Deviations in circulating TNFα levels and TNFα production by mononuclear cells in healthy human populations.

OBJECTIVES: Tumor necrosis factor alpha (TNFα) plays a pivotal role in the inflammatory host response. The serum-level of TNFα and the production of TNFα by lympho/monocytes, however, seem to show high individual variations. The goal of the present study was to investigate the variations and inducibility of TNFα-activity in two age-groups of healthy volunteers. METHODS: Sixty elderly, healthy volunteers were studied. These persons were free of malignant diseases, and within three months, they did not have any trauma or inflammatory disease and were not taking any steroids or nonsteroid anti-inflammatory drugs. Thirty young volunteers were also included. Blood samples were taken; lympho/monocytes were separated and cultured with or without endotoxin (LPS) stimulation. Serum and culture supernatant TNFα levels were determined by bioassay using WEHI 164 cells. RESULTS: The results indicated significant individual variations in TNFα levels of healthy volunteers irrespective of age. Subgroups with low, middle, and high serum TNF-levels were distinguished. In about 50% of volunteers with low serum-TNFα activity, LPS stimulation failed to increase the TNFα production by isolated lympho/monocytes. CONCLUSION: Our data suggest a chance to select individuals with enhanced sensitivity for septic complications.

Assessing mental disability in minors.

Forensic psychiatry devotes a great deal of attention to the "imprecise" and "insufficiently scientific" nature of psychiatric disability assessment, and, for this reason, it is vitally important to establish a reliable method of assessing different levels of disability. The assessment of mental disability in minors is unique in that it involves developmental aspects, which affect the formation and outcome of the disability. The relationship between disability and development is reciprocal: disability can affect development, thereby intensifying the degree of disability, while development affects integration of the disability into the personality and self-image, thereby preventing or reducing the transformation of disability into handicap. Only an understanding of both the psychopathological structure and its interaction with developmental elements can lead to an accurate assessment of the degree of disability. Such an understanding is vital to the proper practice of forensic psychiatry. We hereby propose a new formula for disability quantification which provides an arithmetical means for the calculation of disability percentages in minors, and we recommend its use in the assessment of demands for National Insurance benefits and compensation claims. The relationship between this new formula and the existing Children's Global Assessment Scale (CGAS) functional scale, when tested retrospectively on 50 clinical reports composed by the writers of this article, showed a good correlation in the results obtained independently by each writer. Two case studies are presented here. A further evaluation by objective evaluators is necessary in order to construct a model for a final objective evaluation of disability in children and adolescents.

Informed consent: myth or reality.

The rapidly growing awareness and respect of the social needs and legal rights of the patient in many countries is a sign of cultural maturity of society at large. However, the implementation of these achievements is especially arduous in the field of psychiatry because often mental patients have cognitive restrictions and/or emotional distress both of which may interfere with the exercise of their civil rights. One focus of this paper is the challenging process of obtaining legally valid consent from a severely ill psychiatric patient for diagnostic procedures and for treatment and also for participation in research projects. This paper also analyzes and discusses the new developments in the health legislation in Israel and focuses on the questions that arise in its application to the field of psychiatry. A recommendation for practical assessment of competence is presented. Systematic studies ofthe application of legal regulation and appropriate modifications are needed.

Zuclopenthixol treatment of behavioral disturbances in mentally retarded children and adolescents: an open-label study.

The present open-label study assessed the efficacy of zuclopenthixol, an thioxanthene neuroleptic with combined dopamine receptors (D1/D2) antagonist activity, in the treatment of severe behavioral disturbances in mentally retarded children and adolescents. A sample of 15 (11 males, 4 females) mentally retarded children and adolescents, ages 5-18 years (12.2 +/- 2.3 [mean +/- SD] years), all exhibiting severe behavioral disturbances, was evaluated. The 12-week zuclopenthixol treatment (up to 26 mg/day) was initiated after a week's washout from previous antipsychotic agents. An assessment of the behavioral disturbances was performed using the 14-item Checklist for Behavior Problems Involving Limited or No Social Awareness (CBP-NSA). The Udvalg for kliniske undersøgelser (UKU) Side Effect Rating Scale was used to assess the pharmacologic side effects. Results show a significant reduction in total CBP-NSA scores and in individual items such as hyperactivity, aggressive behavior, and temper tantrums (p < 0.001 for each). It seems that zuclopenthixol monotherapy is effective and well tolerated in the treatment of severe behavioral disturbances in mentally retarded children and adolescents. Double-blind, placebo-controlled studies are needed before definitive conclusions can be drawn regarding the efficacy and safety of zuclopenthixol for this population.

The patient's right to know, in the 1996 Israel law for the rights of the patient: the pains of progress.

The 1996 Israel Law for Patients' Rights, Sections 21 and 22, introduces to the field of health legislation two new entities: internal examination committees and quality-control committees. The former are to be established when there is a need to investigate unusual, irregular or exceptional events related to diagnosis and/or treatment. Furthermore, the 1996 Law directs the internal examination committee to reveal its findings to the patient or to his representatives. This approach has evoked strong controversy up until the present time. On the other hand, the quality-control committees which produce privileged information have been smoothly integrated into psychiatric practice. This paper presents the history of the creation of these two committees based on law, and examines their effect on the daily practice of medicine and the reaction of the physicians' guild to their activation. It also discusses the effect of the implementation of these committees on the level of mutual trust between therapist and patient, and on medical morality and its relationship to the social phenomenon known as defensive medicine. Feasible solutions for controversial issues are presented. These include participation of patients or their representatives in the internal examination committees, privileged peer reviews, increased utilization of quality control committees and of ethics committees.

Theory of mind abilities of children with schizophrenia, children with autism, and normally developing children.

Theory of mind (ToM) abilities of children with schizophrenia, children with high functioning autism, and normally developing children, matched on mental age (MA), verbal MA, and performance MA, were compared. Both clinical groups were matched on chronological age as well, whereas the normally developing children were younger. A fact belief task, a value belief task, a deception task, and a false belief task were administered. The three groups did not differ on the fact belief task. Children with autism performed more poorly than normally developing children on value belief and false belief tasks, and more poorly than individuals with schizophrenia on the deception task. Children with schizophrenia performed more poorly than normally developing children only on the false belief task. Overall, the group with autism passed significantly fewer tasks compared to the normally developing group. ToM abilities correlated with verbal abilities for individuals with autism. The ToM abilities of children with paranoid schizophrenia and children with undifferentiated or disorganized schizophrenia did not differ. Findings strengthen the notion of a limited understanding of ToM in schizophrenia, and support the notion that ToM deficits, although more severe in autism, are not unique to autism.

Clinical characteristics of schizophrenia associated with velo-cardio-facial syndrome.

Velo-cardio-facial syndrome (VCFS) is caused by a microdeletion in the long arm of chromosome 22 and is associated with an increased frequency of schizophrenia and bipolar mood disorder. The purpose of this study was to investigate the genetic, physical, developmental and psychiatric features of schizophrenic patients with VCFS microdeletion. It describes the clinical findings in four schizophrenic inpatients with the characteristic chromosomal deletion. The four patients displayed delayed motor development, language deficits, learning disabilities, mental retardation, early age of onset, chronic and disabling course of illness and poor response to classical neuroleptic drugs and electroconvulsive therapy. Two patients benefited from treatment with clozapine. We suggest that schizophrenic patients with a history of delayed motor development, early onset of the disorder, history of learning disability, mental retardation, congenital cardiac anomalies and/or hypernasal speech should be screened for the velo-cardio-facial syndrome deletion. The implications of this study for psychiatric phenotype, nosology, disease mechanism, and possible new treatments in the future are discussed.

Velocardiofacial manifestations and microdeletions in schizophrenic inpatients.

Velocardiofacial syndrome (VCFS) is associated with an increased frequency of schizophrenia and other types of psychiatric morbidity. In this study, we tried to identify a subgroup of schizophrenic patients with deletions in the VCFS region of the long arm of chromosome 22. For that purpose, we screened the records of two major general hospitals for patients with abnormalities characteristic of VCFS, such as cardiac anomalies and cleft palate, and cross-checked the data with the register of psychiatric hospitalizations in four psychiatric hospitals. Of the 24 patients that qualified, only seven patients could be studied. An additional eight schizophrenic inpatients were ascertained clinically, based on a working VCFS Clinical Scale. FISH studies and molecular analyses, using polymorphic markers from the VCFS region, documented hemizygosity of 22q11 in three out of 15 patients (20.0%). Increased awareness of psychiatrists to signs of VCFS among patients with psychiatric illnesses is encouraged, in order to direct molecular studies effectively. In order to cut down the cost of testing, we suggest screening suspected patients with a single marker, such as D22S941, and to study further only those who have a single electrophoretic band.

An open trial of clozapine in neuroleptic-resistant childhood-onset schizophrenia.

BACKGROUND: Studies performed with schizophrenic adults who were resistant to classical neuroleptics showed improvement in 30% of the patients when treated with clozapine. Very early onset schizophrenic patients benefit only partially from conventional antipsychotics and are at increased risk of developing extrapyramidal symptoms; clozapine may offer an alternative treatment for these patients. METHODS: Eleven neuroleptic-resistant children (< 13 years) with schizophrenia were treated with clozapine. Improvement was monitored during the first 16 weeks using the Brief Psychiatric Rating Scale, Positive and Negative Syndrome Scale and Clinical Global Impression. The mean clozapine dosage was 227.3 (s.d. 34.4 mg/day at the end of the 16 weeks. RESULTS: There was an overall statistically significant reduction in all parameters, especially positive symptoms, implying a favourable outcome. Most of the improvement occurred during the first 6 to 8 weeks. The major side-effects were somnolence and drooling (no agranulocytosis). CONCLUSION: Clozapine may be a promising drug for the treatment of resistant childhood-onset schizophrenia.

Beneficial haemodynamic effect of indomethacin during endotoxin shock in anaesthetized pigsputative involvement of nitric oxide?

Endotoxin shock was induced in 31 anaesthetized pigs by infusion of 5 mug/kg of Escbeicbia coli endotoxin (LPS) over 60 min into the superior mesenteric artery. Fifteen of these pigs died within 30 min of the start of LPS infusion whereas the remaining 16 survived the experimental period of 2 h. In a group of nine pigs indomethacin (2 mg/kg, i.v.)was inected 20-25 rain after the start of LPS infusion at which time mean arterial blood pressure (MABP) had decreased below 40 mmHg indicating imminent death. Indomethacin immediately reversed the hypotension. In another group of five pigs, N(G)-nitro L-arginine-methyl ester (L-NAME, 1 and 3 mg/kg)was iniected 10 and 5 min, respectively, before the expected death without any beneficial effect on the hypotension. Three rain after the last dose of L-NAME, indomethacin (2 mg/kg, i.v.) was iniected. In three animals the hypotension was reserved by indomethacin, although this beneficial effect was delayed in comparison with the LP-Streated group not receiving L-NAME. Four pigs were pretreated with L-NAME, 3 mg/kg, i.v., 10 min prior to LPS infusion. All pretreated animals tended to die within 30 min of the start of the LPS infusion. Five rain before the expected death (20-25 rain after the start of LPS infusion) indomethacin (2 mg/kg) was inected. In three of these animals indomethacin reversed hypotenston and prevented death. Interestingly, this rise in the MABP developed very slowly. These results suggest that the beneficial effect of indomethacin in endotoxin shock might be related partially to interference with nitric oxide, which is not the only factor determining blood pressure levels during endotoxic shock.

Clozapine treatment in very early onset schizophrenia.

Very early onset schizophrenic patients only partially benefit from conventional antipsychotic treatment and are at increased risk for developing tardive dyskinesia (TD). Clozapine, which lacks extrapyramidal side effects including TD, has been proved effective for adult schizophrenic patients who are resistant to other neuroleptics. Clozapine, therefore, may offer an alternative treatment for these patients. The authors report four successful trials of clozapine in children aged 10 to 12 years old with schizophrenia, the youngest group reported on to date, who were unresponsive to conventional neuroleptic treatment.

Protective effect of diclofenac sodium against endotoxic shock in anaesthetized pigs.

The effect of diclofenac sodium was investigated on haemodynamics, haematologic and blood glucose values as well as the release of eicosanoids, tumor necrosis factor (TNF) and platelet activating factor (PAF) in anaesthetized pigs receiving 5 micrograms.kg-1 Escherichia coli lipopolysaccharide (LPS) over 60 min into the superior mesenteric artery. The animals were observed for an additional period of 2 h after the termination of LPS infusion. 15 of the 31 animals infused with LPS and not treated with diclofenac sodium died within 30 min after the commencement of LPS infusion (non-survivors), while the other 16 survived the experimental period of 3-h, though in a shock state (survivors). No alterations were observed in plasma concentrations of PAF or eicosanoids (TXB2, 6-keto PGF1 alpha and LTB4), but a marked increase was detected in TNF release in the non-survivors. A significant, though transient, increase in concentrations of PAF, TNF and eicosanoids studied characterized the survivors. Another group of 7 LPS-infused pigs was treated with diclofenac sodium (2 mg, kg-1, i.v. bolus 60 min before the start of LPS infusion, followed by a continuous infusion of 1 mg kg-1 h-1) 1 mg/kg-1/h-1. This treatment prevented death and shock despite the high concentrations of TNF and PAF. Concentrations of both cyclooxygenase and 5-lipoxygenase enzymes products were reduced. These data indicated that the beneficial effect of diclofenac sodium in LPS induced shock may be related to the reduced production of eicosanoids.

Seizures induced by combined levomepromazine-fluvoxamine treatment.

We report a case of combined levomepromazine-fluvoxamine treatment-induced seizures. It seems that combined treatment of fluvoxamine with phenothiazines may possess proconvulsive activity.

Lethal and non-lethal course of endotoxic shock is determined by interactions between tumor necrosis factor, platelet activating factor and eicosanoids.

Continuous lipopolysaccharide (LPS) infusion in pigs induced death in approximately half of the animals and a prolonged state of shock (up to 3 hours of experimental observation period, i.e., two hours after discontinuation of LPS infusion) in the surviving animals. Lethal-induced shock was marked by huge release of Tumor Necrosis Factor (TNF) into the blood, whereas eicosanoid and Platelet Activating Factor (PAF) levels remained unchanged. In pigs surviving LPS-infusion but still remaining in a state of shock, transient increases in PAF and thromboxane levels were observed, whereas prostacyclin and leukotrienes values remained above normal levels up to the end of the observation period. It is concluded that different types of mediators play a role in LPS-induced lethal shock as compared to non-lethal prolonged state of shock.

Interactions between platelet activating factor and eicosanoids during endotoxic shock in anaesthetized pigs.

The effects of platelet activating factor (PAF) on eicosanoid release during endotoxic shock was investigated in anaesthetized pigs receiving 5 mug kg(-1) Escherichia coli endotoxin (LPS) into the superior mesenteric artery over a 60 min period, by measuring plasma levels of a variety of mediators. Fifteen of the 31 animals infused with LPS and not treated with BN 52021, a PAF receptor antagonist, died within 30 min after the commencement of LPS infusion (non-survivors), while the other 16 survived the experimental period of 3 h, though in a state of shock (survivors). No alterations were observed in plasma concentrations of eicosanoids in the non-survivors. A significant, though transient, increase in eicosanoid concentrations occurred only in the survivors. Treatment with BN 52021 (4 mg kg-1, i.v.) injected 5 min prior to LPS infusion, failed to exert any effect on the survival rate. However, pretreatment with BN 52021 prevented circulatory collapse in the survivors and reduced the concentration of cyclooxygenase enzyme products, without affecting LTB(4) release. Exogenous administration of PAF (0.01 mug kg(-1)) caused hypotension and increased TXB(2) levels although 6-keto PGF(1alpha) and LTB(4) concentrations were unchanged. The data suggest that prostanoid formation may be secondary to PAF release in circulatory collapse evoked by LPS infusion in survivors, and give further support to the suggestion that PAF prostanoid interaction is important during endotoxic shock. However, their role in early death seems to be negligible, indicating the importance of other mediators.

Significance of platelet-activating factor in mesenteric ischemia-reperfusion.

Reperfusion of the ischemic mesenterium is frequently followed by acute circulatory collapse. This review focuses on the possible role of platelet-activating factor (PAF) in ischemia-induced damage. It provides evidence that (i) PAF concentrations are elevated in the mesenteric circulation following temporary ischemia; (ii) administration of exogenous PAF into the superior mesenteric vein mimics many events observed during reperfusion; and (iii) pretreatment of the experimental animals with specific PAF receptor antagonists prevent the circulatory collapse. These findings suggest that PAF may play an important role in the development of circulatory collapse caused by mesenteric ischemia-reperfusion.

Platelet activating factor is one of the mediators involved in endotoxic shock in pigs.

The role of platelet activating factor (PAF) in endotoxic shock was investigated in anaesthetized pigs receiving 5 micrograms/kg E. coli endotoxin (LPS) into the superior mesenteric artery over a 60 min period. Concentrations of PAF and tumor necrosis factor (TNF) were measured in blood obtained from the superior mesenteric vein and aorta before, during and 60 min after the LPS infusion. The effect of 4 mg/kg of BN 52021, a PAF receptor antagonist, given as a bolus injection 5 min prior to LPS infusion and/or PAF administration into the superior mesenteric vein was studied on systemic and regional hemodynamic variables. Eight of the 17 animals infused with LPS died within 30 min after start of LPS, while the other 9 survived the experimental period of 3 h, though in a shock state. In survivors, PAF concentration in both superior mesenteric vein and aorta increased twenty-fold at 30 min of endotoxaemia, but rapidly returned back towards normal values. No changes in PAF release, but a marked rise in TNF production were measured in non-survivors. Exogenous administration of PAF (0.01 micrograms/kg) produced similar hemodynamic effects as observed in survivors. BN 52021 markedly reduced the effects of PAF on arterial blood pressure for over 1 h. Treatment with BN 52021 (4 mg/kg), injected 5 min prior to LPS infusion, failed to exert any effect on the surviving rate. However, in survivors all circulatory and laboratory parameters studied were improved after treatment with BN 52021. PAF release observed during LPS infusion in survivors may play a role in the development of shock; however, its role in the rapid death seems to be negligible. Present results clearly demonstrate that endotoxin shock is not crucially dependent on one class of mediators.