Meta-analysis on anxiety and depression in adult celiac disease.

OBJECTIVE: We used meta-analysis to test hypotheses concerning whether adult celiac disease is reliably linked with anxiety and/or depression. METHOD: We examined published reports on anxiety and depression in adult celiac disease. RESULTS: Eighteen studies on depression and eleven studies on anxiety in adult celiac disease met selection criteria. They show that depression is reliably more common and/or more severe in adults with celiac disease than in healthy adults (overall meta-analysis effect size: 0.97). The fail-safe margin of unpublished reports that would be required to negate the finding exceeds 8000. Adults with celiac disease do not, however, differ reliably in terms of depression from adults with other physical illnesses, nor do they differ reliably from healthy adults or adults with other physical illnesses in terms of anxiety. CONCLUSION: Depression is common in adult celiac disease and resembles the condition in other physical illnesses. We view the findings as support for the notion that non-specific mechanisms mediate emotional disorders in adult celiac disease.

Characterization of annexin A1 glycan binding reveals binding to highly sulfated glycans with preference for highly sulfated heparan sulfate and heparin.

Annexin A1 is a multifunctional, calcium-dependent phospholipid binding protein involved in a host of processes including inflammation, regulation of neuroendocrine signaling, apoptosis, and membrane trafficking. Binding of annexin A1 to glycans has been implicated in cell attachment and modulation of annexin A1 function. A detailed characterization of the glycan binding preferences of annexin A1 using carbohydrate microarrays and surface plasmon resonance served as a starting point to understand the role of glycan binding in annexin A1 function. Glycan array analysis identified annexin A1 binding to a series of sulfated oligosaccharides and revealed for the first time that annexin A1 binds to sulfated non-glycosaminoglycan carbohydrates. Using heparin/heparan sulfate microarrays, highly sulfated heparan sulfate/heparin were identified as preferred ligands of annexin A1. Binding of annexin A1 to heparin/heparan sulfate is calcium- but not magnesium-dependent. An in-depth structure-activity relationship of annexin A1-heparan sulfate interactions was established using chemically defined sugars. For the first time, a calcium-dependent heparin binding protein was characterized with such an approach. N-Sulfation and 2-O-sulfation were identified as particularly important for binding.

Transgenic Leishmania and the immune response to infection.

Genetic manipulation of single-celled organisms such as the Leishmania parasite enables in depth analysis of the consequences of genotypic change on biological function. In probing the immune responses to infection, use of transgenic Leishmania has the potential to unravel both the contribution of the parasite to the infection process and the cellular interactions and mechanisms that characterize the innate and adaptive immune responses of the host. Here, we briefly review recent technical advances in parasite genetics and explore how these methods are being used to investigate parasite virulence factors, elucidate immune regulatory mechanisms and contribute to the development of novel therapeutics for the leishmaniases. Recent developments in imaging technology, such as bioluminescence and intravital imaging, combined with parasite transfection with fluorescent or enzyme-encoding marker genes, provides a rich opportunity for novel assessment of intimate, real-time host-parasite interactions at a previously unexplored level. Further advances in transgenic technology, such as the introduction of robust inducible gene cassettes for expression in intracellular parasite stages or the development of RNA interference methods for down-regulation of parasite gene expression in the host, will further advance our ability to probe host-parasite interactions and unravel disease-promoting mechanisms in the leishmaniases.

A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. The SANAD trial.

OBJECTIVES: To compare clinicians' choice of one of the standard epilepsy drug treatments (carbamazepine or valproate) versus appropriate comparator new drugs. DESIGN: A clinical trial comprising two arms, one comparing new drugs in carbamazepine and the other with valproate. SETTING: A multicentre study recruiting patients with epilepsy from hospital outpatient clinics. PARTICIPANTS: Patients with an adequately documented history of two or more clinically definite unprovoked epileptic seizures within the last year for whom treatment with a single antiepileptic drug represented the best therapeutic option. INTERVENTIONS: Arm A was carbamazepine (CBZ) versus gabapentin (GBP) versus lamotrigine (LTG) versus oxcarbazepine (OXC) versus topiramate (TPM). Arm B valproate (VPS) versus LTG versus TPM. MAIN OUTCOME MEASURES: Time to treatment failure (withdrawal of the randomised drug for reasons of unacceptable adverse events or inadequate seizure control or a combination of the two) and time to achieve a 12-month remission of seizures. Time from randomisation to first seizure, 24-month remission of seizures, incidence of clinically important adverse events, quality of life (QoL) outcomes and health economic outcomes were also considered. RESULTS: Arm A recruited 1721 patients (88% with symptomatic or cryptogenic partial epilepsy and 10% with unclassified epilepsy). Arm B recruited 716 patients (63% with idiopathic generalised epilepsy and 25% with unclassified epilepsy). In Arm A LTG had the lowest incidence of treatment failure and was statistically superior to all drugs for this outcome with the exception of OXC. Some 12% and 8% fewer patients experienced treatment failure on LTG than CBZ, the standard drug, at 1 and 2 years after randomisation, respectively. The superiority of LTG over CBZ was due to its better tolerability but there is satisfactory evidence indicating that LTG is not clinically inferior to CBZ for measures of its efficacy. No consistent differences in QoL outcomes were found between treatment groups. Health economic analysis supported LTG being preferred to CBZ for both cost per seizure avoided and cost per quality-adjusted life-year gained. In Arm B for time to treatment failure, VPS, the standard drug, was preferred to both TPM and LTG, as it was the drug least likely to be associated with treatment failure for inadequate seizure control and was the preferred drug for time to achieving a 12-month remission. QoL assessments did not show any between-treatment differences. The health economic assessment supported the conclusion that VPS should remain the drug of first choice for idiopathic generalised or unclassified epilepsy, although there is a suggestion that TPM is a cost-effective alternative to VPS. CONCLUSIONS: The evidence suggests that LTG may be a clinical and cost-effective alternative to the existing standard drug treatment, CBZ, for patients diagnosed as having partial seizures. For patients with idiopathic generalised epilepsy or difficult to classify epilepsy, VPS remains the clinically most effective drug, although TPM may be a cost-effective alternative for some patients. Three new antiepileptic drugs have recently been licensed in the UK for the treatment of epilepsy (levetiracetam, zonisamide and pregabalin), therefore these drugs should be compared in a similarly designed trial.

Immunization with H1, HASPB1 and MML Leishmania proteins in a vaccine trial against experimental canine leishmaniasis.

The protective capabilities of three Leishmania recombinant proteins - histone 1 (H1) and hydrophilic acylated surface protein B1 (HASPB1) immunized singly, or together as a protein cocktail vaccine with Montanide, and the polyprotein MML immunized with MPL-SE adjuvant - were assessed in beagle dogs. Clinical examination of the dogs was carried out periodically under blinded conditions and the condition of the dogs defined as asymptomatic or symptomatic. At the end of the trial, we were able to confirm that following infection with L. infantum promastigotes, five out of eight dogs immunized with H1 Montanide, and four out of eight dogs immunized with either the combination of HASPB1 with Montanide or the combination of H1+HASPB1 with Montanidetrade mark, remained free of clinical signs, compared with two out of seven dogs immunized with the polyprotein MML and adjuvant MPL-SE, and two out of eight dogs in the control group. The results demonstrate that HASPB1 and H1 antigens in combination with Montanide were able to induce partial protection against canine leishmaniasis, even under extreme experimental challenge conditions.

Short-term changes in maternal and neonatal urinary iodine excretion.

Investigation of maternal urinary iodine (UI) excretion in the immediate antenatal and early postpartum periods showed a precipitous fall in median values from 93 microg/L antenatally to 36 microg/L at delivery subsequently rising to 49 microg/L and 63 microg/L at days 3 and 10 postpartum respectively. The fate of ingested iodine not appearing in the maternal urine is unknown but measurement of UI in babies born to nursing mothers suggested transfer from the mother with median neonatal values of 117 and 159 microg/L being recorded at days 3 and 10. While maternal UI seemed to relatively unaffected by breast feeding, median UI from breast feeding babies (148 microg/L) was significantly greater than in those bottle feeding (50 microg/L). This was also reflected by the finding that no breast feeding baby had a UI values < 50 microg/L in comparison to 50% of bottle feeders. The depressed values in mothers and relatively high values in their infants could present a false picture and suggest the need to defer any investigations of iodine status at this time. The findings do however suggest a need for further investigations aimed at determining the fate of iodine ingested perinatally and its possible physiological significance in maintaining thyroid status in the mother and neonate.

Iodine intake in pregnancy in Ireland--a cause for concern?

BACKGROUND: Adequate dietary iodine intake is necessary to maintain maternal thyroid function at a level permitting normal neuropsychological development of the foetus. AIMS AND METHODS: To determine dietary iodine status by measuring urinary iodine excretion (UIE), proportional to dietary intake, in Irish mothers during the first trimester of pregnancy. RESULTS: Median UIE showed seasonal variations, being lower in summer than in winter. The median values in pregnant women were, summer 45microg/l, winter 68microg/l. Equivalent values for controls were 43 and 91microg/l respectively. UIE required to achieve WHO recommended daily iodine intakes would be 120-180microg/l. In the Irish subjects UIE values suggestive of iodine deficiency (<50microg/l) were observed in 55% of pregnant women tested in summer and 23% in winter. Dairy milk iodine, a major dietary iodine source, showed similar variation. CONCLUSIONS: While there is as yet no available evidence of widespread thyroid hypofunction in the Irish obstetric population, the findings are a cause of concern, which if confirmed by a more comprehensive investigation, may indicate the need for iodine prophylaxis.

Prevention of osteoporosis in glucocorticoid-treated neurology patients.

OBJECTIVES: Iatrogenic, including corticosteroid-induced osteoporosis is preventable with administration of osteoprotective biphosphonates. The best medical practice is published in the National Guidelines: UK Osteoporosis Consensus Group (1998, update 2002). We conducted an audit in prednisolone-treated general neurology patients, to assess compliance to national guidelines, raise awareness of osteoporosis prevention, and improve clinical practice in a tertiary neurology referral centre. METHODS AND RESULTS: Preintervention: Of the 48 cases (21 male) identified twenty-nine (61%) received osteoporosis prophylaxis. Nineteen (40%) were given biphosphonates, while 10 (21%) hormone replacement therapy or calcium and Vitamin D. INTERVENTION: Results were presented to the consultant body. Postintervention: Data were collected prospectively on 48 patients (30 male) in year 2001. Thirty-eight (79%) received prophylaxis: 35 (73%) were started on biphosphonates, while 3 (6%) on calcium and Vitamin D. This process was repeated 2 years later to assess sustainability. Of the 48 patients, 44 (92%) received prophylaxis: 41 (86%) were taking biphosphonates, while 3 (6%) calcium and Vitamin D. CONCLUSION: We present an original and complete audit on osteoporosis prophylaxis in a typical population of neurology patients. Though initial results were similar to previous reports, our audit led to significant improvement in clinical practice. National guidelines could not be followed meticulously, as our centre has no regular access to bone densitometry. Our patient population had other risk factors for osteoporosis apart from steroid use. Therefore, we recommend that neurologists in this setting use osteoporosis prophylaxis for all their patients on long-term corticosteroids.

Epilepsy in the UK: misdiagnosis, mistreatment, and undertreatment? The Wrexham area epilepsy project.

OBJECTIVE: To assess the diagnostic and therapeutic difficulties in patients with epilepsy who had never come into contact with specialist services. METHODS: Assessment was offered to 676 patients diagnosed as having epilepsy and receiving anti-epileptic drug therapy (AED), who had no previous contact with the local epilepsy services. Two hundred and seventy-five patients gave consent and attended for reassessment. We identified the proportion of patients (a) who had previously seen a neurologist, (b) in whom the diagnosis of epilepsy was not secure, (c) in whom planned AED withdrawal could be considered (d) in whom seizure control could be improved. RESULTS: 53/275 (19.3%) of those attending for review had previously been seen by a neurologist. 87/275 (31.6%) patients ultimately received continued specialist care. Diagnostic doubt was expressed in 3/53 (5.6%) and 42/222 (18.9%) of patients diagnosed by neurologist and non-specialist, respectively. Of 133/219 (60.7%) of patients whose epilepsy was in remission, only 6 elected to withdraw or change medication. Of 18 patients with diagnostic doubt who accepted follow-up, 12 successfully stopped treatment. 17/55 (30.9%) patients with active epilepsy (10 partial, 7 generalised) achieved at least a 1 year remission consequent upon treatment in this clinic. In 15 cases this was a first ever remission. CONCLUSION: Approximately 55% of the population of adults receiving treatment for epilepsy have never received specialist advice. Reassessment of these patients uncovers diagnostic uncertainty, failure to classify (leading to sub-optimal therapy) and lack of information and advice about all aspects of epilepsy care. The development of integrated services for people with epilepsy (PWE) must take account of this hidden need. The new General Medical Services contract for general practitioners will bring this need to our attention, and our experience will help predict the measures required to deal with the under-treatent and mistreatment of this group. The majority of PWE, not currently receiving shared care, merit reassessment and approximately one-third will require continued specialist care. Existing services do not have the capacity to process a marked increase in rate of referral. This project informs prioritisation of referrals and service reorganisation.

ARL1 has an essential role in Trypanosoma brucei.

Myristoyl-CoA protein:NMT (N-myristoyl transferase) catalyses the N-myristoylation of cellular proteins with a range of functions and is essential for viability in the protozoan parasites, Leishmania major and Trypanosoma brucei. In our investigations to define the essential downstream targets of NMT, we have focused on the ARF (ADP-ribosylation factor) family of proteins, as growth arrest in Saccharomyces cerevisiae mutants with reduced NMT activity correlates with decreased modification of members of this group of proteins. We have identified nine ARF/ARLs (where ARL stands for ARF-like) encoded in the T. brucei and T. cruzi genomes and ten in L. major. The T. brucei ARL1 protein is expressed only in the mammalian bloodstream form of the parasite, in which it is localized to the Golgi apparatus. RNAi (RNA interference) has been used to demonstrate that ARL1 is essential for viability in these infective cells. Before cell death, depletion of ARL1 protein results in disintegration of the Golgi structure and a delay in exocytosis of the abundant GPI (glycosylphosphatidylinositol)-anchored VSG (variant surface glycoprotein) to the parasite surface.

Sequential studies on thyroid antibodies during pregnancy.

Thyroid antibodies were measured sequentially in 25 pregnant women from a Sri Lankan population. A high prevalence of antithyroid antibodies, particularly antithyroglobulin antibodies (TgAb) had previously been demonstrated in female schoolchildren drawn from this population. In the present study TgAb were detected in 36.8% of nonpregnant controls while thyroid peroxidase antibody (TPOAb) positivity was present in 26.3%. The prevalence of both antibodies in the pregnancy study group showed a progressive decline compared to nonpregnant controls throughout gestation becoming undetectable in the third trimester. The results are consistent with an immunosuppressive effect of pregnancy in a population in whom high thyroid autoantibody titers may have resulted from a recent salt iodization program.

PET evaluation of the uptake of N-[11C]methyl CP-643,051, an NK1 receptor antagonist, in the living porcine brain.

Antagonists of neurokinin receptors such as CP-643,051 are presently under investigation as potential antidepressants, but little is known about the brain uptake and distribution of these agents. We developed a method for the efficient N-[11C]methylation of CP-122,721, yielding the NK1 antagonist N-[11C]methyl CP-643,051. The brain uptake and distribution of N-[11C]methyl CP-643,051 were studied by positron emission tomography (PET) in the anaesthetized pig, first in a baseline condition, and again after displacement of specific binding with the NK1 receptor antagonist L-732,138 (0.6 mg/kg, i.v.). In order to validate this displacement procedure, we tested the effects of L-732,138 on cerebral blood flow (CBF) in one pig. We found that N-[11C]methyl CP-643,051 had a distribution volume close to 3 ml g(-1), and a binding potential (pB) of 0.3 in the pig striatum; this binding was displaceable by the L-732,138 pre-treatment, which evoked a small (10-20%) global increase in CBF. We conclude that of N-[11C]methyl CP-643,051 may serve as a lead structure for the development of PET NK-1 ligands of higher specific binding in vivo.

Inappropriate requests for serum anti-epileptic drug levels in hospital practice.

BACKGROUND: Serum anti-epileptic drug (AED) levels are indicated to assess AED adherence or toxicity, and are applicable to only a few AEDs. Expert consensus views on the clinical role of serum AED levels are summarized in the evidence-based guidelines published by the Scottish Intercollegiate Guidelines Network. AIM: To examine local compliance with these guidelines. DESIGN: Retrospective case-note audit. METHODS: We included all serum AED level measurements requested from our hospital over two months. Our audit standards were first, that serum AED levels should be requested only for suspicion of poor AED adherence or toxicity ('indication-compliant'), and secondly, for 'full compliance', that 'indication-compliant' requests should be made only for AEDs with established dose-response and dose-toxicity relationships (phenytoin, carbamazepine, phenobarbitone). RESULTS: There were 114 measurements in 102 patients. Serum AED level requests were for phenytoin (n = 50), valproate (n = 27), carbamazepine (n = 22), lamotrigine (n = 8), phenobarbitone (n = 7), and were made by physicians (n = 46), paediatricians (n = 30), neurologists (n = 15), neurosurgeons (n = 14), psychiatrists (n = 7), and intensivists (n = 2). AED toxicity was queried in 29 requests (25%), and adherence in 10 (9%); thus 34% of requests were 'indication-compliant'. However, 16 of these were for valproate or lamotrigine; thus only 23 requests (20%) were 'fully compliant'. Clinical management changed in only 17 of the 47 patients whose levels fell outside target ranges, and only two of these followed indication-compliant AED measurement. DISCUSSION: The audit identified a failure locally to comply with standard evidence-based guidelines. If, as is likely, this reflects practice elsewhere in the UK, there are potentially major clinical management and resource implications.

A comparison of adult onset and "classical" idiopathic generalised epilepsy.

OBJECTIVES: To report the characteristics of a population of patients with idiopathic generalised epilepsy (IGE) with age of onset over 20 years, and compare them with patients with "classical" IGE. METHODS: Data were collected from a computerised database of all patients with IGE attending a regional adult epilepsy clinic. Demographic data, epilepsy characteristics, and treatment outcomes were recorded. RESULTS: 72 patients with IGE of a total population of 844 had an age of onset over 20 years (8.5%). There was similar incidence of family history of epilepsy, EEG findings, and remission rates between those with a younger and older age of onset of IGE. There was a lower incidence of previous febrile convulsions in patients with adult onset. There were fewer patients with absence seizures in the adult onset group (15.3% v 46.4% in the "classical" group). CONCLUSIONS: IGE with onset later than the third decade was rare in the population studied. Prolonged EEG in selected patients may be helpful in diagnosing adult onset IGE, but the diagnosis of epilepsy remains clinical. Adult onset IGE shares many features with "classical" IGE, including EEG findings and prognosis, and is likely to represent a genetic epilepsy.

The relationship between treatment with valproate, lamotrigine, and topiramate and the prognosis of the idiopathic generalised epilepsies.

OBJECTIVE: To examine a large population with idiopathic generalised epilepsy (IGE), and estimate the overall remission rates for the IGEs and subsyndromes in a clinic based sample. Remission rates on valproate, lamotrigine, topiramate, and combinations of these antiepileptic drugs were estimated and factors predicting outcome examined. METHODS: All patients with IGE were identified from a computerised database and EEG records at large adult and paediatric epilepsy clinics. Data were recorded retrospectively on demographics and clinical information, seizure types and syndrome diagnosis, antiepileptic drug treatment details, and remission rates. RESULTS: 54.3% of 962 patients had achieved a one year period of remission; this was most likely with valproate monotherapy (52.1%), with lower rates for lamotrigine and topiramate (16.7% and 34.6%, respectively). The combination of valproate and lamotrigine achieved a remission rate of 15.3%. The factor most predictive of a response to a particular antiepileptic drug regimen was the rank order in which it was given. Relapse rate was high (79.9%) after antiepileptic drug withdrawal in remission, particularly with juvenile myoclonic epilepsy (93.6%). CONCLUSIONS: Valproate may be the most effective antiepileptic drug in the treatment of the IGEs. Combination therapy should be initiated if an adequate trial of valproate monotherapy is not effective, rather than switching to alternative monotherapy. Antiepileptic drug treatment needs to be lifelong in many adult patients with IGE.

Evolution of thyroid autoimmunity during iodine prophylaxis--the Sri Lankan experience.

OBJECTIVE: To study the evolution of thyroid autoimmunity, in relation to the change in goitre prevalence, during 3 Years of iodine prophylaxis in Sri Lanka. METHODS: Two groups of Sri Lankan schoolgirls between the ages of 10.8 and 17.5 Years were studied in 1998 (401 girls) and 2001 (282 girls). A prospective study was performed in 42 schoolgirls who were thyroid autoantibody (Ab)-positive (+ve) in 1998. Anthropometric measures, urinary iodine excretion (UIE), thyroid Volume, free thyroxine, free tri-iodothyronine, TSH, and thyroglobulin (Tg) and thyroid peroxidase (TPO) Ab were evaluated in all 683 girls. RESULTS: Goitre prevalence was significantly lower in 2001 compared with 1998 related to age (2.9% compared with 20.2%) and body surface area (11.6% compared with 40.8%), although UIE was unchanged. Prevalence of thyroid Ab in 2001 was also lower (23.4% compared with 49.9%); among those with the Ab, 34.8% had TgAb alone and 46.9% had a combination of TgAb+TPOAb, compared with 82.0% TgAb alone in 1998. In 2001, subclinical hypothyroidism was more frequent in Ab+ve (6.3%) than Ab-negative girls (1.0%). A cohort of 42 Ab+ve schoolgirls in 1998 (34 with TgAb alone, eight with TgAb+TPOAb) were evaluated again in 2001. Only 10 of them (23.8%) remained Ab+ve (mostly TPOAb+/-TgAb) in 2001. CONCLUSIONS: This study demonstrates that: (1) in 2001, goitre prevalence and thyroid autoimmunity rates were significantly lower than in 1998; (2) the pattern of thyroid Ab was different in the two surveys; (3) in 2001 alone, the occurrence of hypothyroidism was correlated with the presence of thyroid autoimmunity. These results indicate an evolution of thyroid autoimmune markers during the course of iodine prophylaxis, which has not been described before.

Foramen ovale recordings: a presurgical investigation in epilepsy.

The aim of our study was to determine when foramen ovale recordings add useful information to scalp EEG recordings and magnetic resonance imaging (MRI) with hippocampal measurements. We evaluated the outcome of 79 patients with non-lesional partial epilepsy with presumed temporal seizure onset. Ictal foramen ovale recordings were performed in 16 patients with normal MRI ('MRI-negative group') and 41 patients with lateralizing MRI but non-lateralizing scalp EEG ('discordant group'). 22 patients with concordant MRI and scalp EEG were not investigated with foramen ovale recordings ('concordant group'). The seizure-free rate was higher in concordant than discordant patients despite additional investigation with foramen ovale electrodes (71 and 55% seizure free, respectively). No useful localizing information was added with foramen ovale recordings in MRI-negative patients.