The Complex Interplay Between Trait Fatigue and Cognition in Multiple Sclerosis.

Cognitive impairments are frequent in patients with Multiple Sclerosis (MS). Yet, the influence of MS-related symptoms on cognitive status is not clear. Studies investigating the impact of trait fatigue along with anxio-depressive symptoms on cognition are seldom, and even less considered fatigue as multidimensional. Moreover, these studies provided conflicting results. Twenty-nine MS patients and 28 healthy controls, matched on age, gender and education underwent a full comprehensive neuropsychological assessment. Anxio-depressive and fatigue symptoms were assessed using the HAD scale and the MFIS, respectively. Six composite scores were derived from the neuropsychological assessment, reflecting the cognitive domains of working memory, verbal and visual learning, executive functions, attention and processing speed. Stepwise regression analyses were conducted in each group to investigate if trait cognitive and physical fatigue, depression and anxiety are relevant predictors of performance in each cognitive domain. In order to control for disease progression, patient's EDSS score was also entered as predictor variable. In the MS group, trait physical fatigue was the only significant predictor of working memory score. Cognitive fatigue was a predictor for executive functioning performance and for processing speed (as well as EDSS score for processing speed). In the healthy controls group, only an association between executive functioning and depression was observed. Fatigue predicted cognition in MS patients only, beyond anxio-depressive symptoms and disease progression. Considering fatigue as a multidimensional symptom is paramount to better understand its association with cognition, as physical and cognitive fatigue are predictors of different cognitive processes.

Implicit learning of two artificial grammars.

This study investigated the implicit learning of two artificial systems. Two finite-state grammars were implemented with the same tone set (leading to short melodies) and played by the same timbre in exposure and test phases. The grammars were presented in separate exposure phases, and potentially acquired knowledge was tested with two experimental tasks: a grammar categorization task (Experiment 1) and a grammatical error detection task (Experiment 2). Results showed that participants were able to categorize new items as belonging to one or the other grammar (Experiment 1) and detect grammatical errors in new sequences of each grammar (Experiment 2). Our findings suggest the capacity of intra-modal learning of regularities in the auditory modality and based on stimuli that share the same perceptual properties.

[Macrocephalic spermatozoa. What would be the impact on reproduction?]. / Les spermatozoïdes macrocéphales. Quels risques pour la fonction de reproduction ?

OBJECTIVE: We want to highlight the risk of infertility and failure of Assisted Reproductive Technologies due to the presence of macrocephalic spermatozoa (MS) in the sperm at rate equalling or superior to 20% in at least one semen analysis. PATIENTS AND METHODS: We did a retrospective analysis of 19 infertile patients presenting MS at average rate between 14.3 and 49.7%. For each patient, at least one semen analysis showed a MS rate equal or superior to 20%. We did an automated analysis of the spermatozoa surface for 13 patients and a detailed analysis of the MS morphology in 18 patients. Thirteen couples benefited of one or more IVF with or without ICSI. RESULTS: The semen analysis shows an impairment of one or more parameter of the sperm in all patients. Three morphological aspects for MS were highlighted: MS with irregular head, MS with regular head, and MS with multiple heads, with a dominance of irregular heads. The spermatozoa surface analysis shows a significant increase of the average surface and of the standard deviation (p<0.0001). The average rate of pregnancies by transfer is decreased compared to usual rates in our laboratories (13% versus 28%). DISCUSSION AND CONCLUSION: We want to sensitize biologist and clinical doctors to the existence of partial forms of this syndrome, which could be related to infertility with impaired sperm parameters and low pregnancy rates after FIV or ICSI.

An original accelerated radiotherapy schedule in stage III to IV head and neck cancers. Results in a multicenter setting.

BACKGROUND: Accelerated radiotherapy delivery has recently been shown to be effective in overcoming repopulation during fractionated radiotherapy. The therapeutic ratio may be particularly favorable for 5-week regimens. This study reports the feasibility and results of a particular accelerated schedule in Stage III to IV head and neck carcinomas used in a multicenter setting. PATIENTS AND METHODS: Seventy-four patients with Stage III (26 patients) or IV (48 patients) head and neck carcinomas were treated with a 5-week accelerated schedule (69.6 to 69.8 Gy in 41 to 40 fractions over a period of 35 to 36 days). Treatment began with 20 Gy in 10 daily fractions to initial involved sites, followed by bi-fractionated radiotherapy (2 x 1.6 Gy to 1.66 Gy/day) to a larger head and neck volume. Thirty-six (49%) patients received induction chemotherapy (median 3 cycles, range 1 to 4 cycles). RESULTS: Grade 3 or 4 (RTOG) confluent mucositis was observed in 57 patients (77%) and Grade 3 dysphagia in 33 patients (44%). Grade 3 or 4 (RTOG-EORTC) late complications were scored in 10.5% of cases. The 5-year actuarial locoregional control rate was 56% (95% CI: 42 to 71). The 5-year overall actuarial survival was 32% (95% CI: 18 to 46). Induction chemotherapy was not associated with a more favorable outcome. CONCLUSIONS: This study demonstrates the feasibility of this schedule in a multicenter setting. The oncologic results appear similar to those obtained by other accelerated regimens, while the rate of late complications seems acceptable. Five-week accelerated regimens warrant further evaluation, particularly in conjunction with concomitant chemotherapy, in the framework of prospective trials.

Double-blind, randomized clinical study comparing hyaluronic acid cream to placebo in patients treated with radiotherapy.

PURPOSE: The effect of hyaluronic acid (Ialugen cream) on acute skin reactions after radiotherapy, was assessed in a randomized, double-blind, placebo-controlled study. MATERIAL AND METHODS: Out of the 152 patients presenting with head and neck, breast or pelvic carcinomas and registered in the study, 134 cases-70 in the Ialugen group (IA) and 64 in the placebo group (PBO)-completed their IA or PBO treatment. At the time of randomisation, these two groups were balanced for sex, age, weight and height. The mean total dose of radiation given during the study was 60.6 +/- 10.9 Gy in the IA group and 64.3 +/- 10.8 Gy in the PBO group (P = 0.47). RESULTS: Acute radio-epithelitis scores were significantly higher in the PBO group than in the IA group, starting from the control at week 3 and throughout the 6 weeks of treatment (P < 0.01 from week 3 to week 7; P < 0.05 at weeks 8 and 10). Likewise, the global efficacy judgement expressed, at the end of treatment, by both the physician and the patient showed a significant difference in favour of Ialugen (P < 0.01 and P < 0.05, respectively). There was no significant difference of tolerance between the IA and PBO treatments (P = 0.18 according to the physician and P = 0.42 from the patient's viewpoint). CONCLUSION: The prophylactic use of a cream with hyaluronic acid is shown to reduce the incidence of high grade radio-epithelitis, suggesting an interesting role of the hyaluronic acid cream as supportive treatment to improve compliance and quality of life in patients undergoing radiation therapy.

Early and long-term results of an original accelerated radiation therapy schedule in head and neck carcinoma.

From November 1985 until October 1988, 39 patients with head and neck carcinoma (6 patients stage I-II and 33 stage III-IV) were treated with an accelerated radiotherapy schedule designed to deliver 69.6 Gy over a period of 5 weeks. Treatment was started with 20 Gy in 10 daily fractions to sites of initial macroscopic involvement, followed by bi-fractionated radiotherapy (2 x 1.6 Gy/day) to a larger head and neck volume. Twenty patients received neo-adjuvant chemotherapy. A homolateral radical neck dissection was performed in 2 patients. Twenty-six patients (66.6%) presented with acute grade 3 complications and 5 patients (13%) with grade 4 complications. Thirteen patients (33.3%) were hospitalized for supportive care. None of the patients who were evaluated on a long-term basis developed grade 3 or 4 late complications. The 5-year loco-regional control and overall survival rates were 62.4% and 33.6% respectively. Although acute toxicity is higher than in monofractionated schedules, it is manageable, and can be considered acceptable in the light of the apparently good loco-regional control thus obtained. This schedule is one of several accelerated radiotherapy programs which might merit study in prospective trials.

Study of the vesicles released during conservation of red cells.

The purpose of this study was to determine the protein composition of the vesicles released from senescent erythrocytes and its variation during their experimental conservation at +4 degrees C in citrate phosphate dextrose (CPD), over a period of 8 weeks. Techniques employed included electron microscopy, SDS-PAGE and immunoblotting. Electron microscopic observation of senescent erythrocytes showed the simultaneous release of one or several vesicles of varying size and shape, while close examination of individual vesicles revealed a slack membrane structure and the presence of band 3 protein. SDS-PAGE and immunoblotting showed the vesicles to be composed mainly of band 3 and its breakdown products and to be lacking in spectrin. Use of specific antibodies demonstrated the presence of free haemoglobin, immunoglobulin G (IgG) and fragment C3b of complement. During conservation for 8 weeks, the concentration of band 3 protein decreased, while the concentrations of IgG and C3b increased and there was no apparent variation in haemoglobin levels.

Chronology of the formation of vesicles and membrane protein aggregates during erythrocyte aging.

The aim of the present work was to study the changes undergone by proteins in ghost cells, vesicles and membrane protein aggregates during erythrocyte aging. As a model of cell, whole blood collected into CPD was stored for eight weeks at +4 degrees C. SDS-PAGE and immunoblotting with antibodies against spectrin and band 3 showed that vesicles were mainly composed of band 3 and were devoid of spectrin, whereas membrane protein aggregates contained several membrane proteins but in a more advanced state of degradation. A study of spectrin and band 3 in the ghosts, vesicles and protein aggregates revealed increasing fragmentation of both proteins with storage time. Since this degradation was most important in membrane protein aggregates, it was possible to establish the chronological order of appearance of vesicles and aggregates. In view of our observations, we propose that membrane protein aggregates may be regarded as replacement structures resulting from membrane rearrangements occurring after the emission of vesicles.

Comparison of six serum ferritin immunoassays and isoferritin spectrotypes in malignancies.

Serum ferritin was measured by six enzyme immunoassays in specimens from patients with digestive cancers (n = 30) and hematologic malignancies (n = 33). Most mean comparisons show significant differences in both groups of patients. In digestive cancers correlations between any two methods are very satisfactory (r > 0.99) but a proportional bias is often observed. In hematologic malignancies, correlations are bad (r < 0.80 in 8 out of 15 correlations) because of many discrepant values. Isoelectric focusing separation of isoferritins was performed in most specimens and the pattern of each serum was compared to the between kit CV. We conclude that an 'acid' spectrotype increases between-kit analytical variability. We try to explain the results taking into account the nature of the immunological systems and the cross-reactions with tissular isoferritins. In conclusion, our results indicate that large differences may be observed in sera from hematologic malignancies (leukemias, lymphomas ... ) We recommend that monitoring be achieved by the same method of measurement.

[Respective value of glycated hemoglobin and fructosamine assays in the care of diabetes mellitus]. / Intérêts respectifs des dosages d'hémoglobine glyquée et de fructosamines dans la surveillance du diabète sucré.

The monitoring of metabolic balance in diabetes mellitus involves the assay of cumulative markers of protein glycation. Glycated hemoglobin, particularly the major component HbA1c, and fructosamine, which reflects glycated plasma protein levels, are the most commonly used parameters. Nevertheless, their utilization is still under discussion with respect to methodologies used, as well as to their respective interest in clinical diabetology. This review shows current opinion concerning the analytical and physiopathological use of these biological indicators.

[Actinic myelitis: diagnosis and treatment]. / La myélite actinique: diagnostique et traitement.

Spinal cord damage is one of the main dose limiting processes in radiation therapy. Radiation myelopathy was first observed in 1941, but it was only in the early 1980s that more clear information on tolerance was available. Animal experimentation in particular has thrown light on pathogenesis and factors playing a role in this pathology. Total dose, dose per fraction, age at irradiation, and interval between fractions are some of the main factors influencing this tolerance. From the literature the risk of progressive chronic radiation myelitis in man is estimated at less than 5%, with doses of 45-50 Gy in 1.8 to 2 Gy per fraction. The risk increases markedly with total dose and dose per fraction increase, and decreasing age. Cases of radiation myelitis are usually due to gross overdosage due to technical errors. More recently hyperfractionated accelerated schedules have occasioned major concern, with several unexpected myelopathies. Total cord dose using the alpha/beta model had appeared safe. Insufficient inter-fraction time (3-4 hours) is therefore likely to be the cause of the cases observed. Long half time for repair (underestimated in the LQ model) of sublethal damage resulting from slow tissue turnover is the most likely underlying mechanism. Morphological alterations are predominantly in white matter: lesions may be partial, focal or reaching total demyelinisation, with necrosis and malacia. Vascular damage may or may not be present. A dual pathogenesis is postulated. Oligodendrocytes and endothelial cells are the most likely target cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary cerebral lymphoma. A retrospective study of 27 cases.

PURPOSE: Primary cerebral lymphoma is a rare disease. The aim of this study is to compare the survival of the patients treated with radiotherapy alone vs. patients treated with a combined schedule of radio-chemotherapy. Our results will be compared with currently published data and main prognostic factors will be briefly discussed. PATIENTS AND METHODS: Between 1974 and 1990, 27 cases of primary cerebral lymphoma were diagnosed at our institution. All patients had biopsy-proven disease, the pathology of which was reviewed for this study. RESULTS: The overall median survival time was 24 months and one-, two- and three-year overall survival was 59, 46 and 29% respectively. The median radiation dose was 46 Gy, ranging from 19.5 to 60 Gy. The median dose per fraction was 2 Gy (ranging from 1.61 to 3 Gy). The median elapsed treatment time was 32 days (ranging from three to 45 days). We were not able to demonstrate any statistically significant difference between patients who received radiotherapy alone (n = 14, median survival time = 24 months) and those who received a combination of chemotherapy and radiotherapy (n = 11, median survival time = 30 months), (p = 0.4). Prognostic factors of survival were tested using a univariate analysis (Wilcoxon test). Parameters such as mass appearance (unilobular, p = 0.048), performance status at the time of the diagnosis (0 to 1, p = 0.014), and CT imaging (hypodense, p = 0.043) influenced positively survival. Centroblastic histology (Kiel) was found associated with a negative prognosis (p = 0.043). CONCLUSION: In our experience, there is no statistically significant difference of survival between patients treated with radiotherapy alone or with a combined treatment of radio-chemotherapy. Other prognostic factors of survival were discovered, although the analysis was univariate, due to the limited number of patients. Multicentric prospective studies should be elaborated in order to optimize the treatment of this disease.

[Glycated hemoglobin: assay methods and problems of standardization]. / Hémoglobine glyquée: méthodes de dosage et problèmes de standardisation.

Glycated hemoglobin can be assayed by methods using different principles, whose performances vary and are difficult to control. The most widely used techniques measure either specifically glycated A1c hemoglobin (HbA1c) or total glycated hemoglobin. They are reviewed in detail in this paper and standardization problems due to the absence of reference materials and methods are discussed. HbA1c seems to be considered the most significant parameter for monitoring diabetic control. Standardization of the assays, calibrated with reference to this parameter, could be performed provided there is strict control of the methods performance.

[Multicenter study of sialic acid deficient transferrin determined by two chromatographic techniques]. / Etude multicentrique du dosage de la transferrine déficiente en acide sialique par deux techniques chromatographiques.

Serum carbohydrate-deficient-transferrin (CDT) was measured by a micro anion-exchange chromatography/enzyme immunoassay. Results obtained on 245 sera analyzed in four laboratories were compared. Moreover, one laboratory used a commercial kit with ready-to-use microcolumns and a radioimmunoassay for measuring eluted CDT. Imprecision was judged to be satisfactory. Within-assay coefficients of variation ranged from 5 to 10%, between-assay coefficients of variation ranged from 9 to 18%. Between-laboratory results were compared for 110 sera from control subjects (daily alcohol intake < 40 g), for 57 sera from chronic ethylic subjects and for 78 sera from patients suffering from non-alcoholic liver diseases. There was a large between-laboratory variation, suggesting that the method is difficult to standardize and that results are not transferable. Results of enzyme and radioimmunoassays were compared on 325 sera. The best correlation was obtained in the groups of ethylic subjects and those with non-alcoholic hepatic diseases. Finally the performance of the CDT-test was evaluated by calculating sensitivity and specificity. With both methods specificity was very high (> 85%) but sensitivity was poor (< 50%).

[Erythrocyte ferritin]. / La ferritine érythrocytaire.

Red cell ferritin is a residue of erythroblast ferritin. It reflects the balance between the iron supply to the erythroid marrow and the need for haemoglobin synthesis. Erythrocyte ferritin can be measured in haemolysates after discarding plasma and leucocytes by different methods. The decrease in erythrocyte ferritin content indicates manifest iron deficiency anaemia. Ferritin levels do not appear to be influenced by inflammation, infection, tissue necrosis or tumors and may be a reliable indicator of iron status in inflammatory diseases. Erythrocyte ferritin is markedly increased in patients with iron overload allowing early diagnosis of hereditary haemochromatosis and the monitoring of phlebotomy therapy. Finally, in some pathologies erythrocyte assay is a more reliable indicator of the iron status than serum ferritin.

HbA1c in children attending summer camps organized by l'Aide aux Jeunes Diabétiques. Evidence for a harmful effect of lipohypertrophies in the early years of diabetes.

Glycated haemoglobin was determined by using the spot test method for blood sampling in all the children and teenagers attending the summer camps organized by l'Aide aux Jeunes Diabétiques in July 1989. A questionnaire was completed for each subject, relating age, the duration of the disease, the insulin regimen, the level of knowledge, the intensivity of urine and blood glucose self monitoring, and the presence of lipohypertrophies. The statistical analysis of the data suggests that the two only parameters which were found to have an influence on the level of glycated haemoglobin were the duration of the disease and the presence of lipohypertrophies: in the early years of diabetes (up to 4 years), HbA1c was significantly lower in patients without lipohypertrophies (7.90 +/- 0.18%, n = 78), than in those with lipohypertrophies (8.60 +/- 0.22%, n = 46, m +/- SEM, p < 0.02). This study should focus the attention of clinicians on the deleterious effect of lipohypertrophies, which can be observed very early on in the course of the disease.

Hemoglobin Thionville. An alpha-chain variant with a substitution of a glutamate for valine at NA-1 and having an acetylated methionine NH2 terminus.

In hemoglobin (Hb) Thionville, the substitution of a glutamic acid for the alpha-chain NH2-terminal valine inhibits the cleavage of the initiator methionine which is then acetylated. The elongation of the alpha-chain NH2 terminus modifies the three-dimensional structure of hemoglobin at a region that is known to have an important role in the allosteric regulation of oxygen binding. Relative to Hb A, Hb Thionville has a lower affinity for oxygen, and the heterotropic allosteric effects of protons, chloride, and bezafibrate are reduced. In contrast, the response to 2,3-diphosphoglycerate is normal. Analysis of oxygen equilibrium data within the framework of the two-state allosteric model indicates that the structure of deoxy Hb Thionville is stabilized relative to that of deoxy Hb A. The x-ray crystal structure of deoxy Hb Thionville shows that the glutamate side chain extends away from the alpha 1-alpha 2 interface, whereas the methionine side chain (which has two conformations) extends into the alpha 1-alpha 2 interface, physically displacing chloride and bezafibrate. The increased stability of deoxy Hb Thionville is due to new intrasubunit and intersubunit contacts made by the methionine. These interactions replace the indirect contacts, made through bound chloride ions, that Val-1 alpha normally contributes to the alpha 1-alpha 2 interface.