[Simple is not always easy: genetics in general psychiatry]. / Drie patiënten met langdurig onopgehelderde psychiatrische klachten waarbij genetische diagnostiek uitkomst bracht.

Many of the patients who attend the outpatient mental health clinics already have a long history of psychiatric problems. Their symptoms seem easy to classify, but the misdiagnosis of the patients' underlying problems can lead to a long series of costly referrals as inpatients or to an ineffective treatment outcome. In this article we focus on three patients whose history and background circumstances had been analysed in detail and who had also been subjected to a genetic analysis. The analyses pointed to an etiology-based diagnosis which had important implications for their future treatment and its outcome.

Atypical Antipsychotics and Relapsing Psychoses in 22q11.2 Deletion Syndrome: A Long-term Evaluation of 28 Patients.

INTRODUCTION: This study includes 28 patients with genetically proven 22q11.2 deletion syndrome referred for treatment-resistant psychoses and aims at the identification of a suitable pharmacological treatment strategy. METHODS: Based on standardized diagnostic procedures, key psychiatric symptoms and cognitive status were assessed. Also, data about previous diagnostic vignettes as well as the history of psychotropic medication and medical conditions were collected. Finally, the effect of the subsequent treatment regimen was periodically re-assessed. RESULTS: Since psychotic symptoms had been shown to be non-responsive to conventional antipsychotics including risperidone, treatment with either clozapine or quetiapine was started. In 21 patients, a substantial reduction of psychotic symptoms was achieved with either one, and in 3-quarters of this group remission was attained over a longer follow-up period. In a significant number of patients, valproic acid was added either for mood stabilizing purposes or to avoid epileptic side effects of clozapine. DISCUSSION: Treatment of psychotic symptoms in patients with 22q11DS with the atypical antipsychotic quetiapine or clozapine in combination with the mood-stabilizing anticonvulsant valproic acid, appears likely to be more effective than with other psychotropic compounds.

22q11.2 deletion syndrome: atypical antipsychotics and relapsing psychoses.

In their letter to the editor, Boot and colleagues comment on the results of treatment with atypical antipsychotics in patients with 22q11.2 deletion syndrome and relapsing psychoses. They identify 3 issues (i. e., description of study rationale and assessments, the importance of endocrine dysfunctions and possible effects of sample bias) and conclude that "until strong evidence to the contrary [is available], standard pharmacological management of psychotic illness in 22q11DS remains recommended." In our reply, we will illustrate the erroneous nature of their conjectures.

[Neuropsychiatry as practised in a highly specialised department of a psychiatric teaching hospital: a successful interdisciplinary approach]. / Topklinische neuropsychiatrie: een succesvolle interdisciplinaire benadering.

BACKGROUND: Psychiatric disorders can be interpreted as a general dysregulation of the interplay between brain and behaviour. This is why, since the late 1990’s, the terms biological psychiatry and behavioural neurology have been gradually replaced by the term neuropsychiatry. Neuropsychiatry, when practiced in combination with clinical neuropsychology, have given rise to a paradigm that is not based solely on the usual classification models but is directed primarily towards diagnosis and treatment that are based on a functional-dimensional approach. AIM: To discuss the daily practice and organisation in a specialised department for neuro-psychiatry located in a psychiatric teaching hospital. METHOD: The interdisciplinary approach is explained and analysed on the basis of 10 case studies. RESULTS: Most of the patients referred to the specialised department already had a long history of visits to the health care facilities where they had been treated by a variety of specialists in single disciplines. Often, however, this trajectory did not involve periodical re-evaluation and updating of the original diagnosis. If this strategy had been adopted, then a clear diagnosis with simplified treatment programme might have been devised which could have resulted in a patient’s successful reintegration into society. CONCLUSION: It is essential that the interdisciplinary approach is adopted in specialised centres for neuropsychiatry because it can make an important contribution to individual patient care and to the spread of specialised knowledge that can benefit the entire field of psychiatry.

Affective functioning and social cognition in Noonan syndrome.

BACKGROUND: Noonan syndrome (NS) is a common genetic disorder, characterized by short stature, facial dysmorphia, congenital heart defects and a mildly lowered IQ. Impairments in psychosocial functioning have often been suggested, without, however, systematic investigation in a clinical group. In this study, different aspects of affective processing, social cognition and behaviour, in addition to personal well-being, were assessed in a large group of patients with NS. METHOD: Forty adult patients with NS were compared with 40 healthy controls, matched with respect to age, sex, intelligence and education level. Facial emotion recognition was measured with the Emotion Recognition Task (ERT), alexithymia with both the 20-item Toronto Alexithymia Scale (TAS-20) and the Bermond-Vorst Alexithymia Questionnaire (BVAQ), and mentalizing with the Theory of Mind (ToM) test. The Symptom Checklist-90 Revised (SCL-90-R) and the Scale for Interpersonal Behaviour (SIB) were used to record aspects of psychological well-being and social interaction. RESULTS: Patients showed higher levels of cognitive alexithymia than controls. They also experienced more social distress, but the frequency of engaging in social situations did not differ. Facial emotion recognition was only slightly impaired. CONCLUSIONS: Higher levels of alexithymia and social discomfort are part of the behavioural phenotype of NS. However, patients with NS have relatively intact perception of emotions in others and unimpaired mentalizing. These results provide insight into the underlying mechanisms of social daily life functioning in this patient group.

X-linked Aarskog syndrome: report on a novel FGD1 gene mutation. Executive dysfunction as part of the behavioural phenotype.

Aarskog-Scott syndrome [OMIM 100050] is a predominantly X-linked disorder that is phenotypically characterized by short stature, craniofacial dysmorphisms, brachydactyly and urogenital abnormalities. The level of intelligence shows a great variability and no specific behavioural phenotype has been described so far. In about 20 percent ofAarskog families, a mutation in the FGD1 gene located in Xp11.21 can be identified. In the present study, four affected males from the fourth generation of a large Dutch family (published in 1983 by Van de Vooren et al. (41)) are described. A novel FGD1 missense mutation (R402W) at position 1204 (1204C>T) was demonstrated. In the patients, the level of intelligence varied between normal and severely disabled. Their behavioural profile showed, among others, elements of attention deficit hyperactivity disorder, primarily reflected by impaired executive attentional processes that may be sensitive to systematic training.

Plasma levels of nitric oxide related amino acids in demented subjects with Down syndrome are related to neopterin concentrations.

Subjects with Down syndrome (DS) have abnormalities in virtually all aspects of the immune system and almost all will be affected with Alzheimer's disease (AD). It is thought that nitric oxide (NO) is involved in the pathophysiology of AD. In the present study, including a total of 401 elderly DS subjects, the spectrum of plasma amino acids and neopterin was investigated and related to development of AD. Concentrations of nearly all amino acids in DS subjects differed significantly from those of healthy controls. Neopterin was increased in DS subjects, especially in dementia. The production of NO as reflected by an increased citrulline/arginine ratio (Cit/Arg ratio) was enhanced during development of clinical dementia. Neopterin concentrations correlated to the Cit/Arg ratio only in the group of prevalent demented subjects (rho = 0.48, P = 0.006). The results of this study are suggestive for an increase in oxidative processes in DS subjects with AD.

Sanfilippo B in an elderly female psychiatric patient: a rare but relevant diagnosis in presenile dementia.

OBJECTIVE: Sanfilippo B is a rare autosomal recessive mucopolysaccharidosis (MPS IIIB) caused by a deficiency of N-acetyl-alpha-D-glucosaminidase (NAGLU). METHOD: A mild mentally retarded elderly female patient is described with a slowly progressive dementia who had given birth to a daughter who developed normally. RESULTS: Metabolic screening revealed an enhanced concentration of heparan sulfate in urine. Enzymatic assay demonstrated deficiency of N-acetyl-alpha-D-glucosaminidase. Mutations in the NAGLU gene were found. One mentally retarded and hospitalized elder brother was also found to have MPS IIIB, whereas a second brother, who had died earlier, is suspected to have had the same metabolic disorder. Prior to the development of dementia, both the patient and her brother showed autistic like features, signs of ideomotor apraxia and weakness in verbal comprehension. CONCLUSION: Screening for metabolic disorders, in particular MPSes, should always be considered in patients with a history of mental deficit and dementia or progressive functional decline.

Psychiatric profile in rubinstein-taybi syndrome. A review and case report.

BACKGROUND: The diagnosis of Rubinstein-Taybi syndrome (RTS) is primarily clinical and based on the characteristic phenotype that is often combined with a variety of somatic anomalies and psychiatric disorders. SAMPLING AND METHODS: In this paper, a review is presented of the psychiatric and behavioural aspects of RTS. This is illustrated with a case report. RESULTS: Behavioural aspects of about 150 patients are described, and include a variable degree of mental retardation, impulsivity, distractibility, instability of mood and stereotypies. In general, patients with RTS are described as sociable and friendly. Information about brain pathology is virtually absent. In about half of the cases, the syndrome is caused by a mutation or deletion of the CREB-binding protein (CBP) gene (16p13.3). The case report deals with an adult male who was referred for impulsivity and temper outbursts. A provisional diagnosis of atypical depression was made, and treatment with citalopram resulted in a remarkable amelioration of his mood and behaviour that persisted for more than 2 years (last observation). CONCLUSION: Patients with undetected genetic syndromes do occur in clinical psychiatry, and the clinician has to consider such disorders in cases with disturbed development, dysmorphias and somatic comorbidity.

[Toxic plasma concentration of clozapine in inflammatory processes]. / Toxische plasmaconcentratie van clozapine bij ontstekingsprocessen.

Clozapine has a narrow therapeutic range. The threshold value for plasma concentrations is 350 µg/l. If plasma concentrations exceed that value, serious side-effects can occur. An increase in plasma concentrations can occur as a result of inflammatory processes which may or may not be caused by an infection. Two cases are discussed in which the plasma concentration of clozapine increased as a result of an inflammatory reaction and signs of intoxication were observed. These developments seemed to be due to cholecystitis and bacterial pneumonia respectively. The clinical presentation and pathophysiology are discussed in relation to inflammatory processes.

A novel duplication of chromosome (13)(q14.1q21.3) in a patient with mental retardation and microcephaly.

We report on a mentally retarded female with behavioural problems, microcephaly, mild facial dysmorphisms, short stature and small hands with thin fingers due to a de novo partial duplication within the long arm of chromosome 13(q14.1q21.3). She was primarily referred to the outpatient department of neuropsychiatry because of short lasting psychotic episodes. No formal psychiatric diagnosis was made and the behavioural problems appeared the result of anxieties provoked by novel situations, enhanced by the intellectual disability. To the author's knowledge, this duplication has not been published previously and it is considered causative of the phenotype.

[An algorithm for psychotropics for the mentally handicapped: psychiatric diagnosis in three stages]. / Een algoritme voor psychofarmaca bij verstandelijk gehandicapten: psychiatrische diagnostiek in drie stappen.

BACKGROUND: Psychiatric treatment of mentally handicapped patients is still in its infancy because these patients are diagnosed by means of inadequate DSM vignettes that were not developed for such a homogeneous group and that do not have the status of diagnoses based on aetiology and pathophysiology. AIM: To raise awareness that the psychiatrist dealing with this group of patients needs to have a thorough knowledge of the syndromes involved which can be accompanied by psychiatric and somatic comorbidity and also needs to have expertise in linked disciplines such as genetics, epileptology and pharmacology. METHOD: On the basis of the international scientific literature an attempt was made to identify the rationale that underlies the current practice of treating challenging behaviour with a fairly random selection of psychotropics. RESULT: A diagnostic algorithm was formulated which can help the psychiatrist to provide evidence-based specialised advice on treatment and which can also prevent the occurrence of harm or damage. CONCLUSION: The top-down orientation of current diagnostic procedures, which tries to link symptoms to an underlying pathology, should be counterbalanced by a bottom-up approach in which the aetiology is the starting point. If this principle is observed, a well-founded proposal about treatment can sometimes be put forward. In all other cases treatment at present is little more than symptomatic pharmacotherapy involving a few well-documented psychotropics.

Design and characterization of dielectric filled TM110 microwave cavities for ultrafast electron microscopy.

Microwave cavities oscillating in the TM110 mode can be used as dynamic electron-optical elements inside an electron microscope. By filling the cavity with a dielectric material, it becomes more compact and power efficient, facilitating the implementation in an electron microscope. However, the incorporation of the dielectric material makes the manufacturing process more difficult. Presented here are the steps taken to characterize the dielectric material and to reproducibly fabricate dielectric filled cavities. Also presented are two versions with improved capabilities. The first, called a dual-mode cavity, is designed to support two modes simultaneously. The second has been optimized for low power consumption. With this optimized cavity, a magnetic field strength of 2.84 ± 0.07 mT was generated at an input power of 14.2 ± 0.2 W. Due to the low input powers and small dimensions, these dielectric cavities are ideal as electron-optical elements for electron microscopy setups.

[Chemotherapy during clozapine treatment. Increased risk of agranulocytosis?]. / Chemotherapie bij gebruik van clozapine; een verhoogde kans op agranulocytose?

In a 37-year-old female, a combined treatment consisting of chemotherapy and radiation was considered for cervical cancer. However, she was using clozapine for the treatment of schizophrenia. As both clozapine and chemotherapy can induce decrease of white blood cell counts, we had to decide if clozapine and chemotherapy could be safely co-prescribed. Hypotheses concerning the mechanisms underlying clozapine-induced decrease of white blood cell counts and case reports on combining chemotherapy and clozapine are discussed. After cessation of clozapine the psychosis recurred despite treatment with risperidone. The decision was made to administer radiotherapy only and to reinstate the treatment with clozapine. The radiotherapy treatment went according to plan and the psychosis receded.

High quality ultrafast transmission electron microscopy using resonant microwave cavities.

Ultrashort, low-emittance electron pulses can be created at a high repetition rate by using a TM110 deflection cavity to sweep a continuous beam across an aperture. These pulses can be used for time-resolved electron microscopy with atomic spatial and temporal resolution at relatively large average currents. In order to demonstrate this, a cavity has been inserted in a transmission electron microscope, and picosecond pulses have been created. No significant increase of either emittance or energy spread has been measured for these pulses. At a peak current of 814 ±â€¯2 pA, the root-mean-square transverse normalized emittance of the electron pulses is ɛn,x=(2.7±0.1)·10-12 m rad in the direction parallel to the streak of the cavity, and ɛn,y=(2.5±0.1)·10-12 m rad in the perpendicular direction for pulses with a pulse length of 1.1-1.3 ps. Under the same conditions, the emittance of the continuous beam is ɛn,x=ɛn,y=(2.5±0.1)·10-12 m rad. Furthermore, for both the pulsed and the continuous beam a full width at half maximum energy spread of 0.95 ±â€¯0.05 eV has been measured.

Time-of-flight electron energy loss spectroscopy by longitudinal phase space manipulation with microwave cavities.

The possibility to perform high-resolution time-resolved electron energy loss spectroscopy has the potential to impact a broad range of research fields. Resolving small energy losses with ultrashort electron pulses, however, is an enormous challenge due to the low average brightness of a pulsed beam. In this paper, we propose to use time-of-flight measurements combined with longitudinal phase space manipulation using resonant microwave cavities. This allows for both an accurate detection of energy losses with a high current throughput and efficient monochromation. First, a proof-of-principle experiment is presented, showing that with the incorporation of a compression cavity the flight time resolution can be improved significantly. Then, it is shown through simulations that by adding a cavity-based monochromation technique, a full-width-at-half-maximum energy resolution of 22 meV can be achieved with 3.1 ps pulses at a beam energy of 30 keV with currently available technology. By combining state-of-the-art energy resolutions with a pulsed electron beam, the technique proposed here opens up the way to detecting short-lived excitations within the regime of highly collective physics.

Theory and particle tracking simulations of a resonant radiofrequency deflection cavity in TM110 mode for ultrafast electron microscopy.

We present a theoretical description of resonant radiofrequency (RF) deflecting cavities in TM110 mode as dynamic optical elements for ultrafast electron microscopy. We first derive the optical transfer matrix of an ideal pillbox cavity and use a Courant-Snyder formalism to calculate the 6D phase space propagation of a Gaussian electron distribution through the cavity. We derive closed, analytic expressions for the increase in transverse emittance and energy spread of the electron distribution. We demonstrate that for the special case of a beam focused in the center of the cavity, the low emittance and low energy spread of a high quality beam can be maintained, which allows high-repetition rate, ultrafast electron microscopy with 100 fs temporal resolution combined with the atomic resolution of a high-end TEM. This is confirmed by charged particle tracking simulations using a realistic cavity geometry, including fringe fields at the cavity entrance and exit apertures.

Meditation-induced psychosis.

BACKGROUND: Meditation is a self-regulatory psychological strategy that is frequently applied in Western as well as non-Western countries for different purposes; little is known about adverse events. SAMPLING AND METHODS: A male patient is described who developed an acute and transient psychosis with polymorphic symptomatology after meditating. A literature search for psychotic states related to meditation was carried out on PubMed, Embase and PsycInfo. RESULTS: In the case presented a diagnosis of acute polymorphic psychotic disorder was made. Other case reports dealt with either a relapse of a pre-existent psychotic disorder or with a brief psychotic reaction in patients without a psychiatric history. CONCLUSION: Meditation can act as a stressor in vulnerable patients who may develop a transient psychosis with polymorphic symptomatology. The syndrome is not culture bound but sometimes classified in culture-bound taxonomies like Qi-gong Psychotic Reaction.

[Autism and catatonia: successful treatment using lorazepam. A case study]. / Autisme en katatonie. Een succesvolle behandeling met lorazepam.

A 24-year-old man who was mentally retarded and had an autistic disorder, developed mutism and motor symptoms. He was diagnosed with catatonia and was treated successfully with lorazepam. Additionally, we review the literature about the diagnosis and treatment of catatonia in patients with autism; in such cases accurate diagnosis is vital but is complicated by overlapping symptoms.

Bipolar mania and plasma amino acids: increased levels of glycine.

Previous studies have suggested that the N-methyl-d-aspartate (NMDA) glutamate receptor complex is implicated in the pathophysiology of several neuropsychiatric disorders. Especially the glycine coagonist site of this receptor has been proposed as a therapeutic target. It has been hypothesized that the NMDA receptor and the serotonergic system, which function is compromised in affective disorders, are functionally coupled. Furthermore, several studies suggest that peripheral levels of amino acids are associated with psychotic symptomatology. We therefore measured plasma levels of glutamate, glycine, tryptophan and the tryptophan ratio in 20 bipolar-I patients during the manic phase and at remission of symptomatology. Data were compared to a matched group of healthy controls and a group of euthymic bipolar-I patients. During the manic phase, a significant increase of both glutamate and glycine was found, that persisted at remission. Tryptophan and the tryptophan ratio were decreased in manic patients. Subsequent analysis showed that changes in glutamate, tryptophan and tryptophan ratio could be attributed to the use of anticonvulsants. The increased glycine, however, was not related to the use of mood stabilizers. Although the exact relationship between peripheral measures of amino acids, e.g., glycine is not fully clear, the results of this study suggest an involvement of glycine and/or its coagonist site of the NMDA receptor in a manic relapse of patients with a bipolar-I disorder.