Complex taxonomy of the 'brush tail' peregrine earthworm Pontoscolex corethrurus.

Pontoscolex corethrurus is the most widespread earthworm species in tropical and sub-tropical zones and one of the most studied in soil science. Although, ecological interactions of P. corethrurus with its environment are well documented, the taxonomic status of the species remains unclear. In this study, we investigated phylogenetic relationships within the genus Pontoscolex, in particular focusing on morphologically indistinguishable (i.e., cryptic) lineages. A total of 792 specimens collected from 25 different countries and islands all over the world were analyzed using two mitochondrial (COI and 16S rDNA) and two nuclear (internal transcribed spacers 2 and 28S rDNA) markers, and a total of 11 morphological characters both internal and external were investigated in all genetically characterized lineages. A large-scale multilocus sequence data matrix was also obtained for Pontoscolex spp. specimens using the Anchored Hybrid Enrichment (AHE) method. Multilocus phylogenetic and phylogenomic analyses, combined with species delimitation methods; including single locus (mPTP, ABGD) and multilocus (BPP) approaches, revealed congruent results. Four cryptic species were supported within the P. corethrurus species complex, and four potentially new species within the genus Pontoscolex. One widespread lineage (L1), within P. corethrurus complex was observed in the current population of Fritz Müller's garden where P. corethrurus was first described in 1856. Cryptic lineages were observed in sympatry at several localities. This, in combination with observed heteroplasmy in COI gene in one population raises an important question of reproductive isolation between these species.

SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours.

BACKGROUND: Gemcitabine is used for the treatment of several solid tumours and exhibits high inter-individual pharmacokinetic variability. In this study, we explore possible predictive covariates on drug and metabolite disposition. METHODS: Forty patients were enrolled. Gemcitabine and dFdU concentrations in the plasma and dFdCTP concentrations in peripheral blood mononuclear cell were measured to 72 h post infusion, and pharmacokinetic parameters were estimated by nonlinear mixed-effects modelling. Patient-specific covariates were tested in model development. RESULTS: The pharmacokinetics of gemcitabine was best described by a two-compartment model with body surface area, age and NT5C2 genotype as significant covariates. The pharmacokinetics of dFdU and dFdCTP were adequately described by three-compartment models. Creatinine clearance and cytidine deaminase genotype were significant covariates for dFdU pharmacokinetics. Rate of infusion of <25 mg m(-2) min(-1) and the presence of homozygous major allele for SLC28A3 (CC genotype) were each associated with an almost two-fold increase in the formation clearance of dFdCTP. CONCLUSION: Prolonged dFdCTP systemic exposures (≥72 h) were commonly observed. Infusion rate <25 mg m(-2) min(-1) and carriers for SLC28A3 variant were each associated with about two-fold higher dFdCTP formation clearance. The impacts of these covariates on treatment-related toxicity in more selected patient populations (that is, first-line treatment, single disease state and so on) are not yet clear.

Use of a fluorescently labeled poly-caspase inhibitor for in vivo detection of apoptosis related to vascular-targeting agent arsenic trioxide for cancer therapy.

Arsenic trioxide (ATO, Trisenox) is a potent anti-vascular agent and significantly enhances hyperthermia and radiation response. To understand the mechanism of the anti-tumor effect in vivo we imaged the binding of a fluorescently-labeled poly-caspase inhibitor (FLIVO) in real time before and 3 h or 24 h after injection of 8 mg/kg ATO. FSaII tumors were grown in dorsal skin-fold window chambers or on the rear limb and we observed substantial poly-caspase binding associated with vascular damage induced by ATO treatment at 3 and 24 h after ATO injection. Flow cytometric analysis of cells dissociated from the imaged tumor confirmed cellular uptake and binding of the FLIVO probe. Apoptosis appears to be a major mode of cell death induced by ATO in the tumor and the use of fluorescently tagged caspase inhibitors to assess cell death in live animals appears feasible to monitor and/or confirm anti-tumor effects of therapy.

Australian pathways and solutions for dealing with older impaired doctors: a prevention model.

Our ageing medical workforce poses many challenges, not the least of which is acknowledging the contributions of ageing practitioners who continue to practise safely and competently while ensuring that those who are incompetent by virtue of impairment are identified, assessed and either rehabilitated or encouraged to retire. Hitherto, there has been little attempt to review approaches to impairment on a national basis in Australia, let alone with a focus on older doctors. Information regarding pathways for dealing with impairment was obtained from the websites and confirmed by representatives of regulatory bodies of every state or territory in Australia. Using a prevention model we outline the current Australian regulatory processes, address some of the barriers and suggest some solutions to dealing with the older impaired doctor. Much of the focus in dealing with the older impaired doctor is tertiary prevention based, that is, reducing the negative influence of established impairment. There is some uniformity in the way that Australian regulatory bodies deal with impairment that espouses the dual goals of protecting the public and rehabilitating the doctor. The approach is typically individualized and multi-levelled, beginning with assessment followed by rehabilitation where appropriate. A range of secondary and primary prevention measures is proposed for dealing with the problem of the older impaired doctor. These include educating the medical community, encouraging early notification and facilitating career planning and timely retirement of older doctors. This will have benefits both in protecting the public as well as preventing an undignified and humiliating end to often-unblemished careers in medicine.

Arsenic trioxide induces selective tumour vascular damage via oxidative stress and increases thermosensitivity of tumours.

It has previously been found that the anti-leukaemia agent Arsenic Trioxide (ATO) causes vascular shutdown in solid tumours and markedly sensitizes tumours to hyperthermia. The present study was designed to evaluate the mechanism of action and dose-dependence of ATO-induced thermosensitization in FSaII and SCK murine tumours. The role of oxidative stress was studied by observing ATO-induced vascular shutdown in vivo and ATO-induced endothelial cell adhesion molecule expression in vitro in the presence or absence of an anti-oxidant. It was found that a dose as low as 2 mg/kg ATO impaired vascular function, as estimated by 86Rb uptake, in the tumour. The degree of tumour growth delay induced by 1 h of hyperthermia at 42.5 degrees C, applied 2 h after ATO injection, was proportional to the dose of ATO administered. In addition, it was found that ATO can directly thermosensitize tumour cells in vitro. The development of massive tissue necrosis in the tumour was observed in the days after treatment, especially with the combination of ATO and heating. ATO-induced adhesion molecule expression in vitro was abolished when the anti-oxidant n-acetyl-cysteine (NAC) was introduced prior to exposure, while the addition of NAC in vivo partially blocked ATO-induced vascular shutdown. These results suggest that the expression of adhesion molecules by the vasculature due to oxidative stress contribute to the ATO-induced selective tumour vascular effects observed and that the clinical use of ATO to increase tumour thermosensitivity via direct cellular and vascular effects appears feasible.

Chronic ethanol intoxication induces adaptive changes at the membrane protein/lipid interface.

Modifications were found to occur at the membrane protein/lipid interface of liver microsomes in animals that had been subjected to chronic ethanol ingestion. The effects were revealed by probing this region with 1,6-diphenyl-1,3,5-hexatriene (DPH), trimethylammonium-DPH (TMA-DPH) and DPH attached to the sn-2 chain of phosphatidylcholine (1-palmitoyl-2-[[2-[4-(6-phenyl-trans-1,3,5-hexatrienyl) phenyl]ethyl]carbonyl]-3-sn-phosphatidylcholine, DPH-PC). In intact membranes, it was found that the decay of the excited state was heterogeneous, this being modeled by fitting the data to a fluorescence lifetime distribution. The full-width of the distribution at half-maximum, which relates to the degree of excited state environmental heterogeneity, increased for each fluorophore, as a result of chronic ethanol treatment. For TMA-DPH and DPH the excited state heterogeneity could have arisen from, (i) the protein/lipid interface and (ii) varied degrees of water penetration into the lipid, due to the ability of these fluorophores to sample along the bilayer normal. By contrast, the DPH in DPH-PC, due to its tethering, was only able to sample the heterogeneity at the protein/lipid interface, as confirmed by a homogeneous decay in vesicles of microsomal lipid extracts. The increased degree of DPH-PC fluorescence decay heterogeneity in microsomes from chronic ethanol-treated animals as compared to controls, was found to persist in vesicles of extracted lipids, when apocytochrome C was included in the vesicle preparations as a model protein. This effectively eliminated a protein modification from being responsible and indicated that a chronic-ethanol induced alteration in the lipids was being expressed in the form of a physico-chemical modification at the protein/lipid interface. The degree of DPH-PC environmental heterogeneity was also directly increased by ethanol, however, membranes from chronic ethanol-treated animals were resistant to this effect, showing that the phenomenon of 'membrane tolerance' extends to the membrane protein/lipid interface.

Synthesis and characterization of a solvatochromic, lipophilic fluorescent oxazone: 1-Pentyl-7-dimethylamino-3H-phenoxazine-3-one.

Olivetol and 4-nitroso-N,N-dimethylaniline were combined under reflux in acetic acid to produce 1-pentyl-7-dimethylamino-3H-phenoxazine-3-one (1-PDMPO). The fluorescent behavior of the purified compound in a variety of solutions and samples was investigated. Excitation and emission spectra in pure solvents and mixtures of solvents demonstrate solvatochromism, indicating that the fluorescence response of this compound is affected by its environment. Nonpolar, aprotic solvents as well as protic, polar solvents diminish fluorescent emission in the spectral regions examined, and trends in the fluorescence decary lifetimes measured in five pure solvents are consistent with these intensity changes. The anisotropy excitation spectrum taken in glycerol for 1-PDMPO at -15°C appears to be consistent with the presence of a single electronic state upon excitation, with anisotropy values approaching 0.35 over 400-600 nm. Fluorescence emission is also diminished at low acid concentrations in methanol, with smaller decreases observed in more highly concentrated basic solutions. Emission peaks in aqueous sodium dodecyl sulfate solutions, extruded egg phosphatidylcholine vesicles, and fatty acid free bovine serum albumin suspensions all lie above 600 nm, with emission in the albumin suspension displaying a broad shoulder extending to 800 nm. The fluorescent properties of this compound suggest that it or structural homologues may have utility as fluorescent biological probes.

Boston Naming Test: shortened versions for use in Alzheimer's disease.

Four new 15-item versions of the Boston Naming Test (BNT), a 15-item version used by the Consortium To Establish a Registry for Alzheimer's Disease (CERAD), and three 30-item BNT versions were studied in 26 subjects with Alzheimer's disease (AD) and 26 nondemented, neurologically normal controls. The four 15-item versions were statistically equivalent. On each version, controls performed significantly better than AD subjects, and scores on each could be extrapolated to a complete 60-item BNT score. The CERAD version also differentiated between AD and control subjects, but it was not equivalent to our four versions and could not be as easily extrapolated to a 60-item score. Even and Odd 30-item BNT versions were confirmed to be equivalent, and we further validated a 30-item Empirical Version designed to maximally discriminate between AD and normal subjects. Equivalent 15- or 30-item versions of the BNT will be useful in repeated assessments requiring independent forms of a naming task, as well as in situations where administration of the complete BNT is not practical.

Analysis of cell membrane micro-heterogeneity using the fluorescence lifetime of DPH-type fluorophores.

Heterogeneity in the lipid organization in lipid bilayers and cell membranes was probed by using the fluorescence decay of 1,6-diphenyl-1,3,5-hexatriene (DPH) and DPH attached to the sn-2 position of phosphatidylcholine (DPH-PC). In the presence of protein, it is proposed that the bulk lipids and boundary lipids can potentially provide distinct enough fluorophore environments for two different lifetime centers to be recovered from the analysis of the fluorescence decay. To test this model experiments were performed with cytochrome b5 in 1-palmitoyl-2-oleoylphosphatidylcholine bilayers. The number of boundary lipids of cytochrome b5 is known from the literature or can be calculated from known dimensions, so that for a known protein:lipid ratio the fraction of lipids in the bulk and boundary lipid regions is known. These values were found to closely correspond to the fractions associated with the lifetime centers recovered from an analysis of the fluorescence decay assuming two major fluorophore populations. This indicated that the DPH distributed in a similar manner to the lipids and that its boundary lipid residency time was greater than the excited state lifetime, showing the validity of the approach. An important requirement was that the protein should influence the fluorophore decay sufficiently enough to enable separate lifetime centers for the bulk and boundary lipid fluorophores to be recovered by the analysis. Attempts were made to analyze the fluorescence decay of DPH in liver plasma membranes and microsomes as arising from two distinct fluorophore populations, however, the basic condition was not satisfied. By contrast, using DPH-PC it was possible to extract two separate lifetime centers. The limitations and potential of this approach are critically assessed and it is concluded that in certain circumstances information pertaining to the protein-lipid interfacial region of membranes can be extracted from fluorescence decay heterogeneity properties.

Effect of proteins on fluorophore lifetime heterogeneity in lipid bilayers.

The effect of three different membrane proteins on the fluorescence lifetime heterogeneity of 1,6-diphenyl-1,3,5-hexatriene (DPH) in phospholipid vesicle systems was investigated. For large unilamellar vesicles of dimyristoylphosphatidylcholine (DMPC) and 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) at 37 degrees C, the fluorescence decay was essentially monoexponential (8.6 and 8.2 ns, respectively) except for a minor component typical of DPH. For gramicidin D reconstituted into DMPC vesicles at a protein/lipid molar ratio of 1/7, the most appropriate analysis of the data was found to be in the form of a bimodal Lorentzian distribution. Centers of the major lifetime components were almost identical with those recovered for vesicles without proteins, while broad distributional widths of some 4.0 ns were recovered. Variation of the protein/lipid molar ratio in sonicated POPC vesicles revealed an abrupt increase in distributional width at ratios approximating 1/15-1/20, which leveled off at about 2.5 ns. For bacteriorhodopsin in DMPC vesicles and cytochrome b5 in POPC, the most appropriate analysis of the data was again found to be in the form of a bimodal Lorentzian also with broad distributional widths in the major component. Lifetime centers were decreased for these proteins due to fluorescence energy transfer to the retinal of the bacteriorhodopsin and heme of the cytochrome b5. Fluorescence energy transfer is distance dependent, and since a range of donor-acceptor distances would be expected in a membrane, lifetime distributions should therefore be recovered independently of other effects for proteins possessing acceptor chromophores.(ABSTRACT TRUNCATED AT 250 WORDS)

On the use of N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)phosphatidylethanolamine in the study of lipid polymorphism.

The change in the fluorescence properties of dioleoyl-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)phosphatidylethanola mine (N-NBD-PE) as an indicator of the (liquid-crystalline) bilayer-to-non-bilayer hexagonalII (HII) phase transition has been investigated. Lipid bilayer systems which are known to undergo the bilayer-to-HII phase transition on addition of Ca2+ were compared with systems which can undergo aggregation and fusion but not HII phase formation. The former included Ca2+-triggered non-bilayer transitions in cardiolipin and in phosphatidylethanolamine mixed with phosphatidylserine. The latter type of system investigated included the addition of polylysine to cardiolipin and Ca2+ to phosphatidylserine. Freeze-fracture electron microscopy was used to confirm that under the experimental conditions used, the formation of HII phase was occurring in the first type of system, but not in the second, which was stable in the bilayer state. It was found that the fluorescence intensity of N-NBD-PE (at 1 mol% of the phospholipids) increased in both types of system, irrespective of the formation of the HII phase. A dehydration at the phospholipid head group is a common feature of the formation of the HII phase, the interaction of divalent cations with phosphatidylserine and the interaction of polylysine with lipid bilayers, suggesting that this may be the feature which affects the fluorescence properties of the NBD. The finding of a fluorescence intensity increase in systems lacking HII phase involvement clearly indicates that the effect is not unique to the formation of the HII phase. Thus, while offering high sensitivity and the opportunity to follow kinetics of lipid structural changes, changes in the N-NBD-PE fluorescence properties should be interpreted with caution in the study of the bilayer-to-HII phase transition.

Spatial disorientation in Alzheimer's disease.

Spatial disorientation was investigated in 28 ambulatory patients meeting the National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association Work Group criteria for "probable" Alzheimer's disease. Based on caregivers' reports, 39% of subjects engaged in at least three of four behavioral measures of spatial disorientation three or more times a week; these patients did not significantly differ from other Alzheimer's disease subjects with regard to age, sex, education, or symptom duration. Using stepwise regression analysis, we found that neuropsychologic measures of memory and visuoconstructive functions, but not disease severity, attention, or language impairment, emerged as significant predictors of spatial disorientation. In the setting of impaired memory, the tendency of some patients with Alzheimer's disease to wander or to get lost may implicate particularly severe dysfunction of right hemisphere neocortical areas concerned with visuospatial processes.

Ethanol causes decreased partitioning into biological membranes without changes in lipid order.

One of the adaptive responses of cell membranes to chronic ethanol consumption is the acquisition of a resistance to fluidization or disordering of the lipids by ethanol in vitro and a reduced partitioning of ethanol into the membrane (membrane tolerance). The degree to which the effects on partitioning and lipid disordering share common features has not previously been explored and in addition the relevance of the value of lipid order in the absence of added ethanol (baseline lipid order) to membrane tolerance has not been established. The location in the bilayer and the nature of the modification underlying these effects is also unknown. The effect of chronic ethanol treatment was examined using 5-doxyl decane as a model hydrophobic compound. Its partitioning into the membranes was determined by utilizing its ability to quench fluorophores (1,6-diphenyl-2,3,5-hexatriene and 3- and 12-anthroyl stearates) by collisional quenching. The partition coefficient of 5-doxyl decane into the bilayer central region was reduced as a result of the chronic ethanol treatment. The effect could also be demonstrated in vesicles of phospholipids and was lost 4 days after withdrawal of the ethanol from the diet. These results closely parallel those relating to resistance to lipid disordering and suggest that both techniques detect a common modification. Lipid order was assessed using fluorescence anisotropy measurements of a range of fluorophores, including those used to determine the partitioning properties of the membrane. No effect of chronic ethanol treatment on lipid order was found, either in the intact membranes or in vesicles of extracted phospholipids. This suggests that changes in baseline order are not critical features of membrane tolerance in liver microsomes. In addition it appears that the altered partitioning of the 5-doxyl decane into the central region of the membrane is not related to lipid order changes in this region. The reduced partitioning of 5-doxyl decane may be a reflection of a redistribution in the lipid bilayer, perhaps due to modifications in other locations in the membrane, such as the lipid head group region.

Boston Naming Test in Alzheimer's disease.

The 60-item Boston Naming Test (BNT) was administered to 55 subjects: 15 mildly-to-moderately demented patients meeting NINCDS-ADRDA criteria for "probable" Alzheimer's disease (AD), 15 age-equivalent normal control (NC) subjects, and--for purposes of validation--25 additional subjects with other forms of dementia (OD). A cutting score of 51 correctly classified 80% of AD patients and 86% of NC subjects. To facilitate rapid screening of confrontation-naming performance in these populations, three 30-item shortened versions of the BNT were constructed. Even and Odd Versions were equivalent for AD, NC, and OD subjects; high correlations between these two and the 60-item BNT permit easy extrapolation to a total BNT score. A new Empirical Version, derived from performance of our AD and NC reference groups, maintained most of the intergroup discrimination of the full BNT.

Properties influencing fluorophore lifetime distributions in lipid bilayers.

The fluorescence lifetime of the membrane fluorophore 1,6-diphenyl-1,3,5-hexatriene has been analyzed according to the distributional approach in a number of lipid bilayer systems. The systems included vesicles of 16:0/18:1-phosphatidylcholine (POPC), egg phosphatidylcholine (EYPC), microsomal phospholipids, and also intact microsomal membranes. With increasing complexity of composition, an increasingly broader width was found in the major component of a bimodal Lorentzian fluorescence lifetime distribution. In order to explain these findings, we propose a model based on environmental heterogeneity and environmental sampling, where the environment is defined as the lipid molecules immediately surrounding the fluorophore. Environmental heterogeneity is thought of as arising from organizational, compositional, and solvent factors. Environmental sampling pertains to the ability of a fluorophore to detect environments in a system and is a function of the fluorophore lifetime and the lipid dynamics. If the fluorescence lifetime is sufficiently short, the fluorophore will only sample a particular environment, and great compositional complexity will mean that each fluorophore in an ensemble will decay to the ground state with a different time. This appears to explain why in our results with DPH a narrow width is obtained for POPC, where vesicles are composed of a single phospholipid molecular species, compared to EYPC and microsomal phospholipid vesicles having complex molecular species composition. This model should serve as a basis for understanding the interrelationships of environmental complexity and lipid dynamics in membranes.

Ethanol-induced modifications to membrane lipid structure: effect on phospholipase A2-membrane interactions.

Chronic ethanol intoxication leads to the development of a resistance to lipid disordering by ethanol, a phenomenon known as "membrane tolerance". In the absence of the added ethanol, the lipid order, as measured by ESR and fluorescence techniques, does not necessarily change as a result of chronic ethanol ingestion (as in liver microsomes, for example). This suggests that the spectroscopic techniques detect tolerance somewhat indirectly, in that the modification responsible may reside in a region distinct from that being probed and also raises the question of whether membrane tolerance is necessarily associated with an alteration in the membrane lipid structure. Here we show that liver microsomes from rats treated chronically with ethanol are rendered relatively resistant to the hydrolytic action of exogenous phospholipase A2, compared to preparations from control animals. This resistance persists in reconstituted lipid vesicles prepared from extracted phospholipids. Since the same substrate (1-palmitoyl-2-N-(4-nitrobenzo-2-oxa-1,3-diazole)amino caproylphosphatidylcholine) was used in both membranes from ethanol-treated animals and controls, the modification appears to reside in the structure and/or organization of the membrane. Further evidence that the lipid structure is modified by chronic ethanol treatment is provided by the observation that perturbance of the membrane structural integrity by increasing levels of oleic acid led to a progressive loss of the ethanol-induced relative resistance to hydrolysis by phospholipase A2. The results of this study support the idea that membrane tolerance involves a modification to lipid structure probably at the bilayer surface. The use of exogenous phospholipase A2 provides a new method for probing the structural modifications induced by chronic ethanol ingestion.

A membrane-bound diacylglycerol kinase that selectively phosphorylates arachidonoyl-diacylglycerol. Distinction from cytosolic diacylglycerol kinase and comparison with the membrane-bound enzyme from Escherichia coli.

The membrane-bound diacylglycerol kinase from Swiss 3T3 cells (M-DG kinase) was characterized with a mixed micellar assay system, and compared with the cytosolic diacylglycerol kinase from 3T3 cells and with the membrane-bound diacylglycerol kinase from Escherichia coli. M-DG kinase selectively phosphorylated arachidonoyl-diacylglycerols, at a rate 2- to 8-fold higher than that for other naturally occurring long-chain diacylglycerols. In contrast, the cytosolic 3T3 enzyme exhibited little or no selectivity among long-chain diacylglycerols but had higher activity with more soluble substrates such as 1,2-didecanoylglycerol. Comparison of the properties of M-DG kinase with those of the bacterial membrane-bound enzyme revealed that selectivity for arachidonoyl-diacylglycerol was unique to the mammalian enzyme. All three kinases were activated by phosphatidylserine, but activation did not alter the arachidonoyl selectivity of M-DG kinase. Phosphatidylserine activated M-DG kinase by increasing Vm and decreasing the apparent Km for diacylglycerol. High concentrations of diacylglycerol reduced the Ka for phosphatidylserine, but did not abolish the phosphatidylserine requirement for maximum activity. Examination of the thermal lability of M-DG kinase revealed that this enzyme was rapidly and selectively inactivated by preincubation with its preferred substrate. This novel effect may have obscured previous attempts to discern substrate selectivity. Taken together, the results provide evidence that M-DG kinase is an arachidonoyl-diacylglycerol kinase that may participate in the formation of arachidonoyl-enriched species of phosphatidylinositol.

Low serum neuroleptic levels predict relapse in schizophrenic patients.

Relapse occurs in a substantial proportion of schizophrenic patients treated with neuroleptics. The determinants of relapse have been elusive. In our study, low serum neuroleptic levels identified patients who had a relapse during a six-month period. Neuroleptic levels were measured by radioreceptor assay in 61 schizophrenic men and their clinical status was assessed in the subsequent six months. Ten patients had relapses, four showing a worsening of chronic psychotic symptoms and six showing eruption of psychotic symptoms after a period of remission. These ten patients had significantly lower normalized neuroleptic levels than those whose conditions remained stable. The lowest neuroleptic levels occurred in patients who had relapses after a period of remission. Serum neuroleptic levels in drug-responsive patients appear to be a critical determinant of remission. If these observations are replicated, a rational basis may be provided for prescribing and monitoring neuroleptic treatment and perhaps for preventing relapse.