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Objective: Tumour necrosis factor (TNF)‐α is a proinflammatory marker and has been shown to affect mitochondrial function in different tissues. We investigated the effect on adipose tissue (AT) inflammation and mitochondrial respiration in patients with hidradenitis suppurativa (HS) after 12 weeks of treatment with adalimumab, a TNF‐α inhibitor. Methods: We sampled blood and an AT biopsy from 13 patients with HS and 10 control subjects after an overnight fast. The patients were retested after at least 12 weeks of treatment with adalimumab (40 mg/week). We measured macrophage content and mitochondrial respiration in the AT and interleukin (IL)‐1β, IL‐6, IL‐10, high‐sensitivity C‐reactive protein (hsCRP), interferon‐γ, TNF‐α, adiponectin and leptin in plasma. Clinical scores and Dermatology Quality of Life Index (DLQI) were assessed. Results: We found a higher anti‐inflammatory macrophage content (CD206+) in the patient group compared with the control group, but no differences between before and after the intervention. No difference in mitochondrial respiration was observed. We observed higher plasma IL‐6 and hsCRP concentrations in patients with HS compared to controls, with no differences before and after the intervention. The difference between controls and HS patients was abolished after the intervention. HS patients improved their DLQI after the intervention with no change in clinical scores. Conclusion: Treatment with adalimumab in patients with HS does not alter AT inflammation or mitochondrial respiratory capacity; however, we did see a higher content of anti‐inflammatory macrophages in the patient group compared with the control group. [ABSTRACT FROM AUTHOR]

Cat's claw creeper (Dolichandra unguis‐cati), native to tropical South America, is a major invasive species and a target for biological control in Australia, South Africa and some South Pacific Island countries. Native range surveys in Argentina, Brazil, Paraguay and Venezuela have identified eight insects and four fungal pathogens as potential agents. Five leaf‐feeding insects a tortoise beetle Charidotis auroguttata, two tingids Carvalhotingis visenda and C. hollandi, a leaf‐tying moth Hypocosmia pyrochroma and a leaf‐mining beetle Hedwigiella jureceki, have been tested and all were released in South Africa. Four of these have become established but are not widespread and cause only limited damage. In Australia, only three of these, C. visenda, H. pyrochroma and H. jureceki were released, while C. auroguttata was not approved due to perceived non‐target risks. All agents have become widely established, except for H. pyrochroma which is restricted to riparian corridors in southeast Queensland. In South Africa, an accidentally introduced leaf‐spot pathogen, Neoramulariopsis unguis‐cati, causes necrotic lesions and premature abscission of leaves in cat's claw creeper infestations, resulting in widespread defoliation. Based on its impact and field‐host specificity in its native range and in South Africa, the pathogen has been prioritised for evaluation as a potential additional agent in Australia. The current priority is to seek approval for the introduction of this leaf‐spot pathogen into Australia. Future research should focus on the gall‐inducing rust Uropyxis rickiana and the seed‐feeding weevil Apteromechus notatus as prospective agents. [ABSTRACT FROM AUTHOR]

Plant species have been introduced increasingly into non‐native ranges, where many have become exotic weeds with adverse impacts on native ecosystems, as well as on farming and other livelihoods. In biological control, the classical or inoculative approach is the one most commonly used for the management of invasive alien weeds and is based on the use of co‐evolved natural enemies from the native range to control the invasive weed. Typically, the inundative or mycoherbicide approach targets problematic weeds using local plant pathogens that, in the case of introduced species, have 'jumped' onto the exotic host. The leaf‐spot fungus, Mycosphaerella polygoni‐cuspidati, co‐evolved with its host, Reynoutria (Fallopia) japonica (Japanese knotweed), in Japan and has a unique history of being investigated both as a classical biological control agent and a mycoherbicide against this highly invasive weed in the United Kingdom and North America. Here, we highlight our research on M. polygoni‐cuspidati as part of a biological control programme for Japanese knotweed and review the potential of mycoherbicides using exotic pathogens for the management of invasive alien weeds. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

The Jostedalsbreen is the largest ice cap in Norway and mainland Europe. Rapid retreat of many of its outlet glaciers since the 2000s has led to the formation of several glacial lakes. Processes causing the formation and expansion of glacial lakes and their interaction with a glacier and terminal moraine have not been widely addressed yet. In this study, we investigate the degradation of the front of the southeast‐facing outlet glacier Austerdalsbreen. Based on a variety of remotely sensed data (UAV‐based and airborne orthophotos and DEMs, satellite images), we analyze the coincident glacial and proglacial changes of Austerdalsbreen and quantify the evolution of this transition zone during the last decades. In particular, we focus on the short‐term evolution of the glacial lake since 2010, we examine the context of a glacier advance in the 1990s, and we report long‐term changes by utilizing 1960s imagery. We discuss the evolution and conditions of Austerdalsbreen compared to other outlet glaciers of Jostedalsbreen. Overall, the glacier terminus has experienced a recession in the last decades. The 1990s terminus advance was more restricted than at other nearby outlet glaciers due to glacier surface debris cover, which is a critical factor for the glacier and lake evolution. However, in the most recent period, since 2012, a distinct expansion of a glacial lake is quantifiable. Since the rates of glacier surface lowering also considerably increased since approximately 2017 and the glacier retreated since the beginning of the 2000s with a clear maximum length decrease in 2015, we interpret the recently formed glacial lake as a contributory factor of glacial changes. [ABSTRACT FROM AUTHOR]

Purpose: Enucleation is a common treatment modality performed for pediatric retinoblastoma patients, and the resultant defects are reconstructed using an ocular prosthesis. The prostheses are modified or replaced periodically, as the child develops due to orbital growth and patient‐error. The purpose of this report is to evaluate the replacement frequency of prostheses in the pediatric oncologic population. Methods: A retrospective review was completed by the two senior research investigators, of patients that had ocular prostheses fabricated following enucleation of their retinoblastoma from 2005 to 2019 (n = 90). Data collected from the medical records of the patient included the pathology, date of surgery, date of prosthesis delivery, and the replacement schedule of the ocular prosthesis. Results: During the 15‐year study period, 78 enucleated observations (ocular prosthesis fabricated) were included for analysis. The median age of the patients at the time of delivery of their first ocular prosthesis was calculated to be 2.6 years (range 0.3–18 years). The median time to the first modification of the prosthesis was calculated to be 6 months. The time to modification of the ocular prosthesis was further stratified by age. Conclusion: Pediatric patients require modification of their ocular prostheses throughout their growth and development period. Ocular prostheses are reliable prostheses with predictable outcomes. This data is helpful to set an expectation among the patient, parent, and provider. [ABSTRACT FROM AUTHOR]

Purpose: The role of locoregional therapy compared to systemic chemotherapy (SYS) for unresectable intrahepatic cholangiocarcinoma (IHC) remains controversial. The importance of hepatic disease control, either as initial or salvage therapy, is also unclear. We compared overall survival (OS) in patients treated with resection, hepatic arterial infusion pump (HAIP) chemotherapy, or SYS as it relates to hepatic recurrence or progression. We also evaluated recurrence after resection to determine the efficacy of locoregional salvage therapy. Patients and Methods: In this single‐institution retrospective analysis, patients with biopsy‐proven IHC treated with either curative‐intent resection, HAIP (with or without SYS), or SYS alone were analyzed. Propensity score matching (PSM) was used to compare patients with liver‐limited, advanced disease treated with HAIP versus SYS. The impact of locoregional salvage therapies in patients with liver‐limited recurrence was analyzed in the resection cohort. Results: From 2000 to 2017, 714 patients with IHC were treated, 219 (30.7%) with resectable disease, 316 (44.3%) with locally advanced disease, and 179 (25.1%) with metastatic disease. Resected patients were less likely to recur or progress in the liver (hazard ratio [HR] 0.41, 95% CI 0.34–0.45) versus those that received HAIP or SYS (HR 0.58, 95% CI 0.50–0.65 vs. HR 0.63, 95% CI 0.57–0.69, respectively). In resected patients, 161 (64.4%) recurred, with 65 liver‐only recurrences. Thirty of these patients received subsequent locoregional therapy. On multivariable analysis, locoregional therapy was associated with improved OS after isolated liver recurrence (HR 0.46, 95% CI 0.29–0.75; p = 0.002). In patients with locally advanced unresectable or multifocal liver disease (with or without distant organ metastases), PSM demonstrated improved hepatic progression‐free survival in patients treated with HAIP versus SYS (HR 0.65; 95% CI 0.46–0.91; p = 0.01), which correlated with improved OS (HR 0.59, 95% CI 0.43–0.80; p < 0.001). Conclusion: In patients with liver‐limited IHC, hepatic disease control is associated with improved OS, emphasizing the potential importance of liver‐directed therapy. [ABSTRACT FROM AUTHOR]

Purpose: Patient Specific QA (PSQA) by direct phantom measurement for all intensity modulated radiation therapy (IMRT) cases is labor intensive and an inefficient use of the Medical Physicist’s time. The purpose of this work was to develop a hybrid quality assurance (QA) technique utilizing 3D dose verification as a screening tool to determine if a measurement is necessary. Methods: This study utilized Sun Nuclear DoseCHECK (DC), a 3D secondary verification software, and Fraction 0, a trajectory log IMRT QA software. Twentytwo Lung stereotactic body radiation therapy (SBRT) and thirty single isocentre multi-lesion SRS (MLSRS) plans were retrospectively analysed in DC. Agreement of DC and the TPS dose for selected dosimetric criteria was recorded. Calculated 95% confidence limits (CL) were used to establish action limits. All cases were delivered and measured using the Sun Nuclear stereotactic radiosurgery (SRS) MapCheck.Trajectory logs of the delivery were used to calculate Fraction 0 results for the same criteria calculated by DC. Correlation of DC and Fraction 0 results were calculated. Phantom measured QA was compared to Fraction 0 QA results for the cases which had DC criteria action limits exceeded. Results: Correlation of DC and Fraction 0 results were excellent,demonstrating the same action limits could be used for both and DC can predict Fraction 0 results. Based on the calculated action limits, zero lung SBRT cases and six MLSRS cases were identified as requiring a measurement.All plans that passed the DC screening had a passing measurement based PSQA and agreed with Fraction 0 results. Conclusion: Using 95% CL action limits of dosimetric criteria, a 3D secondary dose verification can be used to determine if a measurement is required for PSQA. This method is efficient for it is part of the normal clinical workflow when verifying any clinical treatment. In addition, it can drastically reduce the number of measurements needed for PSQA. [ABSTRACT FROM AUTHOR]

Intra-operative hypotension is a known predictor of adverse events and poor outcomes following major surgery. Hypotension often occurs on induction of anaesthesia, typically attributed to hypovolaemia and the haemodynamic effects of anaesthetic agents. We assessed the efficacy of fluid optimisation for reducing the incidence of hypotension on induction of anaesthesia. This prospective trial enrolled 283 patients undergoing radical cystectomy and randomly allocated them to goal-directed fluid therapy (n = 142) or standard fluid therapy (n = 141). Goal-directed fluid therapy patients received fluid optimisation based on stroke volume response to passive leg raise before induction; those with positive passive leg raise received intravenous crystalloid fluid boluses until stroke volume was optimised. Baseline mean arterial pressure was measured on the morning of surgery and on arriving in the operating theatre. This post-hoc analysis defined haemodynamic instability as either a > 30% relative drop in mean arterial pressure compared with baseline or absolute mean arterial pressure < 55 mmHg, within 15 min of induction. Forty-two (30%) goal-directed fluid therapy patients underwent fluid optimisation after finding an intravascular fluid deficit via passive leg raise testing; 106 (75%) goal-directed fluid therapy and 112 (79%) standard fluid therapy patients met criteria for haemodynamic instability. There was no significant difference in the incidence of haemodynamic instability between the goal-directed fluid therapy and standard fluid therapy groups using absolute mean arterial pressure drop below 55 mmHg (p = 0.58) or using pre-surgical testing or pre-surgical mean arterial pressure values as baseline (p = 0.21, p = 0.89, respectively); however, the difference in the incidence of haemodynamic instability was significant using the operating theatre baseline mean arterial pressure (p = 0.004). We conclude that fluid optimisation before induction of general anaesthesia did not significantly impact haemodynamic instability. [ABSTRACT FROM AUTHOR]

μ‐Opioid receptors (μ‐ORs) play a critical role in the modulation of pain and mediate the effects of the most powerful analgesic drugs. Despite extensive efforts, it remains insufficiently understood how μ‐ORs produce specific effects in living cells. We developed new fluorescent ligands based on the μ‐OR antagonist E‐p‐nitrocinnamoylamino‐dihydrocodeinone (CACO), that display high affinity, long residence time and pronounced selectivity. Using these ligands, we achieved single‐molecule imaging of μ‐ORs on the surface of living cells at physiological expression levels. Our results reveal a high heterogeneity in the diffusion of μ‐ORs, with a relevant immobile fraction. Using a pair of fluorescent ligands of different color, we provide evidence that μ‐ORs interact with each other to form short‐lived homodimers on the plasma membrane. This approach provides a new strategy to investigate μ‐OR pharmacology at single‐molecule level. [ABSTRACT FROM AUTHOR]

Background: PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway.Methods: We conducted a single-arm phase 2 study of monotherapy LY3023414. Eligible patients had advanced endometrial cancer of any grade, prior management with 1-4 cytotoxic lines, and PI3K pathway activation prospectively defined as a loss-of-function PTEN alteration or activating alteration in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary objective was best overall response rate (ORR) per RECIST 1.1.Results: Twenty-eight patients were treated; histologies included endometroid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior cytotoxic lines (range, 1-3). The most common alterations involved PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). In the 25 efficacy-evaluable patients, the ORR was 16% (90% CI, 7%-100%), and the clinical benefit rate was 28% (90% CI, 16%-100%). Four patients had a confirmed partial response, and 2 responses lasted for >9 months. The median progression-free survival and overall survival were 2.5 months (95% CI, 1.2-3.0) and 9.2 months (95% CI, 5.0-15.9), respectively. The most common all-grade treatment-related adverse events were anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation between molecular alterations and response was observed.Conclusion: In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single-agent activity and a manageable safety profile. [ABSTRACT FROM AUTHOR]

Aims. Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in beta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysine demethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, we investigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4 methylation for islet function. Materials and Methods. We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain with knockout (KO) of the H3K4 demethylase KDM5B. Results. GSK-J4 administration failed to prevent the development of experimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabetic NOD to NODscid mice. KDM5B-KO mice were growth retarded with altered body composition, had low IGF-1 levels, and exhibited reduced insulin secretion. Interestingly, despite secreting less insulin, KDM5B-KO mice were able to maintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested by insulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged with high-fat diet, KDM5B-deficient mice displayed similar weight gain and insulin sensitivity as wild-type mice. Conclusion. Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity. [ABSTRACT FROM AUTHOR]

Background: DBS in the ventral intermediate nucleus (VIM) of the thalamus has been a revolutionary treatment for patients with essential tremor (ET) by reducing tremor. Unfortunately, some patients develop habituation to DBS and thus experience reduced efficacy and loss of tremor control. There are no standardized methods of addressing habituation to DBS. We propose alternating stimulation patterns as a way to reduce habituation. Methods: This was a randomized, placebo‐controlled trial for patients with VIM DBS for ET. Patients were randomized to either experimental treatment arm of alternating stimulation patterns on a weekly basis or standard care arm of continuous stimulation settings for 12 weeks. Primary outcome was change in the performance subscale of The Essential Tremor Rating Assessment Scale (TETRAS), which was performed at initial visit and 12‐week follow‐up. Secondary outcome included change in the activities of daily living subscale of TETRAS. Results: Twenty‐two patients were enrolled in the trial, and 16 were analyzed at follow‐up. Experimental treatment subjects displayed sustained tremor control compared to standard care, as measured by the change in TETRAS performance subscale (–0.6 vs. 6.7 point change, respectively) with a 7.3 difference between the arms (P = 0.006). Conclusion: Alternating stimulation patterns on a weekly basis for ET patients with VIM DBS reduced habituation in this pilot study. This study suggests that exposure to different stimulation groups may maintain better tremor control compared to constant stimulation parameters. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) rates in low-resource countries, which typically lack CRC screening programs, are rising. This study determined whether a risk model for patients with rectal bleeding could identify patients with curable CRC.Methods: This prospective, cross-sectional study evaluated a model constructed from data from 1 hospital and validated at 2 other hospitals. The primary endpoint was the ability of the model to predict CRC, as diagnosed by colonoscopy, from clinical characteristics. The secondary endpoint was to determine the percentage of patients who had CRC.Results: Consecutive patients who were 45 years old or older and had self-reported rectal bleeding for more than 1 week were evaluated. From January 2014 to July 2016, 362 patients answered a questionnaire and underwent colonoscopy. In the validation cohort, 56% of patients with rectal bleeding, weight loss, and changes in bowel habits had CRC, whereas 2% of patients with bleeding alone did. Overall, 18.2% of the patients had CRC, and 8.6% had adenomas. The proportion of CRC patients with potentially curable stage II or III disease was 74%, whereas the historical rate was 36%. The combination of rectal bleeding with both symptoms significantly predicted CRC in the validation set (odds ratio, 12.8; 95% confidence interval, 4.6-35.4; P < .001).Conclusions: In low-resource settings, patients with rectal bleeding, weight loss, and changes in bowel habits should be classified as high risk for CRC. Patients with a high risk score should be prioritized for colonoscopy to increase the number of patients diagnosed with potentially curable CRC. Cancer 2018;124:2766-2773. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Abstract: Background: The aim of the study was to evaluate the genetic predisposition of congenital cataract in a colony of captive‐bred vervet monkeys. Methods: Four congenital cataract genes: glucosaminyl (N‐acetyl) transferase 2 (GCNT2), heat shock transcription factor 4 (HSF4), crystallin alpha A (CRYAA) and lens intrinsic membrane protein‐2 (LIM2) were screened, sequenced and analysed for possible genetic variants in 36 monkeys. Gene expression was also evaluated in these genes. Results: Fifteen sequence variants were identified in the coding regions of three genes (GCNT2, HSF4 and CRYAA). Of these variations, only three were missense mutations (M258V, V16I and S24N) and identified in the GCNT2 transcripts A, B and C, respectively, which resulted in a downregulated gene expression. Conclusion: Although the three missense mutations in GCNT2 have a benign effect, a possibility exists that the candidate genes (GCNT2, HSF4 and CRYAA) might harbour mutations that are responsible for total congenital cataract. [ABSTRACT FROM AUTHOR]

Key points Obesity during pregnancy and childbirth is associated with labour dystocia leading to instrumental or operative delivery, but the underlying pathophysiological mechanisms remain unclear and insufficient uterine contractility has been suggested., This study examined whether reduced myometrial mitochondrial capacity or quantity could contribute as a pathophysiological mechanism to labour dystocia., Data did not support reduced myometrial mitochondrial capacity or quantity in the myometrium at term in obese women, but a reduced myocyte density with increased triglyceride content was demonstrated, which could lead to poorer uterine contractility., These results add to the understanding of systemic effects of obesity, placing also the myometrium at term as an affected non-adipose tissue., Abstract Obesity is known to increase the risk of labour dystocia and insufficient energy supply, due to reduced mitochondrial capacity or quantity, could be a possible mechanism leading to reduced efficiency of uterine contractility during labour. In the present study of 36 women having an elective Caesarean section at term, obesity did not change mitochondrial phenotype in the myometrial myocyte obtained from uterine biopsies taken at delivery. Respiration rates in isolated mitochondria were unaffected by obesity. No indication of reduced content, investigated by quantification of the complexes of the respiratory chain, or altered regulation, examined by myometrial mRNA levels of genes related to mitochondrial biogenesis and inflammation, was detected. Yet we found increased myometrial triglyceride content in the obese group (2.39 ± 0.26 vs. 1.56 ± 0.20 m m, P = 0.024), while protein content and citrate synthase activity per gram wet weight myometrium were significantly lower in the obese (109.2 ± 7.2 vs. 139.4 ± 5.6 mg g−1, P = 0.002, and 24.8 ± 1.0 vs. 29.6 ± 1.4 U g−1 wet wt, P = 0.008, respectively). These differences were substantiated by our histological findings where staining for nuclei, cytoplasm, glycogen and collagen supported the idea of a smaller muscle content in the myometrium in obese women. In conclusion no indication of myometrial mitochondrial dysfunction in the isolated state was found, but the observed increase of lipid content might play a role in the pathophysiological mechanisms behind labour dystocia in obese women. [ABSTRACT FROM AUTHOR]

Background Non-ketotic hyperglycinaemia ( NKH) is an autosomal recessive inborn error of glycine metabolism characterized by accumulation of glycine in body fluids and various neurological symptoms. Methods This study describes the first screening of NKH in cataract captive-bred vervet monkeys ( Chlorocebus aethiops). Glycine dehydrogenase ( GLDC), aminomethyltransferase ( AMT) and glycine cleavage system H protein ( GCSH) were prioritized. Results Mutation analysis of the complete coding sequence of GLDC and AMT revealed six novel single-base substitutions, of which three were non-synonymous missense and three were silent nucleotide changes. Conclusion Although deleterious effects of the three amino acid substitutions were not evaluated, one substitution of GLDC gene ( S44R) could be disease-causing because of its drastic amino acid change, affecting amino acids conserved in different primate species. This study confirms the diagnosis of NKH for the first time in vervet monkeys with cataracts. [ABSTRACT FROM AUTHOR]

Key points Hepatic insulin resistance in patients with obesity or type 2 diabetes has been suggested to result from hepatic mitochondrial dysfunction., High-resolution respirometry (HRR) can be used to assess oxidative phosphorylation by measuring the mitochondrial oxygen consumption rate in the individual complexes of the mitochondria., By using HRR, the present study demonstrates no difference in hepatic mitochondrial oxidative phosphorylation among subjects with obesity with or without type 2 diabetes and non-obese controls., Furthermore, the amount of mitochondria, assessed by the citrate synthase activity, is not different between the three groups., Together the present findings indicate that hepatic mitochondrial oxidative phosphorylation capacity is not impaired in patients with obesity or type 2 diabetes., Abstract Obese patients with type 2 diabetes (T2DM) and without type 2 diabetes (OB) are characterized by high hepatic lipid content and hepatic insulin resistance. This may be linked to impaired hepatic mitochondrial oxidative phosphorylation (OXPHOS) capacity. The aim of the present study was to investigate and compare hepatic mitochondrial OXPHOS capacity in T2DM, OB and non-obese controls (CON). Seventeen obese patients (nine OB and eight T2DM) and six CON patients had perioperative liver biopsies taken. Samples were divided into three parts to measure (1) complex I, II and IV linked respiration, (2) citrate synthase (CS) activity and (3) lipid droplet (LD) size and area (% of total tissue area filled by LDs). State 3 respiration of complex I, II and IV and the CS activity did not differ in OB, T2DM and CON. LD size was significantly higher in T2DM compared with CON, and LD area tended ( P = 0.10) to be higher in T2DM and OB compared with CON. The present findings indicate that hepatic OXPHOS capacity is not different in patients with markedly different weight and glycaemic control. Furthermore, the results do not support impaired hepatic mitochondrial respiratory capacity playing a major role in the development of obesity-induced type 2 diabetes. [ABSTRACT FROM AUTHOR]

Previous work has shown that male flesh flies (Sarcophaga crassipalpis Macquart) exhibit an ontogeny of behaviour from eclosion through sexual maturity that includes extensive changes in the expression of aggressive, non-aggressive interactive and non-interactive behaviours. To determine how the presence of a female flesh fly influences the manifestation of these behaviours, male flesh flies of different ages post-eclosion are paired with same-age females and their behaviours are monitored in a simple arena during a 50-min observation period. All flies are socially isolated until pairing. Although the levels of expression of aggressive and non-aggressive interactive behaviours are depressed relative to previous findings in male-opponent pairs, the ontogeny of aggression still occurs as indicated by a significant increase, with age, in the agonistic behaviour 'hold'. Similar to male-opponent pairs and individual males, the performance by males of the non-interactive behaviours 'walking' and 'standing' diminishes, whereas 'upside-down' increases with age. By contrast, 'grooming' shows a significant age-related decline. No courtship behaviours are observed in the males, although the aggressive behaviour 'hold' is a significant transition to mating. Females show no obvious courtship or rejection behaviours, although the significant increase in 'upside-down' with age could possibly be a behavioural gateway to mating. The results of this study indicate that extensive age-related changes encompassing the entire behavioural repertoire are intrinsic to male flesh flies and persist under a variety of different social contexts. [ABSTRACT FROM AUTHOR]

Objective Trefoil factor peptides ( TFF) are secreted onto mucosal surfaces together with mucins and occur in high concentrations in pulmonary secretions from patients with chronic obstructive pulmonary disease ( COPD). In the present study, we aimed to explore the concentrations of the peptides in serum and sputum in patients with COPD. Materials and Methods Thirty-five individuals were included in the study, including 11 healthy individuals, 13 indivials with asthma and 11 individuals with COPD. TFF1, TFF2 and TFF3 were measured by enzyme-linked immunosorbent assay ( ELISA) in sputum induced by hypertonic saline inhalation and in serum. Total protein content in sputum was also determined. Results In the sputum samples from COPD patients, we observed an eightfold higher concentration of TFF1 and a fivefold higher concentration of TFF3 compared with controls. In the serum samples from COPD patients, we observed three-, three- and twofold higher concentrations of TFF1, TFF2 and TFF3 respectively compared with controls. Conclusions There is increased secretion of TFF peptides in the lungs of patients with COPD, as well as significant increases in serum levels. This suggests a role for TFF peptides in the pathogenesis of pulmonary diseases with mucus hypersecretion. [ABSTRACT FROM AUTHOR]

The actin binding protein CapG modulates cell motility by interacting with the cytoskeleton. CapG is associated with tumor progression in different nongynecologic tumor entities and overexpression in breast cancer cell lines correlates with a more invasive phenotype in vitro. Here, we report a significant CapG overexpression in 18/47 (38%) of ovarian carcinomas (OC) analyzed by qRealTime-PCR analyses. Functional analyses in OC cell lines through siRNA mediated CapG knockdown and CapG overexpression showed CapG-dependent cell migration and invasiveness. A single nucleotide polymorphism rs6886 inside the CapG gene was identified, affecting a CapG phosphorylation site and thus potentially modifying CapG function. The minor allele frequency (MAF) of SNP rs6886 (c.1004A/G) was higher and the homozygous (A/A, His335) genotype was significantly more prevalent in patients with fallopian tube carcinomas (50%) as in controls (10%). With OC being one of the most lethal cancer diseases, the detection of novel biomarkers such as CapG could reveal new diagnostic and therapeutic targets. Moreover, in-depth analyses of SNP rs6886 related to FTC and OC will contribute to a better understanding of carcinogenesis and progression of OC. [ABSTRACT FROM AUTHOR]

In introductory statistics courses, the concept of power is usually presented in the context of testing hypotheses about the population mean. We instead propose an exercise that uses a binomial probability table to introduce the idea of power in the context of testing a population proportion. [ABSTRACT FROM AUTHOR]

Cirsium arvense (Asteraceae) is known as creeping thistle in its native range in the UK and Canada thistle in its invasive North American range. Recently, the fungus Phoma macrostoma was registered in Canada as a bioherbicide in turfgrass, where it causes severe chlorosis (White Tip disease) and death of C. arvense and other broadleaved weeds. It was hypothesised that the disease originated in the UK on its thistle host and, therefore, that fungal isolates from both countries should be biologically and genetically similar. Twenty-six strains in the genus Phoma- isolated during surveys in the UK - were compared morphologically with the type culture of P. macrostoma, tested for bioherbicidal activity using the inoculum mat bioassay and genetically screened with bioherbicide-specific primers. White tip disease was found to be restricted to the eastern and southern counties of England. Phoma macrostoma was isolated consistently from diseased bleached tissues. Bioherbicidal isolates of P. macrostoma occupy a unique clade, which is phylogenetically distinct but morphologically indistinguishable from the type culture. Most isolates from the UK had the same bioherbicidal activity and similar genetic make-up as strain SRC 94-44B, the active ingredient in the registered Canadian product. The origin of all bioherbicidal strains found to date has a clear presence in both Canada and the UK, with strong genetic similarities, supporting the view of a common ancestry. Thus, on the evidence presented, the 'white tip' clade of P. macrostoma evolved in southern England. Therefore, the bioherbicide based on strain SRC 94-44B should also be eligible for registration in the UK, based on the pest risk assessment data already available. [ABSTRACT FROM AUTHOR]

Animal models are important tools in the development of new drug candidates against the inflammatory bowel diseases (IBDs) Crohn's disease and ulcerative colitis. In order to increase the translational value of these models, it is important to increase knowledge relating to standard drugs. Using the SCID adoptive transfer colitis model, we have evaluated the effect of currently used IBD drugs and IBD drug candidates, that is, anti-TNF-α, TNFR-Fc, anti-IL-12p40, anti-IL-6, CTLA4-Ig, anti-α4β7 integrin, enrofloxacin/metronidazole, and cyclosporine.We found that anti-TNF-α, antibiotics, anti-IL-12p40, anti-α4β7 integrin, CTLA4- Ig, and anti-IL-6 effectively prevented onset of colitis, whereas TNFR-Fc and cyclosporine did not. In intervention studies, antibiotics, anti-IL-12p40, and CTLA4-Ig induced remission, whereas the other compounds did not. The data suggest that the adoptive transfer model and the inflammatory bowel diseases have some main inflammatory pathways in common. The finding that some well-established IBD therapeutics do not have any effect in the model highlights important differences between the experimental model and the human disease. [ABSTRACT FROM AUTHOR]

G erber E, S chaffner U, G assmann A, H inz HL, S eier M & M üller-S chärer H (2011). Prospects for biological control of Ambrosia artemisiifolia in Europe: learning from the past. Weed Research 51, 559-573. Summary The recent invasion by Ambrosia artemisiifolia (common ragweed) has, like no other plant, raised the awareness of invasive plants in Europe. The main concerns regarding this plant are that it produces a large amount of highly allergenic pollen that causes high rates of sensitisation among humans, but also A. artemisiifolia is increasingly becoming a major weed in agriculture. Recently, chemical and mechanical control methods have been developed and partially implemented in Europe, but sustainable control strategies to mitigate its spread into areas not yet invaded and to reduce its abundance in badly infested areas are lacking. One management tool, not yet implemented in Europe but successfully applied in Australia, is biological control. Almost all natural enemies that have colonised A. artemisiifolia in Europe are polyphagous and cause little damage, rendering them unsuitable for a system management approach. Two fungal pathogens have been reported to adversely impact A. artemisiifolia in the introduced range, but their biology makes them unsuitable for mass production and application as a mycoherbicide. In the native range of A. artemisiifolia, on the other hand, a number of herbivores and pathogens associated with this plant have a very narrow host range and reduce pollen and seed production, the stage most sensitive for long-term population management of this winter annual. We discuss and propose a prioritisation of these biological control candidates for a classical or inundative biological control approach against A. artemisiifolia in Europe, capitalising on past experiences from North America, Asia and Australia. [ABSTRACT FROM AUTHOR]

Background Early diagnosis of simian tuberculosis (TB) is vital to prevent transmission of this disease. We evaluated the ability of the QuantiFERON-TB Gold (In-Tube Method) assay (QFG-IT) to detect TB in chacma baboons ( Papio ursinus). Methods Fifty-one baboons were tested using the Tuberculin Skin Test (TST) and the QFG-IT. Baboons testing positive, and animals exposed to infected individuals, were euthanised and subjected to necropsy. Selected tissues were processed for histopathology, mycobacterial culture and genetic speciation. Results Tuberculosis was confirmed in one TST positive/QFG-IT positive animal and one TST negative/QFG-IT positive animal. One TST positive/QFG-IT negative animal and five TST negative/QFG-IT negative animals were confirmed uninfected following necropsy. Conclusion The QFG-IT correctly detected TB in two baboons, including one TST negative individual and correctly identified six baboons as uninfected, including one TST positive individual. The QFG-IT shows promise as a sensitive, specific test for TB in chacma baboons. [ABSTRACT FROM AUTHOR]

Expressed on leucocytes, β2 integrins (CD11/CD18) are specifically involved in leucocyte function. Using a CD18-deficient (CD18−/−) mouse model, we here report on their physiological role in lymphocyte differentiation and trafficking. CD18−/− mice present with a defect in the distribution of lymphocytes with highly reduced numbers of naïve B and T lymphocytes in inguinal and axillary lymph nodes. In contrast, cervical lymph nodes were fourfold enlarged harbouring unconventional T-cell receptor-αβ (TCR-αβ) and TCR-γδ CD3+ CD4− CD8− (double-negative; DN) T cells that expanded in situ. Using adoptive transfer experiments, we found that these cells did not home to peripheral lymph nodes of CD18wt recipients but, like antigen-experienced T or natural killer (NK) T cells, recirculated through non-lymphoid organs. Lacking regulatory functions in vitro, CD18−/− TCR-αβ DN T cells did not suppress the proliferation of polyclonally activated CD4+ or CD8+ (single-positive; SP) T cells. Most interestingly, CD18−/− TCR-αβ DN T cells showed intermediate TCR expression levels, an absent activation through allogeneic major histocompatibility complex and a strong proliferative dependence on interleukin-2, hence, closely resembling NKT cells. However, our data oppose former reports, clearly showing that, because of an absent reactivity with CD1d-αGalCer dimers, these cells are not mature classical NKT cells. Our data indicate that CD18−/− TCR-αβ DN T cells, like NKT and TCR-γδ T cells, share characteristics of both adaptive and innate immune cells, and may accumulate as a compensatory mechanism to the functional defect of adaptive immunity in CD18−/− mice. [ABSTRACT FROM AUTHOR]

Autoantigen-presenting immunomodulatory dendritic cells (DCs) that are used for adoptive transfer have been shown to be a promising therapy for a number of autoimmune diseases. We have previously demonstrated that enteroantigen-pulsed DCs treated with interleukin-10 (IL-10) can partly protect severe combined immunodeficient (SCID) mice adoptively transferred with CD4+ CD25− T cells from the development of wasting disease and colitis. We therefore established an in vitro test that could predict the in vivo function of DCs and improve strategies for the preparation of immunomodulatory DCs in this model. Based on these in vitro findings, we here evaluate three methods for DC generation including short-term and long-term IL-10 exposure or DC exposure to dexamethasone in combination with vitamin D3 (Dex/D3). All DCs resulted in lower CD4+ CD25− T-cell enteroantigen-specific responses in vitro, but Dex/D3 DCs had the most prominent effect on T-cell cytokine secretion. In vivo, Dex/D3 DCs most efficiently prevented weight loss and gut pathology upon CD4+ CD25− T-cell transfer in SCID mice, although the effect on gut pathology was antigen independent. Our data in the SCID T-cell transfer model illustrate some correlation between in vitro and in vivo DC function and document that prevention of experimental inflammatory bowel disease by transfer of immunosuppressive DCs is possible. [ABSTRACT FROM AUTHOR]

Territoriality in the flesh fly Sarcophaga crassipalpis (Diptera: Sarcophagidae) is studied in the laboratory. In rectangular enclosures, male flies exhibit a lower tolerance (occupation of the same physical space) of same-sex conspecifics than do females. In circular arenas, male flies show significantly higher levels of spatial separation among themselves (as determined from nearest neighbour analyses) than do females: males show a slight tendency towards a uniform distribution, whereas females exhibit a slight tendency towards clustering. The male spatial behaviour occurs during the photophase but not the scotophase, suggesting that visual cues are required for maintenance of inter-individual spacing. No significant differences in male spacing behaviour occur between subjective day and subjective night in either constant dark or constant light conditions, suggesting that spatial patterning is not driven by a circadian rhythm. [ABSTRACT FROM AUTHOR]

Fullerenes represent a group of nanoparticles discovered in 1985. They are spherical molecules consisting entirely of carbon atoms (Cx) to which side chains can be added, furnishing compounds with widely different properties. Fullerenes interact with biological systems, for example, by enzyme inhibition, causing phototoxic reactions, being scavengers of reactive oxygen species and free radicals, in addition to being able to initiate free radical reactions. Absorption, distribution and excretion strongly depend on the properties of the side chains. The pristine C60 has a very long biological half-life, whereas the most water-soluble derivatives are eliminated from the exposed animals within weeks. A long biological half-life raises concern about bioaccumulation and long-term effects. In general, the acute oral, dermal and airway toxicity is low. However, few relevant experimental studies of repeated dose toxicity, reproductive toxicity and carcinogenic effect are available. The data suggest that direct DNA damaging effects are low, but formation of reactive oxygen species may cause inflammation and genetic damage. Apparently, it is dose-dependent whether a beneficial or an adverse effect occurs. [ABSTRACT FROM AUTHOR]

Background Pure compounds and herbal medicines, had to be administered orally to vervet monkeys for testing. A reliable method was sought to avoid daily gavaging. Methods Substances were incorporated into the maize meal based diet of this facility for voluntary consumption. Food intake was monitored. Results In all but one case, consumption of the treated food was in excess of 90%. In all cases, the purpose of the study was achieved. Habituation was usually only required to the vehicle, and was accomplished by incremental increases to the desired concentration. Aversion was overcome by the addition of a small amount of honey. Plasma concentrations of a compound metabolite could be measured in one case after gavage and food consumption, and were similar for both methods. Conclusion The method enables reliable voluntary consumption of diverse substances. Since stressful gavaging is avoided, it is a valuable contribution to the 3Rs. [ABSTRACT FROM AUTHOR]

Tumour markers (TM), including alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen (CA) 15-3 and prostate-specific antigen (PSA), are serum markers for malignant diseases. Previous studies investigating the effect of acute and chronic inflammation, cardiopulmonary bypass surgery and cardiopulmonary resuscitation (CPR) on levels of TM showed conflicting results. Cardiopulmonary resuscitation (CPR) may result in a profound inflammatory response, and is frequently associated with severe tissue hypoperfusion. The present study investigated whether AFP, CEA, CA 15-3 and PSA are influenced by CPR. Alpha-fetoprotein (AFP), CEA, CA 15-3 and PSA (only in male patients) were assessed immediately after hospital admission, 6 h, 12 h and 2 days after prolonged CPR in eight male and 12 female patients. Serum levels of AFP, CEA, CA 15-3 did not change significantly after CPR. Prostate-specific antigen (PSA) levels increased significantly with a highest level in the study period 48 h after CPR (3.3 ± 3.1 and 28.3 ± 30.5 ng/mL for baseline and 48 h levels, respectively; P < 0.001). Alpha-fetoprotein (AFP), CEA, CA 15-3 and PSA (in men) values above the normal range were observed in 0%, 13.8%, 3.8% and 46.9% of all measurements respectively. At least one value above the normal range were observed in 0%, 20%, 5% and 75% of all patients for AFP, CEA, CA 15-3 and PSA (in men) respectively. Baseline values of AFP, CEA, CA 15-3 and PSA (in men) were above the normal range in 0%, 15%, 5% and 10% of all patients respectively. Levels for all markers did not differ significantly between survivors and non-survivors. In conclusion, prolonged CPR does not influence AFP, CEA, CA 15-3 serum levels, but is frequently associated with increases of PSA. Thus, in contrast to PSA, interpretation of AFP, CEA, CA 15-3 serum levels is not influenced by recent CPR. [ABSTRACT FROM AUTHOR]

Serotonin (5-HT) stimulates ion secretion in the gastrointestinal tract and the sensitivity for 5-HT might be altered in dyspeptic patients infected with Helicobacter pylori. The purpose of the present study was to characterize the 5-HT-induced electrogenic ion transport in the duodenum of dyspeptic patients with or without Helicobacter pylori infection, and to determine the 5-HT receptor subtypes functionally involved. Biopsies from the second part of duodenum were obtained from 43 dyspeptic patients during routine endoscopy. Biopsies were mounted in modified Ussing chambers with airsuction for measurements of short-circuit current by a previously validated technique. Short-circuit current was measured before and after application of graded cumulative doses of 5-HT and a single dose of bumetanide (an inhibitor of chloride/bicarbonate transport), or one of the selective 5-HT receptor antagonists: ketanserin, ondansetron, or SB-204070 (1-butyl-4 piperidinmethyl-8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate HCl). Histological examination was performed on duodenal biopsies. Helicobacter urease testing and histological examination determined Helicobacter pylori infection. 5-HT induced a dose-dependent and bumetanide-sensitive short-circuit current, which was independent of the presence of Helicobacter pylori infection. All the three 5-HT receptor antagonists failed to significantly effect basal and 5-HT-induced short-circuit current. Our results indicate that in human duodenum 1) 5-HT is a potent stimulator of bumetanide-sensitive secretion, 2) the serotonergic receptor subtype, which acts as the main mediator of 5-HT-induced secretion is different from the 5-HT2, 5-HT3, and the 5-HT4 subtype and, 3) the sensitivity to 5-HT is not altered by Helicobacter pylori infection. [ABSTRACT FROM AUTHOR]

The expression of endometrial β3 integrin and insulin-like growth factor binding protein-1 (IGFBP-1) was studied in cycling and pregnant vervet monkeys. There were clear changes of β3 integrin expression during the menstrual cycle, with the strongest immunostaining observed on day 26. Moderate to strong expression was observed during pregnancy. The expression of IGFBP-1 during the menstrual cycle was weak but upregulated during pregnancy with moderate to strong staining. The administration of a single dose of onapristone at 10 mg/kg on days 17, 21 and 22 of the menstrual cycle, followed by a biopsy on days 22, 22 and 26, respectively, and during pregnancy (34-44 days menstrual age) 24 h before the biopsy, disrupted and desynchronized the endometrium. However, no effect on β3 integrin expression could be observed and staining reflected the untreated patterns. The same applied to IGFBP-1 except that during pregnancy the expression of this protein was reduced or abolished. The results suggest that β3 integrin is associated with endometrial receptivity in vervet monkeys and that IGFBP-1 plays an important role during pregnancy in this species. The administration of onapristone appeared to only influence IGFBP-1 expression. To our knowledge, this is the first time that these endometrial proteins have been investigated in vervet monkeys. This study should therefore contribute to improving our understanding of the reproductive function of this species. [ABSTRACT FROM AUTHOR]

Testing statistical hypotheses introduces new vocabulary, concepts and a way of thinking that some students might initially find difficult. We provide a simple case that can be used in class as a gentle introduction to the ideas and procedures of hypothesis testing. [ABSTRACT FROM AUTHOR]

During a period of 6 years, uni- or bilateral cataracts occurred in 55 captive-bred vervet monkeys, representing 27.6% of all offspring produced in that time. Fifty-eight percent of all cases were detectable only by ophthalmoscopy. A total of 30% of cases were offspring of wild-caught parents, 40% from first-generation captive-bred parents, 4% from second-generation captive-bred parents, and 26% from parents of which one was wild caught. Cataracts that could be observed macroscopically appeared at about 6–8 mo of age. A sample of juvenile vervet monkeys with cataracts and their parents had no antibodies against rubella virus, herpes simplex virus, or toxoplasma gondi , and all except two wild-caught breeding females had no antibodies against cytomegalovirus. Plasma vitamin D3 (25 [OH] D), calcium, phosphorus, and glucose concentrations of six cataract cases were comparable to a control group of healthy individuals. The exclusion of these extraneous factors, as well as the fact that the majority of all cases were related, was considered evidence of hereditary etiology. Males and females that had either produced offspring with cataracts or were related to individuals with cataracts were replaced. To date, 35 babies have been born, and no new cases have since occurred. Am. J. Primatol. 55:43–48, 2001. © 2001 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Reports on the diagnosis and monitoring of twenty early pregnancies in vervet monkeys (Cercopithecus aethiops) by ultrasonography. Gestational cavity of two millimeters as the first definite sign of pregnancy; Relation between the features and plasma steroid concentrations and profiles; Benefits of results to breeding management and reproductive research.

Among the diverse facets of sperm maturation, changes in motility are conspicuous and hence studies of sperm kinematics might provide good indices for sperm maturation. Accordingly, the maturation of sperm motility in the epididymis and vas deferens of the vervet monkey, Cercopithecus aethiops, was assessed using a computer-aided sperm motility analysis system. The results revealed clear trends in the development of both sperm motility per se and in the movement characteristics of motile spermatozoa from different regions of the epididymis, the vas deferens and the ejaculate, reflecting maturational changes associated with the attainment of functional motility and fertility. Motion of spermatozoa from the caput epididymis was sluggish and irregular. As the spermatozoa moved through the corpus epididymis, motility increased sharply, and continued to improve through the cauda epididymis and vas deferens. Despite the high proportion of motile cells, full maturation of motion capabilities was not completed in spermatozoa from the corpus epididymis. Only once spermatozoa had reached the cauda epididymis and vas deferens did they attain their full vigour, and swam rapidly (greater VCL, VSL and VAP) with straightline trajectories (greater LIN, WOB and STR; lower ALH, MAD and CURV). After acquiring their maximal percentage motility and progressive velocity in the cauda epididymis and vas deferens, a slight decline in motility and vigour occurred in ejaculated spermatozoa, and was possibly associated with the ageing of stored spermatozoa. The results from this investigation have revealed clear trends in the maturation of the motility of vervet monkey spermatozoa during their transit through the epididymis and vas deferens and final emergence in the ejaculate, and have provided crucial baseline information on the reproductive physiology of this potentially valuable biomedical model to serve as a reference for future studies in reproductive toxicology. [ABSTRACT FROM AUTHOR]

Synthetic and naturally occurring steroids exert a variety of neural effects that include modulation of nocturnal sleep. The present study focuses on the effect of progesterone receptor (PR) activation on the nocturnal sleep electroencephalogram (EEG) in male volunteers. As a PR ligand, the synthetic progesterone megestrol was used, which has the advantage over progesterone in that it is not metabolized into other steroid compounds which could cloud the progesterone-mediated effects through their own neuroactive properties. Nine healthy male volunteers were investigated in a prospective single-blind randomized study design. They received either placebo tablets or megestrol acetate dosages of 160, 320 or 480 mg at 14.00 h and 19.00 h. Blood samples were drawn half-hourly from 22.00 h until 07.00 h. After 320 mg megestrol, plasma adrenocorticotropin secretion was lower and growth hormone secretion was higher than after 160 mg and 480 mg megestrol or placebo. Similarly, the reduction in the relative amount of rapid eye movement sleep was most pronounced after 320 mg. Thus, progesterone receptor activation, as reflected by the sleep EEG and associated pituitary hormone secretion, follows a nonlinear U-shape dose dependency of a well-defined PR ligand, which may explain the unresolved inconsistencies of neuroendocrine progesterone effects to date. Moreover, employing a CV1 cell line, contransfected with a human glucocorticoid receptor expression vector and a reporter gene-based detection system for transcriptional activity, revealed that a PR agonist such as megestrol may also activate glucocorticoid receptors. This may account for some of the neuroendocrine effects of megestrol and other progestins. [ABSTRACT FROM AUTHOR]