Free fatty acids impair hepatic insulin extraction in vivo

Hyperinsulinemia is a common finding in obesity and results from insulin hypersecretion and impaired hepatic insulin extraction. In vitro studies have shown that free fatty acids (FFAs), which are often elevated in obesity, can impair insulin binding and degradation in isolated rat hepatocytes. To investigate whether FFAs impair hepatic insulin extraction (E(H)) in vivo, either saline (SAL) or 10% Intralipid (0.03 ml x kg(-1) x min(-1)) plus heparin (0.44 U x kg(-1) x min(-1)) (IH) was infused into normal dogs to elevate FFA levels. Insulin was infused intraportally at 18 pmol x kg(-1) x min(-1) for 150 min (period A, high insulin dose), and then at 2.4 pmol x kg(-1) x min(-1) for another 150 min (period B, low insulin dose). After the low portal insulin dose, additional insulin was infused peripherally at 8.4 pmol x kg(-1) x min(-1) for 120 min (period C) to assess the clearance of insulin from the peripheral plasma. In 16 paired experiments, FFA levels were 1,085 +/- 167, 1,491 +/- 240, 1,159 +/- 221 micromol/l (IH) and 221 +/- 44, 329 +/- 72, 176 +/- 44 micromol/l (SAL) in periods A, B, and C, respectively. Peripheral insulin levels were greater with IH (P < 0.001) than with SAL in all periods (1,620 +/- 114, 126 +/- 12, 1,050 +/- 72 pmol/l for IH vs. 1,344 +/- 168, 96 +/- 4.2, 882 +/- 60 pmol/l for SAL). Glucose clearance was impaired by IH in all periods (P < 0.05), whereas glucose production was slightly increased by IH during period B. Peripheral insulin clearance (Cl) and E(H) were calculated from the insulin infusion rate and insulin concentration data in each period by taking into account the nonlinearity of insulin kinetics. Cl was lower (P < 0.01) with IH (9.6 +/- 0.6, 12.0 +/- 0.9, 10.2 +/- 0.6 ml x kg(-1) x min(-1)) than with SAL (11.2 +/- 1, 13.6 +/- 0.7, 11.9 +/- 0.9 ml x kg(-1) x min(-1)) in periods A, B, and C. E(H) was also lower (P < 0.05) with IH (25 +/- 4, 40 +/- 5, 32 +/- 5%) than with SAL (30 +/- 2.8, 47 +/- 3, 38 +/- 3%). We conclude that FFAs can impair hepatic insulin extraction in vivo at high and low insulin levels, an effect that may contribute to the peripheral hyperinsulinemia of obesity.     

Urticarial vasculitis--a syndrome with low complement levels and secondary glomerulopathy

In female patient, aged 41, 3 years ago appeared skin changes of urticarial type, and occasional pain in the joints of shoulders and hands, followed by complete weakness and exhaustion, as well as the occurrence of face and eyelid edema. Laboratory findings confirmed the presence of hypocomplentemia with proteinuria, microhematuria and cylindruria. Histopathologic (HP) finding of skin biopsy was leukocytoclastic vasculitis, and HP finding of the kidneys was mesangioproliferative glomerulonephritis. The regression of skin changes was observed during hospitalization after Dapsone was administered. The therapy started with corticosteroids (Prednisone 40 mg/day with weekly dose from 5 mg to 30 mg). In spite of the therapy, hypocomplementemia and proteinuria up to 335 mg/24 h have maintained for a year in the later controls in an outpatient department. The patient is without discomfort, and renal function is stable.     

Sjögren-Larsson syndrome: clinical and MRI/MRS findings in FALDH-deficient patients

OBJECTIVE: To determine the spectrum of clinical and MRI/1H MRS features of patients with fatty aldehyde dehydrogenase (FALDH) deficiency. BACKGROUND: The Sjogren-Larsson syndrome (SLS) was originally defined as a clinical triad consisting of ichthyosis, spastic di- or tetralegia, and mental retardation, with autosomal recessive inheritance. By now, both the deficiency of the enzyme FALDH, and the genetic mutations on chromosome 17 responsible for this deficiency, have been identified. SLS, defined by fibroblast FALDH deficiency, seems to be a much broader syndrome. METHODS: The clinical findings of 11 FALDH-deficient patients of different ages and one patient with the characteristic SLS-like ichthyosis, but without FALDH deficiency, were evaluated in relation to their cerebral MRI, and to 1H MRS in six patients. RESULTS: The severity of neurologic symptoms showed considerable variation. Fundoscopic perifoveal glistening dots and the characteristic SLS-like ichthyosis were present in all patients. Serial MRI findings showed evidence of retarded myelination and a variable degree of dysmyelination. 1H MRS showed an accumulation of free lipids in the periventricular white matter, even before the stage of visible dysmyelination. CONCLUSIONS: The neurologic consequences of FALDH deficiency show considerable variation. The characteristic pattern of ichthyosis and retinal degeneration are seen consistently, yet they are not pathognomonic. MRI and 1H MRS findings suggest an accumulation of long-chain fatty alcohol intermediates, resulting in retarded myelination and dysmyelination.     

Nitric oxide and l-arginine cause an accumulation of utrophin at the sarcolemma: a possible compensation for dystrophin loss in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD), a severe X-linked recessive disorder which results in progressive muscle degeneration, is due to a lack of dystrophin, a membrane cytoskeletal protein. An approach to treatment is to compensate for dystrophin loss with utrophin, another cytoskeletal protein with over 80% homology with dystrophin. Utrophin is expressed, at the neuromuscular junction, in normal and DMD muscles and there is evidence that it may perform the same cellular functions as dystrophin. So, the identification of molecules or drugs that could up-regulate utrophin is a very important goal for therapy. We show that in adult normal and mdx mice (an animal model of Duchenne myopathy) treated with l-arginine, the substrate of nitric oxide synthase (NOS), a pool of utrophin localized at the membrane appeared and increased, respectively. In normal and mdx myotubes in culture, l-arginine, nitric oxide (NO), or hydroxyurea increased utrophin levels and enhanced its membrane localization. This effect did not occur with d-arginine, showing the involvement of NOS in this process. The NO-induced increase in utrophin was prevented by oxadiazolo-quinoxalin-1-one, an inhibitor of a soluble guanylate cyclase implicated in NO effects. These results open the way to a potential treatment for Duchenne and Becker dystrophies.     

Hereditary prothrombin deficiency presenting as intracranial haematoma in infancy

Hereditary deficiency of prothrombin is a rare autosomal recessive bleeding disorder, with severe bleeding diathesis in homozygotes, but rarely resulting in intracranial haematoma. We describe two infants of consanguineous parents, presenting with acute subdural haematoma. Because such haematomas in infancy are highly indicative of trauma caused by child battering and because the socio-economic status of the family was unstable, there was a suspicion of child battering. However, further investigations revealed a bleeding diathesis due to a prothrombin deficiency. DNA analysis of the prothrombin gene showed homozygosity for a novel mutation, substituting Lys for Glu at codon 7 and resulting in decreased specific clotting activity. We discuss the probability of bleeding diathesis versus child battering in the aetiology of intracranial haematoma.     

Histological characteristics of sternoclavicular beta 2-microglobulin amyloidosis and clues for its histogenesis

BACKGROUND: The pathogenesis of beta 2-microglobulin amyloidosis (A beta 2m) has yet to be fully elucidated. METHODS: We describe the distribution and extent of A beta 2m deposition and macrophagic infiltration in cartilage, capsule, and synovium of sternoclavicular joints obtained postmortem from 54 patients after 3 to 244 (median 46) months of dialysis. Twenty-four nonuremic patients served as a control group. The diagnosis of amyloidosis (A) rested on a positive Congo Red staining (typical birefringence) and that of A beta 2m on positive immunostaining of the A deposits with a monoclonal anti-beta 2m antibody. The size of A deposits was measured. RESULTS: A beta 2m was detected in 32 (59%), and non-beta 2m amyloid (Anon beta 2m) was detected in an additional 8 (15%) of the 54 dialyzed patients. A beta 2m deposits were present in the cartilage of all A beta 2m (+) patients (100%). They were localized solely in the cartilage in 27% of the cases, either as a thin patchy layer or as a continuous thicker layer (identified as stage I). A beta 2m was additionally present in the capsule and/or synovium without macrophages in 27% of the cases (identified as stage II). The correlation between the size of cartilaginous deposits and dialysis duration (P = 0.02) as well as with the prevalence (P = 0.03) and size of capsular deposits (P = 0.02) suggests that stage II is a later stage of A deposition. Clusters of macrophages were detected around capsular and synovial amyloid deposits in 46% of the cases (identified as stage III). The longer duration of dialysis in those with stage III as well as the relationship between the size of the A beta 2m deposits and the prevalence of macrophagic infiltration suggests that stage III is the last stage of A beta 2m deposition. Marginal bone erosions were observed in 9 out of 12 patients with stage III deposits. Their size was correlated with that of cartilaginous deposits (P = 0.01). Among the 24 control patients, Anon beta 2m was detected in 12 patients (cartilage 100%, capsule 8%, synovium 30%). CONCLUSIONS: The earliest stage of A beta 2m deposition occurs in the cartilage. A beta 2m subsequently extends to capsule and synovium. These two first stages do not require macrophage infiltration. Macrophages are eventually recruited around larger synovial or capsular deposits in the final stage. Marginal bone erosions develop in this late stage.     

Flavone and xanthone derivatives related to fluoroquinolones.

A number of flavone and xanthone derivatives bearing some characteristic features of fluoroquinolones such as the fluorine atom and an ortho piperazine ring are described. The new compounds have been tested for possible cytotoxic and antimicrobial activities. Cytotoxicity of both groups of compounds is rather poor, while the antibacterial activity is restricted to xanthones.     

Adult from of basal cell navevus syndrome: A family study

Summary A 32-year-old patient had marked reduction of visual acuity due to falciform folds of the retina and retinal detachment, and severe neurological abnormality: bilateral pyramidal involvement, fasciculation in all limbs and gait ataxia. Skull radiographs showed internal frontal hyperostosis; CT scan showed calcification of the falx cerebri, and multiple arachnoid cysts were shown by myelography. A naevoid lesion had previously been removed from the left forearm. There was a history of ophthalmological symptoms in the mother and the daughter of the propositus. His son has café au lait spot on the abdomen and dentigerous cysts. The diagnosis of an adult form of basal cell naevus syndrome with an autosomal dominant mode of inheritance is discussed.This work was supported by grants from the F.R.S.M. of Belgium no. 3.4543.77 (Prof. P. Danis) and no. 3.4538.76 (Prof. C. Coërs) and the Free University of Brussels     

Synergistic Regulation of Cytosolic Ca2+ Concentration by Adenosine and alpha1-Adrenergic Agonists in Mouse Striatal Astrocytes

Adenosine has a broad array of actions on neurons but astrocytes also possess adenosine receptors. We have previously shown that adenosine, by acting on astrocytes in the striatum, can modulate neuronal responses mediated by receptors coupled to phospholipase C through an astrocyto - neuronal interaction. In addition, adenosine was found to potentiate the alpha1-adrenergic production of inositol phosphates in astrocytes. The mechanism involved in this potentiation was further investigated by examining the effects of adenosine and alpha1-adrenergic receptor agonists on cytosolic Ca2+ in cultured striatal astrocytes from the embryonic mouse in primary culture. When used alone, methoxamine, a selective agonist of alpha-adrenergic receptors or 2-chloroadenosine, a stable analogue of adenosine, induced a transitory increase in cytosolic Ca2+, but their combined addition led to a sustained increase in cytosolic Ca2+, which seems to be due to a Ca2+ influx, because it was not observed in the absence of external Ca2+. Voltage independent Ca2+ channels contribute to this process and different blockers of voltage-operated calcium channels, such as dihydropyridines, phenylalkylamines, La3+ or Co2+ were ineffective in suppressing the sustained cytosolic Ca2+ elevation. Three observations suggest the implication of arachidonic acid in the observed potentiation: (i) arachidonic acid induced a sustained elevation of cytosolic Ca2+ similar to that evoked by the coapplication of methoxamine and 2-chloroadenosine; (ii) the addition of arachidonic acid during the calcic plateau produced by the combined application of the agonists did not increase further cytosolic Ca2+ levels; (iii) in the presence of methoxamine, 2-chloroadenosine induced a release of arachidonic acid. The stimulation of phospholipase C and the resulting activation of protein kinase C induced by methoxamine seem to be required for the potentiating effect of 2-chloroadenosine on cytosolic Ca2+. In fact, the direct activation of protein kinase C by an exogenous diacylglycerol analogue mimicked the effect of methoxamine because, in this condition, 2-chloroadenosine alone evoked a sustained elevation of cytosolic Ca2+. Therefore, methoxamine, through the successive activation of phospholipase C and protein kinase C, could allow a lipase, probably phospholipase A2, to be stimulated by 2-chloroadenosine. Arachidonic acid has already been shown to trigger the opening of K+ channels and the formation of inositol phosphates in other cell types. Therefore, in striatal astrocytes, 2-chloroadenosine, through an arachidonic acid-mediated hyperpolarization, could increase the Ca2+ driving force and thus improve Ca2+ influx through inositol phosphate-gated channels. This hypothesis is further supported by the suppressing effect of a 50 mM KCI-induced depolarization on the long lasting elevation of cytosolic Ca2+ seen in the combined presence of 2-chloroadenosine and methoxamine.