Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes

Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0-34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.     

Traumatic events in a general practice population: the patient's perspective

OBJECTIVES: The aim of the present study was to describe the patient's perspective on the GP's care after violent events: which role is the GP assigned; and how is the care appreciated. Events studied were serious accidents, burglary, robbery, physical and sexual abuse, disasters and war. METHOD: A postal questionnaire was sent to a random sample of 2997 patients (> or =20 years) from the practice population of 32 GPs (67 500 patients). RESULTS: The response was 50%. Forty-two per cent of the respondents had experienced one or more events. Twenty-eight per cent of the victims desired some kind of professional help; more than half of them desired that care from their GP, three-quarters actually seeking it. Most frequently sought care was sympathy, "a number of good talks", and care for physical complaints. Overall, contentment with the GP's contribution was high; patients especially appreciate sympathy and support, as well as initiative on the GP's part in commencing and pursuing care. Of those who felt no need for professional help, 88% found that they could cope with the traumatic event well enough, with or without the help of family and friends. For those who did not seek help, although they did desire it, the main reasons were that they considered their problems insufficiently medical or felt that their GP lacked the time. In the case of physical and sexual abuse, feelings of guilt and issues of patient confidentiality played a role for some patients. CONCLUSIONS: The number of events experienced by our respondents is lower than in previous studies for burglary, robbery, physical and sexual abuse (adults and children); the occurrence of accidents is similar. The majority of the people who experience traumatic events cope with them well enough without professional help. For those seeking help, the GP plays an important role. Care could be improved as follows: the GP should make it clear to patients that he/she can play a role in caring for them in the aftermath of a traumatic event and stress the confidential nature of the consultation. On the whole, GPs should be more supportive and attentive when being consulted about this topic; also patients would like their doctors to be more active in raising the subject, as well as in initiating follow-up.     

Occupational medicine in the Slovene area

Slovenia is a small, fast developing country in the EU with approximately 2,000,000 inhabitants and 700,000 employed. Occupational medicine has been present in Slovenia for as long as 500 yr. Today, 130 specialists of occupational medicine are in charge of health protection of the employed (including transport workers and athletes). There are also 1,100 safety engineers, who take care of the technical side of occupational safety. We are guided in our work by modern occupational health and safety legislation, which is based on EU directive 89/391EEC. The average sick leave rate in Slovenia is about 4.7%, caused mostly by injuries, bone, muscle and connective tissue diseases and respiratory diseases. Sick leave appears most frequently in the textile industries and coal mining. Annually, around 26,000 occupational injuries (32.7 per 1,000 employed) and 25 fatalities (3 per 100,000 employed) occur. Most injuries occur in construction, manufacturing and farming. Each year there are 8,500 disablility cases (2,500 disability retirements-most caused by mental illnesses), but only 30 acknowledged cases of occupational diseases (mostly occupational skin diseases, asthma and asbestosis). Occupational medicine in Slovenia is strongly associated with occupational medicine in the more developed European countries. It is therefore moving out of clinics and into the working environment, where its goals lie in primary prevention, i.e. establishing and keeping healthy working environments that guarantee high productivity, health and well-being of workers as a whole.     

Proinsulin concentration is an independent predictor of all-cause and cardiovascular mortality: an 11-year follow-up of the Hoorn Study

OBJECTIVE: High proinsulin concentration may be a better predictor for cardiovascular disease (CVD) mortality than insulin concentration. Previous observations may have been confounded by glucose tolerance status or lack of precision because of high intraindividual variability. We investigated the longitudinal relation of means of duplicate measurements of insulin and proinsulin with all-cause and CVD mortality in a population-based cohort taking glucose tolerance status into account. RESEARCH DESIGN AND METHODS: Fasting and post-75-g glucose-load (2-h) glucose, insulin, and proinsulin values were determined in duplicate on separate days in 277 participants with normal glucose metabolism, 208 participants with impaired glucose metabolism, and 119 newly detected patients with type 2 diabetes of the Hoorn Study. Insulin resistance and beta-cell function were estimated by homeostasis model assessment (HOMA-IR and HOMA-B, respectively), and the fasting proinsulin-to-insulin ratio was calculated. Subjects were followed with respect to mortality until January 2003. RESULTS: Fasting proinsulin levels were significantly associated with all-cause and CVD mortality. The hazard ratios (HRs) per increase in interquartile range adjusted for age and sex were 1.21 (95% CI 1.04-1.42) for all-cause mortality and 1.33 (1.06-1.66) for CVD mortality. Adjustment for glucose tolerance status and HOMA-IR did not substantially change the associations. CONCLUSIONS: Fasting proinsulin was associated with all-cause and CVD mortality, independent of glucose tolerance status and insulin resistance and largely independent of other CVD risk factors. Proinsulin might play a role in the relationship between insulin resistance and CVD.     

An in vitro model of hippocampal sharp waves: regional initiation and intracellular correlates

During slow wave sleep and consummatory behaviors, electroencephalographic recordings from the rodent hippocampus reveal large amplitude potentials called sharp waves. The sharp waves originate from the CA3 circuitry and their generation is correlated with coherent discharges of CA3 pyramidal neurons and dependent on activities mediated by AMPA glutamate receptors. To model sharp waves in a relatively large hippocampal circuitry in vitro, we developed thick (1 mm) mouse hippocampal slices by separating the dentate gyrus from the CA2/CA1 areas while keeping the functional dentate gyrus-CA3-CA1 connections. We found that large amplitude (0.3-3 mV) sharp wave-like field potentials occurred spontaneously in the thick slices without extra ionic or pharmacological manipulation and they resemble closely electroencephalographic sharp waves with respect to waveform, regional initiation, pharmacological manipulations, and intracellular correlates. Through measuring tissue O2, K+, and synaptic and single cell activities, we verified that the sharp wave-like potentials are not a consequence of anoxia, nonspecific elevation of extracellular K+ and dissection-related tissue damage. Our data suggest that a subtle but crucial increase in the CA3 glutamatergic activity effectively recruits a population of neurons thus responsible for the generation of the sharp wave-like spontaneous field potentials in isolated hippocampal circuitry.     

Optic atrophies in metabolic disorders

Optic nerve involvement in metabolic disorders often results from apoptosis of cells that form or support the optic nerve, the retinal ganglion cell (RGC) axons, the myelin-forming oligodendrocytes, or the supporting vascular system. Given their high energy demands and the long course of their axons, RGCs are particularly sensitive to intracellular metabolic defects. Defects in energy metabolism, formation of reactive oxygen species, and storage of metabolites can all cause apoptosis of RGCs, decreased myelin formation of oligodendrocytes and increased pressure on the optic nerve. Clinically, the loss of RGC axons manifests as pale optic nerves. In general, the ophthalmologist can identify the underlying cause of an optic atrophy by careful examination, neuro-imaging, and family history. In some cases, however, the diagnosis proves elusive. In these instances, and especially when optic atrophy is accompanied by other systemic involvement, a metabolic disorder should be considered. Here, we review the underlying mechanisms of optic atrophy and its significance in metabolic disorders. Early identification of optic atrophy aids the diagnosis and subsequent management of the underlying condition, including anticipation of symptoms, genetic counseling, and possible therapeutic interventions. For many metabolic disorders, molecular testing is available.     

The effect of methionine and S-adenosylmethionine on S-adenosylmethionine levels in the rat brain

OBJECTIVE: S-Adenosylmethionine (SAMe) is a major methyl donor in the brain and is also an antidepressant with few reported side effects; however, SAMe is relatively expensive and unstable. Brain SAMe can be increased by giving methionine to rats, raising the possibility that methionine may be an antidepressant. We aimed to study whether SAMe and methionine, when given orally to rats, could raise levels of SAMe in the central nervous system (CNS). We also aimed to test the relative abilities of SAMe and methionine to increase tail-flick latency after a thermal stimulus. This test was used to measure changes in CNS function. METHODS: Rats were given SAMe and methionine orally at various doses, and biochemical and behavioural testing was carried out at intervals up to 6 hours later. RESULTS: Methionine raised SAMe levels in various regions of the CNS and increased tail-flick latency, both at lower doses than SAMe. CONCLUSION: Methionine should be tested for antidepressant properties in humans.     

Sexually transmitted disease testing protocols, sexually transmitted disease testing, and discussion of sexual behaviors in HIV clinics in Los Angeles County

OBJECTIVE/GOAL: The objective of this study was to evaluate the use of written protocols for sexually transmitted disease (STD) screening, the frequency and types of STD tests performed, and the occurrence and frequency of obtaining sexual risk assessments among HIV clinics. STUDY: A survey was administered to 36 medical directors, clinic directors, and HIV providers representing 48 HIV healthcare clinics in Los Angeles. RESULTS: The use of a written or electronic protocol for STD testing was reported by 50% of clinics. Clinics with written or electronic STD protocols were significantly more likely to report questioning patients at each visit regarding their sexual practices (prevalence ratio, 2.2; 95% confidence interval, 1.4-3.4). Clinics with written or electronic protocols were not more likely to report more frequent STD testing. CONCLUSIONS: Written or electronic protocols for STD testing may promote sexual risk assessment questioning among HIV healthcare providers and may help to ensure STD testing per Centers for Disease Control and Prevention/IDSA guidelines for HIV-positive persons at sexual risk.     

Performance monitoring in obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is associated with hyperactivity of brain structures involved in performance monitoring. It has been proposed that this pathophysiology results in the generation of inappropriate or excessive internal error signals, giving rise to the characteristic symptoms of OCD. We measured an electrophysiological correlate of performance monitoring, error-related negativity (ERN), to study whether OCD patients exhibit enhanced brain activity associated with errors and negative performance feedback. We found that OCD patients (n=16) and healthy control participants (n=16) did not differ in the amplitude of the ERN associated with errors and negative feedback in a probabilistic learning task. The discrepancy between these results and the results from previous studies is discussed.