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Epilepsy is a common neurological condition that shows a marked genetic predisposition. The advent of next-generation sequencing (NGS) has transformed clinical genetic testing by allowing the rapid screen for causative variants in multiple genes. There are currently no NGS-based multigene panel diagnostic tests available for epilepsy as a licensed clinical diagnostic test in Ontario, Canada. Eligible patient samples are sent out of country for testing by commercial laboratories, which incurs significant cost to the public healthcare system.
An expert Working Group of medical geneticists, pediatric neurologists/epileptologists, biochemical geneticists, and clinical molecular geneticists from Ontario was formed by the Laboratories and Genetics Branch of the Ontario Ministry of Health and Long-Term Care to develop a programmatic approach to implementing epilepsy panel testing as a provincial service.
The Working Group made several recommendations for testing to support the clinical delivery of care in Ontario. First, an extension of community healthcare outcomes-based program should be incorporated to inform and educate ordering providers when requesting and interpreting a genetic panel test. Second, any gene panel testing must be “evidence-based” and takes into account varied clinical indications to reduce the chance of uncertain and secondary results. Finally, an ongoing evaluative process was recommended to ensure continued test improvement for the future.
This epilepsy panel testing implementation plan will be a model for genetic care directed toward a specific set of conditions in the province and serve as a prototype for genetic testing for other genetically heterogeneous diseases.
The development and conceptual relationship of the constructs of threat appraisal (TA) and intolerance of uncertainty (IU) are explored in the context of anxiety disorders. A narrative review tracking the development of these constructs and their relationship is undertaken. There is some evidence to suggest that the interaction between the components of threat appraisal (probability × cost) may partially account for or provide a theoretical framework which explains presenting levels of anxiety. Furthermore, research suggested that IU is a construct which contributes to a broad range of anxiety disorders. It was concluded that distinctive cognitive biases linked with IU – such as interpreting ambiguous and uncertain (both positive and negative) information as highly concerning – suggests that IU is interpreted negatively independent of threat appraisal. These findings mean a number of issues remain unclear, including whether IU in anxiety-provoking situations is sufficient in itself – independent of threat appraisal – in eliciting high levels of anxiety. Additionally, it is unclear whether threat appraisal and IU act as independent constructs, or more in an interactive manner in anxiety. To achieve further clarity on these issues, methodological recommendations for future research are made.
Key learning aims
(1)To understand the conceptual foundations of TA and IU in the cognitive model of anxiety.
(2)To understand the empirical evidence supporting the role of both TA and IU in anxiety.
(3)To appreciate the potential relationship between these concepts in anxiety.
A major financial and welfare problem is the loss of 1 to 4 million lambs annually in the United Kingdom (Slee, 1979) with many of these deaths being caused by failure of the lamb to maintain normal thermoregulatory responses in the cold. This may be associated with a change in the response to cold exposure from non-shivering thermogenesis (NST) to shivering thermogenesis (ST) as brown adipose tissue (BAT) is replaced by white adipose tissue over the first 2 weeks of life in the lamb (Symonds, Andrews and Johnson, 1989).
It has been shown that environmental temperature can affect BAT development in the lamb (Gemmel, Bell and Alexander, 1972) and calf (Casteilla, Champigny, Bouilland, Robelin and Riquier, 1989) but it is not known what effect this has on the thermogenic capacity of BAT or how it may alter the ability of the lamb to thermoregulate.
This study investigated the effect of artificially rearing lambs at warm or cold ambient temperatures on the thermogenic capacity of BAT and the extent to which metabolic rate and the ability to respond to warm and cold challenges was altered by these treatments over the first 9 days of life.
In the ovine foetus brown adipose tissue (BAT) is mainly found in the perirenal region and grows rapidly relative to body weight between 70 to 120 days of gestation (Alexander, 1978). After this stage only a small amount of BAT growth occurs in comparison with that of the whole foetus, and in the case of undernutrition may decline (Alexander, 1978). Maternal cold stress, induced by winter shearing twin-bearing pregnant ewes 8 weeks before parturition improves lamb birth weight and lamb growth rate independently of effects on maternal food intake (Symonds, Bryant and Lomax, 1986 and 1990). At the same time this can stimulate the in vivo capacity for non-shivering thermogenesis in newborn lambs (Stott and Slee, 1985). The following study extends these findings by investigating the extent to which changing the maternal metabolic environment influences BAT development over the final month of gestation.
Thirty-two Bluefaced Leicester × Swaledale ewes were housed individually at ambient temperature (−6 to 19°C) 6 weeks prior to lambing and 2 weeks later 15 ewes were shorn. Ewes were offered daily a diet comprising 200 g barley concentrate and 1 kg chopped hay. Between 116 and 145 days of gestation and within 2 h of birth ewes were humanely slaughtered with an overdose of barbiturate and foetal or neonatal perirenal BAT sampled, born from shorn or unshorn ewes. The thermogenic capacity of BAT was assessed by guanosine-5′-diphosphate (GDP) binding to uncoupling protein in mitochondrial preparations (Cooper, Dascombe, Rothwell and Vale, 1989) and the amount of mitochondrial protein measured from cytochrome Coxidase activity.
Dietary fatty acids have been shown to affect the activity of the immune system in a variety of species through eicosanoid dependent or independent mechanisms (Miles 1998, Calder 2001). MLN and spleen are lymphoid tissues which play a key role in the immune function. Changing the fatty acid composition of these tissues could change the profile of eicosanoid produced by immune cells in these tissues and this could alter the immune response. This study was carried out to establish the extent to which different oil supplements could change the fatty acid composition of MLN and spleen in milk fed calves.
Infection by parasites is a major cause of production losses and mortality in young calves. The problem is most prevalent during the first grazing season (Armour, 1989). Eosinophils are important cellular mediators in immunity to gastrointestinal parasites (Baker et al, 1993), but during an extreme hypersensitivity immune response, degranulating eosinophils may lead to tissue pathology which may favour parasite survival (Miller, 1996). Dietary polyunsaturated fatty acids (PUFA) influence the fatty acid composition of immune tissues and cells (Jaffrey, 1998). n-6 and n-3 fatty acids are known to influence various components of immune response via eicosanoid dependent or independent mechanisms which influence the relative proportions of Th1 and Th2 cytokines, including IL-5 an important regulator of eosinophils maturation and recruitment. This study was carried out to establish the extent to which dietary n-6 or n-3 PUFA source affects the numbers of eosinophils in the gut of calves.
The balance between pro and anti-inflammatory elements of the immune system can be influenced by provision of specific dietary polyunsaturated fatty acids (PUFA) (Calder, 1998). The gut associated lymphoid tissue (GALT) is the largest immune organ and an important regulator of tolerance and sensitivity to dietary and environmental antigens in the gut (Harbige and Fisher, 2001). Changing the fatty acid composition of the gut mucosa could influence the immune function of the GALT. This study was carried out to establish the extent to which dietary n-3 or n-6 PUFA-rich oil supplements could change the fatty acid composition of gut mucosa of the neonatal calf.
Dietary polyunsaturated fatty acids (PUFA) are known to influence the fatty acid composition of immune and inflammatory cell membranes (Yaqoob et al, 1995). Changing the fatty acid composition and the n-6/n-3 PUFA ratio of cell membranes has been reported to have profound effects on immune cell functionality (Blok et al, 1996). Immune responses to Cooperia onchophara, a nematode parasite that infects calves, are usually slow to develop and inappropriate. The aim of this experiment was to establish the extent to which supplementation of pre-ruminant calves with an n-6 or n-3 PUFA source may influence ex-vivo lymphocyte response to an L3 C onchophara antigen.
This paper explores the benefits and limitations of a valuation framework as a management tool within a general insurance operation. Two models are presented, one a model of the firm and the other an option valuation model, which together create a robust framework that enables management to analyse how different decisions would affect both the overall firm value and its distribution amongst investors. The model of the firm assists in understanding how key factors such as the momentum of a general insurance portfolio and the allocation of scarce resources affect the value of the firm. The second model, an option framework for corporate liabilities, highlights the critical distinction between the value of the firm and the value of investors' claims on the firm.
β2-1 fructans are considered to be prebiotics. Current literature indicates that β2-1 fructans may modulate some aspects of immune function, improve the host's ability to respond to certain intestinal infections, and modify some inflammatory outcomes in human subjects. However, there is a need to find out more about the modulation of immune markers by β2-1 fructans in humans. Healthy human subjects aged 45–65 years were randomly allocated to β2-1 fructans (Orafti® Synergy1; 8 g/d; n 22) or the digestible carbohydrate maltodextrin as placebo (n 21) for 4 weeks. Blood, saliva and faecal samples were collected at study entry and after 4 weeks. Immune parameters were measured using the blood and saliva samples and bifidobacteria were measured in the faecal samples. Faecal bifidobacteria numbers increased in the Orafti® Synergy1 group (P < 0·001) and were different at 4 weeks from numbers in the placebo group (P = 0·001). There was no significant effect of Orafti® Synergy1 on any of the immune parameters measured (blood immune cell subsets, total serum Ig, salivary IgA, neutrophil and monocyte phagocytosis of Escherichia coli and respiratory burst in response to E. coli or phorbol ester, natural killer cell activity, T cell activation and proliferation, production of six cytokines by T cells). It is concluded that, compared with maltodextrin, Orafti® Synergy1 has a bifidogenic effect in healthy middle-aged human subjects but does not alter immune responses examined in the absence of an in vivo immune challenge.
The consequences of sub-optimal nutrition through alterations in the macronutrient content of the maternal diet will not simply be reflected in altered neonatal body composition and increased mortality, but are likely to continue into adulthood and confer greater risk of metabolic disease. One mechanism linking manipulations of the maternal environment to an increased risk of later disease is enhanced fetal exposure to glucocorticoids (GC). Tissue sensitivity to cortisol is regulated, in part, by the GC receptor and 11β-hydroxysteroid dehydrogenase (11β-HSD) types 1 and 2. Several studies have shown the effects of maternal undernutrition, particularly low-protein diets, on the programming of GC action in the offspring; however, dietary excess is far more characteristic of the diets consumed by contemporary pregnant women. This study investigated the programming effects of moderate protein supplementation in pigs throughout pregnancy. We have demonstrated an up-regulation of genes involved in GC sensitivity, such as GC receptor and 11β-HSD, in the liver, but have yet to detect any other significant changes in these piglets, with no differences observed in body weight or composition. This increase in GC sensitivity was similar to the programming effects observed following maternal protein restriction or global undernutrition during pregnancy.
The results of audio frequency complex impedance studies for vanadyl phosphate and its hydrates (VOPO4*nH2O;n=0,1,2) are reported. Measurements were made at seventeen frequencies between 10 and 105 Hz over the temperature range 5.5-380K. Two lowtemperature features were observed and are correlated with particular water species between the VOPO4 layers. In light of chemical evidence and compleximpedance measurements on related compounds, it is speculated that VOPCO4*nH2O (Pc = P, As) can be thought of as a mixed nonstoichiometric compound [VO(HPcO4)]x[VOPcO4O4]1-x*nH2O and the solid Brϕnsted acid nature of the compound is related to proton movement between layer pnictates and intralayer waters.
Titres of haemagglutination-inhibiting antibody have been measured repeatedly in young women during a period of 6–8 years after the administration of RA27/3 and Cendehill attenuated rubella vaccines. Mean antibody titres were initially 217 after RA27/3 and 159 after Cendehill, but the difference diminished after the first year. Antibody titres were subsequently well maintained in both groups and did not reveal any need for regular revaccination. Mean titres in the Cendehill group were partly maintained by symptomless reinfection which was commoner after Cendehill than after RA27/3. Significant falls in titre were equally common after both vaccines, but low titres of 30 or less were more frequent in subjects who had received Cendehill.
Mean neutralizing antibody titres were initially 15·4 after RA27/3 vaccine and 9 after Cendehill. Titres remained higher after RA27/3 for 3 years, but the difference then diminished and became insignificant during the fifth year.
Revaccination of women with low antibody titres produced significant increases in 69% of subjects when standard RA27/3 vaccine was used; a special preparation of RA27/3 of higher potency produced a similar number of rises (70%) but elicited higher titres and might occasionally be useful for revaccinating women who are likely to come into contact with rubella. Challenge with RA27/3 vaccine produced weaker responses in women who had experienced natural infection than in those whose antibody was vaccine-induced.
Rises in antibody titre after revaccination consisted mainly of IgG, but traces of IgM antibody were detected in one vaccinee who had recently experienced natural reinfection and in 1 woman with naturally acquired antibody who had been challenged with high titre RA27/3 vaccine.
The increase in fractional rate of protein synthesis (Ks) in the skeletal muscle of growing rats during the transition from fasted to fed state has been explained by the synergistic action of a rise in plasma insulin and branched-chain amino acids (BCAA). Since growing lambs also exhibit an increase in Ks with level of feed intake, the objective of the present study was to determine if this synergistic relationship between insulin and BCAA also occurs in ruminant animals. Six 30 kg fasted (72 h) lambs (8 months of age) received each of four treatments, which were based on continuous infusion into the jugular vein for 6 h of: (1) saline (155 mmol NaCl/l); (2) a mixture of BCAA (0·778 μmol leucine, 0·640 μmol isoleucine and 0·693 μmol valine/min·kg); (3) 18·7 μmol glucose/min·kg (to induce endogenous insulin secretion); (4) co-infusion of BCAA and glucose. Within each period all animals received the same isotope of phenylalanine (Phe) as follows: (1) l-[1-13C]Phe; (2) l-phenyl-[ring 2H5]-alanine; (3) l-[15N]Phe; (4) l-[ring 2,6-3H]Phe. Blood was sampled serially during infusions to measure plasma concentrations of insulin, glucose and amino acids, and plasma free Phe isotopic activity; biopsies were taken 6 h after the beginning of infusions to determine Ks in m. longissimus dorsi and vastus muscle. Compared with control (saline-infused) lambs, Ks was increased by an average of 40 % at the end of glucose infusion, but this effect was not statistically significant in either of the muscles sampled. BCAA infusion, alone or in combination with glucose, also had no significant effect on Ks compared with control sheep. Ks was approximately 60 % greater for vastus muscle than for m. longissimus dorsi (P>0·01), regardless of treatment. It is concluded that there are signals other than insulin and BCAA that are responsible for the feed-induced increase in Ks in muscle of growing ruminant animals.
We investigated the influence of exogenous thyroxine
(T4) administration in conjunction with level of feeding
on adipose tissue and liver growth in postnatal lambs.
Pairs of lambs were fed either 100 g (i.e. low fed) or 200
g (i.e. high fed) of milk powder per litre of reconstituted
milk replacer over the first month of life. Half of the
pairs of lambs were fed a bolus dose of T4 (15 mg (kg body weight)-1)
daily until 8 days of age. Perirenal adipose tissue and hepatic tissue
were sampled at either 8 or 35 days of age. High fed lambs grew faster,
possessed more adipose tissue and had larger livers than low fed lambs
at 8 and 35 days of age. T4 administration resulted in a lower
thermogenic activity (i.e. GDP binding) in adipose tissue at 8 days of age
in low, but not high fed lambs. There was no difference between groups
in colonic temperature or oxygen consumption. Between 17 and 35 days
of age high fed lambs previously treated with T4 had lower daily milk
consumption than untreated siblings, but still attained the same growth
rate. Plasma insulin-like growth factor-I concentrations were greater in
high than low fed lambs, a relationship that was not influenced by T4
treatment. In adipose tissue, iodothyronine 5′ deiodinase activity was
not influenced by T4 administration and was greater in high than low
fed lambs. Hepatic iodothyronine 5′ deiodinase activity was not
influenced by T4 administration in low fed lambs, but was reduced by
T4 in high fed lambs. In conclusion, T4 administration over the first 8
days of life can accelerate the rate of decline in thermogenic activity of
uncoupling protein-1. This effect is not observed when the level of
feeding is increased. Following withdrawal of T4 treatment, high fed
T4-treated lambs were able to maintain the same growth rate as
untreated lambs despite having a lower food intake.