Auditory hallucinations in adults with hearing impairment: a large prevalence study.

BACKGROUND: Similar to visual hallucinations in visually impaired patients, auditory hallucinations are often suggested to occur in adults with hearing impairment. However, research on this association is limited. This observational, cross-sectional study tested whether auditory hallucinations are associated with hearing impairment, by assessing their prevalence in an adult population with various degrees of objectified hearing impairment. METHODS: Hallucination presence was determined in 1007 subjects aged 18-92, who were referred for audiometric testing to the Department of ENT-Audiology, University Medical Center Utrecht, the Netherlands. The presence and severity of hearing impairment were calculated using mean air conduction thresholds from the most recent pure tone audiometry. RESULTS: Out of 829 participants with hearing impairment, 16.2% (n = 134) had experienced auditory hallucinations in the past 4 weeks; significantly more than the non-impaired group [5.8%; n = 10/173; p < 0.001, odds ratio 3.2 (95% confidence interval 1.6-6.2)]. Prevalence of auditory hallucinations significantly increased with categorized severity of impairment, with rates up to 24% in the most profoundly impaired group (p < 0.001). The corrected odds of hallucination presence increased 1.02 times for each dB of impairment in the best ear. Auditory hallucinations mostly consisted of voices (51%), music (36%), and doorbells or telephones (24%). CONCLUSIONS: Our findings reveal that auditory hallucinations are common among patients with hearing impairment, and increase with impairment severity. Although more research on potential confounding factors is necessary, clinicians should be aware of this phenomenon, by inquiring after hallucinations in hearing-impaired patients and, conversely, assessing hearing impairment in patients with auditory hallucinations, since it may be a treatable factor.

Peptidyl-Prolyl-cis/trans-Isomerases Mip and PpiB of Legionella pneumophila Contribute to Surface Translocation, Growth at Suboptimal Temperature, and Infection.

The gammaproteobacterium Legionella pneumophila is the causative agent of Legionnaires' disease, an atypical pneumonia that manifests itself with severe lung damage. L. pneumophila, a common inhabitant of freshwater environments, replicates in free-living amoebae and persists in biofilms in natural and man-made water systems. Its environmental versatility is reflected in its ability to survive and grow within a broad temperature range as well as its capability to colonize and infect a wide range of hosts, including protozoa and humans. Peptidyl-prolyl-cis/trans-isomerases (PPIases) are multifunctional proteins that are mainly involved in protein folding and secretion in bacteria. In L. pneumophila the surface-associated PPIase Mip was shown to facilitate the establishment of the intracellular infection cycle in its early stages. The cytoplasmic PpiB was shown to promote cold tolerance. Here, we set out to analyze the interrelationship of these two relevant PPIases in the context of environmental fitness and infection. We demonstrate that the PPIases Mip and PpiB are important for surfactant-dependent sliding motility and adaptation to suboptimal temperatures, features that contribute to the environmental fitness of L. pneumophila Furthermore, they contribute to infection of the natural host Acanthamoeba castellanii as well as human macrophages and human explanted lung tissue. These effects were additive in the case of sliding motility or synergistic in the case of temperature tolerance and infection, as assessed by the behavior of the double mutant. Accordingly, we propose that Mip and PpiB are virulence modulators of L. pneumophila with compensatory action and pleiotropic effects.

Publisher Correction: Associations between subjective well-being and subcortical brain volumes.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group.

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Associations between subjective well-being and subcortical brain volumes.

To study the underpinnings of individual differences in subjective well-being (SWB), we tested for associations of SWB with subcortical brain volumes in a dataset of 724 twins and siblings. For significant SWB-brain associations we probed for causal pathways using Mendelian Randomization (MR) and estimated genetic and environmental contributions from twin modeling. Another independent measure of genetic correlation was obtained from linkage disequilibrium (LD) score regression on published genome-wide association summary statistics. Our results indicated associations of SWB with hippocampal volumes but not with volumes of the basal ganglia, thalamus, amygdala, or nucleus accumbens. The SWB-hippocampus relations were nonlinear and characterized by lower SWB in subjects with relatively smaller hippocampal volumes compared to subjects with medium and higher hippocampal volumes. MR provided no evidence for an SWB to hippocampal volume or hippocampal volume to SWB pathway. This was in line with twin modeling and LD-score regression results which indicated non-significant genetic correlations. We conclude that low SWB is associated with smaller hippocampal volume, but that genes are not very important in this relationship. Instead other etiological factors, such as exposure to stress and stress hormones, may exert detrimental effects on SWB and the hippocampus to bring about the observed association.

A study of genetic and environmental contributions to structural brain changes over time in twins concordant and discordant for bipolar disorder.

This is the first longitudinal twin study examining genetic and environmental contributions to the association between liability to bipolar disorder (BD) and changes over time in global brain volumes, and global and regional measures of cortical surface area, cortical thickness and cortical volume. A total of 50 twins from pairs discordant or concordant for BD (monozygotic: 8 discordant and 3 concordant pairs, and 1 patient and 3 co-twins from incomplete pairs; dizygotic: 6 discordant and 2 concordant pairs, and 1 patient and 7 co-twins from incomplete pairs) underwent magnetic resonance imaging twice. In addition, 57 twins from healthy twin pairs (15 monozygotic and 10 dizygotic pairs, and 4 monozygotic and 3 dizygotic subjects from incomplete pairs) were also scanned twice. Mean follow-up duration for all twins was 7.5 years (standard deviation: 1.5 years). Data were analyzed using structural equation modeling software OpenMx. The liability to BD was not associated with global or regional structural brain changes over time. Although we observed a subtle increase in cerebral white matter in BD patients, this effect disappeared after correction for multiple comparisons. Heritability of brain changes over time was generally low to moderate. Structural brain changes appear to follow similar trajectories in BD patients and healthy controls. Existing brain abnormalities in BD do not appear to progressively change over time, but this requires additional confirmation. Further study with large cohorts is recommended to assess genetic and environmental influences on structural brain abnormalities in BD, while taking into account the influence of lithium on the brain.

High educational performance is a distinctive feature of bipolar disorder: a study on cognition in bipolar disorder, schizophrenia patients, relatives and controls.

BACKGROUND: Schizophrenia is associated with lower intelligence and poor educational performance relative to the general population. This is, to a lesser degree, also found in first-degree relatives of schizophrenia patients. It is unclear whether bipolar disorder I (BD-I) patients and their relatives have similar lower intellectual and educational performance as that observed in schizophrenia. METHOD: This cross-sectional study investigated intelligence and educational performance in two outpatient samples [494 BD-I patients, 952 schizophrenia spectrum (SCZ) patients], 2231 relatives of BD-I and SCZ patients, 1104 healthy controls and 100 control siblings. Mixed-effects and regression models were used to compare groups on intelligence and educational performance. RESULTS: BD-I patients were more likely to have completed the highest level of education (odds ratio 1.88, 95% confidence interval 1.66-2.70) despite having a lower IQ compared to controls (ß = -9.09, S.E. = 1.27, p < 0.001). In contrast, SCZ patients showed both a lower IQ (ß = -15.31, S.E. = 0.86, p < 0.001) and lower educational levels compared to controls. Siblings of both patient groups had significantly lower IQ than control siblings, but did not differ on educational performance. IQ scores did not differ between BD-I parents and SCZ parents, but BD-I parents had completed higher educational levels. CONCLUSIONS: Although BD-I patients had a lower IQ than controls, they were more likely to have completed the highest level of education. This contrasts with SCZ patients, who showed both intellectual and educational deficits compared to healthy controls. Since relatives of BD-I patients did not demonstrate superior educational performance, our data suggest that high educational performance may be a distinctive feature of bipolar disorder patients.

First successful reduction of clinical allergenicity of food by genetic modification: Mal d 1-silenced apples cause fewer allergy symptoms than the wild-type cultivar.

BACKGROUND: Genetic modification of allergenic foods such as apple has the potential to reduce their clinical allergenicity, but this has never been studied by oral challenges in allergic individuals. METHODS: We performed oral food challenges in 21 apple-allergic individuals with Elstar apples which had undergone gene silencing of the major allergen of apple, Mal d 1, by RNA interference. Downregulation of Mal d 1 gene expression in the apples was verified by qRT-PCR. Clinical responses to the genetically modified apples were compared to those seen with the wild-type Elstar using a visual analogue scale (VAS). RESULTS: Gene silencing produced two genetically modified apple lines expressing Mal d 1.02 and other Mal d 1 gene mRNA levels which were extensively downregulated, that is only 0.1-16.4% (e-DR1) and 0.2-9.9% (e-DR2) of those of the wild-type Elstar, respectively. Challenges with these downregulated apple lines produced significantly less intense maximal symptoms to the first dose (Vmax1) than with Elstar (Vmax1 Elstar 3.0 mm vs 0.0 mm for e-DR1, P = 0.017 and 0.0 mm for e-DR2, P = 0.043), as well as significantly less intense mean symptoms per dose (meanV/d) than with Elstar (meanV/d Elstar 2.2 mm vs 0.2 mm for e-DR1, P = 0.017 and 0.0 mm for e-DR2, P = 0.043). Only one subject (5%) remained symptom-free when challenged with the Elstar apple, whereas 43% did so with e-DR1 and 63% with e-DR2. CONCLUSION: These data show that mRNA silencing of Mal d 1 results in a marked reduction of Mal d 1 gene expression in the fruit and reduction of symptoms when these apples are ingested by allergic subjects. Approximately half of the subjects developed no symptoms whatsoever, and virtually all subjects wished to consume the apple again in the future.

Genetic and environmental influences on cortical surface area and cortical thickness in bipolar disorder.

BACKGROUND: The risk of developing bipolar disorder (BD) has been linked to structural brain abnormalities. The degree to which genes and environment influence the association of BD with cortical surface area remains to be elucidated. In this twin study, genetic and environmental contributions to the association between liability to develop BD and surface area, thickness and volume of the cortex were examined. METHOD: The study cohort included 44 affected monozygotic (nine concordant, 12 discordant) and dizygotic (four concordant, 19 discordant) twin pairs, and seven twins from incomplete discordant monozygotic and dizygotic discordant twin pairs. In addition, 37 monozygotic and 24 dizygotic healthy control twin pairs, and six twins from incomplete monozygotic and dizygotic control pairs were included. RESULTS: Genetic liability to develop BD was associated with a larger cortical surface in limbic and parietal regions, and a thicker cortex in central and parietal regions. Environmental factors related to BD were associated with larger medial frontal, parietal and limbic, and smaller orbitofrontal surfaces. Furthermore, thinner frontal, limbic and occipital cortex, and larger frontal and parietal, and smaller orbitofrontal volumes were also associated with environmental factors related to BD. CONCLUSIONS: Our results suggest that unique environmental factors play a prominent role in driving the associations between liability to develop BD and cortical measures, particularly those involving cortical thickness. Further evaluation of their influence on the surface and thickness of the cortical mantle is recommended. In addition, cortical volume appeared to be primarily dependent on surface and not thickness.

Development and heritability of subcortical brain volumes at ages 9 and 12.

Subcortical brain structures are involved in a variety of cognitive and emotional functions and follow different trajectories of increase and decrease in volume from childhood to adulthood. The heritability of development of subcortical brain volumes during adolescence has not been studied comprehensively. In a longitudinal twin study, we estimated to what extent subcortical brain volumes are influenced by genetic factors at ages 9 and 12. In addition, we assessed whether new genes are expressed at age 12 and whether there is evidence for genotype by sex interaction. Brain scans were acquired for 112 and 89 twin pairs at 9 and 12 years of age. In both boys and girls, there was an increase in volumes of the thalamus, hippocampus, amygdala and pallidum, and a decrease in volumes of the caudate and nucleus accumbens. The putamen showed a decrease in boys bilaterally and an increase in girls in the left hemisphere. Heritability was high (>50%) for all structures - except for the left nucleus accumbens - with heritabilities ranging from 0.50 to 0.91 at age 9, and from 0.59 to 0.88 at age 12. There were no significant new genetic effects coming into play at age 12, and there was no evidence for genotype by sex interactions. These findings suggest that despite their sensitivity to environmental effects, the heritability of subcortical brain structures is high from childhood on, resembling estimates found in adult samples.

Longitudinal study of hormonal and physical development in young twins.

CONTEXT AND OBJECTIVE: Information on the correlation of normative reproductive hormone levels with physical development (Tanner stages) during puberty and on the influences of genes and environment on variation in these hormones and Tanner stages is limited. DESIGN, SETTING, AND PARTICIPANTS: One hundred twelve healthy 9-year-old twin pairs (n = 224) took part in a longitudinal study, of which 89 pairs participated again at age 12 years (n = 178). MAIN OUTCOME MEASURES: Morning urinary LH, FSH, estradiol, and salivary testosterone levels, determined by competitive immunoassays, were measured. Tanner stages were determined through physical examination. RESULTS: Over the 3-year interval, all hormone levels showed a 2- to 9-fold increase. LH and FSH at age 9 years predicted sex-specific Tanner stages at age 12 years in both boys and girls. Most of the associations between hormone levels at age 9 years and physical development at 12 years were explained by genetic influences. FSH in 9-year-old boys correlated with all hormone levels and Tanner stages at age 12 years. Moderate to high heritability estimates were found for hormone levels at both ages and in both sexes. In girls a shift from environmental (age 9 years) to genetic influences (age 12 years) was found for estradiol and pubic hair development, and for breast development a shift in the opposite direction was seen. CONCLUSIONS: During development LH and FSH (and testosterone in boys) levels predict secondary sexual characteristics in boys and girls 3 years later. These correlations are largely due to genes that are involved in both early pubertal hormone levels and subsequent physical development.

Genetic influences on thinning of the cerebral cortex during development.

During development from childhood to adulthood the human brain undergoes considerable thinning of the cerebral cortex. Whether developmental cortical thinning is influenced by genes and if independent genetic factors influence different parts of the cortex is not known. Magnetic resonance brain imaging was done in twins at age 9 (N = 190) and again at age 12 (N = 125; 113 repeated measures) to assess genetic influences on changes in cortical thinning. We find considerable thinning of the cortex between over this three year interval (on average 0.05 mm; 1.5%), particularly in the frontal poles, and orbitofrontal, paracentral, and occipital cortices. Cortical thinning was highly heritable at age 9 and age 12, and the degree of genetic influence differed for the various areas of the brain. One genetic factor affected left inferior frontal (Broca's area), and left parietal (Wernicke's area) thinning; a second factor influenced left anterior paracentral (sensory-motor) thinning. Two factors influenced cortical thinning in the frontal poles: one of decreasing influence over time, and another independent genetic factor emerging at age 12 in left and right frontal poles. Thus, thinning of the cerebral cortex is heritable in children between the ages 9 and 12. Furthermore, different genetic factors are responsible for variation in cortical thickness at ages 9 and 12, with independent genetic factors acting on cortical thickness across time and between various brain areas during childhood brain development.

[A man with a classic serious milk-alkali syndrome and a carcinoma of the stomach]. / Een man met een ernstig klassiek melk-alkalisyndroom en een maagcarcinoom.

A 42-year-old man was transferred to the Emergency Department after his friends had found him unresponsive and confused in his room. He had been experiencing upper abdominal complaints for a period of several months. He had taken large amounts of a calcium carbonate/magnesium subcarbonate preparation (Rennie) and had consumed at least 3 litres of dairy products per day. His behaviour was reported as being more and more abnormal during the previous few weeks. On admission he was confused and agitated and had involuntary movements of his limbs. Laboratory investigation indicated a triple acid base disorder, i.e. metabolic alkalosis, respiratory alkalosis and high anion gap metabolic acidosis, with severe dehydration. The metabolic alkalosis was caused by the intake of large amounts of dairy and antacids: milk-alkali syndrome. The metabolic acidosis was the result of hypovolaemia and pre-renal renal failure and the respiratory alkalosis was caused by hyperventilation due to the organic psychosyndrome. The patient was treated with volume expansion by isotonic saline and the administration of potassium and he was sedated with low-dose midazolam, which led to a full respiratory compensation of the metabolic alkalosis. A few days following admission, both the plasma calcium concentration and renal function returned to normal; the acid-base disorder completely normalized and the organic psychosyndrome disappeared. On gastroduodenoscopy a gastric ulcer was found; biopsies revealed a signet ring cell adenocarcinoma of the stomach.

The EuroSCORE as predictor for prolonged hospital and intensive care stay after cardiac surgery?

OBJECTIVE: Validation of the EuroSCORE as predictor for a prolonged hospital and intensive care stay after CABG vs. institution-specific scoring systems. METHODS: For the evaluation of a prolonged hospital stay, 3359 patients were included in the analysis of EuroSCORE vs. the CORRAD morbidity score. For a prolonged intensive care stay, 1638 patients were included in the analysis of the EuroSCORE vs. the PICUS score. RESULTS: There was no significant difference in hospital stay between the three different EuroSCORE risk groups. The difference in hospital stay between the high-risk and low-risk groups, identified by the CORRAD morbidity score, was significant (6.9 vs.11.2 days). For a prolonged intensive care stay, the patients identified as high risk by the EuroSCORE and by the PICUS score also had a significantly longer intensive care stay; however, the discriminatory power was low. CONCLUSION: The EuroSCORE is not of value as a predictive system for a prolonged hospital stay. There is a relation between the high-risk patients identified by the EuroSCORE and a prolonged intensive care stay.

[Life threatening hyperkalemia: the value of the electrocardiogram]. / Levensbedreigende hyperkaliëmie: de waarde van het elektrocardiogram.

In two men, aged 19 and 64, with chronic renal insufficiency and subacute symptoms of malaise and weakness of the leg muscles, broad QRS complexes were seen in the ECG. The younger patient developed an asystole and resuscitation was unsuccessful. His blood potassium level was found to be 8.3 mmol/l. The older patient recovered after administration of calcium gluconate. His blood potassium level was found to be 8.5 mmol/l. An 80-year-old woman who was taking various drugs because of heart failure also complained of muscle weakness. Her blood potassium level was 7.2 mmol/l and her ECG showed narrow complexes. She recovered without calcium gluconate after a change in medication. Hyperkalemia is a potentially life-threatening electrolyte disorder that may require immediate treatment. The changes in the ECG, especially widening of the QRS complexes, are the most important clues to the severity of the hyperkalemia. A treatment protocol based on ECG changes may reduce the mortality in these patients.

Identification of patients at risk for early out-of-hospital mortality after redocoronary artery surgery.

OBJECTIVE: Analyse risk factors and construct a predictive model for identification of patients at risk of early out-of-hospital mortality after coronary reoperations (RECABG). METHODS: 505 patients, discharged from hospital after a RECABG (1987-1998), were studied by univariate and multivariate analysis. A stepwise selective procedure (p<0.05) was used to identify a subset of variables with prognostic value for early out-of-hospital mortality. This subset was used to calculate a prognostic score 'S' and a predicted probability 'p' for early out-of-hospital mortality, p=1/1+ e-s. Sensitivity analysis was used for evaluation. RESULTS: The best predictive variables for early out-of-hospital mortality were diabetes (p=0.002), lung disease (p=0.05), emergency operation (p=0.0001) and a perioperative myocardial infarction (p=0.0001). Emergency operation (p=0.001) and antegrade/retrograde cardioplegia (p<0.0000) were independent predictors of a perioperative myocardial infarction. The prognostic accuracy (ROC area) was 86%. Patients were classified into low risk (5%), intermediate risk (15%), high risk (30%) and very high risk (≥40%). A predicted probability of ≥0.40 was used as cut-off point. The specificity of this test was 99%, sensitivity 33%, predictive value of a positive test 79%, and 95% for a negative test. CONCLUSION: The results show that patients discharged from hospital after RECABG can be stratified according to their early out-of-hospital risk. A perioperative myocardial infarction is the major independent risk factor and can be affected by use of retrograde cardioplegia.

Evaluation of long-term quality of life after reoperative coronary artery surgery: preliminary results.

OBJECTIVE: The risks of reoperative coronary artery bypass surgery (RECABG) still exceed those of a primary revascularisation and late results are not very favourable either. The subject of the present study is an evaluation of the long-term quality of life after RECABG. METHODS: We studied the outcome of 541 patients who underwent a RECABG from January 1987 to December 1998. The endpoint of the study was December 2002, or the patient's death. Quality of life, using the EuroQol registration, was evaluated. RESULTS: Hospital mortality was 6.7%. Follow-up was 95.6% complete, mean 7.7 years. There were 177 late deaths. The cumulative survival rates were 83.8, 76.9, and 60.6%, and cardiac survival rates were 84.8, 78.5, and 66.5%, at the one-year, five-year and ten-year follow-up, respectively. For 255 patients (89%), NYHA and EuroQol information was complete. In total 23% of the patients were in NYHA class I, 51% in class II, 21% in class III and 5% were in class IV. In the EuroQol registration, 54% of the patients declared they had no mobility problems, 85% no problems with self-care, and 65% no problems with usual activities. However, 60% suffered from moderate pain or discomfort, and 33% from anxiety or depression. On the visual analogue scale (mean 63.5), 13% of the patients scored >90, 68% between 50 and 90, and 19% of the patients <50. CONCLUSION: The long-term results of cumulative survival and cardiac survival, and NYHA class in our patient population who underwent RECABG are comparable with other studies. Quality of life is acceptable regarding the high risk of a RECABG.

Papillary fibroelastoma of the mitral valve.

We present a case of a 69-year-old woman with a history of stroke five years previously and an abnormal ECG prior to eye surgery. There were no signs of cardiac disease. Echocardiography disclosed a tumour of the papillary muscle. Surgical excision was performed and histological examination confirmed the diagnosis of a papillary fibroelastoma.