Differential clinical, structural and P300 parameters in schizophrenia patients resistant to conventional neuroleptics.

Schizophrenia is a heterogeneous clinical condition that may reflect a variety of biological processes. In particular, treatment-resistant (TR) schizophrenia may have a distinct neurobiological substrate. Within the context of clinical data, a simultaneous study with different imaging techniques could help to elucidate differences in cerebral substrates among schizophrenia patients with different responses to treatment. In the present work we used a set of biological data (basal and longitudinal volumetry, and P300 event-related potential measurements) to compare TR and treatment-responsive chronic schizophrenia patients with healthy controls. The TR patients showed higher baseline clinical scores, a more severe basal profile of brain alterations, as well as a different outcome as regards to volume deficits. These data support the notion that biological substrates vary among groups of different psychotic patients, even when they have the same diagnosis, and that those substrates may be related to the response to treatment.

Gray matter deficits in bipolar disorder are associated with genetic variability at interleukin-1 beta gene (2q13).

Twin, family and recent molecular studies support the hypothesis of genetic overlapping between schizophrenia and bipolar disorder. Brain structural features shared by both psychiatric disorders might be the phenotypic expression of a common genetic risk background. Interleukin-1 (IL-1) cluster (chromosome 2q13) genetic variability, previously associated with an increased risk both for schizophrenia and for bipolar disorder, has been also associated with gray matter (GM) deficits, ventricular enlargement and hypoactivity of prefrontal cortex in schizophrenia. The aim of the present study was to analyze the influence of IL-1 cluster on brain morphology in bipolar disorder. Genetic variability at IL-1B and IL-1RN genes was analyzed in 20 DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition) bipolar patients. Magnetic resonance imaging (MRI) measurements were obtained for whole-brain GM and white matter, dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus, hippocampus and lateral ventricles. MRI data were corrected for age and cranial size using regression parameters from a group of 45 healthy subjects. A -511C/T polymorphism (rs16944) of IL-1B gene was associated with whole-brain GM deficits (P = 0.031) and left DLPFCGM deficits (P = 0.047) in bipolar disorder patients. These findings support the hypothesis of IL-1 cluster variability as a shared genetic risk factor contributing to GM deficits both in bipolar disorder and in schizophrenia. Independent replication in larger samples would be of interest to confirm these results.

Dorsolateral prefrontal N-acetyl-aspartate concentration in male patients with chronic schizophrenia and with chronic bipolar disorder.

OBJECTIVES: A study of N-acetyl-aspartate (NAA) can provide data of interest about cortical alterations in psychotic illnesses. Although a decreased NAA level in the cerebral cortex is a replicated finding in chronic schizophrenia, the data are less consistent for bipolar disease. On the other hand, it is likely that NAA values in schizophrenia may differ in men and women. METHODS: We used proton magnetic resonance spectroscopy ((1)H MRS) to examine NAA levels in the prefrontal cortex in two groups of male patients, one with schizophrenia (n=11) and the other with bipolar disorder (n=13) of similar duration, and compared them to a sample of healthy control males (n=10). Additionally, we compared the degree of structural deviations from normal volumes of gray matter (GM) and cerebrospinal fluid (CSF) in the dorsolateral prefrontal cortex. RESULTS: Compared to controls, schizophrenia and bipolar patients presented decreased NAA to creatine ratios, while only the schizophrenia group showed an increase in CSF in the dorsolateral prefrontal region. There were no differences in choline to creatine ratios among the groups. CONCLUSIONS: These data suggest that the decrease in NAA in the prefrontal region may be similar in schizophrenia and bipolar disorder, at least in the chronic state. However, cortical CSF may be markedly increased in schizophrenia patients.

Changes in cortical volume with olanzapine in chronic schizophrenia.

INTRODUCTION: Atypical antipsychotics can affect cortical volume differently from traditional drugs. The study of the outcome of grey matter deficits in schizophrenia with olanzapine may be of particular interest in this context. METHODS: In this study, we evaluated the changes in the volume of gray matter in the cortex of 11 schizophrenic patients treated with olanzapine and in 11 healthy controls after three years of follow-up. After MR imaging, acquisition data were processed with a volumetric quantification method based on the Talairach atlas. The longitudinal change of volumetric data was corrected for differences in overall brain size. RESULTS: Patients showed greater reduction than controls in cortical volume in the frontal and parietal regions during follow-up. No relationship was observed between clinical and volumetric changes. CONCLUSION: Our data suggest that the profile of action of olanzapine on the cortical volume of chronically ill patients may be similar to that of typical antipsychotics. Other explanations, however, cannot be completely discarded for that outcome with our data.

Impact of ventricular enlargement on the measurement of metabolic activity in spatially normalized PET.

In pathologic brains with morphological alterations, the process of spatial normalization, as performed by SPM methods, may introduce a confounding effect in the measurement of metabolic activity data. To investigate the effect of the spatial normalization of PET images, we analyzed MRI and PET studies of 20 schizophrenic patients and 18 controls. Using a Talairach-based segmentation procedure and manual segmentation, we measured regional metabolic activity in the untransformed brains and after their spatial normalization. The effect of spatial normalization seems minimal for large ROIs like the main brain lobes, even in brains showing pronounced morphological abnormalities. However, the caudate nucleus shows a considerable change in metabolic activity values after normalization. This normalization effect is much larger in patients than in controls, and leads to artifactual differences between them. We obtained incorrect results (SPM analysis) regarding functional differences between patients and controls in the caudate due to this bias introduced by the spatial normalization. There was a significant correlation between the size of the lateral ventricles and the underestimation of metabolic activity of the caudate. Normalization bias seems to arise from a misalignment of the caudate in the normalized space, pixel overlap between the normalized caudate, and the caudate of the template being on average lower than 50% in both groups. Spatial normalization of the PET images of pathologic brains may introduce a potential source of error that should be taken into account in the analysis of functional data, in particular, in the study of small brain nuclei like the caudate.

Hypofrontality in men with first-episode psychosis.

BACKGROUND: Decreased metabolic activity in the prefrontal cortex during cognitive activation is a recurrent finding and a likely functional marker of schizophrenia. AIMS: To investigate the occurrence of hypofrontality in patients with first-episode psychosis, with or without evolution to schizophrenia. METHOD: We used fluorodeoxyglucose positron emission tomography during the performance of an attention task and magnetic resonance imaging to study the dorsolateral prefrontal region in 13 men with a first episode of psychosis. Data from patients who progressed to schizophrenia were compared with those of patients who did not meet criteria for this diagnosis after 2 years. RESULTS: Patients who developed schizophrenia demonstrated a significant hypofrontality in the dorsolateral prefrontal cortex in comparison with the non-schizophrenia and control groups. CONCLUSIONS: Our results suggest that hypofrontality could be a marker of schizophrenia at the time of the first psychotic episode, in agreement with neurodevelopmental theories of schizophrenia.

The management of infection in arthroplasty of the shoulder.

The management and outcome of treatment in 42 patients (49 shoulders) with an infected shoulder prosthesis was reviewed in a retrospective multicentre study of 2343 prostheses. The factors which were analysed included the primary diagnosis, the delay between the diagnosis of infection and treatment and the type of treatment. Treatment was considered to be successful in 30 patients (71%). Previous surgery and radiotherapy were identified as risk factors for the development of infection. All patients with an infected prosthesis had pain and limitation of movement and 88% showed radiological loosening. In 50% of the shoulders, the antibiotics chosen and the length of treatment were considered not to be optimal. The mean follow-up was 34 months. Antibiotics or debridement alone were ineffective. In acute infection, immediate revision with excision of all infected tissue and exchange of the prosthesis with appropriate antibiotic therapy gave the best results. Multidisciplinary collaboration is recommended.

Influence of the normalization template on the outcome of statistical parametric mapping of PET scans.

Spatial normalization is an essential preprocessing step in statistical parametric mapping (SPM)-based analysis of PET scans. The standard template provided with the SPM99 software package was originally constructed using (15)O-H(2)O PET scans and is commonly applied regardless of the tracer actually used in the scans being analyzed. This work studies the effect of using three different normalization templates in the outcome of the statistical analysis of PET scans: (1) the standard SPM99 PET template; (2) an (18)F-FDG PET template, constructed by averaging PET scans previously normalized to the standard template; and (3) an MRI-aided (18)F-FDG PET template, constructed by averaging PET scans normalized according to the deformation parameters obtained from MRI scans. A strictly anatomical MRI normalization of each PET was used as a reference, under the rationale that a normalization based only upon MRI should provide higher spatial accuracy. The potential bias involved in the normalization process was estimated in a clinical SPM study comparing schizophrenic patients with control subjects. For each between-group comparison, three SPM maps were obtained, one for each template. To evaluate the influence of the template, these SPM maps were compared to the reference SPM map achieved using the anatomical normalization. SPMs obtained by MRI-aided normalization showed the highest spatial specificity, and also higher sensitivity when compared to the standard normalization using the SPM99 (15)O-H(2)O template. These results show that the use of the standard template under inappropriate conditions (different tracer or mental state) may lead to inconsistent interpretations of the statistical analysis.

[Statistical parametric mapping (SPM) in nuclear medicine]. / Mapas de estadísticos paramétricos (SPM) en medicina nuclear.

In the scope of medical research, functional neuroimaging analysis permits the study of pathological or cognitive cerebral processes by using statistical quantification techniques. A tool of increasing use is the SPM (Statistical Parametric Mapping) software due to its wide availability and the variety of statistical studies that can be made. Nevertheless, being unaware of the theoretical background on which it is based may easily lead to inaccurate results and even to the reaching of erroneous conclusions. The present article summarizes these theoretical principles and discusses the main key points of the method without requiring advanced mathematical knowledge.

Mapas de estadísticos paramétricos (SPM) en medicina nuclear / Statistical parametric mapping (SPM) in nuclear medicine

En el ámbito de la investigación médica, el análisis de neuroimágenes funcionales (PET, SPECT y fMRI) mediante técnicas de cuantificación estadística permite el estudio de diversos procesos cerebrales, patológicos o cognitivos. Una herramienta de creciente uso para este fin es el software SPM (Statistical Parametric Mapping) gracias a su amplia disponibilidad y el gran abanico de estudios estadísticos que permite realizar. Sin embargo, el desconocimiento de los fundamentos teóricos en los que se basa puede conducir fácilmente a resultados imprecisos e incluso a conclusiones erróneas. Este artículo presenta brevemente dichos principios teóricos y discute los principales puntos críticos en la utilización del método sin exigir conocimientos matemáticos avanzados del lector. (AU)

Cerebral metabolism and risperidone treatment in schizophrenia.

This paper compares the metabolic changes associated with risperidone treatment in schizophrenia to those induced by haloperidol, as a representative typical neuroleptic. A group of 11 schizophrenic patients of recent onset underwent two [18F] fluoro-desoxi-glucose (FDG)-positron emission tomography (PET) scans at rest: the first one at the moment of the diagnosis, after a minimal treatment with haloperidol followed by wash-out, and the second one after 6 months on risperidone. The study also included 34 patients on chronic haloperidol for comparison. PET images were analyzed using Statistical Parametric Mapping (SPM'99) methods. The only change after treatment with risperidone with respect to the baseline was a slight increase in activity in the primary visual area and the right insula. Patients on chronic haloperidol showed increased activity in the motor cortex and cerebellum, as compared to both minimally treated and risperidone-treated patients. The pattern of metabolic changes induced by risperidone appears to be different from that produced by typical antipsychotics.

[Langerhans's cell histiocytosis in otorhinolaryngology]. / Histiocitosis de células de Langerhans en O.R.L.

Langerhans's cell histiocytosis (LCH) is an uncommon disease characterized by an accumulation of abnormal histiocytes, together lymphocytes and eosinophils in various organs and tissues. The head and neck are frequent sites of initial presentation. We present two cases of LCH with otorhinolaryngologic symptoms. Current recommendations for diagnosis, evaluation and treatment of LCH are also discussed.

[Salivary gland myoepithelioma]. / Mioepitelioma en glándulas salivares.

Myoepithelioma is a rare salivary gland tumor (less than 1%) which are usually located in parotid gland and minor salivary glands. Histology and immunohistochemical features of this tumors are reviewed. We report 2 cases arising in parotid and hard palate.

P300 amplitude as a possible correlate of frontal degeneration in schizophrenia.

The existence of neurodegeneration is a debated issue in schizophrenia research. The P300 component of event-related electrical potentials (ERP) has been related to the different degree of damage to gray and white matter. This study explores the possible relationship between P300 amplitude and/or latency and the existence of degenerative processes in schizophrenia, by assessing its correlation with volume of sulcal CSF and duration of illness, as transversal indicators of neurodegeneration. Nineteen patients (14 males, 5 females) and 13 controls (6 males, 7 females) were studied with MRI and electrophysiological records (P300). The possible influence of sex and age at the time of the exploration was statistically controlled in both groups. The results show a significant negative correlation between P300 amplitude and prefrontal CSF volume in the patient group. A lower though still significant correlation was also found between P300 amplitude and duration of illness, whereas no correlation was found in the control group. These results support the hypothesis that P300 amplitude may be interpreted as a marker of neurodegeneration in schizophrenia.

Histiocitosis de células de Langerhans en O.R.L / Langerhans's cell histiocytosis in otorhinolaryngology

La histiocitosis de células de Langerhans (HCL) es una enfermedad poco frecuente caracterizada por el acúmulo de histiocitos anómalos, junto con linfocitos y eosinófilos en diferentes órganos y tejidos. La presentación inicial en cabeza y cuello es relativamente frecuente. Presentamos dos casos de HCL con síntomas otorrinolaringológicos. Se discuten aspectos relacionados con el diagnóstico, evaluación y tratamiento (AU)

Langerhans's cell histiocytosis (LCH) is an uncommon disease characterized by an accumulation of abnormal histiocytes, together lymphocytes and eosinophils in various organs and tissues. The head and neck are frequent sites of initial presentation. We present two cases of LCH with otorhinolaryngologic symptoms. Current recommendations for diagnosis, evaluation and treatment of LCH are also discussed (AU)

Mioepitelioma en glándulas salivares / Salivary gland myoepithelioma

Los mioepiteliomas son tumores poco frecuentes (menos del 1 por ciento de la patología tumoral) y se localizan principalmente en parótida y glándulas salivares menores del paladar. Describimos las características histológicas e inmunohistoquímicas de este tipo de tumores a propósito de 2 casos intervenidos en nuestro Servicio de ORL (AU)

Myoepithelioma is a rare salivary gland tumor (less than 1%) which are usually located in parotid gland and minor salivary glands. Histology and immunohistochemical features of this tumors are reviewed. We report 2 cases arising in parotid and hard palate (AU)

The National Health Service Corps for the 21st century.

The National Health Service Corps (NHSC) was created in 1970 to provide primary health care clinicians for the underserved. The article includes a review of the peer-reviewed and intragovernmental literature on the NHSC program from 1971 to 1998 and also presents a current profile of the program. Despite significant increases in NHSC field strength since 1991, the 2,439 clinicians meet only 12% of the need for primary health care providers in underserved areas. While the NHSC has successfully addressed clinician diversity and retention issues, community and site development remain barriers to increasing access. Most communities in need are not ready to recruit and support clinicians. The NHSC of the next millennium must work with the neediest communities to reach the appropriate stage of readiness. Only after completing the necessary "preplacement" activities can the NHSC assist in the recruitment and placement of clinicians to increase access.

Effects of estrous cyclicity on the expression of the galanin receptor Gal-R1 in the rat preoptic area: a comparison with the male.

Variations in the number of galanin receptor (Gal-R1)-expressing cells and levels of Gal-R1 messenger RNA (mRNA) were determined in the preoptic area in intact female rats throughout the phases of the estrous cycle and compared with those in the male. Female and male Wistar rats were fixed by perfusion with 4% paraformaldehyde. Cryostat sections were hybridized with a 35S-labeled antisense Gal-R1 riboprobe. The number of Gal-R1 mRNA-expressing cells was lower in the rostral preoptic area than in the medial preoptic area. During the estrous cycle, the highest number of Gal-R1 mRNA-expressing cells in the rostral preoptic region was detected at 0800 h on proestrus, whereas in the medial preoptic area, the maximum number was observed at 1800 h on estrus. Gal-R1 mRNA levels in individual cells were low during diestrus and increased at estrus in both areas. In the male, the number of mRNA-expressing cells and the hybridization signal were significantly lower than those in females during estrus. The results demonstrate that Gal-R1 gene expression in the preoptic area varies during the estrous cycle and is low in males. Short term treatment of ovariectomized rats with estradiol plus progesterone caused significantly decreased preoptic Gal-R1 mRNA levels compared with those after treatment with estrogen only. These observations suggest that in the preoptic area, expression of Gal-R1 is influenced by progesterone. The variation in Gal-R1 expression is likely to influence the extent to which galanin can influence the preoptic cells implicated in the control of neighboring GnRH cells.

Permanent exposure of mucin-secreting HT-29 cells to benzyl-N-acetyl-alpha-D-galactosaminide induces abnormal O-glycosylation of mucins and inhibits constitutive and stimulated MUC5AC secretion.

Previous work has shown that treatment of HT-29 methotrexate (MTX) cells with benzyl-N-acetyl-alpha-D-galactosaminide results in profound changes in mucin oligosaccharide chains. To analyse in depth the effect of this drug, we first determined the structure of mucin oligosaccharide chains synthesized by HT-29 MTX cells and the changes induced by permanent drug exposure. Mucins from untreated cells contained nine monosialylated structures (core types 1, 2, 3 and 4) and four disialylated structures (types 1, 2 and 4). Core 1 structures predominated, in particular NeuAcalpha2-3Galbeta1-3GalNAc-ol. Exposure of HT-29 MTX cells to benzyl-N-acetyl-alpha-D-galactosaminide from days 2-21 resulted in a decrease in intracellular mucins and both their sialic acid and galactose content, and an increased T (Galbeta1-3GalNAcalpha-O-Ser/Thr) and Tn (GalNAcalpha-O-Ser/Thr) antigenicity. A 3-fold increase in both Galbeta1-3GalNAc alpha2, 3-sialyltransferase activity and mRNA expression was detected. At the ultrastructural level, T-antigen was not detectable in mucin droplets in control cells, but was strongly expressed in intracytoplasmic vesicles in treated cells. In these cells, MUC1 and MUC3 transcripts were up-regulated, whereas MUC2, MUC5B and MUC5AC were down-regulated. Furthermore, constitutive and secretagogue-induced MUC5AC secretion was reduced and no mucus layer was detected. In conclusion, benzyl-N-acetyl-alpha-D-galactosaminide induces abnormal O-glycosylation and altered regulation of MUC5AC secretion.

GalNAc-alpha-O-benzyl inhibits NeuAcalpha2-3 glycosylation and blocks the intracellular transport of apical glycoproteins and mucus in differentiated HT-29 cells.

Exposure for 24 h of mucus-secreting HT-29 cells to the sugar analogue GalNAc-alpha-O-benzyl results in inhibition of Galbeta1-3GalNAc:alpha2,3-sialyltransferase, reduced mucin sialylation, and inhibition of their secretion (Huet, G., I. Kim, C. de Bolos, J.M. Loguidice, O. Moreau, B. Hémon, C. Richet, P. Delannoy, F.X. Real., and P. Degand. 1995. J. Cell Sci. 108:1275-1285). To determine the effects of prolonged inhibition of sialylation, differentiated HT-29 populations were grown under permanent exposure to GalNAc-alpha-O-benzyl. This results in not only inhibition of mucus secretion, but also in a dramatic swelling of the cells and the accumulation in intracytoplasmic vesicles of brush border-associated glycoproteins like dipeptidylpeptidase-IV, the mucin-like glycoprotein MUC1, and carcinoembryonic antigen which are no longer expressed at the apical membrane. The block occurs beyond the cis-Golgi as substantiated by endoglycosidase treatment and biosynthesis analysis. In contrast, the polarized expression of the basolateral glycoprotein GP 120 is not modified. Underlying these effects we found that (a) like in mucins, NeuAcalpha2-3Gal-R is expressed in the terminal position of the oligosaccharide species associated with the apical, but not the basolateral glycoproteins of the cells, and (b) treatment with GalNAc-alpha-O-benzyl results in an impairment of their sialylation. These effects are reversible upon removal of the drug. It is suggested that alpha2-3 sialylation is involved in apical targeting of brush border membrane glycoproteins and mucus secretion in HT-29 cells.