Circulating L-arginine predicts the survival of cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the systemic approach to cancer treatment. Most patients receiving ICIs, however, do not derive benefits. Therefore, it is crucial to identify reliable predictive biomarkers of response to ICIs. One important pathway in regulating immune cell reactivity is L-arginine (ARG) metabolism, essential to T-cell activation. We therefore aimed to evaluate the association between baseline plasma ARG levels and the clinical benefit of ICIs. PATIENTS AND METHODS: The correlation between ARG levels and clinical ICI activity was assessed by analyzing plasma samples obtained before treatment onset in two independent cohorts of patients with advanced cancer included in two institutional molecular profiling programs (BIP, NCT02534649, n = 77; PREMIS, NCT03984318, n = 296) and from patients in a phase 1 first-in-human study of budigalimab monotherapy (NCT03000257). Additionally, the correlation between ARG levels and ICI efficacy in preclinical settings was evaluated using a syngeneic mouse model of colorectal cancer responsive to ICIs. Using matched peripheral blood mononuclear cell (PBMC) plasma samples, we analyzed the correlation between ARG levels and PBMC features through multiplexed flow cytometry analysis. RESULTS: In both discovery and validation cohorts, low ARG levels at baseline (<42 µM) were significantly and independently associated with a worse clinical benefit rate, progression-free survival, and overall survival. Moreover, at the preclinical level, the tumor rejection rate was significantly higher in mice with high baseline ARG levels than in those with low ARG levels (85.7% versus 23.8%; P = 0.004). Finally, PBMC immunophenotyping showed that low ARG levels were significantly associated with increased programmed death-ligand 1 expression in several immune cell subsets from the myeloid lineage. CONCLUSIONS: We demonstrate that baseline ARG levels predict ICI response. Plasma ARG quantification may therefore represent an attractive biomarker to tailor novel therapeutic regimens targeting the ARG pathway in combination with ICIs.

Dynamics of clinical biomarkers as predictors of immunotherapy benefit in metastatic melanoma patients

Purpose Baseline LDH, derived neutrophil–lymphocyte ratio (dNLR) and immune-related adverse events (irAEs) are associated with outcomes of patients with metastatic melanoma (MM). We hypothesized whether dynamic shifts in LDH, dNLR and incidence of irAEs may impact the prognosis of MM patients treated with anti-CTLA4 or anti-PD1 as single agents. Methods Retrospective analysis of medical charts from MM patients with prospective monitoring of dNLR, LDH values and irAE incidence. Primary endpoint was overall survival (OS).Results Patients switching from either high dNLR (≥2.5) to low dNLR (HR: 0.14; 0.03–0.74; p = 0.02) or high LDH (≥1.5 × ULN) to low LDH levels (HR: 0.08; 0.01–0.68; p = 0.02) had significantly better OS than those with high dNLR or LDH scores at the end of cycle 2. Longer OS was also observed in patients developing irAEs ≥ grade 2 as compared to no irAEs (HR: 0.2; 0.05–0.89; p = 0.03).Conclusions We found that major shifts in dNLR and LDH measures from baseline to cycle 2 measures and shifts from baseline to cycle 2 are significantly associated with OS in MM patients receiving single agent anti-PD1 therapy. Laboratory changes and clinical variables may help optimize prognostic estimates. (AU)

Dynamics of clinical biomarkers as predictors of immunotherapy benefit in metastatic melanoma patients.

PURPOSE: Baseline LDH, derived neutrophil-lymphocyte ratio (dNLR) and immune-related adverse events (irAEs) are associated with outcomes of patients with metastatic melanoma (MM). We hypothesized whether dynamic shifts in LDH, dNLR and incidence of irAEs may impact the prognosis of MM patients treated with anti-CTLA4 or anti-PD1 as single agents. METHODS: Retrospective analysis of medical charts from MM patients with prospective monitoring of dNLR, LDH values and irAE incidence. Primary endpoint was overall survival (OS). RESULTS: Patients switching from either high dNLR (≥2.5) to low dNLR (HR: 0.14; 0.03-0.74; p = 0.02) or high LDH (≥1.5 × ULN) to low LDH levels (HR: 0.08; 0.01-0.68; p = 0.02) had significantly better OS than those with high dNLR or LDH scores at the end of cycle 2. Longer OS was also observed in patients developing irAEs ≥ grade 2 as compared to no irAEs (HR: 0.2; 0.05-0.89; p = 0.03). CONCLUSIONS: We found that major shifts in dNLR and LDH measures from baseline to cycle 2 measures and shifts from baseline to cycle 2 are significantly associated with OS in MM patients receiving single agent anti-PD1 therapy. Laboratory changes and clinical variables may help optimize prognostic estimates.

Functional analysis of young patients with desmoid-type fibromatosis: Initial surveillance does not jeopardize long term quality of life.

BACKGROUND: With recent conservative strategies, prognosis of patients with desmoid-type fibromatosis (DTF) is about function preservation. We analyzed the long-term quality of life (QoL) of pediatric patients with DTF. METHODS: All French young patients (<21years) treated between 2005 and 2016 for a DTF in the EpSSG NRSTS-05 study were analyzed. A first wait-and-see strategy was recommended. Patients' QoL was analyzed with the internationally validated Child Health Questionnaire (CHQ). We focused on the relevant subscales scores: physical functioning (PF), role social limitations physical (RP), bodily pain (BP), general health perception (GH) and physical (PhS) and psychosocial (PsS) summary measures. RESULTS: Among the 81 patients, 52 families answered the CHQ (median delay since diagnosis = 6.2years; min2.2-max13.3 years). Median age at diagnosis was 11.5 years. Primary site: limbs (52%), head/neck (27%), or trunk (21%). Five year-Progression Free Survival was 39.1% (95%CI: 27.7-50.5%). As initial management for these 52 patients, 30 patients were first observed (57%), 13 had surgery (25%) and 9 received chemotherapy (18%). Total burden of therapy was exclusive surgery (9pts/18%), exclusive chemotherapy (18pts/35%), surgery + chemotherapy (13pts/25%), chemotherapy + radiotherapy (1 pt), surgery + chemotherapy + radiotherapy (1 pt), wait and see (10 pt). Regarding the parent forms, patients have significant lower PF (86.0vs.96.1; p = 0.03), RP (82.0vs.93.6; p = 0.04), GH (60vs.73; p < 0.005) and PhS (46.2 vs.53; p = 0.02) scores compared to healthy population. Comparison of QoL subscales scores according to initial strategy (wait-and-see vs.surgery/chemotherapy) did not reveal any difference (PF = 87.3vs.84.9; p = 0.80/RP = 83.4vs.78.7; p = 0.72/BP = 78.9vs.78.2; p = 0.95/GH = 59.7vs60; p = 0.97). Similar results were found using the children or adult forms. CONCLUSIONS: Initial wait-and-see strategy does not affect long term functional impairment.

Cutaneous toxicities of new treatments for melanoma

New drugs against advanced melanoma have emerged during last decade. Target therapy and immunotherapy have changed the management of patients with metastatic disease. Along with its generalized use, drug toxicities have appeared and the skin is the target organ of a significant part of them. This revision summarizes the most common side effects and consensus management to improve the compliance of therapies and patients’ quality of life. Among the BRAF inhibitors, main cutaneous side effects are photosensitivity, plantar hyperkeratosis, and the appearance of verrucal keratosis or squamous cell carcinoma. Special attention must be paid to the development of new primary melanomas or changes on nevi during BRAF inhibitor therapy. The most common cutaneous side effects of immunotherapy are rash, pruritus, and vitiligo. It remains controversial the possible role of these toxicities as markers of response to therapy

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Cutaneous toxicities of new treatments for melanoma.

New drugs against advanced melanoma have emerged during last decade. Target therapy and immunotherapy have changed the management of patients with metastatic disease. Along with its generalized use, drug toxicities have appeared and the skin is the target organ of a significant part of them. This revision summarizes the most common side effects and consensus management to improve the compliance of therapies and patients' quality of life. Among the BRAF inhibitors, main cutaneous side effects are photosensitivity, plantar hyperkeratosis, and the appearance of verrucal keratosis or squamous cell carcinoma. Special attention must be paid to the development of new primary melanomas or changes on nevi during BRAF inhibitor therapy. The most common cutaneous side effects of immunotherapy are rash, pruritus, and vitiligo. It remains controversial the possible role of these toxicities as markers of response to therapy.

[Fortuitously discovered neutropenia in children: diagnosis and follow-up]. / Neutropénies de découverte fortuite chez l'enfant : diagnostic et suivi.

Neutropenia seems to be quite frequent in current pediatric practice and can confuse the clinician since it may result from a severe cause. The aim of this study was to provide a prospective description of episodes of neutropenia in children to assess its clinical relevance in a general pediatric cohort consulting and/or hospitalized in a French university hospital. In this prospective observational and monocentric study conducted from April 2012 to April 2013, we included all the patients under 18 years of age who presented neutropenia (defined as an absolute neutrophil count [ANC] below 1×10(9)/L before 1 year of age and below 1.5×10(9)/L beyond) on a whole blood count (WBC) performed in our hospital. Patients treated with chemotherapy were not included. Medical records were regularly checked for at least 1 year after inclusion, and clinical and biological data were collected prospectively to compare transient episodes of neutropenia (<3 months) with persistent episodes of neutropenia (>3months). Of 55,018 consultations and 13,967 hospitalizations (chemotherapy excluded), 8966 blood counts were performed and 250 episodes of neutropenia were found in 238 patients. Data concerning clinical progression were available in 195 cases of which 136 had at least one subsequent WBC. Two hundred thirty-one episodes corresponded to new episodes, while neutropenia preexisted before inclusion in the others. The median follow-up was 12.8 months. Most episodes of neutropenia occurred in children <2 years of age (52%), with a median age of 22.2 months. Mean ANC was 0.943×10(9)/L (±0.340) and a few episodes of neutropenia were below 0.5×10(9)/L (9.2%). Neutropenia persisted more than 3 months in only 13.2% of cases. When neutropenia was below 0.5×10(9)/L, it significantly persisted (RR=3.08; 95% CI [1.31-7.22]). Other factors associated with persistent neutropenia were thrombocytopenia, monocytopenia, a CRP more than 70mg/L, significant abnormality on the clinical exam, and age over 24 months. However, multivariate analysis showed that only an ANC below 0.5×10(9)/L was significantly associated with persistence. While etiology could not be determined in 32% of cases, neutropenia resulted mostly from infectious causes (37.8%), with other causes being more anecdotal. The majority of infectious episodes of neutropenia were viral (90.3%). Like other studies, this investigation suggests that most episodes of neutropenia concern young children, are transient, are benign and often due to infectious diseases. Although it may not reflect the medullar stock or the real capacity of neutrophils to fight bacterial infections, it seems that neutropenia below 0.5×10(9)/L is more likely to persist and be complicated, as previous studies also suggest. To conclude, neutropenia is not exceptional in children and, even if it often results from viral infections and mostly evolves favorably, the clinician should closely monitor these patients, especially when neutrophils are below 0.5×10(9)/L.

Evaluación de los márgenes quirúrgicos del carcinoma basocelular según la especialidad del cirujano / Evaluation of Surgical Margins in Basal Cell Carcinoma by Surgical Specialty

Introducción: El tratamiento más utilizado para el carcinoma basocelular (CBC) es la extirpación quirúrgica completa, que en muchas ocasiones es realizada por facultativos no dermatólogos (cirujanos plásticos, cirujanos generales, cirujanos maxilofaciales, oftalmólogos y otorrinolaringólogos). Objetivos: Determinar la prevalencia de márgenes quirúrgicos afectados por el CBC en función del especialista que lo interviene e identificar parámetros clínico-patológicos que puedan justificar las potenciales diferencias en estas prevalencias. Métodos: Estudio retrospectivo de los informes histológicos con diagnóstico de CBC del Hospital Universitari Vall d’Hebron entre enero de 2009 y marzo de 2010, con análisis descriptivo de las características clínico-patológicas y análisis estadístico y multivariable mediante regresión logística. Resultados: Se incluyeron 921 tumores de 750 pacientes. Los dermatólogos extirparon 549 lesiones. Los márgenes de la pieza quirúrgica estaban invadidos por el tumor en un 12,6% de las lesiones. La extirpación fue incompleta en un porcentaje significativamente menor de tumores intervenidos por dermatólogos frente a otros especialistas (6,7 vs 21,5%). El riesgo relativo de que queden márgenes afectados es 3,8 veces mayor si el cirujano no es dermatólogo, independientemente de la edad del paciente, la localización de la lesión, el diámetro máximo de la pieza extirpada y el subtipo histológico del tumor. Conclusiones: La correcta identificación macroscópica de los márgenes tumorales, muchas veces sutiles, y el conocimiento de la historia natural del CBC son claves para un adecuado abordaje quirúrgico; probablemente son los principales factores que justifican el mayor porcentaje de tumores con márgenes libres extirpados por los dermatólogos (AU)

Background: Complete surgical excision is the most common treatment for basal cell carcinoma(BCC), and this intervention is often performed by surgeons who are not dermatologists(e.g., plastic surgeons, general surgeons, oral and maxillofacial surgeons, ophthalmologists, and otorhinolaryngologists). Objectives: To determine positive margin rates in BCCs removed by surgeons from different specialties and to identify clinical and pathologic factors that might explain potential differences between specialties. Methods: We retrospectively reviewed the pathology reports of all BCCs diagnosed at Hospital Universitari Vall d’Hebron between January 2009 and March 2001. The statistical methods included a descriptive analysis of clinical and pathologic variables, standard statistical analyses, and multivariate logistic regression. Results: We included 921 BCCs from 750 patients; 549 of the tumors had been excised by a dermatologist. The overall positive margin rate was 12.6%, but the rate for tumors removed by dermatologists was significantly lower than that for those removed by other specialists (6.7%vs 21.5%). There was a 3.8-fold increased relative risk of positive margins following excision by a surgeon who was not a dermatologist, independently of patient age, tumor site, maximum diameter of the resected specimen, and histologic subtype. Conclusions: Accurate macroscopic identification of tumor margins, which are often difficult to see, and familiarity with the natural history of BCC are key factors in the successful surgical treatment of BCCs. The higher rate of tumor-free margins achieved by dermatologists in this study is probably mainly due to their greater experience in these 2 areas (AU)

Evaluation of surgical margins in Basal cell carcinoma by surgical specialty.

BACKGROUND: Complete surgical excision is the most common treatment for basal cell carcinoma (BCC), and this intervention is often performed by surgeons who are not dermatologists (e.g., plastic surgeons, general surgeons, oral and maxillofacial surgeons, ophthalmologists, and otorhinolaryngologists). OBJECTIVES: To determine positive margin rates in BCCs removed by surgeons from different specialties and to identify clinical and pathologic factors that might explain potential differences between specialties. METHODS: We retrospectively reviewed the pathology reports of all BCCs diagnosed at Hospital Universitari Vall d'Hebron between January 2009 and March 2001. The statistical methods included a descriptive analysis of clinical and pathologic variables, standard statistical analyses, and multivariate logistic regression. RESULTS: We included 921 BCCs from 750 patients; 549 of the tumors had been excised by a dermatologist. The overall positive margin rate was 12.6%, but the rate for tumors removed by dermatologists was significantly lower than that for those removed by other specialists (6.7% vs 21.5%). There was a 3.8-fold increased relative risk of positive margins following excision by a surgeon who was not a dermatologist, independently of patient age, tumor site, maximum diameter of the resected specimen, and histologic subtype. CONCLUSIONS: Accurate macroscopic identification of tumor margins, which are often difficult to see, and familiarity with the natural history of BCC are key factors in the successful surgical treatment of BCCs. The higher rate of tumor-free margins achieved by dermatologists in this study is probably mainly due to their greater experience in these 2 areas.

Direct visualization of retinoic acid in the rat hypothalamus: an immunohistochemical study.

In order to increase our knowledge about the distribution of vitamins in the mammalian brain, we have developed a highly specific antiserum directed against retinoic acid with good affinity (10(-8) M), as evaluated by ELISA tests. In the rat brain, no immunoreactive fibers containing retinoic acid were detected. Cell bodies containing retinoic acid were only found in the hypothalamus. This work reports the first visualization and the morphological characteristics of cell bodies containing retinoic acid in the mammalian paraventricular hypothalamic nucleus and in the dorsal perifornical region, using an indirect immunoperoxidase technique. The restricted distribution of retinoic acid in the rat brain suggests that this vitamin could be involved in very specific physiological mechanisms.

Pitiriasis rubra pilaris aguda postinfecciosa: una dermatosis mediada por superantígenos / Acute Postinfectious Pityriasis Rubra Pilaris: A Superantigen-Mediated Dermatosis

La pitiriasis rubra pilaris (PRP) aguda post infecciosa es una variante de la forma juvenil de PRP (tipo III de Griffiths) caracterizada por la ausencia de antecedentes familiares, curso agudo relacionado con un episodio febril previo y buen pronóstico. Clínicamente puede simular otras enfermedades mediadas por superantígenos, como los exantemas escarlatiniformes o el síndrome de la escaldadura estafilocócica; sin embargo, su histología y tratamiento son distintos. Presentamos 4 casos de PRP aguda post infecciosa que ilustran las características clínicas de este proceso infrecuente y revisamos los posibles mecanismos fisiopatogénicos subyacentes (AU)

Acute postinfectious pityriasis rubra pilaris (PRP) is a variant of juvenile PRP (Griffiths type III) characterized by no family history, an acute course associated with a prior fever, and good prognosis. Clinical features may resemble other superantigen-mediated diseases, such as scarlatiniform rash or staphylococcal scalded skin syndrome, but its histology and treatment are different. We present 4 cases of acute postinfectious PRP that illustrate the clinical features of this uncommon disease and we review possible underlying pathogenic mechanisms (AU)

[Acute postinfectious pityriasis rubra pilaris: a superantigen-mediated dermatosis]. / Pitiriasis rubra pilaris aguda postinfecciosa: una dermatosis mediada por superantígenos.

Acute postinfectious pityriasis rubra pilaris (PRP) is a variant of juvenile PRP (Griffiths type III) characterized by no family history, an acute course associated with a prior fever, and good prognosis. Clinical features may resemble other superantigen-mediated diseases, such as scarlatiniform rash or staphylococcal scalded skin syndrome, but its histology and treatment are different. We present 4 cases of acute postinfectious PRP that illustrate the clinical features of this uncommon disease and we review possible underlying pathogenic mechanisms.

[Cerebrotendinous xanthomatosis: report of 4 patients]. / Xantomatosis cerebrotendinosa: descripción de 4 casos.

Cerebrotendinous xanthomatosis (CTX) is an uncommon autosomal recessive disease caused by mutation of the CYP27A1 gene. It is characterized by the presence of xanthomas in different tissues, principally brain and tendon, due to the accumulation of beta-cholestanol. Diagnosis is confirmed by measurement of serum beta-cholestanol and urinary bile alcohol levels. Therapy with chenodeoxycholic acid has been shown to be the most effective treatment and can halt progression of the disease. We present 4 patients with a history of neurological disorders since childhood and who were diagnosed with CTX after developing tendon xanthomas. Although diagnostic suspicion depends to a large extent on recognition of tendon xanthomas, these are not an early sign of the disease, which can present with neurological disorders, cataracts, and chronic diarrhea. Early diagnosis of CTX therefore rests on measurement of serum beta-cholestanol levels, even in absence of tendon xanthomas.

Vitamins in the monkey brain: An immunocytochemical study.

Using highly specific antisera directed against vitamins, the distribution of pyridoxal-, pyridoxine-, vitamin C- and nicotinamide-immunoreactive structures in the monkey (Macaca fascicularis) brain was studied. Neither immunoreactive structures containing pyridoxine or nicotinamide, nor immunoreactive fibers containing vitamin C were found in the monkey brain. However, this work reports the first visualization and the morphological characteristics of pyridoxal- and vitamin C-immunoreactive cell bodies in the mammalian central nervous system using an indirect immunoperoxidase technique. A high density of pyridoxal-immunoreactive cell bodies was found in the paraventricular hypothalamic nucleus and in the supraoptic nucleus and a low density of the same was observed in the periventricular hypothalamic region, whereas a moderate density of vitamin C-immunoreactive cell bodies was observed in the somatosensorial cortex (precentral gyrus). Immunoreactive fibers containing pyridoxal were only visualized in the anterior commissure. The restricted distribution of pyridoxal and vitamin C in the monkey brain suggests that both vitamins could be involved in very specific physiological mechanisms.

Xantomatosis cerebrotendinosa: descripción de 4 casos / Cerebrotendunous Xanthomatosis: report of 4 patients

La xantomatosis cerebrotendinosa (XCT) es una enfermedad hereditaria infrecuente causada por la mutación del gen CYP27A1. Es característica la aparición de xantomas en diferentes tejidos, principalmente en el cerebro y los tendones, secundarios al depósito de -colestanol. El diagnóstico se confirma mediante la determinación de -colestanol en suero, y de los alcoholes biliares en orina. El ácido quenodesoxicólico es la terapia más eficaz, pudiendo llegar a frenar la progresión de la enfermedad. Presentamos 4 pacientes con alteraciones neurológicas desde la infancia que fueron diagnosticados de XCT tras el desarrollo de xantomas tendinosos. El reconocimiento de los xantomas tendinosos es fundamental para orientar el diagnóstico de XCT, pero estos no son un signo inicial de la enfermedad, que debuta con alteraciones neurológicas, cataratas o diarrea crónica. Por lo tanto, el diagnóstico temprano de la XCT requiere la determinación del -colestanol sérico en estos pacientes, aun en ausencia de xantomas (AU)

Cerebrotendinous xanthomatosis (CTX) is an uncommon autosomal recessive disease caused by mutation of the CYP27A1 gene. It is characterized by the presence of xanthomas in different tissues, principally brain and tendon, due to the accumulation of -cholestanol. Diagnosis is confirmed by measurement of serum -cholestanol and urinary bile alcohol levels. Therapy with chenodeoxycholic acid has been shown to be the most effective treatment and can halt progression of the disease. We present 4 patients with a history of neurological disorders since childhood and who were diagnosed with CTX after developing tendon xanthomas. Although diagnostic suspicion depends to a large extent on recognition of tendon xanthomas, these are not an early sign of the disease, which can present with neurological disorders, cataracts, and chronic diarrhea. Early diagnosis of CTX therefore rests on measurement of serum -cholestanol levels, even in absence of tendon xanthomas (AU)

Postoperative pyoderma gangrenosum: diagnostic value of 16s ribosomal RNA sequencing and review of the literature.

BACKGROUND: Pyoderma gangrenosum (PG) is an uncommon condition, but can lead to the diagnosis of an underlying systemic disease. It can appear spontaneously or as a result of the pathergy phenomenon after trauma or surgery. METHODS: We review three patients with postoperative PG (PPG) and the relevant literature. We also report an accurate method for microbial detection by 16S ribosomal (r)RNA sequencing. RESULTS: A 47-year-old woman and two men aged 54 and 48 years, respectively, presented with sterile ulcerations after surgery. Associated conditions (Crohn's disease and leukaemia) were present. Surgical wound infection was suspected and systemic empirical antibiotics were prescribed. After infection was excluded, PPG was diagnosed and corticosteroids were started. DISCUSSION: PPG should be considered in the differential diagnosis of postsurgical wound complications. Recognition of this condition may prevent unnecessary administration of antimicrobial treatment and development of more extensive ulcerations. It may also be the clue for the diagnosis of an underlying systemic disease. We discuss the usefulness of 16S rRNA sequencing for microbial detection and identification in order to exclude a causative infection in patients who have previously received antibiotic treatment.

Evaluation of the effects of a new drug candidate (GEMSP) in a chronic EAE model.

Chronic Experimental Autoimmune Encephalomyelitis (EAE) was induced in rats to evaluate a new drug candidate (GEMSP) for the treatment of multiple sclerosis. This work is a part of preclinical studies on GEMSP, which is made up of fatty acids, vitamins and amino acids or their derivatives; all these compounds were linked to Poly-L-Lysine. In order to evaluate the effects of GEMSP, animals were divided into three experimental groups: 1) EAE rats treated with GEMSP; 2) EAE rats treated with NaCl; and 3) non-EAE rats. Using immunocytochemical techniques with a pan-leukocyte marker (anti-CD 45), differential leukocyte infiltration was compared in the central nervous systems of the different experimental groups. Antibodies directed against a component of GEMSP, the conjugated methionine, were used in all three groups. We found that: 1) GEMSP was effective in abolishing EAE. The crises and clinical scores were completely abolished in the animals of the first group, but not in the animals belonging to the second group; 2) the degree of leukocyte infiltration varied, depending on the different EAE stages, but was not related to the clinical score; and 3) after using anti-conjugated methionine antibodies, we observed immunoreactivity only in the motoneurons of the ventral horn of the spinal cord in the animals of the first group. This immunoreactivity was not found in the animals of the second or third groups. No methionine immunoreactivity was found in the brain. Our results suggest that GEMSP may be a potential drug candidate against the pathogenic processes involved in multiple sclerosis, inhibiting EAE episodes and brain leukocyte infiltration. Our results also show that one component of GEMSP, the methionine compound, is stored inside motoneurons. The possible physiological actions of GEMSP on spinal cord motoneurons are discussed.

Immunocytochemical visualization of D-glutamate in the rat brain.

Using highly specific antisera directed against conjugated d-amino acids, the distribution of d-glutamate-, d-tryptophan-, d-cysteine-, d-tyrosine- and d-methionine-immunoreactive structures in the rat brain was studied. Cell bodies containing d-glutamate, but not d-glutamate-immunoreactive fibers, were found. Perikarya containing this d-amino acid were only found in the mesencephalon and thalamus of the rat CNS. Thus, the highest density of cell bodies containing d-glutamate was observed in the dorsal raphe nucleus, the ventral part of the mesencephalic central gray, the superior colliculus, above the posterior commissure, and in the subparafascicular thalamic nucleus. A moderate density of immunoreactive cell bodies was observed in the dorsal part of the mesencephalic central gray, above the rostral linear nucleus of the raphe, the nucleus of Darkschewitsch, and in the medial habenular nucleus, whereas a low density was found below the medial forebrain bundle and in the posterior thalamic nuclear group. Moreover, no immunoreactive fibers or cell bodies were visualized containing d-tryptophan, d-cysteine, d-tyrosine or d-methionine in the rat brain. The distribution of d-glutamate-immunoreactive cell bodies in the rat brain suggests that this d-amino acid could be involved in several physiological mechanisms. This work reports the first visualization and the morphological characteristics of conjugated d-glutamate-immunoreactive cell bodies in the rat CNS using an indirect immunoperoxidase technique. Our results suggest that the immunoreactive neurons observed have an uptake mechanism for d-glutamate.

Effects of GSM-900 microwaves on the experimental allergic encephalomyelitis (EAE) rat model of multiple sclerosis.

The effects of acute exposure to GSM-900 microwaves (900 MHz, 217 Hz pulse modulation) on the clinical parameters of the acute experimental allergic encephalomyelitis (EAE) model in rats were investigated in two independent experiments: rats were either habituated or nonhabituated to the exposure restrainers. EAE was induced with a mixture of myelin basic protein and Mycobacterium tuberculosis. Female Lewis rats were divided into cage control, sham exposed, and two groups exposed either at 1.5 or 6.0 W/kg local specific absorption rate (SAR averaged over the brain) using a loop antenna placed over their heads. There was no effect of a 21 day exposure (2 h/day) on the onset, duration, and termination of the EAE crisis.