Alopecia areata is characterized by dysregulation in systemic type 17 and type 2 cytokines, which may contribute to disease-associated psychological morbidity.

BACKGROUND: Alopecia areata (AA) is a common autoimmune disease, causing patchy hair loss that can progress to involve the entire scalp (totalis) or body (universalis). CD8+ NKG2D+ T cells dominate hair follicle pathogenesis, but the specific mechanisms driving hair loss are not fully understood. OBJECTIVES: To provide a detailed insight into the systemic cytokine signature associated with AA, and to assess the association between cytokines and depression. METHODS: We conducted multiplex analysis of plasma cytokines from patients with AA, patients with psoriatic arthritis (PsA) and healthy controls. We used the Hospital Anxiety and Depression Scale (HADS) to assess the occurrence of depression and anxiety in our cohort. RESULTS: Our analysis identified a systemic inflammatory signature associated with AA, characterized by elevated levels of interleukin (IL)-17A, IL-17F, IL-21 and IL-23 indicative of a type 17 immune response. Circulating levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25) were also significantly increased in AA. In comparison with PsA, AA was associated with higher levels of IL-17F, IL-17E and IL-23. We hypothesized that circulating inflammatory cytokines may contribute to wider comorbidities associated with AA. Our assessment of psychiatric comorbidity in AA using HADS scores showed that 18% and 51% of people with AA experienced symptoms of depression and anxiety, respectively. Using linear regression modelling, we identified that levels of IL-22 and IL-17E are positively and significantly associated with depression. CONCLUSIONS: Our data highlight changes in both type 17 and type 2 cytokines among people with AA, suggesting that complex systemic cytokine profiles may contribute both to the pathogenesis of AA and to the associated depression. What's already known about this topic? NKG2D+ CD8+ T cells cause hair loss in alopecia areata (AA) but the immunological mechanisms underlying the disease are not fully understood. AA is associated with changes in levels of interleukin (IL)-6, tumour necrosis factor-α, IL-1ß and type 17 cytokines. Psychiatric comorbidity is common among people with AA. What does this study add? People with AA have increased plasma levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25), in addition to the type 17 cytokines IL-17A, IL-21, IL-23 and IL-17F. Levels of IL-17E and IL-22 positively predict depression score. What is the translational message? AA is associated with increased levels of multiple inflammatory cytokines, implicating both type 17- and type 2 immune pathways. Our data indicate that therapeutic strategies for treating AA may need to address the underlying type 17- and type 2 immune dysregulation, rather than focusing narrowly on the CD8+ T-cell response. An immunological mechanism might contribute directly to the depression observed in people with AA.

Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis.

Inflammatory illness is associated with depression. Preclinical work has shown that chemokines are linked with peripheral-central crosstalk and may be important in mediating depressive behaviours. We sought to establish what evidence exists that differences in blood or cerebrospinal fluid chemokine concentration discriminate between individuals with depression and those without. Following PRISMA guidelines, we systematically searched Embase, PsycINFO and Medline databases. We included participants with physical illness for subgroup analysis, and excluded participants with comorbid psychiatric diagnoses. Seventy-three studies met the inclusion criteria for the meta-analysis. Individuals with depression had higher levels of blood CXCL4 and CXCL7 and lower levels of blood CCL4. Sensitivity analysis of studies with only physically healthy participants identified higher blood levels of CCL2, CCL3, CCL11, CXCL7 and CXCL8 and lower blood levels of CCL4. All other chemokines examined did not reveal significant differences (blood CCL5, CCL7, CXCL9, CXCL10 and cerebrospinal fluid CXCL8 and CXCL10). Analysis of the clinical utility of the effect size of plasma CXCL8 in healthy individuals found a negative predictive value 93.5%, given the population prevalence of depression of 10%. Overall, our meta-analysis finds evidence linking abnormalities of blood chemokines with depression in humans. Furthermore, we have demonstrated the possibility of classifying individuals with depression based on their inflammatory biomarker profile. Future research should explore putative mechanisms underlying this association, attempt to replicate existing findings in larger populations and aim to develop new diagnostic and therapeutic strategies.

Lamotrigine induced lymphadenopathy: Case report and literature review.

Lamotrigine is an anti-epileptic drug often prescribed to children and young females. Side effects include rash, dizziness and diplopia. Over the last twenty years, two cases of lymphadenopathy due to lamotrigine have been reported. We will present the case of a 17-year old female with persistent lymphadenopathy due to lamotrigine. The purpose of this case report is to inform clinicians that lymphadenopathy is a possible side effect of lamotrigine and to highlight the need for further research.

Decreased hippocampal translocator protein (18 kDa) expression in alcohol dependence: a [11C]PBR28 PET study.

Repeated withdrawal from alcohol is clinically associated with progressive cognitive impairment. Microglial activation occurring during pre-clinical models of alcohol withdrawal is associated with learning deficits. We investigated whether there was microglial activation in recently detoxified alcohol-dependent patients (ADP), using [11C]PBR28 positron emission tomography (PET), selective for the 18kDa translocator protein (TSPO) highly expressed in activated microglia and astrocytes. We investigated the relationship between microglial activation and cognitive performance. Twenty healthy control (HC) subjects (45±13; M:F 14:6) and nine ADP (45±6, M:F 9:0) were evaluated. Dynamic PET data were acquired for 90 min following an injection of 331±15 MBq [11C]PBR28. Regional volumes of distribution (VT) for regions of interest (ROIs) identified a priori were estimated using a two-tissue compartmental model with metabolite-corrected arterial plasma input function. ADP had an ~20% lower [11C]PBR28 VT, in the hippocampus (F(1,24) 5.694; P=0.025), but no difference in VT in other ROIs. Hippocampal [11C]PBR28 VT was positively correlated with verbal memory performance in a combined group of HC and ADP (r=0.720, P<0.001), an effect seen in HC alone (r=0.738; P=0.001) but not in ADP. We did not find evidence for increased microglial activation in ADP, as seen pre-clinically. Instead, our findings suggest lower glial density or an altered activation state with lower TSPO expression. The correlation between verbal memory and [11C]PBR28 VT, raises the possibility that abnormalities of glial function may contribute to cognitive impairment in ADP.

Does a history of depression actually mediate smoking-related pain? Findings from a cross-sectional general population-based study.

BACKGROUND: Smokers report more pain and worse functioning. The evidence from pain clinics suggests that depression affects this relationship: The association between smoking and chronic pain is weakened when controlling for depression. This study explored the relationship between smoking, pain and depression in a large general population-based cohort (Generation Scotland: Scottish Family Health Study). METHODS: Chronic pain measures (intensity, disability), self-reported smoking status and a history of major depressive disorder (MDD) were analysed. A multivariate analysis of covariance determined whether smoking status was associated with both pain measures and a history of depressive illness. Using a statistical mediation model any mediating effect of depression on the relationship between smoking and chronic pain was sought. RESULTS: Of all 24,024 participants, 30% (n = 7162) reported any chronic pain. Within this chronic pain group, 16% (n = 1158) had a history of MDD; 7108 had valid smoking data: 20% (n = 1408) were current smokers, 33% (n = 2351) former and 47% (n = 3349) never smokers. Current smokers demonstrated higher pain intensity and pain-related disability scores compared with former and non-smokers (p < 0.001 for all analyses). From the mediation model, the effect on pain intensity decreased (p < 0.001), indicating that the relationship between smoking and a history of depression contributes significantly to the effect of smoking on pain intensity. When applied to smoking-related pain disability, there was no mediation effect. CONCLUSIONS: In contrast to smokers treated in pain clinics, a history of MDD mediated the relationship between smoking and pain intensity, but not pain-related disability in smokers in the community.

Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis.

OBJECTIVE: An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta-analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view. METHOD: Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task. RESULTS: Impairments were found for all 11 test-measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26-0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test-measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression. CONCLUSION: This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta-analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.

Which neurological diseases are most likely to be associated with "symptoms unexplained by organic disease".

Many patients with a diagnosis of neurological disease, such as multiple sclerosis, have symptoms or disability that is considered to be in excess of what would be expected from that disease. We aimed to describe the overall and relative frequency of symptoms 'unexplained by organic disease' in patients attending general neurology clinics with a range of neurological disease diagnoses. Newly referred outpatients attending neurology clinics in all the NHS neurological centres in Scotland, UK were recruited over a period of 15 months. The assessing neurologists recorded their initial neurological diagnoses and also the degree to which they considered the patient's symptoms to be explained by organic disease. Patients completed self report scales for both physical and psychological symptoms. The frequency of symptoms unexplained by organic disease was determined for each category of neurological disease diagnoses. 3,781 patients participated (91% of those eligible). 2,467 patients had a diagnosis of a neurological disease (excluding headache disorders). 293 patients (12%) of these patients were rated as having symptoms only "somewhat" or "not at all" explained by that disease. These patients self-reported more physical and more psychological symptoms than those with more explained symptoms. No category of neurological disease was more likely than the others to be associated with such symptoms although patients with epilepsy had fewer. A substantial proportion of new outpatients with diagnoses of neurological disease also have symptoms regarded by the assessing neurologist as being unexplained by that disease; no single neurological disease category was more likely than others to be associated with this phenomenon.

Guided self-help for functional (psychogenic) symptoms: a randomized controlled efficacy trial.

OBJECTIVES: Functional (psychogenic or somatoform) symptoms are common in neurology clinics. Cognitive-behavioral therapy (CBT) can be an effective treatment, but there are major obstacles to its provision in practice. We tested the hypothesis that adding CBT-based guided self-help (GSH) to the usual care (UC) received by patients improves outcomes. METHODS: We conducted a randomized trial in 2 neurology services in the United Kingdom. Outpatients with functional symptoms (rated by the neurologist as "not at all" or only "somewhat" explained by organic disease) were randomly allocated to UC or UC plus GSH. GSH comprised a self-help manual and 4 half-hour guidance sessions. The primary outcome was self-rated health on a 5-point clinical global improvement scale (CGI) at 3 months. Secondary outcomes were measured at 3 and 6 months. RESULTS: In this trial, 127 participants were enrolled, and primary outcome data were collected for 125. Participants allocated to GSH reported greater improvement on the primary outcome (adjusted common odds ratio on the CGI 2.36 [95% confidence interval 1.17-4.74; p = 0.016]). The absolute difference in proportion "better" or "much better" was 13% (number needed to treat was 8). At 6 months the treatment effect was no longer statistically significant on the CGI but was apparent in symptom improvement and in physical functioning. CONCLUSIONS: CBT-based GSH is feasible to implement and efficacious. Further evaluation is indicated. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CBT-based GSH therapy improves self-reported general health, as measured by the CGI, in patients with functional neurologic symptoms.

Disability, distress and unemployment in neurology outpatients with symptoms 'unexplained by organic disease'.

OBJECTIVES: To determine the disability, distress and employment status of new neurology outpatients with physical symptoms unexplained by organic disease and to compare them with patients with symptoms explained by organic disease. METHODS: As part of a cohort study (the Scottish Neurological Symptoms Study) neurologists rated the extent to which each new patient's symptoms were explained by organic disease. Patients whose symptoms were rated as 'not at all' or only 'somewhat' explained by disease were considered cases, and those whose symptoms were 'largely' or 'completely' explained by disease were considered controls. All patients completed self-ratings of disability, health status (Medical Outcomes Study Short Form 12-Item Scale (SF-12)) and emotional distress (Hospital Anxiety and Depression Scale) and also reported their employment and state financial benefit status. RESULTS: 3781 patients were recruited: 1144 (30%) cases and 2637 (70%) controls. Cases had worse physical health status (SF-12 score 42 vs 44; difference in means 1.7 (95% CI -2.5 to 0.9)) and worse mental health status (SF-12 score 43 vs 47; difference in means -3.5 (95% CI -4.3 to to 2.7)). Unemployment was similar in cases and controls (50% vs 50%) but cases were more likely not to be working for health reasons (54% vs 37% of the 50% not working; OR 2.0 (95% CI 1.6 to 2.4)) and also more likely to be receiving disability-related state financial benefits (27% vs 22%; (OR 1.3, 95% CI 1.1 to 1.6)). CONCLUSIONS: New neurology patients with symptoms unexplained by organic disease have more disability-, distress- and disability-related state financial benefits than patients with symptoms explained by disease.

Who is referred to neurology clinics?--the diagnoses made in 3781 new patients.

OBJECTIVE: Information on the nature and relative frequency of diagnoses made in referrals to neurology outpatient clinics is an important guide to priorities in services, teaching and research. Previous studies of this topic have been limited by being of only single centres or lacking in detail. We aimed to describe the neurological diagnoses made in a large series of referrals to neurology outpatient clinics. METHOD: Newly referred outpatients attending neurology clinics in all the NHS neurological centres in Scotland, UK were recruited over a period of 15 months. The assessing neurologists recorded the initial diagnosis they made. An additional rating of the degree to which the neurologist considered the patient's symptoms to be explained by disease was used to categorise those diagnoses that simply described a symptom such as 'fatigue'. RESULTS: Three thousand seven hundred and eighty-one patients participated (91% of those eligible). The commonest categories of diagnosis made were: headache (19%), functional and psychological symptoms (16%), epilepsy (14%), peripheral nerve disorders (11%), miscellaneous neurological disorders (10%), demyelination (7%), spinal disorders (6%), Parkinson's disease/movement disorders (6%), and syncope (4%). Detailed breakdowns of each category are provided. CONCLUSIONS: Headache, functional/psychological disorders and epilepsy are the most common diagnoses in new patient referral to neurological services. This information should be used to shape priorities for services, teaching and research.

Neurology out-patients with symptoms unexplained by disease: illness beliefs and financial benefits predict 1-year outcome.

BACKGROUND: Patients whose symptoms are 'unexplained by disease' often have a poor symptomatic outcome after specialist consultation, but we know little about which patient factors predict this. We therefore aimed to determine predictors of poor subjective outcome for new neurology out-patients with symptoms unexplained by disease 1 year after the initial consultation. METHOD: The Scottish Neurological Symptom Study was a 1-year prospective cohort study of patients referred to secondary care National Health Service neurology clinics in Scotland (UK). Patients were included if the neurologist rated their symptoms as 'not at all' or only 'somewhat explained' by organic disease. Patient-rated change in health was rated on a five-point Clinical Global Improvement (CGI) scale ('much better' to 'much worse') 1 year later. RESULTS: The 12-month outcome data were available on 716 of 1144 patients (63%). Poor outcome on the CGI ('unchanged', 'worse' or 'much worse') was reported by 482 (67%) out of 716 patients. The only strong independent baseline predictors were patients' beliefs [expectation of non-recovery (odds ratio [OR] 2.04, 95% confidence interval [CI] 1.40-2.96), non-attribution of symptoms to psychological factors (OR 2.22, 95% CI 1.51-3.26)] and the receipt of illness-related financial benefits (OR 2.30, 95% CI 1.37-3.86). Together, these factors predicted 13% of the variance in outcome. CONCLUSIONS: Of the patients, two-thirds had a poor outcome at 1 year. Illness beliefs and financial benefits are more useful in predicting poor outcome than the number of symptoms, disability and distress.

Magnetic resonance imaging studies in bipolar disorder and schizophrenia: meta-analysis.

BACKGROUND: Several magnetic resonance imaging (MRI) studies have identified structural abnormalities in association with bipolar disorder. The literature is, however, heterogeneous and there is remaining uncertainty about which brain areas are pivotal to the pathogenesis of the condition. AIMS: To identify, appraise and summarise volumetric MRI studies of brain regions comparing bipolar disorder with an unrelated control group and individuals with schizophrenia. METHOD: A systematic review and random-effects meta-analysis was carried out to identify key areas of structural abnormality in bipolar disorder and whether the pattern of affected areas separated bipolar disorder from schizophrenia. Significant heterogeneity was explored using meta-regression. RESULTS: Participants with bipolar disorder are characterised by whole brain and prefrontal lobe volume reductions, and also by increases in the volume of the globus pallidus and lateral ventricles. In comparison with schizophrenia, bipolar disorder is associated with smaller lateral ventricular volume and enlarged amygdala volume. Heterogeneity was widespread and could be partly explained by clinical variables and year of publication, but generally not by differences in image acquisition. CONCLUSIONS: There appear to be robust changes in brain volume in bipolar disorder compared with healthy volunteers, although most changes do not seem to be diagnostically specific. Age and duration of illness appear to be key issues in determining the magnitude of observed effect sizes.

Symptoms 'unexplained by organic disease' in 1144 new neurology out-patients: how often does the diagnosis change at follow-up?

It has been previously reported that a substantial proportion of newly referred neurology out-patients have symptoms that are considered by the assessing neurologist as unexplained by 'organic disease'. There has however been much controversy about how often such patients subsequently develop a disease diagnosis that, with hindsight, would have explained the symptoms. We aimed to determine in a large sample of new neurology out-patients: (i) what proportion are assessed as having symptoms unexplained by disease and the diagnoses given to them; and (ii) how often a neurological disorder emerged which, with hindsight, explained the original symptoms. We carried out a prospective cohort study of patients referred from primary care to National Health Service neurology clinics in Scotland, UK. Measures were: (i) the proportion of patients with symptoms rated by the assessing neurologist as 'not at all' or only 'somewhat explained' by 'organic disease' and the neurological diagnoses recorded at initial assessment; and (ii) the frequency of unexpected new diagnoses made over the following 18 months (according to the primary-care physician). One thousand four hundred and forty-four patients (30% of all new patients) were rated as having symptoms 'not at all' or only 'somewhat explained' by 'organic disease'. The most common categories of diagnosis were: (i) organic neurological disease but with symptoms unexplained by it (26%); (ii) headache disorders (26%); and (iii) conversion symptoms (motor, sensory or non-epileptic attacks) (18%). At follow-up only 4 out of 1030 patients (0.4%) had acquired an organic disease diagnosis that was unexpected at initial assessment and plausibly the cause of the patients' original symptoms. Eight patients had died at follow-up; five of whom had initial diagnoses of non-epileptic attacks. Seven other types of diagnostic change with very different implications to a 'missed diagnosis' were found and a new classification of diagnostic revision is presented. One-third of new neurology out-patients are assessed as having symptoms 'unexplained by organic disease'. A new diagnosis, which with hindsight explained the original symptoms, rarely became apparent to the patient's primary care doctor in the 18 months following the initial hospital consultation.

Predicting genetic merit for mastitis and fertility in dairy cattle using genome wide selection and high density SNP screens.

Two novel methods for genome wide selection (GWS) were examined for predicting the genetic merit of animals using SNP information alone. A panel of 1,546 dairy bulls with reliable EBVs was genotyped for 15,380 SNPs that spanned the whole bovine genome. Two complexity reduction methods were used, partial least squares (PLS) and regression using a genetic algorithm (GAR), to find optimal solutions of EBVs against SNP information. Extensive internal cross-validation was used tofind the best predictive models followed by external validation (without direct use of the pedigree or SNP location). Both PLS and GAR provided both accurate fit to the training data set for somatic cell count (SCC) (max r = 0.83) and fertility (max r = 0.88) and showed an accuracy of prediction of r = 0.47 for SCC, and r = 0.72 for fertility. This is the first empirical demonstration that genome wide selection can account for a very high proportion of additive genetic variation in fitness traits whilst exploiting only a small percentage of available SNP information, without use of pedigree or QTL mapping. PLS was computationally more efficient than GAR.

Investigation and control of a cluster of penicillin non-susceptible Streptococcus pneumoniae infections in a care home.

Two elderly residents of a care home were hospitalised with pneumonia over a period of one month. They had bacteraemia with penicillin non-susceptible Streptococcus pneumoniae (PNSP) and both died. All residents and staff of the care home were screened for PNSP using nasopharyngeal swabs, with one resident and one member of staff found to be asymptomatic carriers. Oral rifampicin was given to the carriers. All four strains were found to be serotype 14, and multilocus sequence typing (MLST) showed ST2652, not previously detected in Scotland. Review of care home residents showed that pneumococcal vaccination coverage was low (63%). This is similar to rates found in those aged > or =65 years in the general population and needs to be improved upon.

Genome-wide genetic diversity of Holstein Friesian cattle reveals new insights into Australian and global population variability, including impact of selection.

Past breeding strategies for dairy cattle have been very effective in producing rapid genetic gain to achieve industry targets and raise profitability. Such gains have been largely facilitated by intense selection of sires combined with the use of artificial insemination. However, this practice can potentially limit the level of genetic diversity through inbreeding and selection plateaus. The rate of inbreeding in Australia is increasing, primarily as a result of semen importation from a small number of prominent bulls from the USA. The effect of this genetic influx in the Australian dairy cattle population is poorly understood both in terms of diversity and local adaptation/divergence. This study uses 845 genome-wide SNP genetic markers and 431 bulls to characterize the level of genetic diversity and genetic divergence within the Australian and international Holstein Friesian dairy population. No significant differences in genetic diversity (as measured by heterozygosity [H(o)] and allelic richness [A]) were observed over the 25-year time period (1975-1999) for bulls used in Australia. The importation of foreign semen into Australia has increased the effective population size until it was in effect a sub-sample of the global population. Our data indicate that most individuals are equally closely related to one another, regardless of country of origin and year of birth. In effect, the global population can be considered as one single population unit. These results indicate that inbreeding, genetic drift and selection has had little effect at reducing genetic diversity and differentiating the Australian Holstein Friesian population at a genome-wide level.

International spinal research trust research strategy. III: A discussion document.

STUDY DESIGN: Discussion document. OBJECTIVES/METHODS: To review the Research Strategy of the International Spinal Research Trust (ISRT), which identifies key areas of basic and clinical research that are likely to be beneficial in developing potential treatments for spinal cord injury for funding. This strategy is intended to both guide the programme of research towards areas of priority and stimulate discussion of the different avenues of research. This latest document has been developed to take into account the scientific progress in the 6 years since publication of the previous Research Strategy. RESULTS/DISCUSSION: The latest scientific developments in research designed to repair the spinal cord and restore function following injury and how they might impact on spinal cord injury research are highlighted.

Hydrops fetalis associated with pulmonary hypoplasia in Dexter calves.

The occurrence of severe fetal dystocia due to hydrops fetalis associated with pulmonary aplasia in two male and pulmonary hypoplasia in one female Australian Dexter fetuses from two herds is described. Obstetrical intervention by caesarean section was required for delivery of the fetuses, with mortalities in one dam and the 3 calves. Clinical, pathological and genetic features are tabulated to assist in distinguishing pulmonary hypoplasia-associated hydrops fetalis from the more prevalent disorder of chondrodysplasia in Dexter cattle. Anasarca and complete absence or presence of only rudimentary lung tissue in a large thoracic cavity clearly distinguishes this entity from the lesions of Dexter chondrodysplasia that include severe micromelia and abundant lung tissue in a small thoracic cavity with shortened spine and rib cage. Pedigree information suggested that Dexter hydrops may be transmitted in an autosomal recessive manner.