nor adhesion plaques were labeled on vitronectin or on uncoated plates. Anti-phosphotyrosine antibodies labeled podosomes, adhesion plaques and cell-cell boundaries regardless of the substratum. One of the SH2 domains of the p85 subunit of phosphatidylinositol-3-kinase bound to the PY beta 1 peptide, but not to the non-phosphorylated beta 1 cytoplasmic peptide. Other SH2 domains did not bind to the PY beta 1 peptide. These results show that the phosphorylated form of the beta 1 integrin subunit is detected in a different subcellular localization than the nonphosphorylated form and suggest that the phosphorylation on tyrosine of the beta 1 subunit cytoplasmic domain may affect cellular signaling pathways.


Unilateral hippocampal mossy fiber sprouting and bilateral asymmetric neuron loss with episodic postictal psychosis.
Rarely are both sides of the hippocampus available for pathological study in a patient with intractable temporal lobe epilepsy (TLE). The authors report a patient with TLE investigated with bilateral depth electrodes who had an episode of postictal psychosis. The patient died 4 weeks after temporal lobectomy of unknown reasons, despite complete postmortem examination and clinical evidence of postsurgery seizure control. Pathological examination of surgical and autopsy hippocampal specimens found bilateral asymmetric neuron losses. However, only the resected epileptogenic hippocampus showed the profile of neuron loss typical of mesial temporal sclerosis (MTS) and abnormal mossy fiber synaptic reorganization. Quantitative depth electroencephalographic (EEG) analysis of the postictal psychotic event showed that it was not associated with a cluster of seizures, increased postictal depth EEG spike activity, or insufficient antiepileptic medication. These results support the hypothesis that ipsilateral hippocampal epileptogenesis is associated with MTS and mossy fiber sprouting. The results also suggest that the etiology of postictal psychosis in this patient was initiated by an ictal event and the behavior apparently depended on seizure propagation outside the hippocampus. The relevance of these two findings to the literature is discussed.


Systematic Evidence Map for Over One Hundred and Fifty Per- and Polyfluoroalkyl Substances (PFAS).
Per- and polyfluoroalkyl substances (PFAS) are a large class of synthetic (man-made) chemicals widely used in consumer products and industrial processes. Thousands of distinct PFAS exist in commerce. The 2019 U.S. Environmental Protection Agency (U.S. EPA) Per- and Polyfluoroalkyl Substances (PFAS) Action Plan outlines a multiprogram national research plan to address the challenge of PFAS. One component of this strategy involves the use of systematic evidence map (SEM) approaches to characterize the evidence base for hundreds of PFAS. SEM methods were used to summarize available epidemiological and animal bioassay evidence for a set of ∼150 PFAS that were prioritized in 2019 by the U.S. EPA's Center for Computational Toxicology and Exposure (CCTE) for in vitro toxicity and toxicokinetic assay testing. Systematic review methods were used to identify and screen literature using manual review and machine-learning software. The Populations, Exposures, Comparators, and Outcomes (PECO) criteria were kept broad to identify mammalian animal bioassay and epidemiological studies that could inform human hazard identification. A variety of supplemental content was also tracked, including information on in vitro model systems; exposure measurement-only studies in humans; and absorption, distribution, metabolism, and excretion (ADME). Animal bioassay and epidemiology studies meeting PECO criteria were summarized with respect to study design, and health system(s) were assessed. Because animal bioassay studies with ≥21-d exposure duration (or reproductive/developmental study design) were most useful to CCTE analyses, these studies underwent study evaluation and detailed data extraction. All data extraction is publicly available online as interactive visuals with downloadable metadata. More than 40,000 studies were identified from scientific databases. Screening processes identified 44 animal and 148 epidemiology studies from the peer-reviewed literature and 95 animal and 50 epidemiology studies from gray literature that met PECO criteria. Epidemiological evidence (available for 15 PFAS) mostly assessed the reproductive, endocrine, developmental, metabolic, cardiovascular, and immune systems. Animal evidence (available for 40 PFAS) commonly assessed effects in the reproductive, developmental, urinary, immunological, and hepatic systems. Overall, 45 PFAS had evidence across animal and epidemiology data streams. Many of the ∼150 PFAS were data poor. Epidemiological and animal evidence were lacking for most of the PFAS included in our search. By disseminating this information, we hope to facilitate additional assessment work by providing the initial scoping literature survey and identifying key research needs. Future research on data-poor PFAS will help support a more complete understanding of the potential health effects from PFAS exposures. https://doi.org/10.1289/EHP10343.


Surgical decompression for traumatic brain swelling: indications and results.
Decompressive craniectomy has been performed since 1977 in patients with traumatic brain injury. The authors assess the efficacy of this treatment and the indications for its use. The clinical status of the 57 patients, their computerized tomography (CT) scans, and intracranial pressure (ICP) levels were documented prospectively in a standard protocol. At the beginning of the study, all patients older than 30 years were excluded. As of 1989 patients older than 40 years were excluded until 1991; since that time patients older than 50 years have been excluded. Primary brain or brainstem injury with fully developed bulbar brain syndrome, loss of auditory evoked potentials (AEPs), and/or oscillation flow in a transcranial Doppler ultrasound examination were contraindications to decompressive craniectomy. A positive indication for decompression was given in the case of progressive therapy-resistant intracranial hypertension in correlation with clinical (Glasgow Coma Scale [GCS] score, decerebrate posturing, dilating of pupils) and electrophysiological (electroencephalography, somatosensory evoked potentials, and AEPs) parameters and with findings on CT scans. Unilateral decompressive craniectomy was performed in 31 patients and bilateral craniectomy in 26 patients. In all cases, a wide frontotemporoparietal craniectomy was followed by a dura enlargement covered with temporal muscle fascia. The outcomes of the treatment were surprisingly good. Only 11 patients (19%) died, three of whom died of acute respiratory disease syndrome. Five patients (9%) survived, but remained in a persistent vegetative state; six patients (11%) survived with a severe permanent neurological deficit, and 33 patients (58%) attained social rehabilitation. Two patients (3.5%) did not have a follow-up examination. The GCS score on the 1st day posttrauma and the mean ICP turned out to be the best predictors for a good prognosis. The results demonstrate the importance of decompressive craniectomy in the treatment of traumatic brain swelling. Surgical decompression should be routinely performed when indicated before irreversible ischemic brain damage occurs.


TRIM33 prevents pulmonary fibrosis by impairing TGF-β1 signalling.
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterised by myofibroblast proliferation and abnormal extracellular matrix accumulation in the lungs. Transforming growth factor (TGF)-β1 initiates key profibrotic signalling involving the SMAD pathway and the small heat shock protein B5 (HSPB5). Tripartite motif-containing 33 (TRIM33) has been reported to negatively regulate TGF-β/SMAD signalling, but its role in fibrogenesis remains unknown. The objective of this study was to elucidate the role of TRIM33 in IPF. TRIM33 expression was assessed in the lungs of IPF patients and rodent fibrosis models. Bone marrow-derived macrophages (BMDM), primary lung fibroblasts and 3D lung tissue slices were isolated from Trim33-floxed mice and cultured with TGF-β1 or bleomycin (BLM). Trim33 expression was then suppressed by adenovirus Cre recombinase (AdCre). Pulmonary fibrosis was evaluated in haematopoietic-specific Trim33 knockout mice and in Trim33-floxed mice that received AdCre and BLM intratracheally. TRIM33 was overexpressed in alveolar macrophages and fibroblasts in IPF patients and rodent fibrotic lungs. Trim33 inhibition in BMDM increased TGF-β1 secretion upon BLM treatment. Haematopoietic-specific Trim33 knockout sensitised mice to BLM-induced fibrosis. In primary lung fibroblasts and 3D lung tissue slices, Trim33 deficiency increased expression of genes downstream of TGF-β1. In mice, AdCre-Trim33 inhibition worsened BLM-induced fibrosis. In vitro, HSPB5 was able to bind directly to TRIM33, thereby diminishing its protein level and TRIM33/SMAD4 interaction. Our results demonstrate a key role of TRIM33 as a negative regulator of lung fibrosis. Since TRIM33 directly associates with HSPB5, which impairs its activity, inhibitors of TRIM33/HSPB5 interaction may be of interest in the treatment of IPF.


Missed appointments among rifampicin-resistant tuberculosis (RR-TB) patients at a decentralised RR-TB outpatient clinic in Johannesburg, South Africa.
With the implementation of outpatient (ambulatory) decentralised rifampicin-resistant tuberculosis (RR-TB) treatment in South Africa (SA) since late 2011, the high rates of loss from treatment are a significant concern. Missed appointments lead to treatment interruptions and may contribute to amplification of resistance, ongoing transmission of RR-TB and an increased risk of morbidity and mortality to the patient. To describe characteristics of patients who missed scheduled appointments during ambulatory RR-TB treatment. The study was a retrospective, deidentified electronic medical record review of RR-TB patients at an outpatient clinic in Johannesburg, SA, from March 2013 to December 2014. Associations between missed appointments and clinical and demographic characteristics were analysed using time-to-event Cox proportional hazards regression. Of 172 patients who met the eligibility criteria, 53.5% missed at least one appointment and 39.5% missed three or more. More than half (59.8%) of first missed appointments occurred within the first 3 months after treatment initiation. The median number of days from initiation until the first missed appointment was 82 (interquartile range 52 - 260.5). HIV-infected patients with a CD4 count of ≤100 cells/µL (adjusted hazard ratio (aHR) 4.25, 95% confidence interval (CI) 1.49 - 12.18), patients referred from an inpatient facility (aHR 1.96, 95% CI 1.18 - 3.25) and patients aged 18 - 24 years as opposed to those aged 35 - 44 years (aHR 3.26, 95% CI 1.20 - 8.84) were all more likely to miss one or more appointments. HIV-infected patients with a low CD4 count, patients referred from inpatient care and young patients are at high risk of missing appointments and should receive interventions targeted at improving retention.


Van der Waals Engineering of Ultrafast Carrier Dynamics in Magnetic Heterostructures.
Heterostructures composed of the intrinsic magnetic topological insulator MnBi2Te4 and its nonmagnetic counterpart Bi2Te3 host distinct surface electronic band structures depending on the stacking order and exposed termination. Here, we probe the ultrafast dynamical response of MnBi2Te4 and MnBi4Te7 following near-infrared optical excitation using time- and angle-resolved photoemission spectroscopy and disentangle surface from bulk dynamics based on density functional theory slab calculations of the surface-projected electronic structure. We gain access to the out-of-equilibrium charge carrier populations of both MnBi2Te4 and Bi2Te3 surface terminations of MnBi4Te7, revealing an instantaneous occupation of states associated with the Bi2Te3 surface layer followed by carrier extraction into the adjacent MnBi2Te4 layers with a laser fluence-tunable delay of up to 350 fs. The ensuing thermal relaxation processes are driven by phonon scattering with significantly slower relaxation times in the magnetic MnBi2Te4 septuple layers. The observed competition between interlayer charge transfer and intralayer phonon scattering demonstrates a method to control ultrafast charge transfer processes in MnBi2Te4-based van der Waals compounds.


Biomonitoring detoxification efficiency of an algal-bacterial microcosm system for treatment of coking wastewater: Harmonization between Chlorella vulgaris microalgae and wastewater microbiome.
Nowadays, due to worldwide water shortage, water utilities are forced to re-evaluate treated wastewater. Consequently, wastewater treatment plants need to conduct biomonitoring. Coking wastewater (CWW) has toxic, mutative and carcinogenic components with threatening effect on the environment. CWW was selected as a model for complex highly toxic industrial wastewater that should be treated. CWW from Egypt was treated in a nine-liter photobioreactor using an algal-bacterial system. The photobioreactor was operated for 154 days changing different parameters (toxic load and light duration) for optimization. Optimized conditions achieved significant reduction (45%) in the operation cost. The algal-bacterial system was monitored using chemical assays (chemical oxygen demand and phenol analysis), bioassays (phytotoxicity, Artemia-toxicity, cytotoxicity, algal-bacterial ratio and settleability) and Illumina-MiSeq sequencing of 16S rRNA gene. The algal-bacterial system detoxified (in terms of phytotoxicity, cytotoxicity and Artemia-toxicity) CWW introduced as influent through all phases. A significant difference was recorded in the microbial diversity between influent and effluent samples. Four phyla dominated influent samples; Proteobacteria (77%), Firmicutes (11%), Bacteroidetes (5%) and Deferribacteres (3%) compared to only two in effluent samples; Proteobacteria (66%) and Bacteroidetes (26%). The significant relative-abundance of versatile aromatic degraders (Comamonadaceae and Pseudomonadaceae families) in influent samples conformed to the nature of CWW. Microbial community shifted and promoted the activity of catabolically versatile and xenobiotics degrading families (Chitinophagaceae and Xanthomonadaceae). Co-culture of microalgae had a positive effect on the biodegrading bacteria that was reflected by enhanced treatment efficiency, significant increase in relative abundance of bacterial genera with cyanide-decomposing potential and negative effect on waterborne pathogens.


An eHealth Intervention for Promoting COVID-19 Knowledge and Protective Behaviors and Reducing Pandemic Distress Among Sexual and Gender Minorities: Protocol for a Randomized Controlled Trial (#SafeHandsSafeHearts).
Existing data on COVID-19 disparities among vulnerable populations portend excess risk for lesbian, gay, bisexual, transgender (LGBT) and other persons outside of heteronormative and cisgender identities (ie, LGBT+). Owing to adverse social determinants of health, including pervasive HIV and sexual stigma, harassment, violence, barriers in access to health care, and existing health and mental health disparities, sexual and gender minorities in India and Thailand are at disproportionate risk for SARS-CoV-2 infection and severe disease. Despite global health disparities among LGBT+ populations, there is a lack of coordinated, community-engaged interventions to address the expected excess burden of COVID-19 and public health-recommended protective measures. We will implement a randomized controlled trial (RCT) to evaluate the effectiveness of a brief, peer-delivered eHealth intervention to increase COVID-19 knowledge and public health-recommended protective behaviors, and reduce psychological distress among LGBT+ people residing in Bangkok, Thailand, and Mumbai, India. Subsequent to the RCT, we will conduct exit interviews with purposively sampled subgroups, including those with no intervention effect. SafeHandsSafeHearts is a 2-site, parallel waitlist-controlled RCT to test the efficacy of a 3-session, peer counselor-delivered eHealth intervention based on motivational interviewing and psychoeducation. The study methods, online infrastructure, and content were pilot-tested with LGBT+ individuals in Toronto, Canada, before adaptation and rollout in the other contexts. The primary outcomes are COVID-19 knowledge (index based on US Centers for Disease Control and Prevention [CDC] items), protective behaviors (index based on World Health Organization and US CDC guidelines), depression (Patient Health Questionnaire-2), and anxiety (Generalized Anxiety Disorder-2). Secondary outcomes include loneliness, COVID-19 stress, and intended care-seeking. We will enroll 310 participants in each city aged 18 years and older. One-third of the participants will be cisgender gay, bisexual, and other men who have sex with men; one-third will be cisgender lesbian, bisexual, and other women who have sex with women; and one-third will be transfeminine, transmasculine, and gender nonbinary people. Participants will be equally stratified in the immediate intervention and waitlist control groups. Participants are mainly recruited from online social media accounts of community-based partner organizations. They can access the intervention on a computer, tablet, or mobile phone. SafeHandsSafeHearts involves 3 sessions delivered weekly over 3 successive weeks. Exit interviews will be conducted online with 3 subgroups (n=12 per group, n=36 in each city) of purposively selected participants to be informed by RCT outcomes and focal populations of concern. The RCT was funded in 2020. The trials started recruitment as of August 1, 2021, and all RCT data collection will likely be completed by January 31, 2022. The SafeHandsSafeHearts RCT will provide evidence about the effectiveness of a brief, peer-delivered eHealth intervention developed for LGBT+ populations amid the COVID-19 pandemic. If the intervention proves effective, it will provide a basis for future scale-up in India and Thailand, and other low- and middle-income countries. ClinicalTrials.gov NCT04870723; https://clinicaltrials.gov/ct2/show/NCT04870723. DERR1-10.2196/34381.


Amplification and detection of lentiviral DNA inside cells.
Visna virus and human immunodeficiency virus are prototypes of animal and human lentiviruses, respectively, that persist and are disseminated despite the host immune response because cells in the tissues and the bloodstream harbor viral genomes in a covert state. To facilitate identification of these latently infected cells, the polymerase chain reaction has been adapted to amplify viral DNA in fixed cells for detection by in situ hybridization. By using a multiple primer set that generates DNA segments with overlapping cohesive termini, visna virus DNA can be amplified, retained, and detected in infected cells with sensitivities that exceed those of existing methods by more than 2 orders of magnitude. This advance in single-cell technology should prove useful in diagnosing and gaining insight into the pathogenesis of viral infections and provide new opportunities to look for viruses in chronic diseases of unknown etiology.


Serum potassium and cause-specific mortality in a large peritoneal dialysis cohort.
Unlike hemodialysis (HD), peritoneal dialysis (PD) is a continuous therapy and does not induce myocardial stunning. Yet, the death risk in HD and PD patients is similar. This study tested the hypothesis that serum potassium abnormalities contribute more to the death risk in PD patients than in HD patients. Data from patients treated in DaVita facilities between July 1, 2001 and June 30, 2006 (n=10,468 PD patients; n=111,651 HD patients) were used to determine association of serum potassium with mortality. PD patients were significantly more likely to have serum potassium < 4 mEq/L, with an adjusted odds ratio of 3.30 (95% confidence interval [95% CI], 3.05, 3.56). There was a U-shaped relationship between time-averaged serum potassium and all-cause and cardiovascular mortality of PD patients, with adjusted hazards ratios of 1.51 for all-cause mortality for potassium < 3.5 mEq/L (95% CI, 1.29, 1.76) and 1.52 for potassium ≥ 5.5 mEq/L (95% CI, 1.32, 1.75). The population-attributable risks for all-cause mortality for serum potassium < 4.0 and ≥ 5.5 mEq/L were 3.6% and 1.9%, respectively, in PD patients, and 0.8% and 1.5%, respectively, in HD patients. Abnormalities in serum potassium contribute disproportionately to the high death risk in PD patients. This may, in part, account for the equivalent cardiac risk seen with the two therapies.


Comparison of apical centring ability between incisal-shifted access and traditional lingual access for maxillary anterior teeth.
The aim of this study was to compare the apical centring ability of incisal-shifted access (ISA) with that of traditional lingual access (TLA). Fifteen three-dimensional printed resin models were prepared from the computed tomography data for a human maxillary central incisor and divided into ISA (n = 7), TLA (n = 7) and control (n = 1) groups. After access preparation, these models were shaped to the working length using K-files up to #40, followed by step-back procedures. An apical portion of the model was removed at 0.5 mm coronal to the working length. Microscopic images of each cutting surface were taken to measure the preparation area and the distance of transportation. TLA created a larger preparation area than ISA (P < 0.05). The distance of transportation (mean ± standard deviation) was 0.4 ± 0.1 mm for ISA and 0.7 ± 0.1 mm for TLA (P < 0.05). Access cavity preparation has a significant effect on apical centring ability. ISA is beneficial to maintaining apical configuration.


Patchy distribution of NMDAR1 subunit immunoreactivity in developing visual cortex.
Development of ocular dominance columns is dependent on patterned retinal activity, and yet patterned activity alone cannot explain all aspects of cortical column development. Features intrinsic to the cortex have been proposed to interact with activity to guide the patterning of cortical columns (), and the NMDA receptor, because of its role in experience-dependent plasticity, is an obvious candidate. Using immunohistochemical techniques, we found a transiently patchy distribution of the NMDA receptor 1 (NMDAR1) subunit in kitten visual cortex. Regularly spaced patches of NMDAR1-immunoreactive neurons were found at the top of the cortical plate in the developing visual cortex at 2 weeks of age. At 4-5 weeks of age, the radial extent of the NMDAR1 patches spanned the supragranular layers, and by 12 weeks of age, this nonuniform pattern of NMDAR1 immunostaining was no longer apparent. Monocular visual experience prevented the expression of the NMDAR1 patches, but just 4 d of subsequent binocular visual experience was sufficient to promote expression of the patches. Furthermore, the NMDAR1 patches tended to be associated with the borders of ocular dominance columns. These results suggest that the degree of plasticity associated with NMDA-mediated mechanisms is elevated in local regions across the tangential extent of the visual cortex and that the NMDAR1 patches may participate in sculpting the overall arrangement of visual cortical columns.


Multimodal mismatch responses in associative but not primary visual cortex support hierarchical predictive coding in cortical networks.
A key function of the mammalian neocortex is to process sensory data in the context of current and past stimuli. Primary sensory cortices, such as V1, respond weakly to stimuli that typical in their context but strongly to novel stimuli, an effect known as "deviance detection". How deviance detection occurs in associative cortical regions that are downstream of V1 is not well-understood. Here we investigated parietal associative area (PTLp) responses to auditory, visual, and audio-visual mismatches with two-photon calcium imaging and local field potential recordings. We employed basic unisensory auditory and visual oddball paradigms as well as a novel multisensory oddball paradigm, involving typical parings (VaAc or VbAd) presented at p=.88 with rare "deviant" pairings (e.g. VaAd or VbAc) presented at p=.12. We found that PTLp displayed robust deviance detection responses to auditory-visual mismatches, both in individual neurons and in population theta and gamma-band oscillations. In contrast, V1 neurons displayed deviance detection only to visual deviants in a unisensory context, but not to auditory or auditory-visual mismatches. Taken together, these results accord with a predictive processing framework for cortical responses, wherein modality specific prediction errors (i.e. deviance detection responses) are computed in functionally specified cortical areas and feed-forward to update higher brain regions.


Opioid Analgesics and the Risk of Serious Infections Among Patients With Rheumatoid Arthritis: A Self-Controlled Case Series Study.
Animal studies and in vitro human studies suggest that certain opioid analgesics impair crucial immune functions. This study was undertaken to determine whether opioid use is associated with increased risk of serious infection in patients with rheumatoid arthritis (RA). We conducted a self-controlled case series analysis on a retrospective cohort of 13,796 patients with RA enrolled in Tennessee Medicaid in 1995-2009. Within-person comparisons of the risk of hospitalization for serious infection during periods of opioid use versus non-use were performed using conditional Poisson regression. Fixed confounders were accounted for by design; time-varying confounders included age and use of disease-modifying antirheumatic drugs, glucocorticoids, and proton-pump inhibitors. In additional analyses, risks associated with new opioid use, use of opioids known to have immunosuppressive properties, use of long-acting opioids, and different opioid dosages were assessed. Sensitivity analyses were performed to account for potential protopathic bias and confounding by indication. Among 1,790 patients with RA who had at least 1 hospitalization for serious infection, the adjusted incidence rate of serious infection was higher during periods of current opioid use compared to non-use, with an incidence rate ratio (IRR) of 1.39 (95% confidence interval [95% CI] 1.19-1.62). The incidence rate was also higher during periods of long-acting opioid use, immunosuppressive opioid use, and new opioid use compared to non-use (IRR 2.01 [95% CI 1.52-2.66], IRR 1.72 [95% CI 1.33-2.23], and IRR 2.38 [95% CI 1.65-3.42], respectively). Results of sensitivity analyses were consistent with the main findings. In within-person comparisons of patients with RA, opioid use was associated with an increased risk of hospitalization for serious infection.


Sixteen years of innovation in youth mental healthcare: Outcomes for young people attending Australia's headspace centre services.
Australia's headspace initiative is world-leading in nation-wide youth mental healthcare reform for young people aged 12 to 25 years, now with 16 years of implementation. This paper examines changes in the key outcomes of psychological distress, psychosocial functioning, and quality of life for young people accessing headspace centres across Australia for mental health problems. Routinely collected data from headspace clients commencing an episode of care within the data collection period, 1 April 2019 to 30 March 2020, and at 90-day follow-up were analysed. Participants came from the 108 fully-established headspace centres across Australia, and comprised 58,233 young people aged 12-25 years first accessing headspace centres for mental health problems during the data collection period. Main outcome measures were self-reported psychological distress and quality of life, and clinician-reported social and occupational functioning. Most headspace mental health clients presented with depression and anxiety issues (75.21%). There were 35.27% with a diagnosis: overall, 21.74% diagnosed with anxiety, 18.51% with depression, and 8.60% were sub-syndromal. Younger males were more likely to present for anger issues. Cognitive behavioural therapy was the most common treatment. There were significant improvements in all outcome scores over time (P<0.001). From presentation to last service rating, over one-third had significant improvements in psychological distress and a similar proportion in psychosocial functioning; just under half improved in self-reported quality of life. Significant improvement on any of the three outcomes was shown for 70.96% of headspace mental health clients. After 16 years of headspace implementation, positive outcomes are being achieved, particularly when multi-dimensional outcomes are considered. A suite of outcomes that capture meaningful change for young people's quality of life, distress and functioning, is critical for early intervention, primary care settings with diverse client presentations, such as the headspace youth mental healthcare initiative.