Nicotine dependence is associated with functional variation in FMO3, an enzyme that metabolizes nicotine in the brain.

A common haplotype of the flavin-containing monooxygenase gene FMO3 is associated with aberrant mRNA splicing, a twofold reduction in in vivo nicotine N-oxidation and reduced nicotine dependence. Tobacco remains the largest cause of preventable mortality worldwide. CYP2A6, the primary hepatic nicotine metabolism gene, is robustly associated with cigarette consumption but other enzymes contribute to nicotine metabolism. We determined the effects of common variants in FMO3 on plasma levels of nicotine-N-oxide in 170 European Americans administered deuterated nicotine. The polymorphism rs2266780 (E308G) was associated with N-oxidation of both orally administered and ad libitum smoked nicotine (P⩽3.3 × 10-5 controlling for CYP2A6 genotype). In vitro, the FMO3 G308 variant was not associated with reduced activity, but rs2266780 was strongly associated with aberrant FMO3 mRNA splicing in both liver and brain (P⩽6.5 × 10-9). Surprisingly, in treatment-seeking European American smokers (n=1558) this allele was associated with reduced nicotine dependence, specifically with a longer time to first cigarette (P=9.0 × 10-4), but not with reduced cigarette consumption. As N-oxidation accounts for only a small percentage of hepatic nicotine metabolism we hypothesized that FMO3 genotype affects nicotine metabolism in the brain (unlike CYP2A6, FMO3 is expressed in human brain) or that nicotine-N-oxide itself has pharmacological activity. We demonstrate for the first time nicotine N-oxidation in human brain, mediated by FMO3 and FMO1, and show that nicotine-N-oxide modulates human α4ß2 nicotinic receptor activity in vitro. These results indicate possible mechanisms for associations between FMO3 genotype and smoking behaviors, and suggest nicotine N-oxidation as a novel target to enhance smoking cessation.

Wavelet analysis of the frontal auditory evoked potentials obtained in the passive oddball paradigm in healthy subjects and schizophrenics.

The goal of the present study was to apply the oscillatory brain dynamics model to the structural and quantitative analysis of neurocognitive functions considered as a potential marker of schizophrenia. This was achieved in tests of the detection of auditory events deviating in the regular auditory stream (oddball paradigm, MMN effect). It was hypothesized that the post-stimulus peaks of the oscillation power localized in post-stimulus time in the definite EEG oscillators represented neuro-electrical 'events' evoked in the specific neuronal nets characterized by this oscillation frequency band. We suggest that the time-frequency destination of these events related to the activation of the functional neuronal nets could be used for the determination of specific neurocognitive functions. Thus it was an attempt to distinguish the different neuro-functional parts of auditory processing and to compare these results between healthy subjects and patients with schizophrenia. The present results demonstrate the significant difference between the frontal averaged EEG oscillatory dynamics in healthy subjects and patients with schizophrenia related to neurocognitive function marked by the MMN and orienting response N200/P300a.

Human biologic response modification by interferon in the absence of measurable serum concentrations: a comparative trial of subcutaneous and intravenous interferon-beta serine.

The effect on a range of biologic responses of interferon-beta serine (IFN-beta ser), administered by either the sc or the iv route, was examined in 16 patients. Despite the absence of IFN in the serum of 13 of 16 patients after sc administration, biologic changes associated with IFN administration occurred. Significant increases in peripheral mononuclear cell surface proteins were evident. Monocyte human leukocyte antigen-DR (HLA-DR) showed a 23% increase in mean fluorescent intensity (P = .04) and a 9% increase in percentage of positive cells (P = .02); lymphocyte OKT10 had an 11% increase in percentage of positive cells (P less than .0001) and a 26% increase in mean fluorescent intensity (P = .002). Natural killer cell activity against the Change target increased by 125% (P = .004). Intracellular activity of 2',5'-oligoadenylate synthetase increased 297% at 24 hours and 226% at 48 hours (P less than .0001). Significant increases in serum concentrations of beta 2 microglobulin (24% at 24 hr and 27% at 48 hr, P less than .0001) and neopterin (85%, P = .0001 and 165%, P = .00001) were observed. These alterations after sc administration were similar quantitatively to those resulting from the same dose of IFN-beta ser given iv. Thus, serum IFN concentrations did not have to be measurable for IFN-beta ser to exert biologic activity. The different effects of two dose levels, 45 X 10(6) IU and 180 X 10(6) IU, also were compared independent of route. The higher dose resulted in greater increases over baseline of 2',5'-oligoadenylate synthetase activity (344% vs. 145% at 24 hr; 231% vs. 83% at 48 hr) and serum neopterin concentrations (185% vs. 99% at 24 hr; 271% vs. 153% at 48 hr). For all the other parameters, there was no significant difference between the two doses.

Clinical and immune responses in resected colon cancer patients treated with anti-idiotype monoclonal antibody vaccine that mimics the carcinoembryonic antigen.

PURPOSE: We generated an anti-idiotype antibody, designated CeaVac, that is an internal image of the carcinoembryonic antigen (CEA). We previously demonstrated that the majority of patients with advanced colorectal cancer generate specific anti-CEA responses. The purpose of the current study was to treat patients with surgically resected colon cancer with CeaVac to determine the immune response and clinical outcome to treatment with vaccine. We also compared the immune responses between patients treated with fluorouracil (5-FU) chemotherapy regimens plus vaccine versus vaccine alone. PATIENTS AND METHODS: Thirty-two patients with resected Dukes' B, C, and D, and incompletely resected Dukes' D disease were treated with 2 mg of CeaVac every other week for four injections and then monthly until tumor recurrence or progression. Fourteen patients were treated concurrently with 5-FU chemotherapy regimens. RESULTS: All 32 patients entered onto this trial generated high-titer immunoglobulin G and T-cell proliferative immune responses against CEA. The 5-FU regimens did not have a qualitative or quantitative effect on the immune response. Three of 15 patients with Dukes' B and C disease progressed at 19, 24, and 35 months. Seven of eight patients with completely resected Dukes' D disease remained on study from 12 to 33 months; one patient with resected Dukes' D disease relapsed at 9 months. One patient with incompletely resected Dukes' D disease remained on study at 14 months without evidence of progression; eight experienced disease progression at 6 to 31 months. CONCLUSION: CeaVac consistently generated a potent anti-CEA humoral and cellular immune response in all 32 patients entered onto this trial. A number of very high-risk patients continue on study. 5-FU regimens, which are the standard of care for patients with Dukes' C disease, did not affect the immune response. These data warrant a phase III trial for patients with resected colon cancer.

Clinical and immune responses in advanced melanoma patients immunized with an anti-idiotype antibody mimicking disialoganglioside GD2.

PURPOSE: To determine immune responses and toxicity to the anti-idiotype vaccine, as well as clinical responses and survival, we initiated a clinical trial for patients with advanced melanoma treated with an anti-idiotype antibody (TriGem) that mimics the disialoganglioside GD2. PATIENTS AND METHODS: Forty-seven patients with advanced melanoma received either 1-, 2-, 4-, or 8-mg doses of TriGem (Titan Pharmaceuticals Inc, South San Francisco, CA) mixed with QS-21 adjuvant (Aquila Biopharmaceuticals, Inc, Worcester, MA) 100 microg subcutaneously weekly for 4 weeks and then monthly until disease progression. Median age was 57 years, there were 32 men and 15 women, 43% of patients had undergone prior therapy for metastatic disease, 55% had disease confined to soft tissue, and 45% had visceral metastasis. RESULTS: Hyperimmune sera from 40 of 47 patients showed an anti-anti-idiotype (Ab3) response. Patient Ab3 was truly Ab1' because it specifically bound purified disialoganglioside GD2. The isotypic specificity of the Ab3 antibody consisted of predominantly immunoglobulin (Ig)G, and all IgG subclasses were represented. One patient had a complete response that persisted at 24 months, and 12 patients were stable from 14+ to 37+ months (median, 18+ months). Disease progression occurred in 32 patients on study from 1 to 17 months (median, 5.5 months), and 21 have died at 1 to 16 months (median, 6 months). The Kaplan-Meier-derived overall median survival has not been reached. Median survival has not been reached for the 26 patients with soft tissue disease only and was 13 months for 21 patients with visceral metastasis. Toxicity consisted of local reaction at the site of injection and mild fever and chills. CONCLUSION: TriGem has minimal toxicity and generates robust and specific IgG immune responses against GD2. Objective responses were minimal, but there may be a favorable impact on disease progression and survival that will require prospective randomized trials.

Parathyroid hormone receptors coupled to cyclic adenosine monophosphate formation in an established renal cell line.

We examined the relationship between PTH binding and stimulation of cAMP formation in a cell line derived from opossum kidney (OK). In the presence of isobutylmethylxanthine (1 mM) bovine PTH(1-34) [bPTH(1-34)] (244 nM) stimulated cAMP accumulation in confluent cultures up to 40-fold over basal; this response to PTH was stable for 35 passages. The concentration of bPTH(1-34) required to raise cell cAMP levels half-maximally was 5-12 nM. Binding of [125I]bPTH(1-34) to OK cells was saturable; Scatchard analysis of competitive binding data yielded a dissociation constant (KD) = 6 +/- 2 nM, with 1.0 pmol binding sites/mg cell protein. Under steady state binding conditions 89% of labeled PTH remained precipitable by 10% trichloroacetic acid, suggesting minimal metabolism of the hormone. The PTH antagonist (8Nle, 18Nle, 34Tyr)bPTH(3-34)amide competed for [125I]bPTH(1-34) binding sites and inhibited the action of bPTH(1-34) to raise cAMP levels. The intact PTH molecule, bPTH(1-84), and the weak agonist hPTH(1-34) synthesized by Brewer were both less potent than bPTH(1-34) (6 times and 30 times, respectively) with regard to binding and cAMP production. Calcitonin and arginine vasopressin did not bind to PTH receptors but raised cAMP levels in OK cell cultures 3- and 10-fold, respectively; neither glucagon nor ACTH(1-24) influenced PTH binding of cAMP in OK cells. Varying the extracellular calcium concentration in the medium bathing cells did not influence basal or PTH-stimulated cAMP generation. These data suggest that PTH receptors in OK cells are of high affinity, are selective for PTH, and are coupled to adenylate cyclase. This established epithelial cell line provides a model in which to study the mechanism of action of PTH in the kidney.

Down-regulation of parathyroid hormone (PTH) receptors in cultured bone cells is associated with agonist-specific intracellular processing of PTH-receptor complexes.

Exposure of cultured embryonic chicken bone cells to the PTH agonists bovine (b) PTH-(1-34) and [8Nle, 18Nle, 34Tyr]bPTH-(1-34)amide [bPTH-(1-34)A] reduces the subsequent cAMP response to the hormone and decreases the specific binding of 125I-labeled PTH to these cultures. To determine whether PTH receptor down-regulation in cultured bone cells is mediated by cellular internalization of PTH-receptor complexes, we measured the uptake of [125I]bPTH-(1-34) into an acid-resistant compartment. Uptake of radioactivity into this compartment was inhibited by incubating cells at 4 C with phenylarsineoxide and unlabeled bPTH-(1-34). Tracer uptake into the acid-resistant compartment at any time was directly proportional to total cell binding at 22 C. Thus, it is likely that PTH-receptor complexes are internalized by bone cells. This mechanism may explain the loss of cell surface receptors after PTH pretreatment. To determine whether internalized PTH-receptor complexes are reinserted into the plasma membrane, we measured PTH binding and PTH stimulation of cAMP production after cells were exposed to monensin, a known inhibitor of receptor recycling. Monensin (25 microM) had no effect on PTH receptor number or affinity and did not alter PTH-stimulated cAMP accumulation. However, monensin (25 microM) incubated with cells pretreated with various concentrations of bPTH-(1-34) for 1 h potentiated the effect of the hormone to reduce subsequent [125I]bPTH-(1-34) binding and PTH-stimulated cAMP accumulation by more than 2 orders of magnitude. Chloroquine also potentiated PTH-induced down-regulation of PTH receptors. By contrast, neither agent influenced PTH binding or PTH-stimulated cAMP production in cells pretreated with the antagonist bPTH-(3-34)A. Thus, monensin potentiated PTH receptor loss only in cells pretreated with PTH agonists, indicating that antagonist-occupied receptors may be processed differently from agonist-occupied receptors in bone cells. The data further suggest that the attenuation of PTH stimulation of cAMP production in treated bone cells may be, at least in part, due to receptor-mediated endocytosis of the hormone.

Solubilization of a guanine nucleotide-sensitive parathyroid hormone-receptor complex from canine renal cortex.

Canine renal cortical PTH receptors were solubilized after occupancy of membrane-associated receptors with the agonist ligand [125I]bovine (b) PTH-(1-34). Stabilization of binding during solubilization required the use of high concentrations of BSA (optimally 5%) and appropriate detergents (0.5% 3-[(3-cholamidopropyl)dimethylammonio]2-hydroxy-1-propanesulfonate, 0.5% 3-[(3-cholamidopropanyl)dimethylammonio]1-propanesulfonate, or 0.5-1.0% digitonin). The soluble fraction (240,000 X gav supernatant) contained [125I]bPTH-(1-34) associated with macromolecular components as well as unbound [125I]bPTH-(1-34) that dissociated during solubilization. The soluble macromolecular complex had functional properties expected of a ternary complex consisting of [125I]bPTH-(1-34) receptor stimulatory guanine nucleotide-binding protein (Ns). Thus, the dissociation of labeled PTH at 30 C was slow (t1/2 = 75 min); in the presence of GTP (10(-4) M), 75% of the sites displayed rapid dissociation kinetics (t1/2 = 2.3 min). This effect was nucleotide specific, with GTP approximately equal to GTP gamma S approximately equal to GDP greater than GDP beta S greater than ITP approximately equal to guanylylimidodiphosphate much greater than GMP approximately equal to App(NH)p. ATP was ineffective. GTP produced a half-maximal response at a concentration of 200 nM. These results are consistent with the reported nucleotide specificity and affinity of purified Ns. Treatment of membranes with N-ethylmaleimide during the binding reaction rendered the solubilized complex refractory to GTP. Gel filtration chromatography (Sepharose 6B) revealed a GTP-sensitive complex that eluted in the position expected of a detergent-free spherical protein of 180,000 daltons. This complex may consist of the 60,000 to 70,000-dalton PTH-binding subunit (previously identified by photoaffinity labeling) together with Ns.

Distribution of T-cell phenotypic subsets and surface immunoglobulin-bearing lymphocytes in lymph nodes from male homosexuals with persistent generalized adenopathy: an immunohistochemical and ultrastructural study.

Lymph nodes from homosexual men with persistent generalized adenopathy were evaluated for distribution of T-cell phenotypic subsets and surface immunoglobulin(SIg)-bearing lymphocytes. Electron microscopy revealed tubulovesicular structures within lymphocytes but no multivesicular rosettes. Eight to 33 per cent of the lymphocytes within germinal centers were suppressor T cells, compared with germinal centers from control lymph nodes, in which these cells were rare (P = 0.002). Significantly greater percentage of suppressor/cytotoxic T lymphocytes were also present in the paracortex and follicular mantles of lymph nodes from the homosexual group (P = 0.002 and 0.007, respectively). Percentages of helper T lymphocytes were significantly decreased in germinal centers (P = 0.008) and paracortical regions (P = 0.002). Florid follicular hyperplasia with aberrations in follicular architecture was the most common histologic pattern, but one node with diffuse hyperplasia and subtotal effacement of architecture revealed depletion of SIg-bearing lymphocytes and increased numbers of suppressor T cells. Reversed helper-to-suppressor T-cell ratios in lymph nodes from homosexuals with generalized adenopathy may be related to viral infection and contribute to immune deficiency in this group.

Use of the anti-idiotype antibody vaccine TriAb after autologous stem cell transplantation in patients with metastatic breast cancer.

Between April 1997 and March 1998 we evaluated the immune response and outcome in 11 chemosensitive patients who were treated with the anti-idiotype antibody vaccine TriAb after recovery from intensive therapy and autologous stem cell transplant (ASCT). Triab was commenced after recovery from the acute effects of ASCT; a minimum interval of 1 month was required from completion of consolidation radiotherapy, if given. Nine patients (82%) manifest anti-anti-idiotype antibody (Ab3) responses post ASCT. The maximal Ab3 response was seen after a median of 10 doses (range 5-20), which corresponded to a median of 14 months (range 5-19) post ASCT. Evidence of a T cell proliferative response was seen in eight patients; the response was modest in most of these. At a median follow-up of 24 months (range 22-33) after ASCT, four patients are alive without evidence of disease progression. All four of these patients were in the subgroup with more vigorous immune responses. Subsequent efforts have been directed toward the achievement of higher levels of immune responses more rapidly post ASCT. Bone Marrow Transplantation (2000) 26, 729-735.

Diabetes induced by a high fructose diet.

Long-term fructose feeding to the genetically selected albino rat resulted in the development of diabetes mellitus and diffuse glomerulosclerosis. Siblings of these animals that were starch fed did not develop the metabolic impairments nor did they develop diabetic microangiopathy. These results are similar to those observed following sucrose feeding to these genetically selected animals. Hence, fructose feeding is not different than that of sucrose in producing diabetes and diabetic angiopathy.

Kleptomania: diagnosis and treatment options.

Kleptomania--the inability to resist the impulse to steal objects, not for personal use or monetary gain--is currently classified in psychiatric nomenclature as an impulse control disorder. However, some of the principle features of the disorder, which include repetitive intrusion thoughts, inability to resist the compulsion to perform the thievery and the relief of tension following the act, suggest that kleptomania may constitute an obsessive-compulsive spectrum disorder. Kleptomania is commonly under-diagnosed and is often accompanied by other psychiatric conditions, most notably affective, anxiety and eating disorders, and alcohol and substance abuse. Individuals with the disorder are usually referred for treatment due to the comorbid psychiatric complaints rather than kleptomanic behaviour per se. Over the past century there has been a shift from psychotherapeutic to psychopharmacological interventions for kleptomania. Pharmacological management using selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) and other antidepressants, mood stabilisers and opioid receptor antagonists, as adjuvants to cognitive-behavioural therapy, has produced promising results.

Dolichol-mediated enhanced protein N-glycosylation in experimental diabetes--a possible additional deleterious effect of hyperglycemia.

In liver cells from diabetic rats, an increased incorporation of labeled glucosamine into cellular and secretory proteins was found, when related to the incorporation of labeled leucine. This increased N-glycosylation was present in the face of decreased synthesis of hepatic cellular and secretory proteins evident from reduced leucine incorporation and diminished glycosyltransferase activity. To elucidate the mechanisms involved we incubated isolated hepatocytes with two N-glycosylation inhibitors: tunicamycin and 2-deoxyglucose. Tunicamycin exerted a marked inhibitory effect on the incorporation rate of labeled glucosamine into proteins in liver cells from diabetic rats, while 2-deoxyglucose had a negligible effect on this process in these cells. These diverse effects might be explained by the fact that tunicamycin acts through strong association with the enzyme catalyzing the first step in glycoprotein synthesis, namely, the transfer of UDP-GlcNAc to dolichol-P (indicating noncompetitive inhibition). This enzyme is reduced in liver cells from diabetic animals. On the other hand, 2-deoxyglucose exerts its effect by being attached to dolichol-P, preventing further elongation of oligosaccharide chain on the protein backbone. This latter effect might be eliminated by excess dolichol-P (indicating competitive inhibition). The dolichol content in liver extract from diabetic rats was about 2.5-fold higher compared with nondiabetic rats (51.6 micrograms/g versus 20.6 micrograms/g wet liver weight). These two lines of evidence confirm the notion that the enhanced enzymatic glycosylation in liver from diabetic animals is maintained by an increased hepatic dolichol concentration, which is most probably related to the hyperglycemia. Thus, the dolichol-N-glycosylation pathway may represent another detrimental aspect of hyperglycemia and may operate by dolichol mass action rather than through glycosylating enzyme activity.

Evaluation of compulsory ambulatory treatment in Israel.

The effectiveness of Israel's compulsory ambulatory treatment order was evaluated based on a one-year follow-up of the 326 orders served during the first four years of implementation. Demographic, epidemiological, clinical, and legal data were obtained from patient records. Success was defined as continuous treatment for the entire six-month period of compulsory ambulatory treatment, or as voluntary hospitalization during or after the compulsory treatment period. The compulsory ambulatory treatment order was found to be efficacious in 43.3 percent of the cases; in 32.5 percent it did not succeed in preventing compulsory hospitalization, and in the remaining cases (22.1 percent), success was partial.

The prevention of cardiac arrhythmias produced in an animal model by the topical application of a phenol preparation in common use for face peeling.

We have shown in an animal model that complex ventricular arrhythmias produced by topical application of a phenol preparation that is used in face peeling can be prevented by a brisk diuresis at the time of application or by gradual application of the phenol preparation. We recommend that continuous cardiac monitoring and recording be performed in patients having topical phenol applications in order to determine the true incidence of cardiac arrhythmias and to ascertain if they are prevented by a forced diuresis, by the gradual application of the preparation, or by a combination of both.

Adaptation of immigrant psychiatrists from the former Soviet Union in the Department of Mental Health of the Israel Defense Forces.

Psychiatrists from the former Soviet Union serve in the Department of Mental Health of the Israel Defense Forces. The new immigrant psychiatrists confront a wide range of difficulties during the process of integration to the military system and adaptation to the specifically military aspects of psychiatry. These include unfamiliarity with the military system, cultural clashes with the different groups of soldiers representing the various subgroups of the absorbing society, the psychopathology of soldiers, which is different from that seen in civil psychiatry, and the change in focus in the military mental health service, which emphasizes the importance of evaluating ego strength. Arbitrarily, one can describe four stages of adaptation that the immigrant psychiatrist has to pass through before recruitment and during service until adaptation and integration in the new role take place. Individual and group supervision are the main means by which the assimilation process is eased. The military service smooth the acculturation process and has an important role in helping the immigrant's adaptation to Israeli society and in building his or her professional identity.

Amnestic state in a Holocaust survivor patient: psychogenic versus neurological basis.

Differentiation between psychogenic and organic amnesia is sometimes quite difficult. This paper focuses on the psychogenic and organic components of a complex case of amnesia rooted in remote and prolonged traumatic stress and manifested under circumstances evoking dissociated memories. The Transient Global Amnesia (TGA) of a concentration camp survivor who developed sudden amnesia during a psychiatric intake interview was clearly triggered by the pressure of repressed Holocaust memories. The importance of distinguishing between TGA and dissociative amnesia is emphasized, and the role of psychological upset as a precipitant in TGA is stressed.

Withdrawal from clozapine: the "rebound phenomenon".

Clozapine is an "atypical" antipsychotic agent for treating previously resistant schizophrenic patients. Its main advantages over "typical" neuroleptics are low incidence of extrapyramidal side effects and its capacity to induce therapeutic response in previously treated refractory patients. However, withdrawal from clozapine has been observed to lead to "atypical" clinical characteristics or a "rebound phenomenon," manifested in two interwoven clinical forms: (1) psychotic exacerbation, and (2) cholinergic rebound. The underlying pathophysiological mechanism of this phenomenon is postulated to be a result of cholinergic supersensitivity. In this paper, the "rebound phenomenon" will be discussed and exemplified by three case histories in which abrupt cessation of clozapine led to serious deterioration and psychotic exacerbation, and one case in which gradual titration from the drug was employed in order to preempt this hazardous occurrence.

[Koro syndrome--clinical and cultural aspects].

Koro syndrome is a triad which includes a deep-seated fear that the penis will shrink, disappear into the abdomen, and that death will follow. The patient experiences profound anxiety and performs preventive manoeuvres, such as pulling his penis outward. The disorder is considered culture-related, and is endemic in South-East Asia and China, where it occurs in epidemic and sporadic forms. Sporadic cases appear in the western hemisphere, often in association with an underlying psychiatric or organic disorder, usually of the central nervous system. 6 cases of koro have been published from Israel.

[Compulsory, ambulatory psychiatric treatment].

The Treatment of Mentally Sick Persons Law of 1955, was repealed and replaced by the Law of 1991. Under the latter, the Order for Compulsory Ambulatory Treatment (OCAT) was addressed for the first time (Section 11, a-d). According to this law, the district psychiatrist instead of issuing a hospitalization order, may issue an OCAT, under which the required treatment is given within the scope of a clinic which he designates, for up to 6 months and under conditions which he specifies. This is done on the basis of psychiatric examination, or an application in writing from the director of a hospital or clinic, when continued ambulatory treatment is needed after discharge from hospital or instead of compulsory hospitalization. The district psychiatrist may extend the period of treatment for further periods, none of which is to exceed 6 months. Compulsory ambulatory treatment is to enable patients to benefit from the positive aspects of living freely in the community, while receiving prompt treatment under compulsory conditions. The concept offers a partial solution, achieving a balance between civil liberties and clinical needs, between over-confinement and under-treatment which might be dangerous or neglectful. The clinical impression has been that the OCAT has not fulfilled expectations. The purpose of this study was to examine the topic in a systematic way in Jerusalem and the southern districts for the 4 years since inception of the law. In 44.4% of cases OCAT was proven to be effective, while in 33.1% it was found to be ineffective and did not prevent compulsory hospitalization, one of its main goals. It was partially effective in the rest of the cases. It is recommended that suitable means for the enforcement of the law be allocated and that the subject of forceful hospitalization and OCAT be made a mandatory subject in the residency program of psychiatrists.