Synthesis and SAR study of acridine, 2-methylquinoline and 2-phenylquinazoline analogues as anti-prion agents.

Transmissible spongiform encephalopathies (TSEs) are thought to arise from aggregation of a protease resistant protein denoted PrP(Sc), which is a misfolded isoform of the normal cellular prion protein PrP(C). Using virtual high-throughput screening we have selected structures analogous to acridine, 2-methyquinoline and 2-phenylquinazoline as potential therapeutic candidates for the treatment of TSEs. From the synthesis and screening of constructed libraries we have shown that an electron-rich aromatic ring attached through an amine linker to the position para to the ring nitrogen is beneficial to both binding to PrP(C) and the suppression of PrP(Sc) accumulation for acridine and 2-methylquinoline analogues. 2-Phenylquinazoline analogues appear to utilise a different mode of action by binding at a different location and/or pose. We report IC50s in the nanomolar range.

Patterns of referral in patients with medically unexplained motor symptoms.

OBJECTIVE: To investigate the pattern and reasons for referrals in 64 patients with a stable diagnosis of motor conversion symptoms who had been assessed at the National Hospital for Neurology and Neurosurgery (NHNN). METHOD: Patients were interviewed on average 6 years after their original admission to the NHNN. Hospital notes and GP records were consulted. RESULTS: Psychiatrists at the NHNN saw 75% of patients. Treatment was initiated in 60% of these. During the 6-year follow up, many patients continued to be referred to neurologists and other specialists, but subsequent psychiatric referral was rare. Many changed their GP after discharge from the NHNN and a disproportionate number of re-referrals was made by GPs who had known their patients for less than 6 months. Psychological attribution of symptoms was rare and did not appear to be related to the pattern of referrals. CONCLUSION: The pattern of care of these patients was inconsistent and many felt dissatisfied with the treatment they received. This led to further referrals, unnecessary use of valuable resources and unnecessary exposure to iatrogenic damage. Further studies should aim to assist GPs and other clinicians in deciding when referral is likely to be beneficial.

Discrete neurophysiological correlates in prefrontal cortex during hysterical and feigned disorder of movement.

The clinical distinction between hysterical symptoms and those that are feigned awaits objective validation. We used functional neuroimaging to examine the neural correlates of these two disorders.

Slater revisited: 6 year follow up study of patients with medically unexplained motor symptoms.

OBJECTIVE: To investigate psychiatric and neurological morbidity, diagnostic stability, and indicators of prognosis in patients previously identified as having medically unexplained motor symptoms. DESIGN: Follow up study. SETTING: National Hospital for Neurology and Neurosurgery, London--a secondary and tertiary referral hospital for neurological disorders. SUBJECTS: 73 patients with medically unexplained motor symptoms admitted consecutively in 1989-91. 35 (48%) patients had absence of motor function (for example, hemiplegia) and 38 (52%) had abnormal motor activity (for example, tremor, dystonia, or ataxia). MAIN OUTCOME MEASURES: Neurological clinical diagnosis at face to face reassessment by a neurologist and a psychiatric diagnosis after a standardised assessment interview--the schedule for affective disorders and schizophrenia--conducted by a psychiatrist. RESULTS: Good follow up data were available for 64 subjects (88%). Only three subjects had new organic neurological disorders at follow up that fully or partly explained their previous symptoms. 44/59 (75%) subjects had had psychiatric disorders; in 33 (75%) patients, the psychiatric diagnosis coincided with their unexplained motor symptoms. 31/59 (45%) patients had a personality disorder. Three subjects had developed new psychiatric illnesses at follow up, but in only one did the diagnosis account for the previous motor symptoms. Resolution of physical symptoms was associated with short length of symptoms, comorbid psychiatric disorder, and a change in marital status during follow up. CONCLUSIONS: Unlike Slater's study of 1965, a low incidence of physical or psychiatric diagnoses which explained these patients' symptoms or disability was found. However, a high level of psychiatric comorbidity existed.

Psychosocial risk factors for chronic fatigue and chronic fatigue syndrome following presumed viral illness: a case-control study.

This study investigated psychosocial morbidity, coping styles and health locus of control in 64 cases with and without chronic fatigue identified from a cohort of primary care patients recruited 6 months previously with a presumed, clinically diagnosed viral illness. A significant association between chronic fatigue and psychosocial morbidity, somatic symptoms and escape-avoidance coping styles was shown. Chronic fatigue cases were significantly more likely to have a past psychiatric history and a current psychiatric diagnosis based on a standardized clinical interview. Twenty-three of the cases fulfilled criteria for chronic fatigue syndrome (CFS). Such cases were significantly more fatigued than those not fulfilling criteria, but had little excess psychiatric disorder. A principal components analysis provided some evidence for chronic fatigue being separable from general psychosocial morbidity but not from the tendency to have other somatic complaints. Past psychiatric history and psychological distress at the time of the viral illness were risk factors for psychiatric 'caseness' 6 months later, while presence of fatigue, psychologising attributional style and sick certification were significant risk factors for CFS. These findings extend a previous questionnaire study of predictors of chronic 'post-viral' fatigue.

Cognitive functioning and magnetic resonance imaging in chronic fatigue.

BACKGROUND: This study examines whether cognitive dysfunction in chronic fatigue may be accounted for by depression and anxiety or is due to brain pathology evident on magnetic resonance imaging (MRI). METHOD: Twenty-six subjects with chronic fatigue, with and without coexisting depression, and 18 age-matched normal controls were recruited from primary care following a presumed viral illness six months previously. Comparison was made with 13 psychiatric controls with depressive illness on standardised cognitive tests. MRI determined the presence of cerebral white-matter lesions. RESULTS: No substantial differences in performance were shown between subjects with chronic fatigue, most of whom met the criteria for chronic fatigue syndrome, and controls. Subjective cognitive dysfunction increased with psychopathology. White-matter lesions were found in a minority from all groups. Improvement in fatigue and depression coincided with improved performance on cognitive measures. CONCLUSIONS: Subjective complaints of cognitive impairment are a prominent feature of chronic fatigue, but objective cognitive and MRI abnormalities are not. Such complaints probably reflect psychopathology rather than a post-viral process.

[Epidemiologic study of chronic fatigue in primary care (general practice)]. / Etude épidémiologique de la fatigue chronique en milieu de soins primaires (médecine générale).

The results of a cross sectional study of fatigue in two large samples of patients attending primary care physicians are reported. The level of complaint of fatigue was higher in the prospective sample, which consisted of patients who had been diagnosed as suffering from a viral infection six months earlier. Duration and frequency of experience of fatigue correlated with severity in both samples. Severity, duration and frequency were continuously distributed in these populations. Attribution of fatigue in these two samples was mixed: social stresses, current physical illness and psychological problems all being offered as explanations. 11% of the cross sectional sample and 17% of the prospective sample met study operational criteria for a possible chronic fatigue state. These patients were assessed in greater detail. The majority had a diagnosable psychiatric disorder, predominantly depression. Physical illnesses were not adequate to explain these fatigue states. These studies in primary care do not support a clinical entity of a "chronic fatigue syndrome". Some patients in primary care settings have complaints of fatigue that are both disabling and long lasting, but they do not form a distinct group although the majority are likely however to be suffering from a concurrent psychiatric disorder. In contrast to similar patients with chronic fatigue syndromes attending hospital clinics, primary care patients with complaints of fatigue are much more varied in their ideas of causation with considerable less evidence of disease conviction.

Diversity of psychopathology associated with use of 3,4-methylenedioxymethamphetamine ('Ecstasy')

BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy') has become one of the most widely used illicit substances in the UK. Little is known of the psychiatric morbidity which may be associated with its use. We have examined this association by collecting a series of psychiatric cases in which MDMA use was a prominent feature. METHOD: Patients presenting between 1990 and 1992 with psychiatric symptoms which developed in the context of MDMA use (n = 13) were interviewed, and their psychiatric, medical and drug history, sociodemographic background and mental state were examined in detail. The psychopathology of cases with psychosis (n = 8) was assessed with the Present State Examination and compared with that of substance-naïve psychotic controls (n = 40). RESULTS: Eight patients presented with psychotic syndromes, two experienced visual illusions, hallucinations and palinopsia, one had panic attacks, one suffered from depression, and one described chronic depersonalisation and derealisation. The psychopathology of the patients with psychoses was very similar to that of controls. CONCLUSIONS: Use of MDMA may be associated with a broader spectrum of psychiatric morbidity than heretofore suspected. Cases with psychosis may be clinically similar to psychotic patients with no history of substance use.

Predictors of chronic "postviral" fatigue.

We set out to determine the relation between a general practitioner (GP) diagnosis of viral illness and development of chronic fatigue 6 months later. 618 subjects who attended GPs clinics in London, south, and southwest England and who received a diagnosis of viral illness were followed prospectively and fatigue was assessed by questionnaire after 6 months. At presentation, GPs recorded fatigue in 62.6% of subjects, usually since the onset of symptoms. 502 (81.2%) subjects completed the 6-month questionnaire, of whom 88 (17.5%) met criteria for chronic fatigue and 65 (12.9%) had no reported fatigue before the viral illness. Compared with a similar group of non-postviral GP attenders, the risk ratio for chronic fatigue in the present cohort was 1.45 (95% CI 1.14-2.04). Infective symptoms did not predict fatigue 6 months later. Psychiatric morbidity, belief in vulnerability to viruses, and attributional style at initial presentation were all associated with self-designated postviral fatigue. Logistic regression showed that somatic attributional style, less definite diagnosis by the GP, and sick certification were the only significant predictors of chronic fatigue after viral infection when other factors were controlled for. Chronic severe fatigue 6 months after GP-diagnosed viral illness is related to symptom-attributional style and doctor behaviour, rather than to features of the viral illness. Some subjects with apparent postviral fatigue had complained of tiredness before their presentation with a viral illness.

Postgraduate training for overseas doctors in Britain.

Foreign doctors, other than those from the European Economic Area, who want to train in Britain have to satisfy registration and immigration requirements before they can take up a post. The General Medical Council administers the registration regulations. These are quite separate from the immigration formalities, which are handled by the Home Office. The rules on both are complicated, and doctors should seek advice early to ensure that unnecessary difficulties do not add to the inevitable stresses associated with moving to a new country and working in a strange system.

'Maybe it's a virus?': beliefs about viruses, symptom attributional style and psychological health.

A questionnaire concerning beliefs about viruses was devised and validated as part of a study investigating the relationship between such attitudes, symptom attributional style and psychological morbidity in 283 general practice attenders. It was found, contrary to expectation, that those who believed they were powerless in the face of viruses were more likely to have higher psychological distress and to blame physical symptoms on emotional and psychological factors. Age, sex and the presence of an infective illness exerted only minor effects. Such data are informative in testing hypotheses regarding the development of illnesses where there is a strong belief in a viral aetiology, but where psychological factors are present, such as the post-viral fatigue syndrome.

Cognitive impairment in patients with chronic fatigue: a preliminary study.

Subjective impairment of memory and concentration is a frequent complaint in sufferers from chronic fatigue. To study this, 65 general practice attenders identified as having chronic fatigue were administered a structured psychiatric interview and a brief screening battery of cognitive tests. Subjective cognitive impairment was strongly related to psychiatric disorder, especially depressed mood, but not fatigue, anxiety, or objective performance. Simple tests of attention and concentration showed some impairment but this was influenced by both fatigue and depression. Subjects with high levels of fatigue performed less well on a memory task requiring cognitive effort, even in the absence of depression. There was no evidence for mental fatiguability. The relationship between depression, fatigue, and cognitive function requires further research.