Gnathodiaphyseal dysplasia with a novel R597I mutation of ANO5: Mandibular reconstruction strategies.

Gnathodiaphyseal Dysplasia (GDD) is a rare, often misdiagnosed, autosomal-dominant disorder due to point mutations in the ANO5 gene. GDD combines craniofacial fibro-osseous lesions, dental loss and progressive curvature and cortical thickening of long bones and vertebra, causing pathological fractures. Diagnosis is based on bone pathology and mutation screening. Here we report three GDD cases within a single family with a novel ANO5 mutation: c.1790 G > T (p.Arg597Ile, i.e. R597I) on exon 16. Microsurgical mandibular reconstructions were performed in the three cases. We reviewed the literature on jaw reconstruction in this condition and discussed the challenges of craniofacial reconstruction in GDD due to the diffuse bone anomalies affecting potential flap donor zones and a specific risk for jawbone osteomyelitis.

The deficit of the isometric tetanic tension redeveloped after a release of frog muscle at a constant velocity.

Frog sartorius muscles tetanized isometrically were released at a constant velocity from lengths lL to lS (delta l = lL -lS; Ls greater than lO). The tension PS redeveloped after the release was lower than the isometric tension PS at LS, and higher than the isometric tension PL at lL. The tension deficit D is defined as the difference PS-PS. The timing of the release during the tetanus did not influence D. D/PO was proportional to delta l/lO. The proportionality constant k was equal to 1.35 +/- 0.19 (n = 8) when the velocity of release was 2.5 mm/s. When the muscles were released the same delta l, D was found to be an exponential decreasing function of the velocity. The tension deficit was also found in experiments performed in the region lS less than lO. The proportionality constant k was smaller, but the influence of the velocity of the release on D was not modified. When the velocity of the release was changed during the release, D changed accordingly, showing that the effects of delta l and V are multiplicative. These facts suggest a working hypothesis based on the concept that the actin filaments which enter the overlap region during a release are strained by the tetanic stress and therefore unable to make normal cross-bridges.

Superinduction of c-fos gene expression by estrogen in cultured guinea-pig endometrial cells requires priming by a cycloheximide-dependent mechanism.

The c-fos gene expression is rapidly induced by various mitogenic agents and protein synthesis inhibitors in many cell types. Estradiol-17 beta can induce c-fos gene expression in breast cancer cell lines and in the uterus in vivo, but not in cultured guinea-pig endometrial cells. Using this model, we investigated whether a protein synthesis inhibitor, cycloheximide, could induce the c-fos gene and permit a superinduction by estrogens. In the presence of cycloheximide (10 micrograms/ml), protein synthesis was inhibited at 95% within the first hour. From 190 min after the addition of estradiol-17 beta or diethylstilbestrol (10(-8) M) and cycloheximide (10 micrograms/ml), there was a significant increase (ranging from 3- to 5-fold) of the c-fos messenger RNA level (2.2 kilobase in size), compared with the level in cells treated with cycloheximide alone. Nonestrogenic steroid hormones and estradiol-17 alpha were unable to induce c-fos gene expression in the presence of cycloheximide. The effect of estradiol-17 beta observed in the presence of cycloheximide was completely abolished by 4-hydroxy-tamoxifen or by Ly 156758 or by ICI 164384 (10(-6) M). The c-fos mRNAs were rather stable in cells treated with cycloheximide for 2 h (half-life = 51 +/- 6 min) and there was no further increase in the c-fos messenger RNA stability after the addition of cycloheximide plus estradiol-17 beta (half-life = 40 +/- 3 min). The overall results suggest a response at the transcriptional level. In conclusion, cycloheximide transmits activating signals to the c-fos gene which act as priming elements to allow the estrogen action in cultured guinea-pig endometrial cells.

Effects of 17 beta-estradiol and growth factors on c-fos gene expression in endometrial epithelial cells in primary culture.

Primary culture of guinea-pig endometrial cells was made quiescent by serum depletion. When added to quiescent cells, 17 beta-estradiol (E2) alone affected neither c-fos and c-myc gene expression, nor DNA synthesis and cell proliferation. Insulin or epidermal growth factor (EGF) only induced DNA synthesis. An association of both growth factors allowed significant cell proliferation without inducing c-fos or c-myc expression. A response including c-fos induction (maximal expression at 75 min), but not c-myc expression, DNA synthesis and a marked cell proliferation was only obtained when 17 beta-estradiol was associated with insulin plus EGF. In this case, cycloheximide raised the c-fos gene expression. These data suggest that in endometrial epithelial cells, E2 is mitogenic only when it acts in association with EGF plus insulin and the c-fos gene expression may not be correlated with cell proliferation.

Regeneration after free muscle grafting in normal and dystrophic (mdx) mice.

Soleus muscles from C57BL/10 and mdx mice were isotransplanted to induce a cycle of degeneration/regeneration. Sixty days post-surgery, transplanted and contralateral soleus muscles were removed for mechanical and biochemical analyses. The regeneration which occurs after transplantation, induces in both mdx and C57BL/10 soleus muscles a decrease in maximal isometric force, together with an increase of the velocity of contraction. This increase in velocity is accompanied by the expression of typically fast-type myosin heavy chains. Thus degeneration/regeneration of both mdx and normal mice are very similar, causing a shift towards physiologically 'faster' muscle. Previous physiological and biochemical studies of mdx muscles have shown that mdx muscle is shifted towards 'slower' muscle compared to normal mice. One explanation of these findings was that the degeneration/regeneration cycles inherent in dystrophin-deficient mdx muscle causes a shift towards 'slow'. Our results argue against this hypothesis: degeneration/regeneration in both normal and mdx mice causes a shift towards 'fast'.

[Influence of arterial hypertension on diabetic retinopathy]. / Influence de l'hypertension artérielle sur la rétinopathie diabétique.

In the industrialized countries, diabetic retinopathy represents the most frequent cause of blindness during the period of active life. It occurs as two distinct clinical entities: non proliferating retinopathy characterized by dilatation of the retinal capillary bed and alterations in their vascular wall responsible for an increase in permeability, and proliferating retinopathy characterized by the appearance of pre-retinal neovessels secondary to the presence of vast zones of retinal ischemia. Numerous risk factors are implicated in the development of diabetic retinopathy: the primordial factor is the optimal equilibration of blood glucose levels. The primum movens of these diabetic lesions could be intoxication of the pericipets and endothelial cells of the retinal capillaries by an accumulation of sorbitol and fructose in this region. Additionally, the hyperglycemia suppresses the functioning of the retinal blood flow feed back system. An increase in systemic blood pressure will therefore be transmitted directly to the damaged capillary bed. In type II diabetes (NID), worsening of the diabetic retinopathy correlates with elevation of the systolic blood pressure. In type I diabetes (ID), worsening of the diabetic retinopathy correlates with an elevated diastolic blood pressure. A diastolic pressure of less than 74 mm Hg is a statistically significant protective factor against the worsening of type I diabetic retinopathy.

[Prevention of ocular infections in the hospital operating room]. / Prévention des infections oculaires en salle d'opération à l'hôpital.

Prevention of ocular nosocomial infections in the operation room requires control of several parameters: contamination of the air, a very important step of cleaning and sterilization and a staff trained to avoid infectious risk. The problem of PRION infection requires a particular attention especially about sterilization.

[The interaction of actin with myosin in fast and slow muscles of the mouse]. / Izuchenie vzaimodeistviia aktina s miozinom v bystrykh i medlennykh myshtsakh myshi.

Conformational changes of actin, during the transition of glycerinated muscle fibers of fast (EDL) and slow (SOL) mouse muscles from relaxation to rigor, were investigated by the polarized fluorescent technique. Changes in orientation and mobility of the fluorescent probe, i.e. rhodamin-phalloidin complex bound specifically to actin, testified the alteration of actin structure. The results show that during the transition of muscle fibers from relaxation to rigor the flexibility of actin filaments for EDL and SOL changes differently: increases for the former and practically does not change for the latter. The analysis of heavy myosin chains points out that SOL contains 65.43 +/- 7.26% myosin heavy chains 1 (MHC 1) and 34.57 +/- 7.26% myosin heavy chains 2A (MHC 2A). In contrast, EDL has 4.57 +/- 2.56% MHC 2A and 96.43 +/- 2.56% myosin heavy chains 2B (MHC 2B). No MHC 1 were revealed in EDL. A proposal is made that the isoformal composition of myosin heavy chains defines the character of actin-myosin interaction in slow and fast mouse muscles.

Regeneration of mammalian striated muscle.

Six main factors limit the regeneration of mammalian striated muscles: the myogenic cells, the basal membranes, the vascular supply, the innervation, the mechanical forces and the functional utilization. Their rôle is shortly discussed.

Effects of nitric oxide on the contraction of skeletal muscle.

A review of the literature suggests that the effects of nitric oxide (NO) on skeletal muscles fibers can be classified in two groups. In the first, the effects of NO are direct, due to nitrosation or metal nitrosylation of target proteins: depression of isometric force, shortening velocity of loaded or unloaded contractions, glycolysis and mitochondrial respiration. The effect on calcium release channels varies, being inhibitory at low and stimulatory at high NO concentrations. The general consequence of the direct effects of NO is to 'brake' the contraction and its associated metabolism. In the second group, the effects of NO are mediated by cGMP: increase of the shortening velocity of loaded or unloaded contractions, maximal mechanical power, initial rate of force development, frequency of tetanic fusion, glucose uptake, glycolysis and mitochondrial respiration; decreases of half relaxation time of tetanus and twitch, twitch time-to-peak, force maintained during unfused tetanus and of stimulus-associated calcium release. There is negligible effect on maximal force of isometric twitch and tetanus. The general consequence of cGMP-mediated effects of NO is to improve mechanical and metabolic muscle power, similar to a transformation of slow-twitch to fast-twitch muscle, an effect that we may summarize as a 'slow-to-fast' shift.

Equilibrium of nucleotides in frog sartorius muscle during an isometric tetanus at 20 degrees C.

1. The concentrations of creatine, phosphorylcreatine (PC), ATP, ADP, AMP and IMP have been measured in frog sartorius muscles at 20 degrees C during isometric tetani lasting from 0.5 to 12 sec. Each muscle was tetanized once only for the chosen duration. The muscles were poisoned with iodoacetic acid and nitrogen to prevent oxidative and glycolytic activity.2. The rate of PC splitting decreased exponentially with the duration of the tetanus (alpha = 0.16 sec(-1)). Net ATP splitting began after 2 sec, accompanied by an increase in AMP and ADP; inosine monophosphate (IMP) also appeared both earlier and faster than adenosine monophosphate (AMP).3. On the basis of two equilibrium reactions, the Lohmann and myokinase reactions, the concentration of adenosine nucleotides should be a function of the ratio creatine/phosphorylcreatine.4. The agreement between nucleotide concentrations predicted by this equilibrium hypothesis and those observed experimentally was good provided it was assumed that 90% of the acid-labile ADP found in resting muscle was bound in vivo and remained so throughout the tetanus. The validity of this assumption is discussed.5. The IMP concentration was an exponential function of the ratio creatine/phosphorylcreatine.

Maximal shortening velocities, isomyosins and fibre types in soleus muscle of mice, rats and guinea-pigs.

1. Guinea-pig soleus contains only type I fibres and slow isomyosin, SM2. Rat and mouse soleus contain about 70% of type I fibres and a mixture of isomyosins: slow, SM2 and intermediate, IM. Many rat soleus muscles contain a third isomyosin of a slow type, SM1. 2. The maximal velocity of unloaded shortening, V0, is largest in mouse soleus (6.11 Lf s-1), slowest in guinea-pig soleus (1.67 Lf s-1) and intermediate in rat soleus (4.16 Lf s-1) (Lf = fibre length). 3. In guinea-pig soleus, V0 is equal to the maximal velocity (Vmax) computed using the Hill force-velocity relationship; V0 is approximately twice as large as Vmax in mouse and rat soleus. 4. V0 measures the unloaded shortening velocity of the fastest fibres whereas Vmax is a function of the force-velocity characteristics of all the fibres contained in the muscle. 5. V0 increases according to the isomyosin composition of the fibres in the sequence SM2 less than SM1 + IM less than IM.

Time course of regeneration of minced frog muscles estimated by the level of energetic substrates.

1. Gastrocnemius muscles of frogs have been excised, chopped and put back into the leg. 2. The weight of the implanted muscles increases until the 8th day after the operation and then decreases to 1/3 of that of the control by the 30th day. 3. The inulin space is twice as high in regenerating muscle as in the unoperated controls. 4. Adenosine nucleotides are in an enzymatic equilibrium set by the ratio creatine/phosphorylcreatine during regeneration of the muscle. 5. Glycolytic intermediates (hexose monophosphate, fructose-1,6-diphosphate, alpha-glycerophosphate and lactate) have been measured during the course of muscle regeneration up to the 30th day. The results suggest that the glycolysis of regenerating muscle is very active. 6. The total creatine (sum of creatine and phosphorylcreatine) is very low after the operation: 5% of that of the controls; it rises sharply after the 8th day, and reaches 30% of that of the control on the 30th day. 7. The amount of total creatine seems proportional to the progress of the muscle regeneration. It is suggested to use this substance as a biochemical reference for biochemical works on muscle regeneration.

Force-velocity relation and isomyosins in soleus muscles from two strains of mice (C57 and NMRI).

We compared soleus muscles from two strains of mice, NMRI and C57. Soleus muscles from NMRI mice produced slower twitches and lower maximum tetanic force (Fo) but higher maximum tetanic stress (So), (owing to their smaller weight). Their Hill's velocity constant (b) was lower, but their force constant (a/So), their maximum velocity of unloaded shortening (Vu) and their maximal mechanical power (Pmax) were similar. All soleus muscles contained two isomyosins (SM2 and IM) and the two myosin heavy chains (MHC1 and MHC2A) corresponding to type I fibres and type IIA fibres; however, soleus muscles from NMRI strain had higher proportions of isomyosin SM2 and of myosin heavy chain 2A. Regression equations were computed between the mechanical variables and the myosin heavy chain content. Using a simple hypothesis, the results were used to estimate the mechanical properties of type I and type IIA fibres. We conclude that type IIA fibres from soleus muscle are mechanically more similar to slow-twitch type I fibres than to fast-twitch type II fibres. The results also suggest a hypothesis to account for the diversity of isomyosins, by a matching diversity of mechanical properties based on a separate physiological control of the three factors that control Pmax.