Role of the C-C chemokine receptor-2 in a murine model of injury-induced osteoarthritis.

OBJECTIVE: We previously found in our embryonic studies that proper regulation of the chemokine CCL12 through its sole receptor CCR2, is critical for joint and growth plate development. In the present study, we examined the role of CCR2 in injury-induced-osteoarthritis (OA). METHOD: We used a murine model of injury-induced-OA (destabilization of medial meniscus, DMM), and systemically blocked CCR2 using a specific antagonist (RS504393) at different times during disease progression. We examined joint degeneration by assessing cartilage (cartilage loss, chondrocyte hypertrophy, MMP-13 expression) and bone lesions (bone sclerosis, osteophytes formation) with or without the CCR2 antagonist. We also performed pain behavioral studies by assessing the weight distribution between the normal and arthritic hind paws using the IITS incapacitance meter. RESULTS: Testing early vs delayed administration of the CCR2 antagonist demonstrated differential effects on joint damage. We found that OA changes in articular cartilage and bone were ameliorated by pharmacological CCR2 blockade, if given early in OA development: specifically, pharmacological targeting of CCR2 during the first 4 weeks (wks) following injury, reduced OA cartilage and bone damage, with less effectiveness with later treatments. Importantly, our pain-related behavioral studies showed that blockade of CCR2 signaling during early, 1-4 wks post-surgery or moderate, 4-8 wks post-surgery, OA was sufficient to decrease pain measures, with sustained improvement at later stages, after treatment was stopped. CONCLUSIONS: Our data highlight the potential efficacy of antagonizing CCR2 at early stages to slow the progression of post-injury OA and, in addition, improve pain symptoms.

Correction to: 'Current strategies with implementation of 3D cell culture: The challenge of quantification' (2022) by Temple et al.

[This corrects the article DOI: 10.1098/rsfs.2022.0019.][This corrects the article DOI: 10.1098/rsfs.2022.0019.].

Sensitization of food reinforcement is related to weight status and baseline food reinforcement.

BACKGROUND: Food reinforcement is an empirical index of motivation to obtain food. Higher levels of food reinforcement are associated with increased energy intake and increased body weight. Food reinforcement can vary over repeated food presentations, as people may show reduced reinforcing value if they satiate to repeated reinforcers, or they may show sensitization, or an increase in reinforcing value with repeated presentations. Over the past few years, our laboratory has been studying the impact of repeated administration of large portions of high energy density snack foods on food reinforcement. We have shown in three separate studies that the majority of non-obese individuals become satiated after 2 weeks of the same snack food administration, but that a subset of obese individuals sensitize after this same manipulation. OBJECTIVE: The purpose of the study presented here was to identify predictors of reinforcer satiation or sensitization. SUBJECTS: For the analyses presented here, we combined data sets from three previous studies for a total of 67 adult participants. RESULTS: We found that higher body mass index (BMI) and higher baseline motivation to eat predicted sensitization, and baseline motivation to eat moderated the effects of BMI, such that higher baseline responding for food predicted sensitization in obese individuals, but satiation in non-obese individuals. CONCLUSIONS: These data suggest that repeated exposure to high energy density snack foods may result in sensitization to those foods, with similar effects as drugs of abuse in susceptible individuals, and that an individual's BMI and baseline responding act as predictors of this response.

Intra-tumour genetic heterogeneity and poor chemoradiotherapy response in cervical cancer.

BACKGROUND: Intra-tumour genetic heterogeneity has been reported in both leukaemias and solid tumours and is implicated in the development of drug resistance in CML and AML. The role of genetic heterogeneity in drug response in solid tumours is unknown. METHODS: To investigate intra-tumour genetic heterogeneity and chemoradiation response in advanced cervical cancer, we analysed 10 cases treated on the CTCR-CE01 clinical study. Core biopsies for molecular profiling were taken from four quadrants of the cervix pre-treatment, and weeks 2 and 5 of treatment. Biopsies were scored for cellularity and profiled using Agilent 180k human whole genome CGH arrays. We compared genomic profiles from 69 cores from 10 patients to test for genetic heterogeneity and treatment effects at weeks 0, 2 and 5 of treatment. RESULTS: Three patients had two or more distinct genetic subpopulations pre-treatment. Subpopulations within each tumour showed differential responses to chemoradiotherapy. In two cases, there was selection for a single intrinsically resistant subpopulation that persisted at detectable levels after 5 weeks of chemoradiotherapy. Phylogenetic analysis reconstructed the order in which genomic rearrangements occurred in the carcinogenesis of these tumours and confirmed gain of 3q and loss of 11q as early events in cervical cancer progression. CONCLUSION: Selection effects from chemoradiotherapy cause dynamic changes in genetic subpopulations in advanced cervical cancers, which may explain disease persistence and subsequent relapse. Significant genetic heterogeneity in advanced cervical cancers may therefore be predictive of poor outcome.

Spectral Characterization of Bennu Analogs Using PASCALE: A New Experimental Set-Up for Simulating the Near-Surface Conditions of Airless Bodies.

We describe the capabilities, radiometric stability, and calibration of a custom vacuum environment chamber capable of simulating the near-surface conditions of airless bodies. Here we demonstrate the collection of spectral measurements of a suite of fine particulate asteroid analogs made using the Planetary Analogue Surface Chamber for Asteroid and Lunar Environments (PASCALE) under conditions like those found on Earth and on airless bodies. The sample suite includes anhydrous and hydrated physical mixtures, and chondritic meteorites (CM, CI, CV, CR, and L5) previously characterized under Earth- and asteroid-like conditions. And for the first time, we measure the terrestrial and extra-terrestrial mineral end members used in the olivine- and phyllosilicate-dominated physical mixtures under the same conditions as the mixtures and meteorites allowing us better understand how minerals combine spectrally when mixed intimately. Our measurements highlight the sensitivity of thermal infrared emissivity spectra to small amounts of low albedo materials and the composition of the sample materials. As the albedo of the sample decreases, we observe smaller differences between Earth- and asteroid-like spectra, which results from a reduced thermal gradient in the upper hundreds of microns in the sample. These spectral measurements can be compared to thermal infrared emissivity spectra of asteroid (101955) Bennu's surface in regions where similarly fine particulate materials may be observed to infer surface compositions.

Fetal MEG evoked response latency from beamformer with random field theory.

Analysis of fetal magnetoencephalographic brain recordings is restricted by low signal to noise ratio (SNR) and non-stationarity of the sources. Beamformer techniques have been applied to improve SNR of fetal evoked responses. However, until now the effect of non-stationarity was not taken into account in detail, because the detection of evoked responses is in most cases determined by averaging a large number of trials. We applied a windowing technique to improve the stationarity of the data by using short time segments recorded during a flash-evoked study. In addition, we implemented a random field theory approach for more stringent control of false-positives in the statistical parametric map of the search volume for the beamformer. The search volume was based on detailed individual fetal/maternal biometrics from ultrasound scans and fetal heart localization. Average power over a sliding window within the averaged evoked response against a randomized average background power was used as the test z-statistic. The significance threshold was set at 10% over all members of a contiguous cluster of voxels. There was at least one significant response for 62% of fetal and 95% of newborn recordings with gestational age (GA) between 28 and 45 weeks from 29 subjects. We found that the latency was either substantially unchanged or decreased with increasing GA for most subjects, with a nominal rate of about -11 ms/week. These findings support the anticipated neurophysiological development, provide validation for the beamformer model search as a methodology, and may lead to a clinical test for fetal cognitive development.

HBV reactivation after fludarabine chemotherapy identified on investigation of suspected transfusion-transmitted Hepatitis B virus.

BACKGROUND & AIMS: Multi-transfused patients often receive treatments inducing various levels of immunodeficiency. Acute viral infections may then be attributed either to transfusion-transmitted infection (TTI) or reactivation of a past infection. METHODS: A patient with chronic lymphocytic leukemia (CLL) who had >250 blood donor exposures developed acute Hepatitis B virus (HBV) infection. Routine donor testing for HB core antibodies (anti-HBc) was in place in the relevant period and investigations undertaken on the blood donors were negative. RESULTS: Review of historical, molecular, and antigenic evidence demonstrated reactivation of a recovered HBV infection dating >30 years and the selection of a rare escape mutant that briefly replicated and caused acute liver disease. This mutant was unreactive with several HBsAg assays and poorly reactive with an HBV vaccine plasma. Correcting the C139Y substitution by site directed mutagenesis of recombinant surface proteins re-established assay reactivity. CONCLUSIONS: Fludarabine, but not Chlorambucil, appeared sufficiently immunosuppressive to trigger reactivation despite low levels of neutralizing antibodies. Differentiating between TTI and reactivation of HBV becomes more challenging with the increasing frequency of immunocompromised blood recipients. Chemotherapy with Fludarabine alone should be considered as carrying high risk of viral reactivation. Pre-treatment testing and peripheral blood sample archiving may be indicated in HBsAg negative patients.

Pregabalin in the treatment of post-traumatic peripheral neuropathic pain: a randomized double-blind trial.

BACKGROUND: Pregabalin is effective in the treatment of peripheral and central neuropathic pain. This study evaluated pregabalin in the treatment of post-traumatic peripheral neuropathic pain (including post-surgical). METHODS: Patients with a pain score >or=4 (0-10 scale) were randomized and treated with either flexible-dose pregabalin 150-600 mg/day (n = 127) or placebo (n = 127) in an 8-week double-blind treatment period preceded by a 2-week placebo run-in. RESULTS: Pregabalin was associated with a significantly greater improvement in the mean end-point pain score vs. placebo; mean treatment difference was -0.62 (95% CI -1.09 to -0.15) (P = 0.01). The average pregabalin dose at end-point was approximately 326 mg/day. Pregabalin was also associated with significant improvements from baseline in pain-related sleep interference, and the Medical Outcomes Study sleep scale sleep problems index and sleep disturbance subscale (all P < 0.001). In the all-patient group (ITT), pregabalin was associated with a statistically significant improvement in the Hospital Anxiety and Depression Scale anxiety subscale (P < 0.05). In total, 29% of patients had moderate/severe baseline anxiety; treatment with pregabalin in this subset did not significantly improve anxiety. More patients reported global improvement at end-point with pregabalin than with placebo (68% vs. 43%; overall P < 0.01). Adverse events led to discontinuation of 20% of patients from pregabalin and 7% from placebo. Mild or moderate dizziness and somnolence were the most common adverse events in the pregabalin group. CONCLUSION: Flexible-dose pregabalin 150-600 mg/day was effective in relieving neuropathic pain, improving disturbed sleep, improving overall patient status, and was generally well tolerated in patients with post-traumatic peripheral neuropathic pain.

Assessing the role of contact tracing in a suspected H7N2 influenza A outbreak in humans in Wales.

BACKGROUND: The detailed analysis of an outbreak database has been undertaken to examine the role of contact tracing in controlling an outbreak of possible avian influenza in humans. The outbreak, initiating from the purchase of infected domestic poultry, occurred in North Wales during May and June 2007. During this outbreak, extensive contact tracing was carried out. Following contact tracing, cases and contacts believed to be at risk of infection were given treatment/prophylaxis. METHODS: We analyse the database of cases and their contacts identified for the purposes of contact tracing in relation to both the contact tracing burden and effectiveness. We investigate the distribution of numbers of contacts identified, and use network structure to explore the speed with which treatment/prophylaxis was made available and to estimate the risk of transmission in different settings. RESULTS: Fourteen cases of suspected H7N2 influenza A in humans were associated with a confirmed outbreak among poultry in May-June 2007. The contact tracing dataset consisted of 254 individuals (cases and contacts, of both poultry and humans) who were linked through a network of social contacts. Of these, 102 individuals were given treatment or prophylaxis. Considerable differences between individuals' contact patterns were observed. Home and workplace encounters were more likely to result in transmission than encounters in other settings. After an initial delay, while the outbreak proceeded undetected, contact tracing rapidly caught up with the cases and was effective in reducing the time between onset of symptoms and treatment/prophylaxis. CONCLUSIONS: Contact tracing was used to link together the individuals involved in this outbreak in a social network, allowing the identification of the most likely paths of transmission and the risks of different types of interactions to be assessed. The outbreak highlights the substantial time and cost involved in contact tracing, even for an outbreak affecting few individuals. However, when sufficient resources are available, contact tracing enables cases to be identified before they result in further transmission and thus possibly assists in preventing an outbreak of a novel virus.

Correction of ultrasonic array images to improve reflector sizing and location in inhomogeneous materials using a ray-tracing model.

The use of ultrasonic arrays has increased dramatically within recent years due to their ability to perform multiple types of inspection and to produce images of the structure through post-processing of received signals. Phased arrays offer many advantages over conventional transducers in the inspection of materials that are inhomogeneous with spatially varying anisotropic properties. In this paper, the arrays are focused on austenitic steel welds as a representative inhomogeneous material. The method of ray-tracing through a previously developed model of an inhomogeneous weld is shown, with particular emphasis on the difficulties presented by material inhomogeneity. The delay laws for the structure are computed and are used to perform synthetic focusing at the post-processing stage of signal data acquired by the array. It is demonstrated for a simulated austenitic weld that by taking material inhomogeneity and anisotropy into account, superior reflector location (and hence, superior sizing) results when compared to cases where these are ignored. The image is thus said to have been corrected. Typical images are produced from both analytical data in the frequency domain and data from finite element simulations in the time domain in a variety of wave modes, including cases with mode conversion and reflections.

Susceptibility to insecticides used for control of Piezodorus guildinii (Heteroptera: Pentatomidae) in the United States and Brazil.

Limited information exists on the insecticide susceptibility of redbanded stink bug, Piezodorus guildinii (Westwood) (Heteroptera: Pentatomidae), despite its impact on soybean, Glycine max (L.) Merr., production in Brazil and the United States. Therefore, this study set out to 1) determine baseline levels of susceptibility to currently recommended pesticides using topical and vial bioassays, 2) determine the levels of esterase activity in populations in the United States and Brazil, and 3) compare control among products in field trials. In topical bioassays conducted in the United States using technical grade materials, the LC50 values of lambda-cyhalothrin, acephate, and methamidophos were 4-25, 141-295, and 40-151 ng per insect, respectively. The LC50 values of imidacloprid and thiamethoxam were 11 and 27 ng per insect, respectively. In vial bioassays conducted in the United States using technical grade materials, the LC50 values of cypermethrin, acephate, and methamidophos were 0.4-0.9, 3.8, and 1.6 microg per vial, respectively. In topical bioassays conducted in Brazil by using commercially formulated products, the LC50 values of acephate, methamidophos, endosulfan, and imidacloprid were 0.90-1.9, 0.4-0.6, 1.5-6.6, and 0.2-0.3 microg per insect, respectively. In vial bioassays conducted in Brazil using commercially formulated products, the LC50 values of endosulfan, methamidophos, and lambda-cyhalothrin were 4-32 and 2-24 microg/cm2 for thiamethoxam and imidacloprid. Esterase activity in Louisiana (United States) populations ranged from 251 to 658 nmol alpha-naphthol formed/min/mg protein. Esterase activity levels in Londrina (Brazil) populations averaged 163 nmol/min/mg. In field tests, P. guildinii in Louisiana were controlled by organophosphates thiamethoxam and imidacloprid and in Brazil, with combinations of neonicotinoids and pyrethroids.

People with obsessive-compulsive disorder often remain symptomatic following psychological treatment: A clinical significance analysis of manualised psychological interventions.

BACKGROUND: Previous meta-analyses conclude that efficacious psychological treatments for obsessive-compulsive disorder (OCD) exist. However, determining the efficacy of psychological treatments requires multiple forms of assessment. We conducted an individual patient data meta-analysis of randomised controlled trials (RCTs) of manualised psychological therapy for adults with OCD. METHODS: Four electronic databases were searched from their inception until July 2019. IPD were available for 24 (n = 1626) of 43 (n = 2455) eligible RCTs. Treatment efficacy was evaluated using clinical significance analyses (using standardised Jacobson methodology) and standardised mean difference within-group effect-size analyses. Outcomes were Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores at post-treatment and follow-up. RESULTS: At follow-up, large within-group effect sizes were found for treated patients (g = 1.45) and controls (g = 0.90). Treated patients were significantly more likely than controls to recover, but recovery rates were low; post-intervention, only 32% of treated patients and 3% of controls recovered; rising to 38% and 21% respectively at follow-up. Regardless of allocation, only 20% of patients were asymptomatic at follow-up. Individual cognitive therapy (CT) was most efficacious, followed by group CT plus exposure and response prevention. Self-help interventions were generally less efficacious than face-to-face approaches. LIMITATIONS: Data were analysed from 24 of the 43 eligible RCTs. We were unable to consider the long-term efficacy of treatments because only two RCTs provided long-term (> 12 month) follow-up data. CONCLUSION: Almost 80% of treated patients remain symptomatic. The efficacy of psychological interventions for patients with OCD must be enhanced.

Correlation of serum protein biomarkers with disease activity in psoriatic arthritis.

Objective: To assess the correlation of serum protein biomarkers with disease activity across different domains of psoriatic arthritis (PsA).Material and methods: A cross-sectional cohort of 45 adult patients with PsA fulfilling the classification for psoriatic arthritis (CASPAR) criteria was recruited from University of California San Diego (UCSD) Arthritis Clinics. Clinical data and serum samples were collected and serum was analyzed for protein biomarkers hypothesized to be relevant to disease activity in PsA. Correlations were evaluated for clinical disease activity measures across disease domains.Results: Biomarkers with the highest correlation to the composite indices and disease domains were SAA, IL-6, YKL-40, and ICAM-1. In addition, several biomarkers were moderately correlated with individual composite indices and/or disease domains. Low or no correlation was observed with some biomarkers, e.g. MMP-3, MMP-1, EGF, VEGF, and IL-6R. In contrast, the correlation of all biomarkers with certain disease domains was low; specifically, pain, percent body surface area of psoriasis, and patient global assessment. The multi-biomarker disease activity score (MBDA) developed for rheumatoid arthritis (RA) showed high correlations with most composite indices and some disease domains in PsA.Conclusions: These data suggest biomarker analysis can reflect disease activity across disease domains in PsA. Certain domains would likely benefit from the evaluation of additional biomarkers.

Influence of Nezara viridula feeding on cotton yield, fiber quality, and seed germination.

The influence of southern green stink bug, Nezara viridula (L.), adults (males and females) and fourth to fifth instars on cotton, Gossypium hirsutum L., boll abscission, seedcotton yield, fiber quality, and seed viability was evaluated in field studies conducted during 2004 and 2005. Cotton bolls representing several age classes ranging from 0-600 heat units were individually infested with a specific gender or life stage of southern green stink bug. Adults and nymphs induced abscission of bolls that accumulated 0-280 heat units after anthesis. Seedcotton yield was significantly lower in bolls infested with adults (males and females) and late instars through approximately 500 heat units after anthesis. Southern green stink bug feeding on bolls significantly affected the physical fiber properties of micronaire (measure of fiber fineness or maturity), strength, uniformity, and fiber length. Discolored cotton lint in the stink bug-infested bolls was more common than in noninfested bolls. Seed germination and development of normal seedlings for seed harvested from stink bug-infested bolls that accumulated < or =500 heat units beyond anthesis were significantly lower compared with noninfested bolls. No significant differences in boll abscission, yield, fiber quality, and seed germination were detected between southern green stink bug males and females or between adults and fourth to fifth instars.

Developmental changes in GABA receptor subunit composition within the gonadotrophin-releasing hormone-1 neuronal system.

It is becoming increasingly evident that GABA plays an important role in the regulation of gonadotrophin-releasing hormone (GnRH)-1 neurones via the GABAA receptor. The aim of the present study was to characterise expression of the GABAA receptor within the GnRH-1 system across development. The expression pattern of five GABAAalpha subunits and one GABAAbeta subunit was first examined within individual GnRH-1 neurones by the polymerase chain reaction. A significant increase in the expression of GABAAalpha2 and a significant decrease in the expression of GABAAalpha6 over time were found. Of the other subunits examined, two (alpha1 and alpha3) showed no differences in expression and two (alpha4 and beta3) showed variable low incidence of expression. Given the reciprocal relationship of alpha2 and alpha6 expression, we hypothesised that there is a developmental switch in the expression of these subunits in GnRH-1 neurones. To investigate this hypothesis, single- and double-label immunocytochemistry for GABAAalpha2 and alpha6 and GnRH-1 was performed in tissue from ages E12.5 to adulthood, as well as in nasal explants. We show that GABAAalpha2 and alpha6 are present in the GnRH-1 neuronal system both in vivo and in vitro and that the levels of expression are altered as a function of age.

Estrogen receptor beta regulates sexually dimorphic neural responses to estradiol.

Estrogen receptors (ERs) mediate many sexual dimorphisms in the neuroendocrine system and in behavior. We examined the consequences of the loss of functional estrogen receptor beta (ERbeta) on two sexually differentiated neural responses to estrogen. In wild type (WT) male mice, but not in females, estradiol (E(2)) treatment decreased estrogen receptor alpha immunoreactive (ERalpha-ir) cell numbers in the arcuate nucleus (ARC), the preoptic area (POA), and the ventromedial nucleus (VMN). These sex differences were reversed in ERbeta knockout (ERbetaKO) mice. Castrated ERbetaKOs did not show any change in ERalpha-ir cell number after E(2) treatment. Yet, E(2) decreased ERalpha-ir cell number in ovariectomized ERbetaKOs. Estradiol treatment increased progesterone receptor immunoreactive (PR-ir) cell number in WT female VMN and POA, but no change was noted in brains of WT castrates. In ERbetaKO mice the opposite relationship was found, E(2) treatment increased PR-ir cell number in male, but not in female, brains. Our results show that ERbeta influences several sexually dimorphic neural responses to estrogen. Moreover the data clearly show that ERbeta can modulate neural expression of ERalpha.

Evidence for tissue-specific forms of glutaminyl cyclase.

Glutaminyl cyclase (QC) is responsible for the presence of pyroglutamyl residues in many neuroendocrine peptides. An examination of the bovine tissue distribution of QC immunoreactivity, enzyme activity, and mRNA confirmed that QC was abundant in brain and pituitary by all three measures. However, enzymatic activity was considerably more widespread than either immunoreactivity or mRNA, suggesting multiple enzyme forms. Partially purified QC from bovine spleen differed significantly from the known bovine pituitary QC in physical and catalytic properties. We propose that this form of glutaminyl cyclase plays a role in the posttranslational processing of constitutively secreted pGlu-containing proteins.

The "muscular variant" of Pompe disease: clinical, biochemical and histologic characteristics.

We report on a 2-yr-old boy with progressive muscular weakness and respiratory failure. There was no clinical evidence of heart muscle involvement. Autopsy showed marked intralysosomal glycogen deposition in skeletal muscle and liver with no histological evidence of glycogen deposition in cardiac muscle. The activity of the lysosomal enzyme alpha-1,4-glucosidase was deficient in skin fibroblasts, skeletal muscle, cardiac muscle, and liver; however, the enzymatic activity in peripheral blood leukocytes was in the low normal range. The child's mother had normal enzymatic activity in leukocytes but heterozygote levels in skin fibroblasts.