[The value of re-evaluation and thorough family history taking for the diagnostic work-up of chorea]. / Het diagnostisch proces bij chorea: het belang van heroverwegen en de familieanamnese.

The differential diagnosis of chorea encompasses a broad range of disorders. In psychiatry, tardive dyskinesia may be difficult to discern from other causes, particularly when the family history is negative. A 59-year-old man with an unclear medical history had been using risperidone for over a decade when we first saw him. He presented with severe dyskinesia in all extremities. The family history for neuropsychiatric disorders was negative. We interpreted the movement disorder as tardive dyskinesia, but later he turned out to suffer from Huntington’s disease. To improve diagnostic accuracy, we should have more frequently re-evaluated the differential diagnosis and our family history should have been more thorough. We outline the diagnostic considerations in patients presenting with chorea. Finally, we highlight the value of diagnostic re-evaluation and thorough family history taking to optimize diagnostic accuracy in neuropsychiatry.

Suicidal ideation and subsequent completed suicide in both psychiatric and non-psychiatric populations: a meta-analysis.

AIMS: Several authors claimed that expression of suicidal ideation is one of the most important predictors of completed suicide. However, the strength of the association between suicidal ideation and subsequent completed suicide has not been firmly established in different populations. Furthermore, the absolute suicide risk after expression of suicidal ideation is unknown. In this meta-analysis, we examined whether the expression of suicidal ideation predicted subsequent completed suicide in various populations, including both psychiatric and non-psychiatric populations. METHODS: A meta-analysis of cohort and case-control studies that assessed suicidal ideation as determinant for completed suicide in adults. Two independent reviewers screened 5726 articles for eligibility and extracted data of the 81 included studies. Pooled risk ratios were estimated in a random effects model stratified for different populations. Meta-regression analysis was used to determine suicide risk during the first year of follow-up. RESULTS: The risk for completed suicide was clearly higher in people who had expressed suicidal ideation compared with people who had not, with substantial variation between the different populations: risk ratio ranging from 2.35 (95% confidence interval (CI) 1.43-3.87) in affective disorder populations to 8.00 (95% CI 5.46-11.7) in non-psychiatric populations. In contrast, the suicide risk after expression of suicidal ideation in the first year of follow-up was higher in psychiatric patients (risk 1.40%, 95% CI 0.74-2.64) than in non-psychiatric participants (risk 0.23%, 95% CI 0.10-0.54). Past suicide attempt-adjusted risk ratios were not pooled due to large underreporting. CONCLUSIONS: Assessment of suicidal ideation is of priority in psychiatric patients. Expression of suicidal ideation in psychiatric patients should prompt secondary prevention strategies to reduce their substantial increased risk of suicide.

[Delayed diagnosis of Huntington's disease in a psychiatric setting]. / Vertraagde diagnose van de ziekte van Huntington in een psychiatrische setting.

Huntington's disease (hd) is characterised by a triad of neuropsychiatric symptoms, motor disturbances and cognitive decline. If initial symptoms are of neuropsychiatric nature they maybe misinterpreted, which can lead to delayed diagnosis. Three examples of delayed hd diagnosis in a psychiatric setting are discussed.

Microdosing of a Carbon-14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages.

Preclinical development of new biological entities (NBEs), such as human protein therapeutics, requires considerable expenditure of time and costs. Poor prediction of pharmacokinetics in humans further reduces net efficiency. In this study, we show for the first time that pharmacokinetic data of NBEs in humans can be successfully obtained early in the drug development process by the use of microdosing in a small group of healthy subjects combined with ultrasensitive accelerator mass spectrometry (AMS). After only minimal preclinical testing, we performed a first-in-human phase 0/phase 1 trial with a human recombinant therapeutic protein (RESCuing Alkaline Phosphatase, human recombinant placental alkaline phosphatase [hRESCAP]) to assess its safety and kinetics. Pharmacokinetic analysis showed dose linearity from microdose (53 µg) [(14) C]-hRESCAP to therapeutic doses (up to 5.3 mg) of the protein in healthy volunteers. This study demonstrates the value of a microdosing approach in a very small cohort for accelerating the clinical development of NBEs.

Hypothalamic-pituitary-adrenal axis functioning in Huntington's disease and its association with depressive symptoms and suicidality.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in Huntington's disease (HD). In non-HD populations, alterations in HPA axis activity have been associated with depression and suicidality. The present study aims to compare HPA axis activity between HD mutation carriers and controls, and examine its association with depressive symptoms and suicidality. To this end, salivary cortisol concentrations at seven time points, as well as depressive symptoms and suicidality, were assessed in 49 pre-motor, 102 motor symptomatic mutation carriers and 55 controls, at baseline and follow-up combined. Differences in parameters of HPA axis activity between these three groups, and their associations with depressive symptoms and suicidality in HD mutation carriers, were analysed using multilevel regression analyses. There were no differences in parameters of HPA axis activity between mutation carriers and controls, whereas pre-motor symptomatic mutation carriers had a significantly higher area under the curve to the increase (AUCi ) compared to motor symptomatic mutation carriers. In the entire HD cohort, HPA axis activity was not associated with depressive symptoms or suicidality. After stratifying mutation carriers into pre-motor, early and advanced disease stages, ß values differed between these groups. Remarkably, a higher AUCi was significantly associated with depressive symptoms in pre-motor and early disease stage mutation carriers, with a reverse nonsignificant association in advanced disease stage mutation carriers. The lower AUCi in motor symptomatic mutation carriers and the varying associations with depressive symptoms and suicidality in pre-motor, early and advanced disease stages could possibly be explained by exhaustion of the HPA axis after prolonged stress-induced HPA axis hyperactivity and deserves further longitudinal study.

Acute-phase proteins in relation to neuropsychiatric symptoms and use of psychotropic medication in Huntington's disease.

Activation of the innate immune system has been postulated in the pathogenesis of Huntington's disease (HD). We studied serum concentrations of C-reactive protein (CRP) and low albumin as positive and negative acute-phase proteins in HD. Multivariate linear and logistic regression was used to study the association between acute-phase protein levels in relation to clinical, neuropsychiatric, cognitive, and psychotropic use characteristics in a cohort consisting of 122 HD mutation carriers and 42 controls at first biomarker measurement, and 85 HD mutation carriers and 32 controls at second biomarker measurement. Significant associations were found between acute-phase protein levels and Total Functioning Capacity (TFC) score, severity of apathy, cognitive impairment, and the use of antipsychotics. Interestingly, all significant results with neuropsychiatric symptoms disappeared after additional adjusting for antipsychotic use. High sensitivity CRP levels were highest and albumin levels were lowest in mutation carriers who continuously used antipsychotics during follow-up versus those that had never used antipsychotics (mean difference for CRP 1.4 SE mg/L; P=0.04; mean difference for albumin 3 SE g/L; P<0.001). The associations found between acute-phase proteins and TFC score, apathy, and cognitive impairment could mainly be attributed to the use of antipsychotics. This study provides evidence that HD mutation carriers who use antipsychotics are prone to develop an acute-phase response.

Psychiatric disorders in Huntington's disease: a 2-year follow-up study.

OBJECTIVE: This study investigates the presence and course of formal psychiatric disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) in 142 Huntington's disease (HD) mutation carriers in a two-year follow-up design. METHOD: Of the 142 mutation carriers, 106 (75%) participated in the second measurement of an ongoing cohort study on psychopathology in HD. Presence of psychiatric disorders was assessed using the Composite International Diagnostic Interview. RESULTS: Of the 91 patients without a formal psychiatric disorder at baseline, 14 (15%) had a psychiatric disorder after 2 years, mostly a major depressive disorder (MDD) (64%). The baseline characteristics of lower education, having no children, a lower level of global daily functioning, a lifetime psychiatric diagnosis, and the use of psychotropic medication were predictive of incident psychiatric disorders after 2 years. Of the 15 patients with a psychiatric diagnosis at baseline, eight (53%) no longer had a psychiatric disorder at follow-up. All seven patients (47%) with a persistent psychiatric disorder were female and their most prevalent diagnosis was generalized anxiety disorder. CONCLUSION: This cohort study confirms that psychiatric disorders, in particular MDD, frequently occur in patients with HD. Professionals working with HD patients should therefore be aware of the high risk of psychopathology in HD because early diagnosis and treatment of psychiatric disorders may improve the quality of life of patients and their caregivers.

Suicidality in Huntington's disease.

BACKGROUND: In Huntington's disease (HD) the risk of suicide is increased. Since suicidality may precede suicide, this study investigates prevalence, clinical associations and predictors of suicidality in HD. METHODS: Suicidality was investigated in 152 mutation carriers and 56 non-carriers, and was considered present if the score on the item 'suicidal ideation' of the Problem Behaviours Assessment (PBA) was >1 point. After 2 years, 100 mutation carriers who were free of suicidality at baseline were re-assessed. Associations and predictors of suicidality were analyzed using multivariate logistic regression analysis. RESULTS: Eleven (20%) pre-motor and 20 (20%) motor symptomatic mutation carriers were considered suicidal compared to none of the non-carriers. Cross-sectionally, suicidal mutation carriers were more likely to use antidepressants (odds ratio=5.3), were more often apathetic (OR=2.8), more often had a depressed mood according to the PBA (OR=5.9), and were more often diagnosed with a DSM-IV depression diagnosis (OR=4.7). Independent associations were more frequent use of antidepressants (OR=4.0) and presence of a depressed mood (OR=4.2). Longitudinally, depressed mood (OR=10.6) at baseline was the only independent predictor of suicidality at follow-up. LIMITATIONS: Selection bias might have occurred which could have affected the suicidality rate. CONCLUSION: It is important to screen both pre-motor and motor symptomatic HD mutation carriers for suicidality. The presence of a depressed mood is both associated with and predictive of suicidality in HD and assessment of depressed mood can help to identify individuals with increased risk for suicide.

Adverse childhood experiences of persons at risk for Huntington's disease or BRCA1/2 hereditary breast/ovarian cancer.

Huntington's disease (HD) is known to have a negative impact on family life. Offspring of HD patients may be exposed to adversity in childhood because of the parent's disease and its psychological consequences. BRCA1/2 hereditary breast and ovarian cancer (BRCA1/2) increases the risk for offspring of being exposed to parental disease or loss. Childhood adversity is associated with psychopathology and various other problems in later life. Adverse childhood experiences (ACEs) before age 16 were assessed in adults at 50% risk for HD (n = 74) or BRCA1/2 (n = 82) and in controls (n = 101), using the Negative Life Events Scale. Mean number and occurrence of ACEs were compared between groups. The odds of having experienced adversity in childhood were higher in HD offspring and BRCA1/2 offspring than in controls. HD offspring reported a higher mean number of ACEs than controls or BRCA1/2 offspring. In HD offspring, the prevalence of parental disease and parental dysfunction experienced before age 16 was higher than in controls. In BRCA1/2 offspring, the prevalence of parental loss before age 16 was higher than in controls. This study indicates that 53% of HD offspring and 45% of BRCA1/2 offspring are exposed to adversity in childhood or adolescence. The relevance of these findings for counseling in predictive testing programs, reproductive decision-making, and child rearing matters is discussed.

Correlates of apathy in Huntington's disease.

The authors aim to study prevalence and clinical correlates of apathy in Huntington's disease. Apathy was defined as an Apathy Scale score > or =14 points in 152 Huntington's disease mutation carriers and 56 noncarriers. Correlates of apathy were analyzed cross-sectionally in mutation carriers using multivariable logistic regression analysis. Forty-nine (32%) Huntington's disease mutation carriers showed apathy compared to none of the noncarriers. After exclusion of 10 depressed patients, apathy was independently associated with male sex, worse global functioning, and higher use of neuroleptics and benzodiazepines.

Psychopathology in verified Huntington's disease gene carriers.

Huntington's disease is characterized by motor, cognitive, and neuropsychiatric symptoms. This study reviews original research on psychopathology in Huntington's disease that uses standardized instruments in verified gene carriers. Frequently reported neuropsychiatric symptoms are depressed mood, anxiety, irritability, and apathy, with prevalences of 33% to 76%. Obsessive-compulsive symptoms and psychosis occur less often with prevalences of 10% to 52% and 3% to 11%, respectively. Available research provides little insight into the true prevalences of psychopathology in Huntington's disease due to small sample sizes, use of different methodologies, and lack of comparison groups. Future research requires larger cohorts stratified to disease stage, consistent methodologies, and adequate comparison groups.

A narrow-band injection-seeded pulsed titanium:sapphire oscillator-amplifier system with on-line chirp analysis for high-resolution spectroscopy.

A narrow-band tunable injection-seeded pulsed titanium:sapphire laser system has been developed for application in high-resolution spectroscopic studies at the fundamental wavelengths in the near infrared as well as in the ultraviolet, deep ultraviolet, and extreme ultraviolet after upconversion. Special focus is on the quantitative assessment of the frequency characteristics of the oscillator-amplifier system on a pulse-to-pulse basis. Frequency offsets between continuous-wave seed light and the pulsed output are measured as well as linear chirps attributed mainly to mode pulling effects in the oscillator cavity. Operational conditions of the laser are found in which these offset and chirp effects are minimal. Absolute frequency calibration at the megahertz level of accuracy is demonstrated on various atomic and molecular resonance lines.

[Electroconvulsive therapy in patients with Huntington's disease and depression]. / Elektroconvulsietherapie bij patiënten met de ziekte van Huntington en depressie.

Two patients, a 50-year-old man and a 51-year-old woman, with genetically confirmed Huntington's disease (HD) were admitted to a psychiatric department because of therapy-resistant major depression. Both patients were successfully treated with electroconvulsive therapy (ECT). The lifetime prevalence of depression in HD patients is high and, together with movement and cognitive disturbances, causes a heavy disease burden for patients and their families. ECT is an effective and relatively fast antidepressive treatment. Although ECT use has been reported in only 11 depressive HD patients in the literature, in our opinion it is an adequate antidepressive treatment that should be considered before further drug treatment for patients who are substantially limited in their daily functioning.

Production of narrowband tunable extreme-ultraviolet radiation by noncollinear resonance-enhanced four-wave mixing.

Fourier-transform-limited extreme-ultraviolet (XUV) radiation (bandwidth approximately < 300 MHz) tunable around 91 nm is produced by use of two-photon resonance-enhanced four-wave mixing on the Kr resonance at 94 093 cm(-1). Noncollinear phase matching ensures the generation of an XUV sum frequency 2 omega1 + omega2 that can be filtered from auxiliary laser beams and harmonics by an adjustable slit. Application of the generated XUV light is demonstrated in spectroscopic investigations of highly excited states in H2 and N2.

Deep-ultraviolet cavity ringdown spectroscopy.

The sensitive optical detection technique of cavity ringdown spectroscopy is extended to the wavelength range 197-204 nm. A novel design narrowband Fourier-transform-limited laser is used, and the technique is applied to gas-phase extinction measurements in CO2, SF6, and O2. Further demonstration of the system capabilities is given in high-resolution recordings of the Schumann-Runge (0, 0), (1,0), and (2, 0) bands in O2.

Interfacial positioning and stability of transmembrane peptides in lipid bilayers studied by combining hydrogen/deuterium exchange and mass spectrometry.

Nano-electrospray ionization mass spectrometry (ESI-MS) was used to analyze hydrogen/deuterium (H/D) exchange properties of transmembrane peptides with varying length and composition. Synthetic transmembrane peptides were used with a general acetyl-GW(2)(LA)(n)LW(2)A-ethanolamine sequence. These peptides were incorporated in large unilamellar vesicles of 1,2-dimyristoyl-sn-glycero-3-phosphocholine. The vesicles were diluted in buffered deuterium oxide, and the H/D exchange after different incubation times was directly analyzed by means of ESI-MS. First, the influence of the length of the hydrophobic Leu-Ala sequence on exchange behavior was investigated. It was shown that longer peptide analogs are more protected from H/D exchange than expected on the basis of their length with respect to bilayer thickness. This is explained by an increased protection from the bilayer environment, because of stretching of the lipid acyl chains and/or tilting of the longer peptides. Next, the role of the flanking tryptophan residues was investigated. The length of the transmembrane part that shows very slow H/D exchange was found to depend on the exact position of the tryptophans in the peptide sequence, suggesting that tryptophan acts as a strong determinant for positioning of proteins at the membrane/water interface. Finally, the influence of putative helix breakers was studied. It was shown that the presence of Pro in the transmembrane segment results in much higher exchange rates as compared with Gly or Leu, suggesting a destabilization of the alpha-helix. Tandem MS measurements suggested that the increased exchange takes place over the entire transmembrane segment. The results show that ESI-MS is a convenient technique to gain detailed insight into properties of peptides in lipid bilayers by monitoring H/D exchange kinetics.

Excess cancer mortality in six Dutch pedigrees with the familial atypical multiple mole-melanoma syndrome from 1830 to 1994.

An increased incidence of systemic cancers has been described in some reports of familial atypical multiple mole-melanoma kindreds. If the gene defect underlying the familial atypical multiple mole-melanoma syndrome is not only important for the development of melanoma of the skin, the impact of the defect on life expectancy may be much higher than previously thought. We investigated all-cause mortality from 1830 to the present and causes of death from 1941 to 1994 in proven, obligate, and potential CDKN2 mutation carriers to obtain an estimate of the impact of a hereditary defect of the CDKN2 gene on mortality. From 1830 to 1994 there were 65 deaths, although only 42 deaths were expected [standardized mortality ratio (SMR) 1.6, 95% confidence interval (CI) 1.2-2.0] and the SMR doubled with calendar time. Excess mortality was shown in most of the families, but was confined to ages 35-70 y (SMR 2.1, 95%CI 1.5-2.9). Excess mortality could be fully attributed to cancer mortality, especially to pancreatic carcinoma and melanoma of the skin. There appeared to be some heterogeneity among the families, especially due to the specific cancer pattern within a family. The impact of the defect of the CDKN2 gene is rising over calendar time, mainly because the mortality in the general population has been falling. Excess mortality was not only due to melanoma, but also to pancreatic carcinoma. Therefore, follow-up programs of affected family members should not be confined to a regular check of the atypical nevi.