Effects of preferential social associations on pigs' response to weaning.

Farm animals can form preferential associations within their social group. Research has shown that the presence of familiar conspecifics can help to cope with stressful situations. Nonetheless, whether the strength of the relationship matters is largely unknown. Our aim was to investigate the influence of the strength of the social relationship between familiar partners during a stressful event. Pigs (n = 116) were observed pre-weaning for their social interactions and spatial proximity with littermates. From this, preferential associations were calculated based on sociality indices of non-agonistic social behaviours (SIsoc) and spatial proximity (SIprox). Pigs were weaned into groups of unfamiliar pigs together with one littermate. The partner was selected based on the strength of their relationship pre-weaning, with pairs from across the SIsoc and SIprox distribution. SIprox and non-agonistic social behaviour (SIsoc) were included in the statistical analysis as measures of relationship strength. Focal pigs were observed postweaning for their social behaviour and spatial proximity, skin lesions and growth, and salivary cortisol concentration pre-weaning and at 4 h and 48 h postweaning. The strength of the social relationship pre-weaning did not significantly influence the behaviour or proximity towards the familiar partner postweaning, or the amount of skin lesions or weight gain. Pigs who were weaned with a littermate with whom they were strongly affiliated based on active social behaviour (SIsoc) tended to have a lower proportional increase in their cortisol concentration after weaning (P = 0.07). Pigs differed in their behaviour towards the familiar partner as compared to the unfamiliar pigs, by directing more aggression towards unfamiliar pigs (P < 0.001), and more non-agonistic social behaviours towards the familiar pig (P < 0.001). The familiar partner was on average in 12.2% of the observations the nearest neighbour, which in small groups did not differ from random choice while in large groups, this occurrence was higher than expected by chance. The results show that pigs clearly distinguish between familiar and unfamiliar pigs, but that the strength of the relationship with a familiar partner seems to have limited effects at weaning. Although preferential associations in young pigs seem weak, studies on older pigs are needed to investigate whether this is due to the relatively little time they have to establish social preferences prior to weaning.

Predicting the diagnosis of autism in adults using the Autism-Spectrum Quotient (AQ) questionnaire.

BACKGROUND: Many adults with autism spectrum disorder (ASD) remain undiagnosed. Specialist assessment clinics enable the detection of these cases, but such services are often overstretched. It has been proposed that unnecessary referrals to these services could be reduced by prioritizing individuals who score highly on the Autism-Spectrum Quotient (AQ), a self-report questionnaire measure of autistic traits. However, the ability of the AQ to predict who will go on to receive a diagnosis of ASD in adults is unclear. METHOD: We studied 476 adults, seen consecutively at a national ASD diagnostic referral service for suspected ASD. We tested AQ scores as predictors of ASD diagnosis made by expert clinicians according to International Classification of Diseases (ICD)-10 criteria, informed by the Autism Diagnostic Observation Schedule-Generic (ADOS-G) and Autism Diagnostic Interview-Revised (ADI-R) assessments. RESULTS: Of the participants, 73% received a clinical diagnosis of ASD. Self-report AQ scores did not significantly predict receipt of a diagnosis. While AQ scores provided high sensitivity of 0.77 [95% confidence interval (CI) 0.72-0.82] and positive predictive value of 0.76 (95% CI 0.70-0.80), the specificity of 0.29 (95% CI 0.20-0.38) and negative predictive value of 0.36 (95% CI 0.22-0.40) were low. Thus, 64% of those who scored below the AQ cut-off were 'false negatives' who did in fact have ASD. Co-morbidity data revealed that generalized anxiety disorder may 'mimic' ASD and inflate AQ scores, leading to false positives. CONCLUSIONS: The AQ's utility for screening referrals was limited in this sample. Recommendations supporting the AQ's role in the assessment of adult ASD, e.g. UK NICE guidelines, may need to be reconsidered.

Six-year follow-up study of combined type ADHD from childhood to young adulthood: Predictors of functional impairment and comorbid symptoms.

BACKGROUND: ADHD in childhood is associated with development of negative psychosocial and behavioural outcomes in adults. Yet, relatively little is known about which childhood and adulthood factors are predictive of these outcomes and could be targets for effective interventions. To date follow-up studies have largely used clinical samples from the United States with children ascertained at baseline using broad criteria for ADHD including all clinical subtypes or the use of DSM III criteria. AIMS: To identify child and adult predictors of comorbid and psychosocial comorbid outcomes in ADHD in a UK sample of children with DSM-IV combined type ADHD. METHOD: One hundred and eighteen adolescents and young adults diagnosed with DSM-IV combined type ADHD in childhood were followed for an average of 6years. Comorbid mental health problems, drug and alcohol use and police contact were compared for those with persistent ADHD, sub-threshold ADHD and population norms taken from the Adult Psychiatric Morbidity Study 2007. Predictors included ADHD symptomology and gender. RESULTS: Persistent ADHD was associated with greater levels of anger, fatigue, sleep problems and anxiety compared to sub-threshold ADHD. Comorbid mental health problems were predicted by current symptoms of hyperactivity-impulsivity, but not by childhood ADHD severity. Both persistent and sub-threshold ADHD was associated with higher levels of drug use and police contact compared to population norms. CONCLUSIONS: Young adults with a childhood diagnosis of ADHD showed increased rates of comorbid mental health problems, which were predicted by current levels of ADHD symptoms. This suggests the importance of the continuing treatment of ADHD throughout the transitional years and into adulthood. Drug use and police contact were more common in ADHD but were not predicted by ADHD severity in this sample.

An assessment of the impacts of the REDD+ pilot project on community forests user groups (CFUGs) and their community forests in Nepal.

REDD+ has the potential to reduce greenhouse gas emissions, meet climate stabilisation targets and protect biological diversity. Consequently, millions of dollars are being channelled into developing countries rich in forests, for pilot projects that will provide data for the design of REDD+ projects that are based on incentives and performance. This paper evaluates the impacts of REDD+ pilot projects on community forests and associated user groups (CFUGs) in Nepal. A field study targeted eight CFUGs that participated in a REDD+ pilot project funded by the Forest Carbon Trust Fund in Nepal. The pilot project increased the participation of Dalit, Indigenous people, women and the poor, and was able to provide some social safeguards. However, when all the additional costs and foregone benefits of the project are considered, REDD+ is not an attractive market-based option for Nepalese CFUGs. A better approach would be a bilateral or multilateral approach that is not market based, but provides incentives beyond environmental and social safeguards. The results of this study will be useful in designing REDD+ policies and programmes for community forest-based REDD+ stakeholders in developing countries.

Pharmacokinetic analysis of high-dose toremifene in combination with doxorubicin.

PURPOSE: Toremifene (Fareston) is an orally administered triphenylethylene derivative with chemosensitizing activity in vitro in estrogen receptor-negative multidrug-resistant human breast cancer cells. The purpose of this study was to evaluate the effects of high-dose toremifene (600 mg/day for 5 days) on the plasma pharmacokinetics of doxorubicin in humans. The 600-mg dose had been previously established as the maximum tolerated dose in a phase I study of 35 patients. METHODS: Doxorubicin was administered as an intravenous (i.v.) bolus over 15 min at a dose of 60 mg/m2 to 11 patients in the absence of toremifene pretreatment to establish baseline doxorubicin pharmacokinetics. Six of these patients received 600 mg/day toremifene for 5 days 4 weeks later, followed by an i.v. bolus dose of doxorubicin (60 mg/m2) on day 5. During toremifene pre-treatment, blood specimens (5 ml) were drawn at 0, 2, 4, and 24 h after dosing to assess peak levels. Following doxorubicin administration in each cycle, blood specimens were collected over a 72-h period for determination of the terminal half-life of elimination. Plasma concentrations of doxorubicin and toremifene were assessed by high-performance liquid chromatography (HPLC). Cumulative linear areas under the time-concentration curve (AUC) for doxorubicin were calculated using a noncompartmental model. RESULTS: Prior to toremifene dosing, baseline doxorubicin pharmacokinetic studies showed an average terminal half-life of elimination of 40.04+/-7.86 h in 4 patients, and an average AUC of 135 600+/-67 600 microg/ml.h in 11 patients. In 4 of the patients receiving 600 mg/day toremifene for 5 days, the average terminal half-life of elimination was 38.12+/-7.81 h, and the average AUC was 141 900+/-62 900 microg/ml.h in 6 patients, i.e. a slight increase of 4.6%. No statistically significant change in the doxorubicin elimination kinetics with or without toremifene therapy was observed. CONCLUSIONS: Toremifene does not appear to interfere with the elimination kinetics of doxorubicin.

Intratumoral toremifene therapy and tissue distribution in the baboon.

The purpose of the present study was to evaluate the tissue distribution of toremifene (TOR) in baboons following intra-tissue injections and to examine the effectiveness of intratumoral TOR therapy of baboons with various spontaneous neoplasms. Five healthy baboons (Papio sp.) were used to examine the distribution of TOR following intra-tissue injections. Twenty-three different tissue specimens were collected for HPLC analysis. In addition, four baboons with various spontaneous neoplasms (myxoma, squamous cell carcinoma, lymphosarcoma and adenocarcinoma) were treated with intratumoral TOR and their responses were evaluated. Tissue TOR distribution was also examined in these animals. In the tissue distribution study, target tissue/serum TOR concentration ratios ranged from 138 to 8873 and the target tissue/other tissue ratios ranged from 1.2 to 2428. The distribution of TOR was very favorable, with the highest concentrations outside the injection sites noted in adjacent organs. A marked response was observed in the myxoma and partial responses were observed in the other three cases. Drug level analysis data from these four animals revealed tissue concentrations similar to those seen in the TOR tissue distribution study. Intratumoral administration of TOR can achieve effective local tumor and tissue concentrations, while systemic distribution via circulation to other organs is limited.

Tissue distribution of transdermal toremifene.

PURPOSE: Toremifene is an orally administered triphenylethylene derivative with antiestrogenic activity that is primarily used in the treatment of patients with metastatic breast cancer. The purpose of this study was to evaluate the therapeutic advantage of local (transdermal) administration of toremifene in several animal models. Local (subcutaneous and skin) versus systemic concentrations of toremifene were evaluated serially following transdermal application of the drug. With high local concentrations and minimal distribution to other organs via the circulation, topical toremifene may deliver maximal therapeutic effects to local tissue while avoiding the side effects seen with systemic therapy. METHODS: Three animal models (nude mice, baboons, and a horse) were used to examine topically administered toremifene for kinetic measurements. RESULTS: In nude mice implanted subcutaneously with MDA-MB-231 human breast tumors, topical toremifene (2.5 mg/day x 5 days) produced greater than 50-fold higher tumor concentrations compared with intraperitoneal (i.p.) administration (1.0 mg/day x 5 days). Systemic distribution in plasma, uterus, and liver was lower following topical than following i.p. administration. In nude mice inoculated subcutaneously with estrogen receptor-positive (ER +) MCF-7 human breast cancer cells, topical toremifene and 4-hydroxytoremifene (4-OH) prevented tumor growth in the presence of estradiol. In four nontumor-bearing baboons that were given transdermal toremifene, relatively high distribution of drug was noted in normal breast tissue and fat, compared with undetectable serum concentrations. Finally, a new topical formulation of toremifene (a gel preparation for human use, Orion-Farmos, Finland) achieved high local tumor toremifene concentrations in a horse melanoma, with minimal systemic distribution. CONCLUSIONS: Transdermal toremifene can achieve high local tissue concentrations with minimal systemic distribution.

Haloenol lactone: a new synergist of chemotherapy in vitro.

Over-expression of glutathione S-transferases (GST) has been found to play a significant role in multiple drug resistance in cancer chemotherapy. To combat GST-mediated drug resistance, GST inhibitors are being studied as potential synergists for effective cancer chemotherapy. We have designed and synthesized a haloenol lactone derivative as a mechanism-based inactivator of GST-pi isozyme. In the current study, we examined the inhibitory effect of the haloenol lactone compound on GST of a human renal carcinoma cell line UOK130 and found that this compound shows time-dependent GST inhibition in these cancer cells. The enzyme activity lost upon incubation with the haloenol lactone could not be restored by extensive dialysis against buffer. Pretreatment of the cancer cells with 1.0 microM of haloenol lactone increased cytotoxicity induced by cisplatin in the UOK130 cell line. This report further supports the possibility of synergizing alkylating agents in cancer chemotherapy by use of selective GST inhibitors.

Recurrent headaches: what every allergist should know.

OBJECTIVE: To provide the allergist information regarding the recognition, diagnosis, classification, and management of headaches. DATA SOURCES: Literature and relevant articles pertaining to various types of headache are reviewed and the clinical experience of the authors is presented. CONCLUSIONS: After reading this article, the allergist should know the various causes of headache, recognize the warning signs of serious neurologic disease, and determine whether allergy or adverse food reactions are playing a role.

MR findings in oculocerebrorenal syndrome.

Oculocerebrorenal syndrome is an X-linked recessive disorder characterized by congenital ocular abnormalities, mental retardation, renal disease, and metabolic bone disease. We report a case of oculocerebrorenal syndrome and, using T1-, proton density-, and T2-weighted imaging sequences, are able to characterize two distinct white matter abnormalities: one lesion is punctate and has signal characteristics that parallel that of cerebrospinal fluid; a second lesion, found in association with the first, consists of patchy white matter abnormalities that are hypointense on T1-weighted images but hyperintense on proton density- and T2-weighted images.

Product deactivation in recombinant Streptomyces.

The production of tyrosinase by Streptomyces antibioticus (p1J7O2) was investigated as a model system for recombinant protein production by Streptomyces. Product deactivation was found to have a severe effect on the levels of tyrosinase obtained. Tyrosinase deactivation was detected during all phases of batch cultures, with higher specific deactivation rates observed during the stationary phase. The specific deactivation rate exhibited an Arrhenius dependence on temperature, with approximately a twofold increase in the deactivation rate between 25 degrees C and 30 degrees C. The effect of deactivation on the determination of tyrosinase production kinetics is discussed. A strategy was implemented to increase tyrosinase productivity by enriching the growth medium and reducing the culture temperature during the period of maximum tyrosinase production. This strategy resulted in a shorter culture time and a 2.5-fold increase in tyrosinase activity compared to a culture grown at 25 degrees C using a standard growth medium.

Pharmacokinetics of toremifene and its metabolites in patients with advanced breast cancer.

A multicenter phase I pharmacokinetic study of a new triphenylethylene antiestrogen, toremifene, was examined in 70 patients with advanced breast cancer. Patients were randomized to receive single daily oral doses of either 10, 20, 40, 60, 200, or 400 mg for 8 weeks. Plasma toremifene and its major metabolites. N-desmethyltoremifene and 4-hydroxytoremifene, were determined weekly during therapy and at 0, 7, 14, and 21 days after the discontinuation of therapy. The time to reach steady-state plasma concentrations was between 1 and 5 weeks, with steady-state being achieved earlier (1-2 weeks) at daily doses of 200 and 400 mg. The time to peak concentration following oral doses of toremifene ranged from 1.5 to 4.5 h. The terminal half-life of elimination was 5.0, 6.0, and 5.0 days for toremifene, desmethyltoremifene, and 4-hydroxytoremifene, respectively. Plasma concentrations of 4-hydroxytoremifene were detectable only at high doses (200 and 400 mg/day) of toremifene. The results of this phase I pharmacokinetic study show that toremifene has metabolic and kinetic patterns that are similar to those previously reported with tamoxifen.

Effect of agitation rate and impeller design on oxygen transfer coefficients in small bioreactors using surface aeration.

The effects of agitation rate and impeller type on the combined oxygen mass-transfer coefficient (kL a) in four different benchtop bioreactors have been examined. Surface oxygenation of a cell culture medium supplemented with fetal bovine serum and distilled deionized water has been studied by passing air through the bioreactor headspace at approximately one headspace volume per minute. A new ribbon-type impeller design using strips of Teflon has been shown to be superior to conventional impeller designs for oxygen transfer.

Control of Escherichia coli-Candida utilis continuous, competitive mixed-culture system using the dynamic matrix control algorithm.

The control of the continuous, competitive mixed culture of the yeast Candida utilis (ATCC 8205) and the bacterium Escherichia coli B/r (ATCC 12407) was examined. A modified version of the dynamic matrix control (DMC) algorithm was tested in simulation and then was successfully implemented. This represents the first report of the location and stabilization of a competitive mixed culture at a metastable equilibrium point using automatic control.

Fed-batch fermentation for the production of alpha-amylase by Bacillus amyloliquefaciens.

Fed-batch cultures were performed to maximize the alpha-amylase activity in a bioreactor. Kinetic equations containing a catabolite repression effect were used to model the enzyme formation from Bacillus amyloliquefaciens. Fed-batch culture experiments were performed using maltose to implement the optimal feeding strategy. Optimal fed-batch culture based on sequential parameter estimation was performed successfully using off-line analysis while the fermentation was in progress. The enzyme activity from the fed-batch culture employing maltose was higher than that of the batch culture by 60%. Enzyme production using starch showed similar trends to those obtained using maltose.

Kinetics of alpha-amylase synthesis from Bacillus amyloliquefaciens.

The microbial production of alpha-amylase from Bacillus amyloliquefaciens was investigated. The microorganism was grown using media containing glucose or maltose at 37 degrees C and under aerobic conditions in a 16-L fermentor. The alpha-amylase synthesis from maltose was not found to be inducible but was found to be subject to catabolite repression. The maltose uptake rate was observed to be the rate-limiting step compared to the conversion rate of maltose to glucose by intracellular alpha-glucosidase. The alpha-amylase activity achieved with maltose as a substrate was higher than that achieved with glucose. A slower growth rate and a higher cell density were obtained with maltose. The enzyme production pattern depended upon the nutrient composition of the medium.

Some observations on the role of type 1 fimbriae in Escherichia coli autoflocculation.

Techniques are reviewed for the identification and enrichment of fimbriae-positive and fimbriae-negative Escherichia coli. Fimbriae-positive E. coli were observed to form a semistable suspension of pH 7.0 which settled at a rate much slower than the fimbriae-negative bacteria. Intense autoflocculation of fimbriae-positive E. coli was noted at pH values below 5.2.

Evaluation of Escherichia coli and Candida utilis as a model continuous, competitive mixed culture system.

The yeast Candida utilis and the bacterium Escherichia coli B/r were evaluated as a candidate experimental, continous, competitive mixed culture system under ammonia-nitrogen limited conditions at 30 degrees C. High dilution rates favored yeast dominance, while low dilution rates favored bacterial dominance. The hydrogen ion concentration was also demonstrated to be an effective manipulative variable for control of the yeast-bacterial mixed culture. Through trial-and-error manipulation of the pH for the mixed culture operating at constant dilution rate, it was possible to locate a metastable equilibrium point and to operate in the vicinity of that point for more than 24h. The reproducible emergence of a variant E. coli was also noted in this study.

The response of a nitrogen-limited chemostat culture of Escherichia coli B/r to pH and dilution rate steps.

The effects of four pH steps and one dilution rate step are described for an ammonia-nitrogen-limited continuous culture of Escherichia coli B/r. Two of the pH steps, 6.06-5.49 and 5.96-5.60, led to prolonged transients in both cell density and rate-limiting nutrient concentration. The other two pH steps, 6.20-5.96 and 5.60-6.20, had almost no effect on the culture. The dilution rate step led to a sharp transition in the steady-state external pyruvate concentration. Monitoring of the external pyruvate concentration for the pH 5.96-5.60 step revealed that the transient phase continued long after the cell density and rate-limiting nutrient concentration returned to steady-state values. The implications for industrial and laboratory fermentations are discussed.