Mapping ligand binding pockets in chloride ClC-1 channels through an integrated in silico and experimental approach using anthracene-9-carboxylic acid and niflumic acid.

BACKGROUND AND PURPOSE: Although chloride channels are involved in several physiological processes and acquired diseases, the availability of compounds selectively targeting CLC proteins is limited. ClC-1 channels are responsible for sarcolemma repolarization after an action potential in skeletal muscle and have been associated with myotonia congenita and myotonic dystrophy as well as with other muscular physiopathological conditions. To date only a few ClC-1 blockers have been discovered, such as anthracene-9-carboxylic acid (9-AC) and niflumic acid (NFA), whereas no activator exists. The absence of a ClC-1 structure and the limited information regarding the binding pockets in CLC channels hamper the identification of improved modulators. EXPERIMENTAL APPROACH: Here we provide an in-depth characterization of drug binding pockets in ClC-1 through an integrated in silico and experimental approach. We first searched putative cavities in a homology model of ClC-1 built upon an eukaryotic CLC crystal structure, and then validated in silico data by measuring the blocking ability of 9-AC and NFA on mutant ClC-1 channels expressed in HEK 293 cells. KEY RESULTS: We identified four putative binding cavities in ClC-1. 9-AC appears to interact with residues K231, R421 and F484 within the channel pore. We also identified one preferential binding cavity for NFA and propose R421 and F484 as critical residues. CONCLUSIONS AND IMPLICATIONS: This study represents the first effort to delineate the binding sites of ClC-1. This information is fundamental to discover compounds useful in the treatment of ClC-1-associated dysfunctions and might represent a starting point for specifically targeting other CLC proteins.

A review of altered biochemistry in the anterior cingulate cortex of first-episode psychosis.

Relevant biochemicals of the brain can be quantified in vivo, non-invasively, using proton Magnetic Resonance Spectroscopy (¹H MRS). This includes metabolites associated with neural general functioning, energetics, membrane phospholipid metabolism and neurotransmission. Moreover, there is substantial evidence of implication of the frontal and prefrontal areas in the pathogenesis of psychotic disorders such as schizophrenia. In particular, the anterior cingulate cortex (ACC) plays an important role in cognitive control of emotional and non-emotional processes. Thus the study of its extent of biochemistry dysfunction in the early stages of psychosis is of particular interest in gaining a greater understanding of its aetiology. In this review, we selected ¹H MRS studies focused on the ACC of first-episode psychosis (FEP). Four studies reported increased glutamatergic levels in FEP, while other four showed preserved concentrations. Moreover, findings on FEP do not fully mirror those in chronic patients. Due to conflicting findings, larger longitudinal ¹H MRS studies are expected to further explore glutamatergic neurotransmission in ACC of FEP in order to have a better understanding of the glutamatergic mechanisms underlying psychosis, possibly using ultra high field MR scanners.

Progressive disability and prefrontal shrinkage in schizophrenia patients with poor outcome: A 3-year longitudinal study.

INTRODUCTION: Schizophrenia is a severe disabling disorder with heterogeneous illness courses. In this longitudinal study we characterized schizophrenia patients with poor and good outcome (POS, GOS), using functional and imaging metrics. Patients were defined in accordance to Keefe's criteria (i.e. Kraepelinian and non-Kraepelinian patients). METHODS: 35 POS patients, 35 GOS patients and 76 healthy controls (H) underwent clinical, functioning and magnetic resonance imaging (MRI) assessments twice over three years of follow-up. Information on psychopathology, treatment, disability (using the World Health Organization Disability Assessment Scale II, WHO-DAS-2) and prefrontal morphology was collected. Dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) were manually traced. RESULTS: At baseline, subjects with POS showed significantly decreased right dorsolateral prefrontal cortex (DLPFC) white matter volumes (WM) compared to healthy controls and GOS patients (POS VS HC, p<0.001; POS vs GOS, p=0.03), with shrinkage of left DLPFC WM volumes at follow up (t=2.66, p=0.01). Also, POS patients had higher disability in respect to GOS subjects both at baseline and after 3years at the WHO-DAS-2 (p<0.05). DISCUSSION: Our study supports the hypothesis that POS is characterized by progressive deficits in brain structure and in "real-life" functioning. These are particularly notable in the DLPFC.

Twin studies for the investigation of the relationships between genetic factors and brain abnormalities in bipolar disorder.

The pathogenesis of bipolar disorder (BD) is to date not entirely clear. Classical genetic research showed that there is a contribution of genetic factors in BD, with high heritability. Twin studies, thanks to the fact that confounding factors as genetic background or family environment are shared, allow etiological inferences. In this work, we selected twin studies, which focus on the relationship between BD, genetic factors and brain structure, evaluated with magnetic resonance imaging. All the studies found differences in brain structure between BD patients and their co-twins, and also in respect to healthy controls. Genetic effects are predominant in white matter, except corpus callosum, while gray matter resulted more influenced by environment, or by the disease itself. All studies found no interactions between BD and shared environment between twins. Twin studies have been demonstrated to be useful in exploring BD pathogenesis and could be extremely effective at discriminating the neural mechanisms underlying BD.

ClC-1 mutations in myotonia congenita patients: insights into molecular gating mechanisms and genotype-phenotype correlation.

KEY POINTS: Loss-of-function mutations of the skeletal muscle ClC-1 channel cause myotonia congenita with variable phenotypes. Using patch clamp we show that F484L, located in the conducting pore, probably induces mild dominant myotonia by right-shifting the slow gating of ClC-1 channel, without exerting a dominant-negative effect on the wild-type (WT) subunit. Molecular dynamics simulations suggest that F484L affects the slow gate by increasing the frequency and the stability of H-bond formation between E232 in helix F and Y578 in helix R. Three other myotonic ClC-1 mutations are shown to produce distinct effects on channel function: L198P shifts the slow gate to positive potentials, V640G reduces channel activity, while L628P displays a WT-like behaviour (electrophysiology data only). Our results provide novel insight into the molecular mechanisms underlying normal and altered ClC-1 function. ABSTRACT: Myotonia congenita is an inherited disease caused by loss-of-function mutations of the skeletal muscle ClC-1 chloride channel, characterized by impaired muscle relaxation after contraction and stiffness. In the present study, we provided an in-depth characterization of F484L, a mutation previously identified in dominant myotonia, in order to define the genotype-phenotype correlation, and to elucidate the contribution of this pore residue to the mechanisms of ClC-1 gating. Patch-clamp recordings showed that F484L reduced chloride currents at every tested potential and dramatically right-shifted the voltage dependence of slow gating, thus contributing to the mild clinical phenotype of affected heterozygote carriers. Unlike dominant mutations located at the dimer interface, no dominant-negative effect was observed when F484L mutant subunits were co-expressed with wild type. Molecular dynamics simulations further revealed that F484L affected the slow gate by increasing the frequency and stability of the H-bond formation between the pore residue E232 and the R helix residue Y578. In addition, using patch-clamp electrophysiology, we characterized three other myotonic ClC-1 mutations. We proved that the dominant L198P mutation in the channel pore also right-shifted the voltage dependence of slow gating, recapitulating mild myotonia. The recessive V640G mutant drastically reduced channel function, which probably accounts for myotonia. In contrast, the recessive L628P mutant produced currents very similar to wild type, suggesting that the occurrence of the compound truncating mutation (Q812X) or other muscle-specific mechanisms accounted for the severe symptoms observed in this family. Our results provide novel insight into the molecular mechanisms underlying normal and altered ClC-1 function.

Pin1 contribution to Alzheimer's disease: transcriptional and epigenetic mechanisms in patients with late-onset Alzheimer's disease.

BACKGROUND: Neurofibrillary tangles and senile plaques are hallmarks of Alzheimer's disease (AD) although the molecular basis of their coexistence remains elusive. The peptidyl-prolyl cis/trans isomerase Pin1 acts on both tau and amyloid precursor protein to regulate their functions by influencing tau phosphorylation and amyloid precursor protein processing. OBJECTIVE: In order to identify potential biomarkers for AD in easily accessible cells and to gain insight into the relationship between the brain and peripheral compartments in AD pathology, we investigated Pin1 expression and activity in the peripheral blood mononuclear cells of subjects with late-onset AD (LOAD) and age-matched controls (CT). METHODS: Gene and protein expression, promoter methylation, Ser(16) phosphorylation and activity of Pin1 were evaluated in 32 samples from subjects with LOAD and in 28 samples from CT. RESULTS: In LOAD subjects, there was a statistically significant reduction in Ser(16) phosphorylation (-30%; p = 0.041) and promoter methylation (-8%; p = 0.001), whereas Pin1 expression was significantly increased (+74%; p = 0.018). CONCLUSION: The modifications of Pin1 found in LOAD subjects support its involvement in the pathogenesis of the disease with an important role being played by epigenetic mechanisms.

High frequency repetitive transcranial magnetic stimulation decreases cerebral vasomotor reactivity.

OBJECTIVE: Repetitive Transcranial Magnetic Stimulation (rTMS) has been recently employed as a therapeutic strategy for stroke, although its effects on cerebral hemodynamics has been poorly investigated. This study aims to examine the impact of high frequency rTMS on cerebral vasomotor reactivity (VMR). METHODS: Twenty-nine healthy subjects were randomly assigned to real (19) or sham 17-Hz rTMS, applied on primary motor cortex (M1) of the dominant hemisphere. All subjects underwent Transcranial Doppler of the middle cerebral arteries to evaluate mean flow velocity and VMR before (T(0)) and within 10 min (T(1)) following rTMS. Four subjects underwent further VMR evaluations at 2 (T(2)), 5 (T(3)) and 24 h (T(4)) after rTMS. As a control condition, 10 subjects underwent real (5) or sham rTMS on calcarine cortex. In addition, five acute stroke patients underwent five daily rTMS sessions on the affected hemisphere mimicking a therapeutic trial. RESULTS: Following real rTMS on M1 (p=0.002) and calcarine cortex (p<0.001) VMR decreased with respect to T(0) in both hemispheres, while no change was observed after sham rTMS (p>0.6). VMR tended to remain lower than T(0) until T(3.) Cerebral VMR decreased independently of the stimulated side also in the patients' group. CONCLUSIONS: High frequency rTMS reduces cerebral VMR, possibly as a secondary effect on autonomic control of cerebral hemodynamics. SIGNIFICANCE: The effect of rTMS on cerebral hemodynamics should be carefully considered before proceeding toward a therapeutic application in stroke patients.

Increased cerebral vasomotor reactivity in migraine with aura: an autoregulation disorder? A transcranial Doppler and near-infrared spectroscopy study.

Migraine with aura (MA) is associated with changes in cerebral blood flow (CBF), whereas the role of cerebral autoregulation is uncertain. This study aimed to evaluate basal CBF, cerebral blood volume (CBV) and vasomotor reactivity (VMR) in MA patients. Twenty-one controls and 16 MA patients (eight with side predominance) underwent simultaneous examination of flow velocity in the middle cerebral arteries by transcranial Doppler (TCD) and of near-infrared spectroscopy (NIRS) parameters [oxygen haemoglobin saturation: oxygen%, and total haemoglobin content (THC)] at rest and after hypercapnia. Cerebral VMR, THC and oxygen% increases were significantly greater on the predominant compared with the non-predominant migraine side, with both sides of patients without side predominance and with controls. These findings suggest altered autoregulation in MA patients, possibly secondary to impaired cerebrovascular autonomic control. Simultaneous TCD and NIRS investigation could represent a non-invasive approach to evaluate cerebral haemodynamics at the cortical and subcortical level.

Neuroimaging experimental studies on brain plasticity in recovery from stroke.

Topographical cortical organization of sensorimotor area has been shown to be highly plastic, altering his configuration in response to training in different tasks in healthy controls and neurological patients. The term ''brain plasticity'' encompasses all possible mechanisms of neuronal reorganization: recruitment of pathways that are functionally homologous to, but anatomically distinct from, the damaged ones (eg, non-pyramidal corticospinal pathways), synaptogenesis, dendritic arborisation and reinforcement of existing but functionally silent synaptic connections (particularly at the periphery of core lesion). The study of neuroplasticity has clearly shown the ability of the developing brain--and of the adult and ageing brain--to be shaped by environmental inputs both under normal conditions (ie, learning) and after a lesion. Neuronal aggregates adjacent, or distant to a lesion in the sensorimotor area can progressively adopt the function of the injured area. Imaging studies indicate that recovery of motor function after a lesion (i.e. stroke) is associated with a progressive change of activation patterns in specific brain structures. Transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG) can detect reshaping of sensorimotor areas; they have a high temporal resolution but have several limitations. TMS can only provide bidimensional scalp maps and MEG depicts three-dimensional spatial characteristics of virtual neural generators obtained by use of a mathematical model of the head and brain. However, the use of objective methods that assess brain reactivity to a physical stimulus (i.e., TMS) or to a sensory input (ie, electrical stimulation to hand and fingers) can integrate information from self-paced motor tasks, because the resolution of abnormal activation over time could be secondary to recovery. Functional MRI (fMRI) and positron emission tomography (PET), on their own, have insufficient time resolution to follow the hierarchical activation of relays within a neural network; however, because of their excellent spatial resolution, they can integrate the findings of TMS and MEG. An integrated approach constitutes, at present, the best way to assess the brain plasticity both under normal conditions and after a lesion.

What is the relationship among atherosclerosis markers, apolipoprotein E polymorphism and dementia?

Evidence suggests the important role of vascular factors both in vascular dementia (VaD) and Alzheimer disease (AD) pathogenesis. However, the relationship between apolipoprotein E (APOE) polymorphism and markers of atherosclerosis is still controversial. The aim of the study was to investigate the interplay between APOE polymorphisms and atherosclerosis in patients with AD and VaD. In this cross-sectional study, 101 demented (68 AD and 33 VaD) patients underwent APOE genotyping and neck vessel ultrasound to evaluate carotid artery disease [intima-media thickness (IMT) and plaques]. Patients with AD carrying epsilon4 allele presented increased IMT values with respect to non-epsilon4 carriers and VaD patients, whereas no relation was found between APOE polymorphisms and the presence or grade of carotid plaques both in AD and VaD patients. The epsilon4 APOE allele may promote intima-media thickening, interacting with other factors contributing to AD development.

Parsing the clinical phenotype of depression: the need to integrate brief depressive episodes.

OBJECTIVE: To expand the concept of recurrent brief depression (RBD) to brief depression (BD) and to test its clinical relevance. METHOD: Subjects (N = 591) were studied prospectively six times from ages 20/21 to 40/41 years. RBD was defined according to DSM-IV as episodes under 2 weeks with about monthly recurrence and work impairment. BD embraces RBD and brief depressive episodes with a frequency of 1-11 per year. RESULTS: Pure BD and pure major depressive episodes (MDE) did not differ in treatment rates, family history of mood and anxiety disorders or comorbidity with bipolar spectrum and anxiety disorders but they differed in work impairment, suicide attempt rates and distress self-ratings. The combination of BD + MDE identified a very severe group of MDE, comparable with combined depression (MDE + RBD) and double depression (MDE + dysthymia). CONCLUSION: Our data argue for the use of BD as a diagnostic specifier for severe MDE. RBD remains an important independent subgroup.

Altered neocortical cell density and layer thickness in serotonin transporter knockout mice: a quantitation study.

The neurotransmitter serotonin (5-HT) plays morphogenetic roles during development, and their alteration could contribute to autism pathogenesis in humans. To further characterize 5-HT's contributions to neocortical development, we assessed the thickness and neuronal cell density of various cerebral cortical areas in serotonin transporter (5-HTT) knockout (ko) mice, characterized by elevated extracellular 5-HT levels. The thickness of layer IV is decreased in 5-HTT ko mice compared with wild-type (wt) mice. The overall effect on cortical thickness, however, depends on the genetic background of the mice. Overall cortical thickness is decreased in many cortical areas of 5-HTT ko mice with a mixed c129-CD1-C57BL/6J background. Instead, 5-HTT ko mice backcrossed into the C57BL/6J background display increases in supragranular and infragranular layers, which compensate entirely for decreased layer IV thickness, resulting in unchanged or even enhanced cortical thickness. Moreover, significant increases in neuronal cell density are found in 5-HTT ko mice with a C57BL/6J background (wt:hz:ko ratio = 1.00:1.04:1.17) but not in the mixed c129-CD1-C57BL/6J 5-HTT ko animals. These results provide evidence of 5-HTT gene effects on neocortical morphology in epistatic interaction with genetic variants at other loci and may model the effect of functional 5-HTT gene variants on neocortical development in autism.

Postpartum cerebellar infarction and haemolysis, elevated liver enzymes, low platelet (HELLP) syndrome.

Pregnancy is considered to be a hypercoagulable state per se with an increased risk for cerebrovascular events, however cerebellar infarction has been rarely described in pregnant women. A nulliparous pre-eclamptic woman at 25 weeks' gestation was submitted to an echocardiographic exam that showed an impaired cardiac structure and function. After 2 h, the patient underwent caesarean section for diagnosis of haemolysis, elevated liver enzymes, low platelet (HELLP) syndrome. Afterwards her platelet count raised, and eight days later she developed nystagmus, ataxia, dysmetria and motor deficit in the right limbs and sensory impairment in the right side of the face and in the left limbs. Cerebral magnetic resonance imaging (MRI) demonstrated a right cerebellar and median posterior bulbar infarction. Colour-coded sonography of cerebral vessels showed an occlusion of the right vertebral artery. Coagulation pattern analysis evidenced double heterozygosis of the methylenetetrahydrofolate reductase (MTHFR) gene and single mutation of the prothrombin gene. This case report gives evidence of the importance of considering the different risk factors involved in stroke occurrence during pregnancy.

Mechanical and ultrastructural evaluation of quartz post-endodontic reconstructions.

Aesthetics is a very important element in dentistry, but requires the support of good mechanical performance. Quartz fiber used in post-endodontic reconstruction is an aesthetic material, although there is little research concerning its mechanical properties. This study evaluated the retentive property of post-endodontic reconstruction, composed of a quartz fiber post. Different thermal stresses were applied in vitro to post-endodontic reconstructions, in order to simulate oral thermal action on post-system dental structure linkage. We chose 30 human extracted teeth, endodontically treated and restored, and then divided them into three groups of 10 teeth. A different treatment was applied to each group before mechanical testing: in the 1st group no treatment was done (controls); in the 2nd group teeth were subjected, in a climatic chamber, to 10 thermo-cycles between 4 degrees C and 58 degrees C; in the 3rd group teeth were stored in a saline solution at 37 degrees C for 48 hr. The teeth then underwent tensile shear stress tests at break point using a computerized electronic dynamometer. After mechanical testing, two teeth from each group were longitudinally half-sectioned, sputter-coated in gold and observed by scanning electron microscopy (SEM). The extracted quartz fiber post of each tooth also underwent SEM observation. Mechanical test results demonstrated that thermal cyclic variations could affect bond stability between dental structures and posts in quartz fiber reconstructions, whereas their bond strength seemed unaffected by humidity increases. Quartz fiber post SEM observation demonstrated a homogeneous structure and a regular fiber disposition. Dental root canal morphology SEM images always showed a different thickness in the cement layer. (Journal of Applied Biomaterials & Biomechanics 2004; 2: 156-61).

Does cerebrovascular disease affect the coupling between neuronal activity and local haemodynamics?

The relationship between neurophysiological and cerebrovascular-metabolic findings in patients affected by severe cerebrovascular deficits was investigated by comparing magnetoencephalographic (MEG-evoked fields) and blood oxygen level-dependent functional MRI (BOLD fMRI) responses to median nerve electric stimulation. Despite the use of identical stimuli, the two techniques elicited always-detectable responses in the control group (10 subjects), but demonstrated uncorrelated activation properties in our patient sample (10 subjects). All patients showed clear MEG signals in both the affected and unaffected hemispheres, indicating well synchronized, stimulus-locked firing of neurons in the primary sensorimotor cortex, but some patients showed no fMRI activation in either the affected or the unaffected hemisphere. In order to clarify the origin of this uncoupling, we investigated the possible role of lesion site, white matter hyperintensities, current medication, risk factors, anatomy of the neck vessels, and cerebral vasomotor reactivity (VMR) as measured by transcranial Doppler (TCD) during CO2 inhalation. Neither neuronal activation properties nor any of the considered factors were related to the lack of fMRI activation, with the exception of altered vasomotor reactivity, which was, on the contrary, strongly related. Preserved VMR was paired with absent BOLD bilaterally in the only patient affected by microangiopathy. This finding suggests that BOLD contrast could be more sensitive than TCD to chronic microvascular impairments, measuring small- rather than large- vessel reactivity.

Clinical and subclinical body dysmorphic disorder.

BACKGROUND: The aim of the study was to define the main demographic and clinical characteristics of Body Dysmorphic Disorder (BDD) and subclinical BDD (sBDD) in a sample derived by a screening survey done on a population of individuals referring to aesthetical medicine centers. METHOD: 487 subjects referring to hospital centers for aesthetical medicine were administered the SCID-I and the Yale-Brown Obsessive-Compulsive Scale adapted for BDD (BDD-YBOCS). The sample was thus sub-divided in three sub-samples: 1) BDD, 2) sub-clinical BDD, and 3) controls. The main demographic and clinical variables were considered and compared between the BDD and the sBDD samples. RESULTS: As previously reported, the prevalence of BDD and sBDD was 6.3% and 18.4%, respectively. The most frequent comorbid diagnosis in both BDD and sBDD patients and their relatives was Obsessive-Compulsive Disorder (OCD). A higher severity of symptoms was found in male BDD patients, while no gender-related differences were found in the sBDD group. Suicidal ideation was found in 12.1% of the sBDD and in 49.7% of the BDD patients. CONCLUSIONS: These results support the hypothesis of BDD and sBDD belonging to the OCD spectrum, and appear to advise long-term follow-up studies on the course and the prognosis of sBDD.

Haptoglobin polymorphism and schizophrenia: genetic variation on chromosome 16.

Recently, it was shown that schizophrenia is accompanied by an activation of the inflammatory response system with signs of an acute phase response, such as increased plasma haptoglobin (Hp) concentrations. Hp is characterized by a molecular variation with three known phenotypes, i.e. Hp 1-1, Hp 2-1 and Hp 2-2. The aim of the present study was to examine Hp phenotypic and genotypic frequencies in schizophrenic patients. Hp phenotyping was carried out in 98 Northwestern Italian schizophrenic patients and the phenotypic and genotypic distributions were compared with the distributions established in the Northwestern Italian population. Plasma Hp concentrations were determined by means of a laser nephelometric method. The allele frequency of the Hp phenotypes in schizophrenia, i.e. Hp 1-1 (9.2%), Hp 2-1 (38.8%) and Hp 2-2 (52.0%), was significantly different from that in the Northwestern Italian population, i.e. Hp 1-1 (17.0%), Hp 2-1 (51.3%) and Hp 2-2 (38.5%). The frequency of the Hp-2 gene was significantly higher in schizophrenic patients (71.7%) as compared with the observed frequency in the Northwestern Italian population (62.5%). The alterations in Hp phenotypic and genotypic distribution were more pronounced in the schizo-affective, disorganized, undifferentiated and residual schizophrenic patients than in paranoid schizophrenic patients. More than a third (35.7%) of the schizophrenic patients showed plasma Hp concentrations which were higher than the upper limits of normality. Schizophrenia is accompanied by an altered distribution of the Hp phenotypes and genotypes, suggesting that genetic variation on chromosome 16 may be associated with schizophrenia.

Association between -G308A tumor necrosis factor alpha gene polymorphism and schizophrenia.

Dysregulation of the inflammatory response system has been linked to pathophysiology of schizophrenia. Evidence of immune activation has derived from the detection of abnormal levels of proinflammatory cytokines and their receptors in peripheral blood and cerebrospinal fluid from schizophrenic patients. Cytokines are involved in normal CNS development as well as in the pathogenesis of many neuro-psychiatric disorders, acting directly on neural cells or modulating neurotransmitter and neuropeptide systems. In particular tumor necrosis factor alpha (TNFalpha), depending on its concentration, can exert both neurotrophic and neurotoxic effects and influence neural cell growth and proliferation. Moreover, TNFalpha gene is located on the small arm of chromosome 6 (6p21.1-21.3), a locus associated with genetic susceptibility to schizophrenia. We studied the distribution of -G308A TNFalpha gene polymorphism in 84 schizophrenic patients and in 138 healthy volunteers. This biallelic base exchange polymorphism directly affects TNFalpha plasma levels. Frequency of the TNF2(A) allele is significantly increased in schizophrenic patients as compared to controls (P = 0.0042). Genotype distribution is also significantly different (P = 0.0024). TNF2 homozygotes are represented only in the patient group (P = 0.002). These data suggest a potential role of TNFalpha as a candidate gene for susceptibility to schizophrenia and suggest that immune dysregulation in schizophrenic patients could also have a genetic component.

Risk and preventive factors of post-traumatic stress disorder (PTSD): alcohol consumption and intoxication prior to a traumatic event diminishes the relative risk to develop PTSD in response to that trauma.

BACKGROUND: Previous reports examined the effects of selected pre- (e.g. female gender, previous trauma), peri- (e.g. the horror of the trauma, threatened death) or post-exposure (e.g. the physical injury caused by the trauma) risk factors on the development of post-traumatic stress disorder (PTSD), an anxiety disorder associated with a traumatic event outside the range of usual human experience. We hypothesized that alcohol consumption prior to traumatic events may reduce the incidence rate of PTSD. The aim of this study was to examine the effects of the above risk factors and preventive factors, such as alcohol consumption, on the development of PTSD. METHODS: An epidemiological cohort study was carried out on 127 victims trapped in a ballroom fire. Data were collected, 7-9 months after the traumatic event, by means of the Composite International Diagnostic Interview (CIDI) and structured interviews, aimed to assess the above pre-, peri- and post-exposure factors. Logistic regression analysis was used to examine the association of PTSD with the etiologic factors and to delineate those risk factors which contribute most to the development of PTSD. RESULTS: Female gender, the number of previous trauma, a past history of simple phobia, threatened death, trauma exposure, hospitalization for trauma-induced injuries and the presence of burns increased the odds of PTSD, whereas a sense of control during the trauma, and alcohol consumption and intoxication decreased the odds of PTSD. Six factors made independent contributions to the prediction of PTSD, i.e. the number of previous trauma, a past history of simple phobia, loss of control (increase the odds), a sense of control, alcohol consumption and alcohol intoxication (decrease the odds). CONCLUSIONS: The results of this study show that the development of PTSD is determined by the effects of pre-, peri- and post-exposure risk factors and may be prevented by the effects of peri-traumatic factors, such as sense of control, alcohol consumption and intoxication.