Calciphylaxis – a topical overview

'Calciphylaxis', a calcification syndrome associated with ischaemic cutaneous necrosis, is acquired naturally in humans in disease states. It is a life and limb-threatening complication, usually observed in patients with renal disease and secondary hyperparathyroidism, but known to occur in the absence of renal or parathyroid disease. The reported mortality rate, which ranges from 60-80%, relates to wound infection, sepsis and organ failure. It is a small-vessel vasculopathy, which is estimated to occur in about 4% of haemodialysis patients. Clinically, violaceous, reticulate areas of cutaneous necrosis and eschar may be evident, particularly in the extremities. In addition to the clinical picture, a raised calcium phosphorous product, an elevated parathyroid hormone level, radiographic evidence of vessel and soft-tissue calcification and the finding of mural calcification affecting small arteries and arterioles on histopathology help to confirm the diagnosis of this entity which generally has a poor prognosis. A high index of suspicion and an active multidisciplinary management approach, with rigorous attention to wound care and prevention of sepsis, are vital in the management of these patients. In this overview, we discuss the pathophysiology, clinical features and associations, risk factors, diagnosis and management issues relating to calciphylaxis.     

Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy

The dominant cone-rod dystrophy gene CORD6 has previously been mapped to within an 8 cM interval on chromosome 17p12-p13. The retinal- specific guanylate cyclase gene (RETGC-1), which maps to within this genetic interval and previously was implicated in Leber's congenital amaurosis, was screened for mutations within this family and in a panel of small families and individuals with various cone and cone- rod dystrophy phenotypes. A missense mutation (E837D) was identified in affected members of the CORD6 family, as well as a second missense mutation (R838C) in three other families with dominant cone-rod dystrophy. RETGC-1 is only the fourth gene to be implicated in cone-rod dystrophy and this is the first report of dominant mutations in this gene.      

Comparison between testosterone oenanthate-induced azoospermia and oligozoospermia in a male contraceptive study. IV. Suppression of endogenous testicular and adrenal androgens

Administration of supraphysiological doses of testosterone to normal men causes inhibition of spermatogenesis, but while most become azoospermic, 30-55% maintain a low rate of spermatogenesis. We have investigated whether there are differences in endogenous androgen production, of testicular and adrenal origin, which may be related to the degree of suppression of spermatogenesis. Thirty-three healthy Caucasian men were given weekly i.m. injections of 200 mg testosterone oenanthate (TE), 18 became azoospermic, while 15 remained oligozoospermic. Urinary excretion of epitestosterone, a specific testicular product, was reduced to <10% of pretreatment values, with no differences between the groups. Similar results were obtained for other markers of testicular steroidogenesis. Urinary and plasma adrenal androgens were also reduced during TE treatment: a statistically significant decrease in both (P < 0.001 and P < 0.05 respectively) was seen in the azoospermic but not oligozoospermic responders. These results suggest that testicular steroidogenesis is decreased to <10% by the administration of supraphysiological doses of exogenous testosterone. Differences in the degree of ongoing steroidogenesis in the testis do not appear to account for incomplete suppression of spermatogenesis, thus differences in androgen metabolism may underlie this heterogeneous response. A small but significant reduction in secretion of adrenal androgens was also detectable, the relevance of which is unclear.      

A locus for autosomal dominant anterior polar cataract on chromosome 17p

Inherited cataract is a clinically and genetically heterogeneous disease. Here we report the identification of a new locus for an autosomal dominant anterior polar cataract on the short arm of chromosome 17. To map this new locus we performed genetic linkage analysis with microsatellite markers in a four-generation pedigree. After exclusion of seven candidate loci for cataract, we obtained significant positive LOD scores for markers D17S849 (Z = 4.01 / theta = 0.05) and D17S796 (Z = 4.17 / theta = 0.05). Multipoint analysis gave a maximum LOD score of 5.2 (theta max = 0.06) between these two markers. From haplotype analysis, the cataract locus lies in the 13 cM interval between markers D17S849 and D17S796. This study provides the first genetic mapping of an autosomal dominant anterior polar cataract.      

Biomechanics of the hip: forces exerted during walking

Summary Since the work of Pauwels, the forces exerted on the coxofemoral joint during walking have been studied either in different spatial planes (frontal, sagittal and horizontal) or by three-dimensional spatial analysis. Starting from the findings of our own studies, our aim was to compare the two methods of analysis (two-dimensional and three-dimensional) in order to provide a better understanding of the benefits and limitations of each method. In pursuit of this aim, we studied the pressure forces exerted on the coxofemoral joint, using a geometric plane technique following a method similar to that of Pauwels [20], and with a three-dimensional modelling technique using the finite element method. The material, taken from the published literature, was the same in both our studies. The results are expressed in terms of the size and orientation of the pressure force exerted on the coxofemoral joint during the monopodal weightbearing phase of walking. A comparison of these two methods of analysis clearly demonstrates the simplicity of two-dimensional analysis (which must incorporate as a minimum the frontal plane and the sagittal plane) and the richness of the three-dimensional analysis. The latter method, by appropriate manipulation of the information obtained, provides a starting point for computer simulations performed with the aim of testing a biomechanical or therapeutic hypothesis.

---

Biomécanique de la hanche : les sollicitations à la marche

Résumé Depuis Pauwels, les sollicitations exercées sur l'articulation coxofémorale au cours de la marche ont été étudiées soit dans les différents plans de l'espace (frontal, sagittal et horizontal), soit par des analyses spatiales tridimensionnelles. A partir d'études personnelles, nous avons voulu comparer ces deux méthodes d'analyse (bidimensionnelle et tridimensionnelle) afin de dégager au mieux les apports et les limites de chacune. Pour cela, nous avons étudié les sollicitations en pression s'exerçant sur l'articulation coxofémorale, d'une part selon une étude géométrique plane dont la méthodologie s'apparente à celle de Pauwels [20], d'autre part selon une modélisation tridimensionnelle par la méthode des éléments finis. Le matériel, emprunté à la littérature, est commun à nos deux études. Les résultats intéressent l'intensité et l'orientation de la force en pression exercée sur l'articulation coxofémorale pendant la phase d'appui monopodal de la marche. La comparaison des deux types d'analyse met en valeur la simplicité de l'analyse bidimensionnelle (qui doit combiner le plan frontal et le plan sagittal au minimum) et la richesse de l'analyse tridimensionnelle qui, par la manipulation des informations obtenues, ouvre sur les simulations informatiques, en vue de tester une hypothèse biomécanique ou thérapeutique.

     

Differential expression of FMR1, FXR1 and FXR2 proteins in human brain and testis

Lack of expression of the fragile X mental retardation protein (FMRP) results in mental retardation and macroorchidism, seen as the major pathological symptoms in fragile X patients. FMRP is a cytoplasmic RNA- binding protein which cosediments with the 60S ribosomal subunit. Recently, two proteins homologous to FMRP were discovered: FXR1 and FXR2. These novel proteins interact with FMRP and with each other and they are also associated with the 60S ribosomal subunit. Here, we studied the expression pattern of the three proteins in brain and testis by immunohistochemistry. In adult brain, FMR1, FXR1 and FXR2 proteins are coexpressed in the cytoplasm of specific differentiated neurons only. However, we observed a different expression pattern in fetal brain as well as in adult and fetal testis, suggesting independent functions for the three proteins in those tissues during embryonic development and adult life.      

Greffe Intertibio-péronière dans le Traitement des Pseudarthroses Fistuleuses Diaphysaires de Jambe

Résumé Les auteurs présentent une série de 30 pseudarthroses fistuleuses de jambe traitées par greffe intertibiopéronière, revues avec un recul allant de 3 à 9 ans.La voie d'abord utilisée pour la greffe est le plus souvent rétropéronière; dans 14 cas l'immobilisation a été réalisée par un plâtre et dans 16 cas par un fixateur externe (chez 9 malades, l'opération a été réalisée après mise en place du fixateur). 28 guérisons sont constatées (25 rapides en 3 à 8 mois, 3 plus lentes) et 2 échecs.Les auteurs insistent sur l'intérêt de la voie rétropéronière qui permet le plus souvent de rester à distance des parties molles «septiques» et du fixateur externe comme moyen de contention.L'indication de cette méthode concerne surtout les pseudarthroses infectées anciennes avec des extrémités osseuses atrophiques ou en cas de perte de substance osseuse. Dans les autres cas, la décortication de Judet est plus simple et permet d'obtenir d'excellents résultats.

---

Intertibio-peroneal graft in the treatment of infected non-united legs

Summary The authors present a series of 30 cases of fistular non united fractures of the leg treated by interosseous bone graft. Survey was performed from 3 to 9 years.In most cases, the surgical approach is made behind the fibula; in 14 cases, immobilization by means of a plaster cast and in 16 cases by means of external fixation (in 9 cases, external fixation bar + screws was realised first).Healing occured in 28 cases (quick in 25 cases, i.e. within 3–8 months, slow in 3 cases) and 2 failures.The authors emphasize the value of the posterior (retrofibular) approach, which avoids the distal septic soft areas, and of the bar-screws device.The procedure is mostly relevant in old infected non united fractures, with atrophic bony extremities or with boneloss.In the other cases, Judet's procedure is more simple and allows excellent results.

     

Adaptive changes in the nigrostriatal pathway in response to increased 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration in the mouse

Although several adaptive mechanisms have been identified that mask the existence of Parkinson's disease and delay the onset and aggravation of motor symptoms, the timescale and implications of this compensatory process remain an enigma. In order to examine: (i) the nature of the dopaminergic adaptive mechanisms that come into action; (ii) their sequential activation in relation to the severity of degeneration; and (iii) their efficacy with regard to the maintenance of a normal level of basal ganglia activity, we analysed the brains of mice treated daily with 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP, 4 mg/kg, i.p.) and killed at 5-day intervals from day 0 (D0) to D20. Our results demonstrate the sequential activation of two compensatory mechanisms: (i) an increase in striatal tyrosine hydroxylase (TH) protein content attested by the persistence of TH immunolabelling up to D15, contrasting with the decrease observed in both the number of nigral TH-immunoreactive neurons (-70.2%) and striatal dopamine content (-38.4%); (ii) a downregulation of DA uptake in surviving terminals at D20 (73.4% of nigral degeneration). At this point, the failure of adaptive mechanisms to maintain striatal dopaminergic homeostasis is also illustrated by an increase in the cytochrome oxidase activity of substantia nigra pars reticulata, a marker of neuronal function. It has been postulated that an increase in dopamine release per pulse could constitute an adaptive mechanism. The data we present from our MPTP mice model infirm this hypothesis. This study explores the link between the degree of nigral degeneration and the sequential activation of dopaminergic compensatory mechanisms in the nigrostriatal pathway and, in so doing, proposes a rethink of the paradigm applied to these mechanisms.