World Association for the Advancement of Veterinary Parasitology (W.A.A.V.P.): Third edition of the guideline for evaluating efficacy of anthelmintics in ruminants (bovine, ovine, caprine).

This guideline is aimed at those who are involved in the assessment of anthelmintic efficacy in ruminant livestock species (bovine, ovine and caprine). The intent is to provide a framework that can be adopted worldwide for the testing of anthelmintics in ruminants, such that studies carried out in different countries can be compared and thereby unnecessary duplication can be reduced. Recommendations are made for the selection, housing and feeding of study animals, the type of studies required, the method used to conduct those studies, the assessment of results and the standards for defining anthelmintic efficacy.

Introduction of a Simple Second Tier Screening Test for C5 Isobars in Dried Blood Spots: Reducing the False Positive Rate for Isovaleric Acidaemia in Expanded Newborn Screening.

In 2015 the English Newborn Screening programme expanded to include Isovaleric Acidaemia (IVA). Screening is performed by flow injection analysis tandem mass spectrometry of isovalerylcarnitine. Isovalerylcarnitine is isobaric with pivaloylcarnitine which can be present in blood due to the use of pivalic ester pro-drugs or pivalic acid derivatives used as emollients in some nipple creams; the potential for false positives (FP) is well documented. A pilot study in England screened 438,164 babies, 18 had presumptive positive results but only 4 were confirmed as true positives (TP). We developed a simple test to separate the isobaric compounds and investigate these samples further.We studied newborn screening blood spots from 122 randomised controls and 34 infants with an initial raised C5 result. Dried blood spots were eluted with 30% acetonitrile (150 µL) and injected into a Waters Acquity UPLC coupled to a Waters Premier XE tandem mass spectrometer operating in positive ion mode. Isocratic separation of isovalerylcarnitine, pivaloylcarnitine, valerylcarnitine and 2-methylbutyrylcarnitine was achieved within 8 min. Assay performance characteristics were acceptable and non-parametric reference ranges (n = 122) were determined for each analyte.If this method had been used as a second tier test for the 34 presumptive positive samples, the number of FP's would have reduced from 24 to 8 and the positive predictive value of the screening test would have increased from 29 to 56%. Introduction of this test into the screening protocol has the potential to significantly reduce FP results for IVA and prevent unnecessary anxiety.

The orthodontic condition of children in the United Kingdom, 2003.

BACKGROUND: The 2003 Children's Dental Health Survey is the fourth in a series of decennial national children's dental health surveys in the United Kingdom. AIMS: This paper reports on the orthodontic condition of children aged 12 and 15 years. METHODOLOGY: A representative sample of children across the UK were invited to participate in a clinical dental examination in school. Two thousand, five hundred and ninety-five 12-year-olds and 2,142 15-year-olds were examined. Current and past orthodontic treatment and type of appliance worn were recorded. Orthodontic treatment need was assessed by the Modified IOTN in those not undergoing treatment. A postal questionnaire sought parents' views on the orthodontic condition of their children and perceived need for treatment. RESULTS: At age 12, 35% were judged to have an orthodontic treatment need, 57% had no need and 8% were wearing an appliance. The corresponding figures at age 15 were, 21% (need), 65% (no need) and 14% (wearing appliance). A higher proportion of girls (p < 0.05) were wearing an appliance than boys. A greater proportion of 15-year-olds were undergoing treatment than in the 1993 and 1983 surveys and the use of fixed appliances had increased. CONCLUSIONS: In this representative sample of UK children, one in five were still judged as having an orthodontic treatment need at age 15 years, as determined by the modified index of orthodontic treatment need. However, considerable variation was observed between professional and lay perceptions of need.

The orthodontic condition of children in England, Wales and Northern Ireland 2013.

Background The 2013 Children's Dental Health Survey is the fifth in a series of national surveys.Aims This paper reports the orthodontic condition of 12- and 15-year-olds and how they and their parents feel about the appearance of their teeth.Methodology A representative sample of children (5y, 8y, 12y, 15y) in England, Wales and Northern Ireland were invited to participate in dental examinations. A modified Index of Orthodontic Treatment Need (IOTN) was used as a measure of orthodontic treatment need for 12- and 15-year-olds. Children and parents were invited to complete a questionnaire about oral health behaviour and attitudes.Results Nine percent of 12-year-olds and 18% of 15-year-olds were undergoing orthodontic treatment at the time of the survey. Forty-four percent of 12-year-olds and 29% of 15-year-olds expressed a desire for straighter teeth, however over half of this group would not qualify for NHS treatment. Unmet treatment need was higher in children eligible for free school meals (P <0.05 at 15y).Conclusions Provision of and demand for orthodontic treatment is increasing, with a significant proportion of children who desire orthodontic care not eligible to receive it. Children from deprived backgrounds have greater unmet orthodontic treatment need.

Mechanism of action of eukaryotic topoisomerase II and drugs targeted to the enzyme.

Topoisomerase II is a ubiquitous enzyme that is essential for the survival of all eukaryotic organisms and plays critical roles in virtually every aspect of DNA metabolism. The enzyme unknots and untangles DNA by passing an intact helix through a transient double-stranded break that it generates in a separate helix. Beyond its physiological functions, topoisomerase II is the target for some of the most active and widely prescribed anticancer drugs currently utilized for the treatment of human cancers. These drugs act in an insidious fashion and kill cells by increasing levels of covalent topoisomerase II-cleaved DNA complexes that are normally fleeting intermediates in the catalytic cycle of the enzyme. Over the past several years, we have made considerable strides in our understanding of the catalytic mechanism of topoisomerase II and the mechanism of action of drugs targeted to this enzyme. These advances have provided novel insights into the physiological functions of topoisomerase II and have led to the development of more efficacious chemotherapeutic regimens and novel anticancer drugs. Considering the importance of topoisomerase II to the eukaryotic cell and to cancer chemotherapy, it is essential to understand its enzymatic function and pharmacological properties. Therefore, this review will discuss the mechanism of action of eukaryotic topoisomerase II and topoisomerase II-targeted drugs.

Beta 1-selective adrenoceptor antagonists. 3. 4-Azolyl-linked phenoxypropanolamines.

A series of 4-substituted phenoxypropanolamines has been prepared and examined for beta-adrenoceptor activity. The 4-substituents, di- and triazole ring systems connected to the phenoxy ring by different length chains, were chosen as a means of introducing cardioselectivity. This has been achieved, especially in the 1-[4-[(4-chloropyrazol-1-yl)methoxy] phenoxy]-3-(isopropylamino)-2-propanol (11), the 4-[(2H-1,2,3-triazol-2-yl)methoxy] analogue (21), and the 4-[2-(2H-1,2,3-triazol-2-yl)ethoxy] analogue (22), which show potent beta 1-blockade with selectivity ratios in excess of 100:1. Structure-activity relationships are discussed, and the optimum position of the heteroatom in the 4-substituent is defined.

beta 1-selective adrenoceptor antagonists. 2. 4-ether-linked phenoxypropanolamines.

A series of 4-substituted phenoxypropanolamines was prepared and examined for beta-adrenoceptor activity. Some of the compounds, especially the [4-[2-[[2-(4-fluorophenyl)ethyl] oxy]ethoxy]phenoxy]propanolamines (14, 15, and 24), showed potent beta 1-blockade with virtually no beta 2-blockade at doses over a 1000 times greater. The compounds also possessed partial agonist activity. Structure-activity relationships are discussed, and conclusions are drawn about the binding sites on beta-adrenoceptors.

An investigation of the tachycardia produced by intracerebro-ventricular injections of isoprenaline in mice.

1. Isoprenaline, 3.5-20 ng, injected intracerebroventricularly in atropinized mice under pentobarbitone anaesthesia produced a dose-dependent tachycardia. 2. Pretreatment with either reserpine or pempidine blocked nervously-mediated tachycardia as shown by marked reduction of that due to stimulation of the spinal outflow in pithed mice. After pretreatment with these drugs, intracerebroventricular isoprenaline caused tachycardia of a similar degree and time course to that in mice not so pretreated. 3. Pretreatment with either reserpine or pempidine caused supersensitivity to the tachycardia due to intravenous isoprenaline. 4. When allowance was made for this supersensitivity in the effect of intracerebroventricular isoprenaline in pretreated mice, a small dose-dependent residual effect remained that could be attributed to leakage of isoprenaline into the peripheral circulation. 5. This was confirmed by the appearance of a late-developing tachycardia on intracerebroventricular injection of isoprenaline in spinal mice. 6. It is therefore concluded that the tachycardia caused by intracerebroventricular isoprenaline in mice is, at least initially, of central origin.

Assessment of the effectiveness of -adrenoceptor blocking agents towards cardiac and bronchiolar responses of the pithed guinea-pig to electrical stimulation of the spinal outflow.

1. The responses of heart rate and resistance to lung inflation of the pithed guinea-pig on electrical stimulation of the thoracic spinal roots could be related to similar responses to injected catecholamines, such that dose-stimulus frequency relations could be plotted.2. The range of frequency of stimulation that was equi-effective with a dose range of injected catecholamines was higher for effects on air overflow than for heart rate. The slope of the relations for heart rate also differed from that for air overflow. These features may reflect a difference in effectiveness of the sympathetic innervation of heart and bronchial tree.3. Propranolol was equally effective in reducing the responses of heart rate and air overflow to injected noradrenaline. Practolol was somewhat more active against the effects of noradrenaline on air overflow than on heart rate, though equally active against the effects of isoprenaline.4. For the assessment of equivalent blockade of the effects of cord stimulation on heart rate and air overflow, frequency-ratios corresponding to a noradrenaline dose-ratio of 2 were derived from the slopes of the dose-frequency relations; for air overflow this value was approximately 2 and for heart rate approximately 1.4.5. When the doses required to produce these degrees of blockade were computed from the dose-response relations for blockade of the effects of cord stimulation by propranolol, they were found to be similar for effects on heart rate and air overflow. For practolol, the effective dose for block of heart rate increase was found to be lower than that for air overflow.

Effect of beta-adrenoceptive blocking agents on the response to bronchoconstrictor drugs in the guinea-pig air overflow preparation. Appendix describing a new modification of the air overflow method.

1. Propranolol augmented the bronchoconstrictor response to methacholine or histamine, recorded by air overflow in the anaesthetized, vagotomized guinea-pig.2. After adrenalectomy, propranolol was still active, though less so than before.3. In the pithed guinea-pig, there was no augmentation of the effect of bronchoconstrictors on air overflow. The action of propranolol could thus be due to the beta-adrenoceptor blockade of compensatory sympathetic bronchodilator activity, as concluded by McCulloch, Proctor & Rand (1967).4. Electrical stimulation of the thoracic region of the spinal cord of the pithed guinea-pig reduced the effect of bronchoconstrictors on air overflow. This reduction could be blocked by propranolol; practolol was much less effective.

Hypotensive responses following oral adminstration of beta-adrenoceptor blocking drugs to the conscious cat.

On oral administration, the non-selective beta-adrenoceptor blocking drugs (+/-)-bufuralol, (-)-bufuralol, propanolol, oxprenolol, pindolol and alprenolol produced hypotensive responses in the conscious cat; (+)-bufuralol was without effect. The selective beta-adrenoceptor blocking drugs practolol and atenolol had no effect on blood pressure but tolamolol elicited a hypotensive response. All the drugs tested reduced the tachycardia due to intravenous isoprenaline in the conscious cat; however, not all doses of these drugs reduced blood pressure. (+)-Bufuralol was devoid to beta-adrenoceptive blocking activity. Only tolamolol reduced the pressor response to i.v. phenylephrine in the conscious cat, indicating that alpha-adrenoceptive blocking activity may contribute to its hypotensive action. The results suggest that beta-adrenoceptive blocking activity is necessary for the hypotensive responses of these drugs. However, for the different drugs, there was no correlation between peripheral beta-adrenoceptive blocking activity and hypotensive response.

Psoriasis in children: a guide to its diagnosis and management.

Psoriasis often presents in childhood. The diagnosis may be challenging if the disease is mild or the presentation is atypical. All of the forms recognised in adults are encountered in childhood (plaque, guttate, erythrodermic and pustular). Guttate and flexural forms are particularly common in children. Successful management requires education of the child and parents regarding the course of the disease and treatment options. Environmental triggers should be sought out and eliminated where possible. Most patients respond to topical treatment with emollients, coal tar, anthralin (dithranol) or calcipotriol. Treatment is tailored according to patient age, extent and distibution of psoriasis. For those who fail to respond, daycare or inpatient care is appropriate. Phototherapy with UVB may be combined with topical agents. Systemic therapy is required in a minority, usually those with resistant or erythrodermic disease, pustular psoriasis and arthropathic psoriasis. Retinoids are probably the systemic agent of choice. There are few data regarding the use of methotrexate or cyclosporin in childhood psoriais.

Fasciola hepatica: attempts to immunise rats and mice with metabolic and somatic antigens derived from juvenile flukes.

Attempts were made to vaccinate rats and mice against Fasciola hepatica using either somatic or metabolic antigens derived from juvenile flukes between 10 and 16 days old. None of the regimes tried induced a good resistance to subsequent infection, though metabolic antigens derived from 13-14-day-old flukes when injected subcutaneously into rats with adjuvant did produce some protection to challenge.

Effectiveness of a personalised referral letter following orthodontic screening.

No data exist on the usefulness of orthodontic screening in guiding those children who need orthodontic treatment towards professional advice. This study evaluated the effectiveness of a personalised referral letter following an orthodontic screening programme employing an objective measure of treatment need, the Index of Orthodontic Treatment Need (IOTN). Out of a total sample of 924 children aged 11-12 yr, 201 were in need of orthodontic treatment and no orthodontic treatment was planned. From this subsample test and control groups matched for sex, socio-economic background, dental disease and aesthetic impairment were created. Following screening, the parents of the test group only were sent a specific orthodontic referral letter. The dental practitioners of the children in the test and control groups were contacted during a follow-up investigation carried out 8 months later, this revealed that significantly more children entered orthodontic treatment pathways from the test group. This study demonstrated that a screening programme, using IOTN as a screening test, and a referral procedure which provided parents with specific information were successful in guiding over one third of children with a need for orthodontic treatment towards orthodontic advice.

Modified IOTN: an orthodontic treatment need index for use in oral health surveys.

This paper reports the results of a study of the reliability of a modified version of the Index of Orthodontic Treatment Need (IOTN) for use in oral health surveys. Twelve non-specialist dental examiners were trained in the use of the Modified IOTN using a standardised teaching protocol lasting approximately 1.5 hours. Following a school-based calibration exercise it was found that nearly all the examiners achieved either good or excellent agreement (mean Kappa=0.74). The average sensitivity and specificity scores were 0.90 and 0.84, respectively. The Modified IOTN appears to overcome the training and reliability problems that often accompany the use of orthodontic indices by non-specialists in oral health surveys.

Calibration of dentists in the use of occlusal indices.

Dentists' opinions as to both need for and outcome of orthodontic treatment show wide variation. Within the profession there is an opportunity to reduce subjective bias and standardise criteria by the use of occlusal indices. The results of this study demonstrate that a group of dentists can easily be trained to record the Aesthetic and Dental Health Components of the Index of Orthodontic Treatment Need and the PAR index to a satisfactory level.

Fasciola hepatica: the flukicidal effect of some anaesthetics and analgesics in common use.

The anaesthetic halothane and the sedative xylazine were shown to have anthelmintic properties in rats against the liver fluke Fasciola hepatica. Flukes in rats treated with the local anaesthetic lignocaine or the anaesthetic/analgesic ketamine were unaffected.