Accelerated cortical thinning and volume reduction over time in young people at high genetic risk for bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a familial psychiatric disorder associated with frontotemporal and subcortical brain abnormalities. It is unclear whether such abnormalities are present in relatives without BD, and little is known about structural brain trajectories in those at risk. METHOD: Neuroimaging was conducted at baseline and at 2-year follow-up interval in 90 high-risk individuals with a first-degree BD relative (HR), and 56 participants with no family history of mental illness who could have non-BD diagnoses. All 146 subjects were aged 12-30 years at baseline. We examined longitudinal change in gray and white matter volume, cortical thickness, and surface area in the frontotemporal cortex and subcortical regions. RESULTS: Compared to controls, HR participants showed accelerated cortical thinning and volume reduction in right lateralised frontal regions, including the inferior frontal gyrus, lateral orbitofrontal cortex, frontal pole and rostral middle frontal gyrus. Independent of time, the HR group had greater cortical thickness in the left caudal anterior cingulate cortex, larger volume in the right medial orbitofrontal cortex and greater area of right accumbens, compared to controls. This pattern was evident even in those without the new onset of psychopathology during the inter-scan interval. CONCLUSIONS: This study suggests that differences previously observed in BD are developing prior to the onset of the disorder. The pattern of pathological acceleration of cortical thinning is likely consistent with a disturbance of molecular mechanisms responsible for normal cortical thinning. We also demonstrate that neuroanatomical differences in HR individuals may be progressive in some regions and stable in others.

Structural dysconnectivity of key cognitive and emotional hubs in young people at high genetic risk for bipolar disorder.

Emerging evidence suggests that psychiatric disorders are associated with disturbances in structural brain networks. Little is known, however, about brain networks in those at high risk (HR) of bipolar disorder (BD), with such disturbances carrying substantial predictive and etiological value. Whole-brain tractography was performed on diffusion-weighted images acquired from 84 unaffected HR individuals with at least one first-degree relative with BD, 38 young patients with BD and 96 matched controls (CNs) with no family history of mental illness. We studied structural connectivity differences between these groups, with a focus on highly connected hubs and networks involving emotional centres. HR participants showed lower structural connectivity in two lateralised sub-networks centred on bilateral inferior frontal gyri and left insular cortex, as well as increased connectivity in a right lateralised limbic sub-network compared with CN subjects. BD was associated with weaker connectivity in a small right-sided sub-network involving connections between fronto-temporal and temporal areas. Although these sub-networks preferentially involved structural hubs, the integrity of the highly connected structural backbone was preserved in both groups. Weaker structural brain networks involving key emotional centres occur in young people at genetic risk of BD and those with established BD. In contrast to other psychiatric disorders such as schizophrenia, the structural core of the brain remains intact, despite the local involvement of network hubs. These results add to our understanding of the neurobiological correlates of BD and provide predictions for outcomes in young people at high genetic risk for BD.

Abnormalities in left inferior frontal gyral thickness and parahippocampal gyral volume in young people at high genetic risk for bipolar disorder.

BACKGROUND: Fronto-limbic structural brain abnormalities have been reported in patients with bipolar disorder (BD), but findings in individuals at increased genetic risk of developing BD have been inconsistent. We conducted a study in adolescents and young adults (12-30 years) comparing measures of fronto-limbic cortical and subcortical brain structure between individuals at increased familial risk of BD (at risk; AR), subjects with BD and controls (CON). We separately examined cortical volume, thickness and surface area as these have distinct neurodevelopmental origins and thus may reflect differential effects of genetic risk. METHOD: We compared fronto-limbic measures of grey and white matter volume, cortical thickness and surface area in 72 unaffected-risk individuals with at least one first-degree relative with bipolar disorder (AR), 38 BD subjects and 72 participants with no family history of mental illness (CON). RESULTS: The AR group had significantly reduced cortical thickness in the left pars orbitalis of the inferior frontal gyrus (IFG) compared with the CON group, and significantly increased left parahippocampal gyral volume compared with those with BD. CONCLUSIONS: The finding of reduced cortical thickness of the left pars orbitalis in AR subjects is consistent with other evidence supporting the IFG as a key region associated with genetic liability for BD. The greater volume of the left parahippocampal gyrus in those at high risk is in line with some prior reports of regional increases in grey matter volume in at-risk subjects. Assessing multiple complementary morphometric measures may assist in the better understanding of abnormal developmental processes in BD.

Interhemispheric white matter integrity in young people with bipolar disorder and at high genetic risk.

BACKGROUND: White matter (WM) impairments have been reported in patients with bipolar disorder (BD) and those at high familial risk of developing BD. However, the distribution of these impairments has not been well characterized. Few studies have examined WM integrity in young people early in the course of illness and in individuals at familial risk who have not yet passed the peak age of onset. METHOD: WM integrity was examined in 63 BD subjects, 150 high-risk (HR) individuals and 111 participants with no family history of mental illness (CON). All subjects were aged 12 to 30 years. RESULTS: This young BD group had significantly lower fractional anisotropy within the genu of the corpus callosum (CC) compared with the CON and HR groups. Moreover, the abnormality in the genu of the CC was also present in HR participants with recurrent major depressive disorder (MDD) (n = 16) compared with CON participants. CONCLUSIONS: Our findings provide important validation of interhemispheric abnormalities in BD patients. The novel finding in HR subjects with recurrent MDD - a group at particular risk of future hypo/manic episodes - suggests that this may potentially represent a trait marker for BD, though this will need to be confirmed in longitudinal follow-up studies.

Neuropsychological and social cognitive function in young people at genetic risk of bipolar disorder.

BACKGROUND: Impairments in key neuropsychological domains (e.g. working memory, attention) and social cognitive deficits have been implicated as intermediate (endo) phenotypes for bipolar disorder (BD), and should therefore be evident in unaffected relatives. METHOD: Neurocognitive and social cognitive ability was examined in 99 young people (age range 16-30 years) with a biological parent or sibling diagnosed with the disorder [thus deemed to be at risk (AR) of developing BD], compared with 78 healthy control (HC) subjects, and 52 people with a confirmed diagnosis of BD. RESULTS: Only verbal intelligence and affective response inhibition were significantly impaired in AR relative to HC participants; the BD participants showed significant deficits in attention tasks compared with HCs. Neither AR nor BD patients showed impairments in general intellectual ability, working memory, visuospatial or language ability, relative to HC participants. Analysis of BD-I and BD-II cases separately revealed deficits in attention and immediate memory in BD-I patients (only), relative to HCs. Only the BD (but not AR) participants showed impaired emotion recognition, relative to HCs. CONCLUSIONS: Selective cognitive deficits in the capacity to inhibit negative affective information, and general verbal ability may be intermediate markers of risk for BD; however, the extent and severity of impairment in this sample was less pronounced than has been reported in previous studies of older family members and BD cases. These findings highlight distinctions in the cognitive profiles of AR and BD participants, and provide limited support for progressive cognitive decline in association with illness development in BD.

Are there subtypes of bipolar depression?

OBJECTIVE: To investigate for subtypes of bipolar depression using latent class analysis (LCA). METHOD: Participants were recruited through a bipolar disorder (BD) clinic. LCA was undertaken using: (i) symptoms reported on the SCID-IV for the most severe lifetime depressive episode; (ii) lifetime illness features such as age at first depressive and hypo/manic episodes; and (iii) family history of BD and unipolar depression. To explore the validity of any demonstrated 'classes', clinical, demographic and treatment correlates were investigated. RESULTS: A total of 243 BD subjects (170 with BD-I and 73 with BD-II) were included. For the combined sample, we found two robust LCA solutions, with two and three classes respectively. There were no consistent solutions when the BD-I and BD-II samples were considered separately. Subjects in class 2 of the three-class solution (characterised by anxiety, insomnia, reduced appetite/weight loss, irritability, psychomotor retardation, suicidal ideation, guilt, worthlessness and evening worsening) were significantly more likely to be in receipt of government financial support, suggesting a particularly malign pattern of symptoms. CONCLUSION: Our study suggests the existence of two or three distinct classes of bipolar depression and a strong association with functional outcome.

Video Q&A: allergies and allergen immunotherapy--an interview with Alfred William Frankland.

In this video Q&A, we talk to Dr Alfred William Frankland about the highlights of his career, including working alongside Sir Alexander Fleming, co-founding the British Allergy Society, and introducing pollen counts to UK weather forecasts. We also discuss his opinions on why misconceptions about allergies and allergen immunotherapy still exist. Please see related article: http://www.biomedcentral.com/1741-7015/11/255.

Allergen immunotherapy and allergic rhinitis: false beliefs.

BACKGROUND: Over the last 100 years, several persistent misconceptions or 'false beliefs' have built up around allergen immunotherapy and its use in allergic rhinitis. This is perhaps because enthusiastic physicians administered complex allergen extracts to a diverse population of patients suffering from heterogeneous atopic conditions. Here, we review evidence that counters seven of these 'false beliefs.' DISCUSSION: 1. The symptoms of allergic rhinitis can be more heterogeneous, more severe and more troublesome in everyday life than many physicians believe. Large-scale epidemiological surveys show that the majority of allergic rhinitis patients have at least one symptom severe enough to interfere with sleep quality, productivity and/or well-being. 2. Allergen immunotherapy is not necessarily suitable for all allergic rhinitis patients (notably those with mild symptoms). Recent evidence from double-blind, placebo-controlled, randomized clinical trials suggests that the more severe the disease, the greater the treatment effect. 3. Allergen immunotherapy is often accused of lack of efficacy (relative to pharmacotherapy, for example). However, there are now many meta-analyses, systematic reviews and high-quality clinical trials that find overwhelmingly in favor of the efficacy of allergen immunotherapy (including sublingual formulations) in allergic rhinitis induced by pollen and, increasingly, other allergens. 4. Natural-exposure and challenge-chamber trials have shown that symptom relief may become apparent within months or even weeks of the initiation of allergen immunotherapy. 5. In pollen-induced allergic rhinitis, several years of subcutaneous or sublingual allergen immunotherapy are associated with sustained clinical efficacy after subsequent treatment cessation - confirming the disease-modifying nature of this therapy. 6. Most patients seeking treatment for allergic rhinitis are polysensitized, and allergen immunotherapy has proven efficacy in large, robust clinical trials in these groups. Polysensitization is not a contraindication to allergen immunotherapy. 7. Sublingual allergen immunotherapy is safe for home administration. A recent review calculated that 1 billion doses were administered worldwide between 2000 and 2010 and found that the 11 case reports of anaphylaxis (all non-fatal) corresponded to non-standard practice. SUMMARY: Modern, evidence-based medicine has generated more than enough robust evidence to remove misconceptions about allergen immunotherapy and allergic rhinitis.

Bipolar disorder in a national survey using the World Mental Health Version of the Composite International Diagnostic Interview: the impact of differing diagnostic algorithms.

OBJECTIVE: The World Mental Health Version of the Composite International Diagnostic Interview (WMH-CIDI) DSM-IV bipolar disorder diagnostic algorithms were recalibrated in about 2006 following evidence of over-diagnosis of bipolar I disorder. There have been no reports of the impact of this recalibration on epidemiological findings. METHOD: Data were taken from the 2007 Australian National Survey of Mental Health and Wellbeing. Findings for cases identified by the recalibrated bipolar disorder definition were contrasted against those identified by the un-recalibrated definition. RESULTS: The 12-month prevalence of recalibrated bipolar disorder and un-recalibrated bipolar disorder were 0.9% and 1.7% respectively. The un-recalibrated bipolar disorder group was younger and more likely to have never married than the recalibrated bipolar disorder group. They were also more likely to have a comorbid alcohol use disorder, substance use disorder and asthma or arthritis. While they were more likely to have at least severe interference in at least one of the Sheehan Scale domains of functioning, they were less likely to have made a suicide attempt. Similarly, they were less likely to have consulted a psychiatrist. CONCLUSION: It is not possible to be certain about the nature of these differences. Some may be artifactual (reflecting greater statistical power to detect differences with the larger un-recalibrated bipolar disorder defined sample), while others may be indicative of the inclusion of a clinically distinct subpopulation with the un-recalibrated bipolar disorder definition, thereby producing a more heterogeneous sample. These findings indicate the need for clarity in the diagnostic algorithm used in epidemiological reports on bipolar disorder using the World Mental Health Version of the Composite International Diagnostic Interview.

Moresby food isn't good: food security, nutritional information and adherence to antiretroviral therapy in Papua New Guinea.

The relationship between HIV (human immunodeficiency virus), food security and nutrition has become increasingly important to practitioners, policy makers and people living with HIV. In this paper we describe for the first time the connection between HIV and antiretroviral therapies, the extent of nutritional counselling for HIV-positive people and food security in Papua New Guinea (PNG). A total of 374 HIV-positive people who were over the age of 16 and who had been on antiretroviral therapy (ART) for more than two weeks were recruited from six provinces, using a non-probability, convenience sampling methodology. A subsample of 36 participants also completed an in-depth qualitative interview. Participants received nutritional advice when beginning ART which focused on three main domains, of which the first two were the most frequently mentioned: what foods to avoid; what foods to eat; and how frequently to eat. 72% of the sample reported that they had experienced an increase in their appetite. Of those who reported that their appetite had increased on ART 33% reported that they did not have enough food to satisfy hunger. People who lived in the capital city, Port Moresby, within the Southern Region of PNG, had significantly more difficulty with food security than those who lived in other regions of the country. Not having enough food was the third most commonly recorded reason for non-adherence to ART. Responses to the HIV epidemic in Papua New Guinea must also begin to address the phenomenon of food insecurity for people with HIV, in particular those who are receiving antiretroviral therapies and who live in the urban areas.

Transfusion on the Burma Railway: The life of Jacob Markowitz.

At the surrender of Singapore on 15 February 1942, over 100,000 men became prisoners of the Japanese. This included many medical officers who, over the ensuing years, treated men (and some women) suffering the ravaging effects of disease, worsened by the inhumane conditions of captivity. Many medical officers stand out for their work. One in particular, Jacob Markowitz, developed a blood transfusion service, under the most extreme conditions, for the sick working as slave labour on the Burma Railway. Although he qualified 20 years before the outbreak of war, little has been written of Markowitz's early life, or of the impact of this on his war-time contributions.

Current issues in care and support for HIV-positive gay men in Sydney.

We explored current access to care among HIV-positive people in Australia. In 2006, 270 HIV-positive gay men from a community-based Positive Health cohort in Sydney were asked about their health (including medical and social) service needs and, subsequently, about difficulty in accessing services. We report the prevalence of specific needs, barriers and associated factors. Participants most commonly used general practitioners (64%) for HIV management and needed at least one HIV-related medical service (usually several: doctors experienced in HIV management, dentists and hospital pharmacies). Most participants were able to access them. Barriers in accessing services were related to their convenience rather than lack or quality. Cost emerged as a substantial barrier to dental care and psychological counselling (91% and 48% respectively of those in need). Need for an HIV-related social service was reported by 46% of respondents. Difficulties in accessing these related to poor services and staff attitudes. Income was associated with limited access to multiple services. In Australia, HIV-related medical service needs outweigh those for social services. Complex health services remain essential to HIV-positive people, but some services are currently not meeting their needs. To remain adequate, services need to understand and constantly adapt to the changing needs of HIV-positive people.

Improvements in sexual health testing among gay men in Sydney, Australia, 2003-2007.

In order to be effective, sexually transmitted infection (STI) testing should be comprehensive based on the clients' sexuality and risk practices. Using data from the Sydney Gay Community Periodic Survey, we explored trends in and factors associated with STI testing among gay men during 2003-2007. Among men who were not HIV-positive, 68% were tested for HIV in 2007. HIV testing was more common than STI testing and remained stable during 2003-2007. Use of swabs and urine samples increased significantly (P-trend<0.001 for each). However, until 2007, 33% of men were not tested. Sexual behaviours (higher number of partners, having casual partners and engaging in unprotected anal intercourse with them) were associated with STI testing. HIV-negative men were tested for STI less often than HIV-positive men (prevalence ratio=0.56; 95% CI: 0.47-0.68). STI testing among HIV-negative men has improved significantly but remains inadequate for STI control and HIV prevention. It should not be assumed that appropriate and comprehensive STI screening is always provided to clients.

Flight Lieutenant Peach's observations on Burning Feet Syndrome in Far Eastern Prisoners of War 1942-45.

INTRODUCTION: 'Burning Feet Syndrome' affected up to one third of Far Eastern Prisoners of War in World War 2. Recently discovered medical records, produced by RAF Medical Officer Nowell Peach whilst in captivity, are the first to detail neurological examinations of patients with this condition. METHODS: The 54 sets of case notes produced at the time were analysed using modern diagnostic criteria to determine if the syndrome can be retrospectively classed as neuropathic pain. RESULTS: With a history of severe malnutrition raising the possibility of a peripheral polyneuropathy, and a neuroanatomically plausible pain distribution, this analysis showed that Burning Feet Syndrome can now be described as a 'possible' neuropathic pain syndrome. CONCLUSION: After 70 years, the data painstakingly gathered under the worst of circumstances have proved to be of interest and value in modern diagnostics of neuropathic pain.

A new and highly sensitive method for measuring 3-methoxytyramine using HPLC with electrochemical detection. Studies with drugs which alter dopamine metabolism in the brain.

3-Methoxytyramine (3-MT) is a minor metabolite of dopamine which is suggested to reflect the turnover and utilization of dopamine. A novel, isocratic HPLC method has been developed which can be used to analyse 3-MT in homogenates of rat brain without the need for additional purification procedures. Furthermore, the coulometric electrochemical detection system is sensitive enough to measure 3 pg of 3-MT (equivalent to 0.6 ng/g tissue wet weight). 3-Methoxytyramine was measured in the striatum and n. accumbens after decapitation and rapid freezing, using 3-methoxy-4-hydroxybenzylamine as the internal standard. The effects of dopaminergic and other drugs on this metabolite were examined using this method. alpha-Methyl-p-tyrosine (200 mg/kg i.v.) produced parallel linear decreases in dopamine and 3-MT in naive rats, but not those pretreated with tranylcypromine (5 mg/kg i.p.). Methamphetamine (0.3-10 mg/kg i.p.) and amphetamine (0.3-10 mg/kg i.p.) both dose-dependently increased 3-MT in naive and tranylcypromine-pretreated rats. In naive animals, 3-MT was not altered by intraperitoneal injection of the dopamine reuptake inhibitors, bupropion (10 mg/kg) and nomifensine (10 mg/kg) or by sibutramine HCl (3 mg/kg), amitriptyline (10 mg/kg), desipramine (10 mg/kg) and zimeldine (10 mg/kg). 3-Methoxytyramine was decreased by apomorphine (5 mg/kg i.p.) and also by large doses of the selective D2 antagonist, BRL 34778 (5 mg/kg i.p.) or L-DOPA (50 mg/kg i.p.). The selective D1 antagonist, SCH 23390 (0.1 or 5 mg/kg i.p.) was without effect. In tranylcypromine-pretreated rats, 3-MT was dose-dependently reduced and increased by apomorphine (0.01-5 mg/kg i.p.) and BRL 34778 (0.1-5 mg/kg i.p.), respectively. The drug SCH 23390 (0.1-5 mg/kg i.p.) produced much smaller increases in 3-MT which were probably mediated through the striatonigral pathway. Overall, the data suggest that measurement of 3-MT, after inhibition of monoamine oxidase, is a useful index of the release and utilization of dopamine. However, after substantial and prolonged depletion of dopamine, levels of 3-MT in naive animals are a better index. Also, the formation of 3-MT in naive rats rats provides a sensitive method for distinguishing between dopamine releasing agents and reuptake inhibitors.

A comparison of the effects of sibutramine hydrochloride, bupropion and methamphetamine on dopaminergic function: evidence that dopamine is not a pharmacological target for sibutramine.

Sibutramine hydrochloride, a novel monoamine reuptake inhibitor antidepressant, has been studied to determine whether it alters dopaminergic function in the brain. Its effects have been compared with bupropion, a dopamine reuptake inhibitor, and methamphetamine, a dopamine reuptake inhibitor and releasing agent. Sibutramine (0.1-3 mg/kg PO) and methamphetamine (0.3-30 mg/kg PO) both prevented reserpine (0.75 mg/kg IV) ptosis in rats with ED50 values of 0.6 mg/kg and 4.2 mg/kg, respectively. Bupropion (10-100 mg/kg PO) was ineffective against reserpine ptosis. The efflux of [3H]-dopamine from preloaded rat striatal slices was not altered by 10(-7)-10(-5) M concentrations of sibutramine, BTS 54,354, BTS 54,505 (secondary and primary amine metabolites, respectively) or bupropion. In contrast, methamphetamine (10(-8)-10(-4) M) caused a significant concentration-dependent increase in [3H]-dopamine release. Sibutramine (3 mg/kg IP or 6 mg/kg PO) and bupropion (10 mg/kg IP or 30 mg/kg PO) did not alter 3-methoxytyramine (3-MT) levels in rat striatum. Striatal 3-MT concentrations were, however, dose-dependently increased by methamphetamine (0.3-10 mg/kg IP or 0.42-4.2 mg/kg PO). Sibutramine (6 mg/kg PO) did not induce circling in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopaminergic neuronal tract. Bupropion (10-100 mg/kg PO) did not induce circling at the lowest dose, but caused increasing ipsilateral rotation at higher doses. Methamphetamine (0.42 or 4.2 mg/kg PO) induced ipsilateral circling with marked effects at the higher dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Autologous, split skin transplantation on the lower limbs of horses.

The skin grafting experiments were carried out on the cannon regions of horses to throw light on four matters relating to split skin transplantation. They were: The thickness of donor split skin that would provide good wound cover and still leave adequate tissue to permit uneventful healing at the donor site; whether split skin grafts were more readily accepted on fresh than on granulating wounds; the size of wounds that would benefit from grafting; and the maximum size of graft that would be readily accepted. The findings were: Split skin grafts 0.76 mm thickness gave the best results although grafts 0.63 mm thickness were satisfactory; split skin grafts were accepted more readily on fresh wounds than on granulating tissue; wounds which exceeded 1/10th of the skin area on the cannon region justified grafting; the upper limit in size was not established as the largest grafts used were more readily accepted than smaller grafts.

Use of porcine dermal collagen in the repair of perineal hernia in dogs--a preliminary report.

Porcine dermal collagen was used for the repair of 27 perineal hernias in 21 dogs. The material was generally well tolerated and the overall success rate was 59.3 per cent.

Free, autologous, skin transplantation in the horse.

Seven pieces of autologous skin were transplanted onto freshly created, full thickness skin defects on the limbs and back of a one-year-old, male, piebald, Shetland pony. The transplantations were completed in two operative sessions, the transplants on the left side were done in the first session and the right side in the second. The sizes of the transplants varied from 20 sq cm to 2 sq cm and their thicknesses from whole skin to very thin, split skin. Donor sites were both rumps and the right side of the neck. Six of the seven grafts and two thirds of the remaining graft, were accepted. Both whole thickness transplants grew hair, whereas no hair growth was detected at the 26th and 16th week following surgery on the split thickness transplants placed on the left and right sides respectively. The full thickness donor sites healed by granulation, contraction and epithelialisation. Healing at the split skin donor sites was rapid and uneventfull, epithelialisation being completed within one week and hair growth manifest by one month.

Nasal allergy.

Allergic rhinitis is often trivialised but accurate diagnosis and institution of therapy greatly alleviate its symptoms. Diagnosis requires a careful history and nasal mucosal examination. Nasal smear eosinophil staining and skin tests can be helpful, but skin and nasal provocation testing should be controlled and related specifically to a patient's history. Recent advances in symptomatic treatment, particularly antihistamines and most cell stabilising drugs, and immunotherapy are considered.