[Trends in social inequities in diabetes care in the Provence-Alpes-Côte-d'Azur region of France between 2008 and 2011]. / Évolution des inégalités sociales de suivi du diabète en région Provence-Alpes-Côte-d'Azur entre 2008 et 2011.

BACKGROUND: Social inequities in healthcare are known to exist for the management of many chronic diseases in France, including diabetes. The recession that began in 2008 has led to increased income disparities but has it also exacerbated health inequities. The aim of this study was to describe trends in inequities in diabetes-related healthcare between 2008 and 2011 in the PACA region (Provence-Alpes-Côte-d'Azur). METHODS: This analysis used two sources of data: the regional national health insurance fund (PACA region) reimbursement database and the socio-demographic databases of the national statistics office (INSEE) for four full years (2008 to 2011). It included individuals who had been reimbursed for three purchases of oral diabetes drugs during the previous year and assessed the association between the median household income (weighted by number and age of household members) of each patient's municipality of residence and seven indicators of diabetes monitoring and care. Using adjusted mixed logistic models, including an interaction term between time (number of years) and the median household income of the municipality, we examined the performance of the indicators for each year. RESULTS: The total number of patients with diabetes in the 941 municipalities of the PACA region varied by year from 142,055 to 164,929. Models showed that living in a town with a high or intermediate household income was significantly associated with better performance of the seven indicators and that the interaction term was significant for six of them. The effect of the municipal median income decreased significantly between 2008 and 2011 for five indicators: HbA1c, LDL-cholesterol, microalbuminuria, ophthalmoscopy and diabetes specialist visit. CONCLUSION: Social inequities in diabetes-related healthcare persisted between 2008 and 2011 but appeared to be decreasing, despite the recession.

Antimycin resistance and ubiquinol cytochrome c reductase instability associated with a human cytochrome b mutation.

Progressive exercise intolerance was associated with a decreased maximal rate of ubiquinol cytochrome c reductase (complex III) activity in the muscle mitochondria of the studied patient and with a thirty five-fold increase in the I50 for antimycin A. In contrast, myxothiazol sensitivity was not altered. Complex III activity was stable at 37 degrees C, but progressively decreased at 4 degrees C. An heteroplasmic G to A mutation at position 15615 of the mitochondrial DNA, resulting in the replacement of the highly conserved Gly290 in cytochrome b by Asp, was identified. Histochemical studies showed increased cytochrome oxidase and succinate dehydrogenase activities under the sarcolemma of type I fibres. After partial extraction of mitochondria from the muscle, the residual pellet contained a lower percentage of the mutation than did whole muscle, suggesting that the percentage of mutation is higher in the most readily extracted mitochondria, most probably present under the sarcolemma. In the current 8 transmembrane helix model of cytochrome b, Gly290 lies at the end of the sixth transmembrane helix, facing the intermembrane space and close to the presumed sites of interaction between cytochrome b, the iron-sulfur protein and the 9.5 kDa protein. Since immunoblotting experiments showed a relative decrease in the proportions of these three subunits in the patient's mitochondria compared with the other complex III subunits, it is probable that the complex III instability and the relative decrease in these subunits are related to the mutation. The relationship between the decrease in the apparent affinity for antimycin A and the instability of complex III are discussed.

Variations of muscle mitochondrial creatine kinase activity in mitochondrial diseases.

Mitochondrial creatine kinase (mtCK) activity has been measured in the mitochondria isolated from the muscle of 69 patients suspected of mitochondrial diseases. The isolated mitochondria did not contain significant amounts of the muscle isoform of creatine kinase, as checked by an immunoassay performed after electrophoretic separation of the various isoforms. Hence, the enzyme assay reliably represented the mtCK activity. Therefore, a simple measurement of CK activity in isolated mitochondria permitted the measurement of mtCK activity. An absence of mtCK activity in muscle was never observed. The lowest activities were not associated to defined mitochondrial diseases linked to defects of respiratory chain complexes or to defects of citric cycle enzymes. On the contrary, mtCK activity was significantly increased in the muscle of patients exhibiting ragged red fibers. This increase was generally associated to an increase of citrate synthase activity. Since ragged-red fibers and elevated mtCK activities were generally not found in children younger than 3 years, even in cases of characteristic oxidative phosphorylation deficiency, it is suggested that the increase in mtCK activity as well as the appearance of ragged-red fibers are not the first events which occur during the evolution of mitochondrial diseases but would rather be long-term secondary processes which slowly develop in deficient mitochondria.

Identification of a large-scale mitochondrial deoxyribonucleic acid deletion in endocrinopathies and deafness: report of two unrelated cases with diabetes mellitus and adrenal insufficiency, respectively.

In recent years, a broad variety of chronic diseases have been related to different mitochondrial DNA (mtDNA) rearrangements. We have investigated two 16-yr-old unrelated girls with unexplained endocrine disorders for a mtDNA mutation. One initially presented with an adrenal crisis at the age of 4 yr. Complete adrenal insufficiency for nearly 15 yr was the main clinical manifestation, along with insiduous growth retardation and sensorineural hearing loss since age 6. The other girl presented with ketoacidosis at the age of 15 yr. She exhibited incomplete deafness since age 6 and poor growth. In both patients, brain magnetic resonance imaging abnormalities and raised cerebrospinal fluid protein concentration indicated mild leucodystrophy. Biopsy of skeletal muscle showed a mitochondrial dysfunction; molecular analysis using a PCR screening procedure revealed a 7.4 kb deletion of the mtDNA in skeletal muscle but not in leucocytes. Direct sequence analysis of the junctional regions showed that the deletion spanned 7.436 kb (nucleotide 8649 to nucleotide 16084). The relative amount of deleted mtDNA estimated by Southern blot analysis was 25 and 15%, respectively. No deletion was present in leukocytes obtained from the asymptomatic mothers. The presence of the same mutation in different patients with various endocrine conditions supports the view that the 7.4 kb mtDNA deletion should be considered as one of the candidate causes for phenotypically uncommon cases of endocrinopathies, specially in children with deafness. This is the first report of a mitochondrial disease with primary adrenocortical insufficiency as the clinical onset.

Immunolabelling of mitochondrial superoxide dismutase and of Hsp60 in muscles harbouring a respiratory chain deficiency.

In mitochondrial encephalomyopathies, impairment of the electron transfer chain may lead to overproduction of reduced oxygen species because oxygen consumption is decreased. Whether heat shock proteins (Hsp) are induced or not in mitochondria against oxidative stress is questionable. Muscle ragged-red fibres are the histological hallmark of most respiratory chain deficiencies in humans. They exhibit abnormal mitochondria which accumulate mainly under their sarcolemma. Within these fibres, immunolabelling demonstrated strong expression of mitochondrial manganese-dependent superoxide dismutase and a lack of expression of mitochondrial Hsp60 within the subsarcolemmal spaces. In contrast, Hsp60 was overexpressed within the intermyofibrillar mitochondria. These findings suggest enhanced generation and dismutation of superoxide anions and that processing and integration of imported precursor proteins is impaired within the subsarcolemmal mitochondrial aggregates of ragged-red fibres, whereas protein import and assembly may still be efficient in the intermyofibrillar mitochondria of these fibres.

Decreased expression of ubiquinol-cytochrome c reductase subunits in patients exhibiting mitochondrial myopathy with progressive exercise intolerance.

The expression of mitochondrial proteins of two patients suffering from myopathy with progressive exercise intolerance and exhibiting a deficiency in the enzymatic activity of complex III (ubiquinol-cytochrome c reductase) has been analyzed by immunological titration. In both patients, the Fe-S protein, the cytochrome b and the 9.5 kDa protein were decreased while the expression of the other complex III subunits were close to normal values. This data indicates that, in some mitochondrial myopathies, proteins of the respiratory chain complexes can be accumulated in mitochondria without being integrated into a functional complex. This may be explained either by a lack of control of the coordination between the synthesis of subunits of mitochondrial and nuclear origin or by a difference in the degradation rate of the various subunits which are not properly assembled.

[Proliferation of the transverse tubular system during a tardive and familial myopathy]. / Prolifération du système tubulaire transversal au cours d'une myopathie tardive et familiale

The authors report a case of non-progressive, late-onset, recessive, sex-linked myopathy. Electron microscopy reveals a striking proliferation of the T system. This proliferation might be interpreted as indicating an abortive attempt of muscle to regenerate, which could explain the clinical course. Some basic ultrastructural aspects concerning the T system are reported. The signification of the findings of numerous "zebra bodies" is discussed.

[Hemispheric asymmetries of the human brain]. / Etude de certaines asymétries hémisphériques du cerveau humain.

The authors studied 181 brains, 103 of which were dissected. They observed a "T1-T2 bridge" over the first temporal and second temporal gyri more often on the left side than on the right. This asymmetry was more frequent in males than in females. The maximal width of the superior aspect of the second temporal gyrus was greater on the right side in the majority of cases. By contrast, the fusiform gyrus was found wider on the left side in most subjects. The length of the precuneus was greater on the right. The greater size of the left planum temporale could be correlated with the sectional area of the anterior white commissure. The same correlation was found between the length of the precuneus and the area of the latter commissure. Anatomical asymmetries of the two cerebral hemispheres in man seem to be numerous. The interpretation of these asymmetries is difficult; some are likely to be related to functional asymmetries. In the future, the study of morphological asymmetries in routine neuropathology, in patients who have been submitted to detailed neuropsychological examination, would appear to be desirable.

[Heterogeneity of glycogenosis with alpha-1,4-glucosidase deficiency: enzymatic studies in three families (author's transl)]. / Hétérogénéité de la glycogénose par déficit en alpha-1,4-glucosidase: etude enzymatique dans trois familles.

The authors describe four cases of atypical forms of glycogenosis with alpha-1,4-glucosidase (acid maltase) deficiency. The results of clinical, microscopic, histochemical, enzymological and immunological studies are described. Acid maltase activity has been studied in muscle, leukocytes and fibroblasts. The authors show no difference in the properties of acid maltase; the authors study the purified enzyme from various tissues.

Carnitine metabolism in early stages of Duchenne muscular dystrophy.

Muscle carnitine deficiency was found in 12 children affected with Duchenne muscular dystrophy (DMD), the diagnosis being made at a preclinical stage or at the beginning of the clinical symptoms. Enzymatic activities related to fatty acid transport and carnitine metabolism were studied in these patients and normal subjects: palmitoyl carnitine transferase was increased, palmitoyl carnitine hydrolase was not found in the muscle, palmitoyl coenzyme A synthetase was normal and palmitoyl coenzyme A hydrolase was increased.

[Primary cardiomyopathy in children with lipid infiltration of the myocardium and skeletal muscles and demonstration of a palmityl-carnitine transferase deficiency. Apropos of 4 cases]. / Myocardiopathie primitive de l'enfant avec surcharge lipidique des fibres myocardiques et musculaires et mise en évidence d'un déficit en enzyme palmityl-carnitine-transférase. A propos de 4 observations.

The authors report four cases of metabolic cardiomyopathy with lipid infiltration diagnosed by skeletal muscle and myocardial biopsy in children with no clinical signs of muscular dystrophy. Normal or increased serum and urinary carnitine levels excluded a primary carnitine deficiency. A deficiency in muscular-palmityl-carnitine-transferase was demonstrated. This pathogenic mechanism may be an indication for treatment with carnitine, but the results are less spectacular than in primary carnitine deficiency states.

[Lipidic myopathy with severe cardiomyopathy caused by a generalized carnitine deficiency. Favourable course during carnitine hydrochloride treatment]. / Myopathie lipidique avec cardiomyopathie sévère par déficit généralisé en carnitine. Evolution favorable sous un traitement par chlorhydrate de carnitine.

The case of a girl who presented with gastrointestinal upsets with nausea, vomiting and occasional hypoglycaemic attacks during childhood is reported. At about 5 years of age generalised muscular weakness with severe amyotrophy, cardiomegaly with a cardiothoracic ratio of 0,63, left ventricular hypertrophy on electrocardiography and left ventricular dilatation with hypokinesis on echocardiography were observed. A few weeks later she developed severe cardiac failure. Muscle biopsy showed muscular dystrophy with lipid infiltration due to carnitine deficiency )serum carnitine 9 nmoles/ml, normal values: 46 +/- 6,9 nmoles/ml; muscle carnitine 0,27 nmoles/mg, normal values: 3,0 +/- 0,79 nmoles/mg fresh frozen weight). She improved rapidly with carnitine chlorhydrate and a diet low in lipids and high in medium chain triglycerides. Regression of muscular symptoms and cardiac failure was observed. After 13 months follow-up with no tonicardiac therapy she is much improved; the signs of heart failure have disappeared, the cardiothoracic ratio is now 0,55 and the electrocardiogramme and echocardiogramme are normal.

Selective neurotomy of the tibial nerve in the spastic hemiplegic child: an explanation of the recurrence.

A series including 13 unilateral selective tibial neurotomies for spastic foot in hemiplegic children is reported. The results were considered excellent in three cases. Two cases needed additional corrective casts postoperatively. Eight cases had poor result with recurrence of the same deformity. The authors conclude that the effect of tibial neurotomy for spastic foot in hemiplegic children is transient in 61% of cases with a recurrence of the same deformity. Four of the patients with failed treatment underwent orthopedic surgery with muscle biopsies. Histologic data clearly demonstrate that previously denervated muscle fibers were reinnervated carrying into extensive motor units. This finding can explain the recurrence of the foot spasticity and deformity in neurotomized children.

[MELAS syndrome with pure vascular manifestation?]. / Syndrome "MELAS" à expression vasculaire pure?

Two stroke-like episodes then a grand mal seizure occurred within nine years in a 42-year-old patient. Neuroradiological findings (CT-scan and MRI) led to the diagnosis of incomplete MELAS syndrome. MRI with T2-weighted images (TR: 1000ms; TE: 35ms) showed two small asignal lesions possibly resulting from hemosiderine. Metabolic studies are required to help decide on muscular biopsies. Histological findings are needed for diagnosis of this form of mitochondrial cytopathy with only stroke-like manifestations.

[Physiopathological and neuropathological study of a cerebral decortication syndrome]. / Etude physiopathologique et neuropathologique d'un syndrome de décortication cérébrale

Detailed observation of a case of laminar necrosis of almost the whole of the cerebral cortex has led to several deductions concerning the physiology of the cortex in man. It suggests that the cortex has a limited influence on sleep, interfering particularly in the electro-encephalographic translation of slow sleep and, curiously, in the organisation of sleep, paradoxical sleep is hardly affected at all. It confirms the importance of the human cortex in the acquisition of elementary skills and describes a new oculomotor pattern in a decorticate man.

[Mitochondrial diabetes complicated by or associated with "MELAS" syndrome?]. / Diabète mitochondrial compliqué ou associé à un syndrome MELAS?

We report the case of fifty-two year-old mentally deficient female who presented with diabetes mellitus, deafness, stroke-like episodes, cardiomyopathy, and macular pattern dystrophy of the retina. Her brain exhibited calcification within basal ganglia, lactacidaemia was not increased. Although her skeletal muscles had never been clinically impaired, a quadriceps biopsy led to the diagnosis of mitochondrial disease because it exhibited ragged red fibers and heteroplasmic point-mutation at position 3243 of the mitochondrial DNA, although not any detectable respiratory chain complex deficiency was found. The mutant percentage in muscle was 70 p.100 and 5 to 10 p.100 in leukocytes. The question of whether a diabetic microangiopathy may be responsible stroke-like episodes is discussed. We suggest it was rather a complicated form of diabetes-deafness than a incomplete MELAS syndrome associated with mitochondrial diabetes.

[Use of local cobalt therapy in peripheral neuropathies associated with chronic lymphopathies (lymphoses). 2 cases with histo-immunologic and ultrastructural records]. / Intérêt de la cobaltothérapie locale dans les neuropathies périphériques des lymphopathies chroniques (lymphoses). Deux observations avec documents histo-immunologiques et ultrastructuraux.

In two cases of peripheral neuropathy, associated with a chronic lymphopathy, cobalt therapy to the lower limbs provided considerable relief of pain, with partial motor recovery. The disappearance after cobalt therapy of the lymphoid infiltrate of the peripheral nerve leads to discussion of the pathogeni role of this infiltrate. Immunofluorescent and electron microscopic studies form the basis of a discussion of the mechanism of involvement of the peripheral nerve non-secreting lymphopathies (chronic lymphoid leukaemia) and in secreting lymphopathies (Waldenström's disease).

[Neuropathology of trichopoliodystrophy (Menkes' disease). Anatomoclinical observation]. / Neuropathologie de la trichopoliodystrophie (maladie de Menkes). Une observation anatomo-clinique

The authors describe an anatomo-clinical case of trichopoliodystrophy in many ways similar to cases already published. The original features of the case are as follows: the ultrastructure of the duodenal mucosa is normal; the endoplasmatic reticulum of the putaminal neurons contains many-layered lamellar structures probably composed of protein; type II fibres predominate in the striated skeletal muscle suggesting abnormal neuromuscular maturation.

[Neurological manifestations in monoclonal gammapathies. Pure neurological manifestations. Immunofluorescence study]. / Manifestations neurologiques des gammapathies monoclonales. Formes neurologiques pures.--Etude en immunofluorescence

Analysis of 105 peripheral and central nervous system complications in 1062 monoclonal gammapathies draws attention to two types of phenomena. The possibility of pure neurological manifestations of IgM monoclonal gammapathies with macroglobulinorachia leads to discussion of their nosological position in relation to Waldenström's disease, Burkitt's lymphoma and Marek's disease. It is suggested that these cases should be reclassified under the heading "secreting neurolymphomatosis". Immunofluorescence and electron microscopy of 10 biopsies of the peripheral nerve showed deposits of monoclonal immunoglobulin whose function in determining peripheral neuropathies is discussed. The simultaneous presence of lymphoid infiltration, amyloid deposits and the monoclonal immunoglobulin (M component) suggests that this immunoglobulin could be the link between the cellular infiltrate secreting it and amyloid infiltration which would be the visible manifestation of it.

[A case of myopathy with carnitine deficiency]. / Un cas de myopathie avec déficit en carnitine.

Clinical and biological criteria of myopathies associated with carnitine deficiency allow to distinguish a muscular and a systemic form of the condition. In this report, the results of clinical, pathological and electrophysiological data obtained from a patient with carnitine deficiency-linked myopathy are described. The patient was a 23-year-old girl who was previously known to suffer from muscle weakness when suddenly acidosis associated with a severe drop in plasma carnitine appeared. In addition there were hypermetabolic symptoms similar to those described in Luft's syndrome. Biopsy from the quadriceps femoris muscle before treatment revealed that all type I fibers were either hypotrophic or atrophic. They showed lipid overloading manifested by triglyceride droplets adjacent to the mitochondrial membrane. Furthermore, the level of soluble muscle carnitine was 83 p. 100 less than in controls and membrane linked muscle carnitine was also 73.5 p. 100 less than in controls. The patient rapidly recovered after the initiation of daily treatment with 4.40 g carnitine chlorhydrate associated with 50 g Lipogram 20. Nine months later, lipid overloading completely disappeared and the level of plasma carnitine returned to near normal whereas the level of both soluble and linked carnitine remained very low. To provide more information on the origin of the myopathy (myogenic, neurogenic or humoral) we carried out an electrophysiological investigation of cultured skeletal muscle cells from the patient and from biopsies of patients not known to be suffering from myopathy. The electrophysiological data showed that the patient myotubes were less polarized than myotubes from control patients. Furthermore, the amplitude of the action potential was smaller than the amplitude of the action potential measured in control cells. Daily addition of 50 microM carnitine chlorhydrate to the cultured myotubes induced a recovery of the action potential amplitude. Taken together these results indicate that the carnitine deficiency reported here was probably of systemic origin in addition to a myogenic component. Muscle deficiency could be either linked to an alteration in the carnitine pathway or to overconsumption of carnitine by muscle. This latter point is discussed.