Familial aggregation of MATRICS Consensus Cognitive Battery scores in a large sample of outpatients with schizophrenia and their unaffected relatives.

BACKGROUND: The increased use of the MATRICS Consensus Cognitive Battery (MCCB) to investigate cognitive dysfunctions in schizophrenia fostered interest in its sensitivity in the context of family studies. As various measures of the same cognitive domains may have different power to distinguish between unaffected relatives of patients and controls, the relative sensitivity of MCCB tests for relative-control differences has to be established. We compared MCCB scores of 852 outpatients with schizophrenia (SCZ) with those of 342 unaffected relatives (REL) and a normative Italian sample of 774 healthy subjects (HCS). We examined familial aggregation of cognitive impairment by investigating within-family prediction of MCCB scores based on probands' scores. METHODS: Multivariate analysis of variance was used to analyze group differences in adjusted MCCB scores. Weighted least-squares analysis was used to investigate whether probands' MCCB scores predicted REL neurocognitive performance. RESULTS: SCZ were significantly impaired on all MCCB domains. REL had intermediate scores between SCZ and HCS, showing a similar pattern of impairment, except for social cognition. Proband's scores significantly predicted REL MCCB scores on all domains except for visual learning. CONCLUSIONS: In a large sample of stable patients with schizophrenia, living in the community, and in their unaffected relatives, MCCB demonstrated sensitivity to cognitive deficits in both groups. Our findings of significant within-family prediction of MCCB scores might reflect disease-related genetic or environmental factors.

Impact of Mood Spectrum Spirituality and Mysticism Symptoms on Suicidality in Earthquake Survivors with PTSD.

The aim of the present study was to explore the correlations between Spirituality/Mysticism/Psychoticism symptoms and suicidality in young adult survivors of the L'Aquila earthquake. The sample included 475 subjects recruited among high school seniors who had experienced the April 6, 2009, earthquake. Assessments included: Trauma and Loss Spectrum-Self Report and Mood Spectrum-Self Report (MOODS-SR). Mysticism/Spirituality dimension and suicidality were evaluated by means of some specific items of the MOOD-SR. The Spirituality/Mysticism/Psychoticism MOODS-SR factor score was significantly higher among subjects with PTSD diagnosis with respect to those without. Similarly, subjects with suicidal ideation, as well as those who committed a suicide attempt, reported significantly higher scores than those without.

A Comparison of Humiliation Measurement in a Depressive Versus Non-clinical Sample: A Possible Clinical Utility.

OBJECTIVE: We aimed to deepen the clinical utility of humiliation assessment in the study of depression. METHOD: We performed a correlational analysis of the relationship between humiliation, depression, resilience, and negative primary familial environment in 80 clinically depressed subjects (41 men and 39 women; mean age = 40.71, standard deviation SD = 9.94) and a strictly matched sample of 80 non-clinical subjects (41 men and 39 women; mean age = 40.64, SD = 10.24). We also implemented a hierarchical multiple regression analysis for each sample, to test the prediction of these variables on depression. RESULTS: Humiliation showed positive correlations with depressive factors, while negative correlations emerged with resilience in both samples. The hierarchical multiple regression analysis showed humiliation to be the most predictive factor of depression in the clinical sample only. CONCLUSION: This study improves the understanding of the relationship of humiliation and depression in both clinical and non-clinical populations.

Emotional reactivity in bipolar depressed patients.

OBJECTIVE: Emotional reactivity in bipolar affective disorders has received increased attention as a relevant issue with regard to the ability to respond to emotional external stimuli for individual real world adaptation. We investigated emotional reactivity using the International Affective Picture System (IAPS) paradigm in bipolar patients during the depressive phase compared to healthy controls. METHOD: Twenty-three bipolar patients with a major depressive episode without manic symptoms and 27 healthy control subjects were recruited. They were asked to judge their emotional reactivity while viewing 90 pictures selected from the IAPS. Their ratings were categorized according to the emotional valence and arousal in response to pleasant, neutral, and unpleasant stimuli. RESULTS: The patients showed lower valence ratings for neutral pictures compared to healthy subjects. No significant between-group differences were found for the pleasant and unpleasant pictures. Higher activation for patients to all emotional stimuli was seen. CONCLUSION: Patients during the depressive phase gave more negative valence to neutral images. This can suggest that they are more pessimistic in the way they perceive the environment as more reactive to emotional cues.

Anti-IFI16 antibodies and their relation to disease characteristics in systemic lupus erythematosus.

OBJECTIVE: Several studies have shown the presence of anti-IFI16 antibodies in systemic lupus erythematosus (SLE), Sjögren Syndrome (SjS), systemic sclerosis (SSc) and other autoimmune diseases. However, the significance of anti-IFI16 antibodies in SLE has not been fully characterized. The aim of this study was to investigate associations between anti-IFI16 antibodies and clinical and serologic parameters of SLE. METHODS: An enzyme-linked immunosorbent assay (ELISA) kit was used to measure anti-IFI16 antibodies in the sera of 168 SLE patients, 46 patients with any type of primary glomerulonephritis (GN) and 182 healthy controls (HCs). Associations between anti-IFI16 antibodies and clinical and serologic parameters of SLE were statistically evaluated using both univariate and multivariate analysis. RESULTS: Significantly higher anti-IFI16 titres were observed in SLE patients compared to both non-SLE GN and HCs (median levels: 270.1 U/ml vs 132.1 U/ml, p = 0.001, and 52.9 U/ml, p < 0.0001, respectively). With cut-off levels corresponding to the 95th percentile of the control population (113 U/ml), 63% of the SLE patients tested positive for anti-IFI16 autoantibodies, compared to just 24% of patients with primary non-SLE GN and 5% of HCs. The presence of anti-IFI16 antibodies inversely correlated with proteinuria (univariate analysis) and C3 hypocomplementaemia (univariate and multivariate analyses). CONCLUSIONS: The inverse correlations observed between anti-IFI16 positivity, proteinuria and C3 hypocomplementaemia suggest that anti-IFI16 antibodies do not contribute to renal inflammation in SLE; indeed they may even prevent complement consumption. Anti-IFI16 antibodies hold the potential to serve as a new biomarker of disease activity in SLE.

Severe acute nephrotoxicity in a kidney transplant patient despite low tacrolimus levels: a possible interaction between donor and recipient genetic polymorphisms.

WHAT IS KNOWN AND OBJECTIVE: Tacrolimus has a narrow therapeutic index and shows large interindividual variations in pharmacokinetics, which may be partly explained by genetic variability in metabolic enzymes of the cytochrome P450 (mainly CYP3A4 and CYP3A5) and transport P-glycoprotein (encoded by the ABCB1 gene). Genetic variability in the expression of biotransformation enzymes and drug transporters may also predispose individuals to tacrolimus-induced nephrotoxicity. CASE SUMMARY: We report a case of severe biopsy-proven Tacrolimus (TAC) nephrotoxicity that occurred 1 month after renal transplantation despite persistently low TAC levels. The donor genotype was CYP3A5*3/*3 (loss-of-function genotype), whereas that of the recipient was CYP3A5*1/*3. The donor and recipient genotypes did not differ with respect to either CYP3A4 rs35599367C>T (both were CC homozygotes) or ABCB1 gene polymorphisms (both TT homozygotes for the 1236C>T polymorphism and CT heterozygotes for the 3435C>T polymorphism). WHAT IS NEW AND CONCLUSION: This case study suggests that donor/recipient genetic mismatch in metabolic enzymes may have an important role in modulating tacrolimus nephrotoxicity. It provides a possible explanation for the intriguing observation that for a subset of patients, cumulative TAC doses appear to correlate better with nephrotoxicity than trough levels.

Endovascular treatment of transplanted renal artery stenosis with PTA/stenting.

PURPOSE: We evaluated the effectiveness of endovascular treatment with percutaneous transluminal balloon angioplasty (PTA)/stenting of transplanted renal artery stenosis (TRAS). MATERIALS AND METHODS: Between January 2005 and December 2010, 17 patients (4 women, 13 men; mean age 60.9 years) with TRAS underwent PTA/stenting. The parameters analysed were: technical success, pre- and post-treatment serum creatinine (SCr) and blood pressure (BP), average number of antihypertensive drugs administered before and after treatment and vessel patency on colour Doppler ultrasound (CDUS) at 1, 3, 6 and 12 months and once a year thereafter. RESULTS: Technical success was 100%. During a mean follow-up of 28.3±18.7 months, there was a statistically significant reduction in SCr and BP values. In 18 % of cases, moderate (<60%) restenosis was observed on CDUS without renal failure and not requiring new treatment. There was a reduction in antihypertensive drugs from an average of 3.5±0.5 to 1.5±0.5. CONCLUSIONS: Consistent with the literature data, our experience shows that endovascular treatment with PTA/stenting is a safe and effective option for managing TRAS and can thus be considered the method of choice.

The interactions of age, sex, body mass index, genetics, and steroid weight-based doses on tacrolimus dosing requirement after adult kidney transplantation.

PURPOSE: The aim of this study was to evaluate the effect of different clinical covariates on tacrolimus dose requirements in adult kidney transplant patients with a specific focus on drug interactions. PATIENTS: Tacrolimus dosing requirement, normalized by drug levels and expressed as the concentration/dose (C/D) ratio as a surrogate index of tacrolimus bioavailability, was employed to identify four categories of tacrolimus dosing requirement, namely, very high, high, small, and very-small, in very fast, fast, slow, and very slow metabolizers, respectively. Steroid weight-based doses were analyzed instead of fixed doses, and genetic analysis of cytochrome P450 (CYP) 3A5*1/*3 and multi-drug resistance 1 (MDR1) C3435T and C1236T polymorphisms were performed RESULTS: Multivariate analysis on 450 adult transplant patients identified six risk factors for being slow metabolizers and therefore requiring small tacrolimus doses: male sex (OR 1.615, p = 0.020); age >60 years (OR 2.456, p = 0.0005); body mass index ≥ 25 (OR 1.546, p = 0.046), hepatitis C virus positivity (OR 2.800, p = 0.0004); low steroid dose <0.06 mg/kg (OR 3.101, p < 0.0001). Patients with a small tacrolimus requirement were at increased risk for multiple infections (OR 1.533, p = 0.0008) and higher systolic blood pressure (OR 1.385, p = 0.022) and showed a significant association with the CYP3A5*3/*3 genotype adjusted by MDR1 polymorphisms C3435T and C1236T (OR 8.104, p = 0.0001). CONCLUSIONS: Our results demonstrate the importance of the interaction among genetic and clinical factors in conditioning tacrolimus disposition, with corticosteroid weight-based dose being the only modifiable risk factor for tacrolimus requirement. As the tacrolimus dosing requirement increases with increasing tacrolimus clearance through concomitant steroid use, undesirable changes in tacrolimus levels may occur when steroid doses are tapered, predominantly in slow metabolizers. This often neglected drug interaction has to be monitored to optimize tacrolimus exposure in kidney transplant patients.

Life expectancy of women with lupus nephritis now approaches that of the general population.

Immunosuppressive treatment has changed the prognosis of Lupus nephritis over time, but improvement in prognosis is difficult to analyze in different historical periods, and should be better demonstrated in comparison with life expectancy of sex-and age-matched people. Long-term patient and renal survival of 90 patients diagnosed with Lupus nephritis at our center from 1968 to 2001 with a follow-up time of 14+/-8 years was retrospectively evaluated. Patient and kidney survival significantly increased over time. Multivariate analyses show that risks of patient and renal death decreased by 8% at each year of follow-up, and increased by more than 5 time in patients aged > 30 years at diagnosis. As only 14 patients were men, relative survival as compared to that of the sex- and age-matched general population of the Piedmont Region was calculated for the 76 women. Improvement in the survival of the cohort of women was seen at any time of follow-up: in particular, it was sharply lower in the first period (relative survival at 5, 10 and 15 years = 0.784, 0.665, and 0.620, respectively) and increased in the second (relative survival at 5, 10 and 15 years = 0.939, 0.921, and 0.850, respectively) nearly approaching that expected for the general population, i.e. 0.993, 0.983 and 0.967, respectively. Taken together, our data allow us to draw the conclusion that life expectancy in women with Lupus nephritis has improved over time, paralleling an improved awareness of the disease and a significant increase in steroid pulse therapy as induction/remission phase. Improvement in survival is for the first time demonstrated to cover the gap with life expectancy of the general population for women with Lupus nephritis.

Dimensional, non-taxonic latent structure of psychotic symptoms in a student sample.

INTRODUCTION: We examined the construct of psychosis using the self-report instrument CAPE (Community Assessment of Psychic Experiences) in a sample of 1,323 students. MATERIALS AND METHODS: Taxometric analysis was carried out using Taxometric Programs for the R Computing Environment. The MAXCOV CCFI was 0.34, indicating a dimensional latent structure. All other taxometric analysis yielded very similar results indicative of dimensional structure. CONCLUSION: In this study, using powerful analytic techniques designed expressly for the purpose, i.e. taxometric analysis, the latent construct of psychosis in a sample of young students appeared to be consistent with a dimensional, non-taxonic latent structure.

Improvement in relative survival of patients with vasculitis: study of 101 cases compared to the general population.

Immunosuppressive treatment has changed the prognosis of renal vasculitis over time, but improvement in prognosis is difficult to analyze in different historical periods, and can be better demonstrated by comparison with life expectancy of sex- and age-matched people. Long-term survival of 101 patients diagnosed with systemic vasculitis at our center from 1975 to 2002 was retrospectively evaluated in comparison with that of the Region's age- and sex-matched population. Patient and kidney survival significantly increased over time. Multivariate analyses showed that risks of patient and renal death decreased by 10% and 7%, respectively, at each year of follow-up, and increased by 6.3% and 5.2% for each year of age. Relative survival significantly improved over time, approaching that of the general population for cases diagnosed after 1993, mainly in women < 60 years (from 0.671 at 5-years in the first period to 0.916 in the last period), while 5-year-relative-survival was still 0.530 and 0.682 in men and women greater than 60 years, respectively. Poisson-based multinomial analyses confirmed the significant risk of the first periods of diagnosis and of dialysis in worsening of the relative survival of patients compared to that of the general population. Life expectancy in patients with renal vasculitis has improved over time, paralleling a significant increase in steroid pulse/cyclophosphamide association therapy and an earlier diagnosis due to the introduction of the ANCA test. Relative survival has considerably improved, and now approaches that expected in the general population for women, but not for men.

Quality of life in renal transplant patients over 60 years of age.

Kidney transplantation not only drastically improves the life-expectancy of hemodialyzed patients, but it also affords psychological and social advantages with improvements in short- and long-term personal and working lives. Quality of life (QoL) is one of the parameters of psychological well-being. There is an improvement of QoL from pre- to posttransplant, but it is not to the level of healthy samples. The aim of this study was to examine QoL in older renal transplant recipients. All recipients older than age 60 were included, with a minimum follow-up of 12 months. To measure QoL, the nationally standardized ShortForm-36 (SF-36) questionnaire was administered. The SF-36 responses by our patients were compared with national age- and gender-appropriate norms, and also between genders. The enrolled population included 19 women (36.5%) and 33 men (63.5%), with a mean age of 66.8 years (range, 60-73 years). Enrolled women reported significant limitations compared to gender- and age-matched norms in social activities (42.11 vs 70.58), perception of pain (22.11 vs 59.17), and general health perception (39.58 vs 48.69). Enrolled men reported significant limitations compared to gender- and age-matched norms in social activities (46.59 vs 78.35), perception of pain (18.18 vs 73.62), psycho-physical energy (50.15 vs 67.88), and general health perception (37.33 vs 61.66). No significant differences were noted between the genders. This study clearly showed how the psychological state was not as good as the clinico-physical recovery following renal transplantation in older recipients.

Human papilloma virus infection and cervical intraepithelial neoplasia in transplanted patients.

Progress in diagnosis and treatment has led to an increased number of transplantation patients who consequently have immunological depression and emergence of tumors. The incidence of cervical neoplasia, according to previous studies, is 11%; this tumor is the only one that can be investigated by screening before and after a graft. Our purpose was to evaluate whether transplanted patients showed an increased incidence of genital human papilloma virus (HPV) infection and whether this infection produced greater progression of disease in cases of low-risk HPV infections. Our study involved 151 transplant patients who underwent Papanicolaou (Pap) and HPV tests. Patients listed for grafts underwent Pap and HPV tests 6 months before and 6 months after transplantation. All patients had negative Pap tests before their grafts. After their grafts 16 patients (10.59%) had negative Pap tests, but positive viral typing. Eleven patients (7.28%) showed positive Pap tests, 6 of whom had low-grade squamous intraepithelial lesion (SIL) and 5 patients high-grade SIL. The final HPV infection incidence (15.23%) was consistent with the literature. The incidence of lower female genital tract intraepithelial lesions (7.28%) was higher than the healthy population or analogous studies (4.5%-8.5%). We showed a constant association between high-risk HPV infection and gynecologic intraepithelial neoplasia, whereas there was no association between low-risk broods HPV infection and neoplasia. In conclusion, screening should start at almost 6 months before grafting to avoid an irreversible situation that is difficult to treat.

[Audit on quality of life of patients with chronic kidney disease on dialysis and after transplant]. / Audit sulla qualità di vita nei pazienti in insufficianza renale cronica, dialisi e trapianto.

Since the improvement of quality of life (QOL) in patients with chronic disease on dialysis (D-CKD) has been demonstrated to have significant effects on clinical outcome, QOL has been included among the principal targets for these patients. QOL is among the objectives of the Healthy People 2010 program of the United Nations and CKD is one of the 18 focus areas of the program. The process of improving clinical outcome for D-CKD patients is obviously correlated with the continuing attempts to improve the adequacy of dialysis, and this remains a milestone. Some recent studies, including the HEMO study, have demonstrated that the present standards for dialytic efficiency are adequate for morbidity and mortality outcomes. However, these concepts are rapidly evolving and there are emerging factors which should be monitored, such as a) frequency of hospitalization, b) QOL, c) patient's satisfaction, and d) transplantation rate. Each aspect should be taken into consideration when the general well-being of D-CKD patients is at stake. However, there is a lack of validated standards, and there are confounding effects related to different geographical areas, different degrees of morbidity, and different therapies. Health is defined by the WHO as the complete feeling of well-being, and transplantation obviously is a way to overcome the many difficulties encountered by D-CKD patients. It is true that QOL after transplant is affected by uncertainty about the final result, fear of having to go back on dialysis, or anger about unexpected complications. For these reasons special questionnaires have been designed for transplanted patients (e.g., SF-36). These indicate an improvement of QOL for transplanted compared with D-CKD patients, although QOL remains below the level of that of the healthy population. Post-transplant QOL tends to improve over time and will become superimposable to that of the healthy population in the long run. It is of paramount importance that each dialysis and transplantation center provide psychological support not only to patients but also to doctors and nurses.

Does premorbid IQ have a pathoplastic effect on symptom presentation in schizophrenic and bipolar disorders?

INTRODUCTION: The poor premorbid IQ has been considered as a predisposing factor for the development of schizophrenia and other psychoses as well as predictive of poor long-term outcome. We hypothesise that premorbid IQ could influence symptom expression during an index episode (i.e. a short-term outcome). AIM OF THE STUDY: We studied 48 patients with schizophrenic disorder and 56 with bipolar disorder during an 'index episode' using the test di intelligenza breve (TIB) for the premorbid IQ evaluation, and the positive and negative syndrome scale (PANSS). RESULTS: Using the premorbid IQ as a criterion variable (i.e. low versus high IQ groups) the one-way ANOVA analysis showed that low IQ schizophrenic patients had more PANSS positive symptoms and "thought disturbances" than both high and low IQ bipolars. The low IQ schizophrenic patients showed more cognitive symptoms than bipolar patients with high IQ. Furthermore, no PANSS differences were seen between high IQ schizophrenics and low IQ bipolars. In the total and bipolar groups the correlation coefficients between TIB scores and PANSS scales reached statistical significance for the cognitive cluster only. No correlations were seen in the schizophrenic group. CONCLUSION: This categorisation (i.e. low versus high IQ) adds clinically relevant knowledge to patients who, in spite of having similar symptom profile (i.e. high IQ schizophrenic patients and low IQ bipolar patients), fall into different diagnostic categories.

Dual effect of methylprednsolone pulses on apoptosis of peripheral leukocytes in patients with renal diseases.

It is well known that change in apoptosis may modulate the natural story of illness, and that many drugs may act through modulation of apoptosis, but the role of steroids in acting through apoptosis in different settings, including renal diseases, has still to be elucidated. We studied the in vivo effects of steroids by oral assumption (10 to 25 mg/deltacortene) or by intravenous pulses (300 to 1000 mg/dose) on apoptosis and cellular subsets of peripheral lymphocytes, by evaluating DNA-fragmentation and lymphocyte subsets in 79 subjects: 22 controls and 57 patients with various renal diseases (25 Lupus-GN, 19 membranous-GN (MGN), 6 rapidly progressive-GN (RPGN), 2 acute interstitial nephritis (AIN), 5 on chronic dialysis. Baseline apoptosis was present in 1/22 (4.5%) of controls, 3/25 (12%) SLE, 2/6 (33.3%) RPGN and 10/19 (52.6%) MGN. A significant decrease in CD3+CD8+ cell count and a significant increase of the CD3+CD4/CD3+CD8+ ratio were found in apoptosis-positive subjects. DNA fragmentation did not change after oral steroids, paralleling a 22 to 32% decrease in total lymphocytes. Following intravenous methylprednisolone pulses, a deeper drop of all lymphocyte subsets was observed, while DNA fragmentation turned from present to absent in 2 MGN, but not in 2 RPGN, and from absent to present in 1 ARF and 1 SLE, independently of the dosage. We demonstrated that the presence of apoptosis in renal diseases is associated with decreased CD3+CD8+ cell count. Furthermore, steroid intravenous pulses, besides inducing a profound decrease in lymphocyte subsets, do exert a dual effect on baseline leukocyte apoptosis, eventually leading to a reversal of baseline patterns, either turning from negative to positive or from positive to negative. Oral steroid therapy did not influence baseline apoptosis.

[The Italian Society of Nephrology Guidelines (3rd Edition): principles and methods]. / I principi ed i metodi della III edizione delle Linee Guida della Società Italiana di Nefrologia (2005-2006).

Scientific Societies at both a local and international level are making big effort to prepare their clinical practice guidelines. The Italian Society of Nephrology has already published in two previous editions a series of guidelines relating to various aspects of management and diagnosis of different renal diseases. In this review we present the criteria of the 3(rd) edition of the Italian Society of Nephrology guidelines. This 3(rd) edition of guidelines will be based on the availability of scientific evidence in different areas of nephrology, dialysis and transplantation. Ten key intervention questions have been identified, based on the availability of systematic reviews of randomized trials or individual randomized address them. Systematic reviews and randomized trials are the optimal study design to address intervention questions. These have been summarized based upon rigid methodological criteria and strictly reflect the evidence basis. The different phases of development and publication of the 3(rd) edition of the Italian Society of Nephrology guidelines are presented.

Cerebellar vermal size in schizophrenia: a male effect.

Magnetic resonance (MR) was used to examine the cerebellar vermis in 23 patients with schizophrenia and 16 matched controls. MR midsagittal images were processed with computerized image analysis to control partial volume effects as precisely as possible. No between-group differences were found for vermal-to-cerebrum ratio. When gender differences were examined, male patients showed a lower vermal-to-brain ratio than their female counterparts, mainly because of a reduction of the lobules I-V.

Association between striatal reduction and poor Wisconsin card sorting test performance in patients with schizophrenia.

Several findings support the hypothesis that the striatum is implicated in executive functions and in the modulation of goal-directed behavior, and could play a key role in the pathophysiology and in the production of symptoms and signs in schizophrenia. We have studied the relationship between the objective measures of the striatal structures, as evaluated by magnetic resonance imaging (MRI), and the Wisconsin Card Sorting Test (WCST) performance in a schizophrenic sample. Thirty-five schizophrenic patients underwent MRI scans of striatal structure and neuropsychological evaluation of executive functions by WCST. Poor WCST performers had a reduction of the left caudate nucleus and putamen, and right total striatum when compared to 24 healthy controls. Significant correlation coefficients were also observed between neuropsychological indexes and left striatal measures. The findings suggest the existence of a relationship between abnormalities of striatal structure and abnormal executive-type or organizational cognitive functions.

Hemispheric asymmetries and schizophrenia: a preliminary magnetic resonance imaging study.

A magnetic resonance imaging (MRI) study of 20 chronic schizophrenic outpatients (5 women and 15 men) and 20 healthy volunteers, individually matched for age and sex, was conducted. Schizophrenics showed a statistically significant lateral ventricular enlargement and smaller corpus callosum: brain ratio than controls. There were no statistically significant differences in hemispheric measurements between groups. Nevertheless, we found a wider right frontal width versus the left in the patient group but not in the control group, and more frontal protuberances in the right hemisphere in the patient group. Possible meanings and implications of these findings for a pathophysiological hypothesis are discussed.