MRI of transplanted pancreatic islets.

A promising treatment method for type 1 diabetes mellitus is transplantation of pancreatic islets containing beta-cells. The aim of this study was to develop an MR technique to monitor the distribution and fate of transplanted pancreatic islets in an animal model. Twenty-five hundred purified and magnetically labeled islets were transplanted through the portal vein into the liver of experimental rats. The animals were scanned using a MR 4.7-T scanner. The labeled pancreatic islets were clearly visualized in the liver in both diabetic and healthy rats as hypointense areas on T2*-weighted MR images during the entire measurement period. Transmission electron microscopy confirmed the presence of iron-oxide nanoparticles inside the cells of the pancreatic islets. A significant decrease in blood glucose levels in diabetic rats was observed; normal glycemia was reached 1 week after transplantation. This study, therefore, represents a promising step toward possible clinical application in human medicine.     

Inflammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and T cells.

Recent studies have shown inflammatory markers in affected neural tissues of amyotrophic lateral sclerosis (ALS) patients. We examined immunocytochemically spinal cord tissues of six patients with ALS, two with corticospinal tract degeneration secondary to cerebral infarcts and three control subjects without neuropathologic abnormalities. ALS spinal cords had dense macrophage infiltration (one log greater than control spinal cords) involving the white and gray matter, with heaviest infiltration of lateral and ventral columns and, in one patient, prefrontal gyrus and the occipital lobes of the brain. Macrophages in ALS spinal cord showed strong expression of cyclooxygenase-2 (COX-2) (one log greater than control tissues) and inducible nitric oxide synthase. In the gray matter, macrophages surrounded and appeared to phagocytize neurons (NeuN-positive) that appeared to be dying. Vessels showed damage to the tight junction protein ZO-1 in relation to perivascular CD40 receptor-positive macrophages and CD40 ligand-positive T lymphocytes. ALS spinal cords, but not control cords, were sparsely infiltrated with mast cells. In control cases with corticospinal tract degeneration following hemispheric cerebral infarction, macrophage infiltration of the white matter was COX-2-negative and restricted to lateral and anterior corticospinal tracts. Our data suggest that inflammation in ALS spinal cord and cortex is based on innate immune responses by macrophages and mast cells and adaptive immune responses by T cells.     

Multiple myeloma: epidemiological features in a well-defined population in Burgundy, France

Epidemiological features of multiple myeloma were studied over a seven-year period (1980-86) in the department of C?te d'Or (population 478,000). The crude annual incidence rates were 3.7/100,000 for males and 4.0/100,000 for females. The corresponding age-standardized rates were 2.5 and 2.1. The sex ratio was 1.2. Cumulative rates were 0.3% for both sexes. Age and specific incidence were low before 50 and increased with advancing age up to 85 years in males and females. There was no significant variation in incidence over the seven-year period. The risk of multiple myeloma was slightly higher in urban than in rural areas (the variations were not significant). The period between the beginning of the symptoms and the diagnosis was often short, less than one month in 56% of the cases. When compared to other population based registries the incidence rates are similar to those reported all over the world (except for registries with a high proportion of blacks in the population). Cases have been staged according to Durie and Salmon classification: 32% of the cases were classified as Stage I. This result suggests that globally cases diagnosed in a well-defined population are less severe than those reported in hospital statistics. Survival showed significant differences: there were better rates for patients under 75 and for patients at stage I and II compared with stage III patients. Percentage and morphology of plasma cells also influenced prognosis.     

Eccrine gland involvement in Krabbe's disease

Summary Lysosomal storage inclusions were observed in skin eccrine gland secretory and myoepithelial cells in three cases of Krabbe's disease. In addition to storage there were numerous degenerative changes, occasionally resulting in cell necrosis. These findings suggest a generalized nature of the storage process in this lysosomal enzymopathy and point to high galactocerebroside turnover in eccrine gland epithelium. This knowledge may be of value in the biopsy diagnosis of Krabbe's disease.     

Tissue inhibitor of metalloproteinase 1 activates normal human granulocytes, protects them from apoptosis, and blocks their transmigration during inflammation

Urinary levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) higher than those of matrix metalloproteinase 9 (MMP-9) during acute pyelonephritis have previously been associated with a higher degree of acute inflammation and of postinfective renal scarring. The aim of the present study was to evaluate possible mechanisms by which TIMP-1 could affect the scarring process already during the acute phase of inflammation. The growth of Escherichia coli, bactericidal activity of fresh human blood, and respiratory burst, spontaneous apoptosis, and trans-basement membrane migration of normal human granulocytes were studied in vitro in the presence of different concentrations of recombinant human TIMP-1. To imitate the "normal" environment during inflammation in the kidney, granulocytes were also incubated with a conditioned medium from E. coli-stimulated renal epithelial cells. In order to compare our data with the in vivo situation, blood and urinary leukocyte levels were analyzed for 40 children with acute pyelonephritis, together with urinary MMP-9 and TIMP-1 levels. TIMP-1 at a concentration of 500 ng/ml increased the bactericidal activity of blood, increased the respiratory burst of granulocytes, decreased phosphatidylserine exposure and caspase 3 activity, which are features of spontaneous apoptosis, and inhibited granulocyte transmigration. Moreover, in the patients with pyelonephritis, MMP-9/TIMP-1 ratios in urine correlated with the degree of leukocyte transmigration. Thus, our data suggest that TIMP-1 specifically blocks the transmigration of granulocytes into urine. Entrapped and activated granulocytes, protected from apoptosis, might excessively destroy renal parenchyma and thus contribute to the pathogenesis of renal scarring following acute pyelonephritis.     

Limb reduction defects in Emilia Romagna, Italy: epidemiological and genetic study in 173,109 consecutive births.

Epidemiological and genetic variables in limb reduction defects (LRD) were analysed during the years 1978 to 1987 in a case control study in Emilia Romagna, northern Italy. During the observation period, 83 neonates out of 173,109 consecutive births had LRD (4.8 per 10,000). Cases were divided into five subgroups: transverse, intercalary, longitudinal, split, and multiple types of LRD. Of all cases, 64% were upper limb, 21% lower limb, and 15% both. Coexisting non-limb malformations were found in 10 cases (12%), five with recognised syndromes and five with other associated defects. About 7.2% of first degree relatives had defects involving the skeletal system. In two cases the mother had the same type of LRD (a split). No recurrence among sibs was observed. Risk factors correlated with LRD were found to be low birth weight (2500 g or less), vaginal bleeding, and threatened abortion.     

Failure of oocyte maturation: possible mechanisms for oocyte maturation arrest

For human IVF, the patient's ovaries are hormonally stimulated to ensure the collection of fully matured oocytes that are at the metaphase II stage. Only these oocytes can be successfully fertilized either when mixed with sperm or after ICSI. Nevertheless, in some cases immature or maturing oocytes are recovered from follicles. Surprisingly, sometimes these oocytes do not complete maturation when cultured in vitro, for unknown reasons. In this article we discuss some possible mechanisms that may be responsible for those atypical arrests.     

The role of relative osteoneural growth in the gross morphogenesis of the skeleton: A hypothesis

Summary A unifying concept of gross skeletal (neurocranial, neurospinal and appendicular) morphogenesis is proposed. It is based on a close developmental relationship of bone and the nervous tissue, most evident in the neurocranium. The neurospinal developmental interrelationship is modified by the neurovertebral growth differential, which appears to influence the development of spinal curvatures and the gross morphological features of the individual vertebrae. Disproportion in osteoneural growth, as a general biological phenomenon, would be expected to affect the development of the appendicular skeleton. The gross shape of the long bones (physiological curvature and epimetaphyseal widening/modelling) appear to result from a buildup of rapidly forming skeletogenic material adjacent to slower growing nervous trunks, as is the case with the enchondrally developing vertebral body.Pathological accentuation of vertebro-osteoneural growth disproportion, brought about mainly by inhibition of the vulnerable neural growth, will result in abnormal gross features of the skeleton, i.e., pathological curvatures, terminal or general thickening and shortening of bones, or dislocation of joints. Experimental and clinical deformities, such as idiopathic scoliosis, achondroplastic conditions, congenital dislocation of the hip joint, and some other bone dysplasias confined in their onset and progression to the growth period of life, seem to be related to the suggested mechanism. For the above-mentioned skeletal disorders the term osteoneural growth pathology is proposed.

---

Le rôle de la croissance relative ostéo-neurale dans la morphogénèse du squelette. Une hypothèse

Résumé On propose une conception unitaire de la morphogénèse normale et pathologique du squelette axial et appendiculaire, à partir des relations les plus étroites existant entre la croissance des systèmes osseux et nerveux; la région neurocraniale en est la manifestation la plus expressive. La disproportion de croissance neuro-vertébrale en longueur exerce une influence décisive sur l'installation des courbures vértébrales physiologiques et sur les caractères morphologiques de chacune des vertèbres, aussi bien dans les dimensions des corps vértébraux que la forme du trou vertébral et des trous de conjugaison. Evoquant un phénomène biologique général, la disproportion de croissance ostéo-neurale agit de même sur le développement du squelette des membres. La forme, c'est-à-dire leurs courbures physiologiques et le modelage de la région épi-métaphysaire peuvent aussi être rattachés à un phénomène d'amassement de tissus osseux proliférant plus rapidement le long des troncs nerveux périphériques.L'accentuation pathologique de la disproportion de croissance ostéo-neurale, du fait principalement de l'inhibition de la croissance des structures nerveuses peut aboutir à des modifications des parties correspondantes du squelette avec effets de raccourcissement, de courbures pathologiques, d'élargissement partiel ou total et éventuellement, de dislocation articulaire. La conception proposée s'appuie sur des observations expérimentales de croissance ostéo-neurale chez des embryons d'oiseaux et d'amphibiens. On peut expliquer certaines déformations du squelette expérimentales ou cliniques comme la scoliose idiopathique, l'achondroplasie et la dysplasie congénitale de hanche par un même mécanisme d'adaptation des os en croissance à des troubles du développement des structures nerveuses avoisinantes. Une dénomination commune est proposée pour ces troubles de la croissance: pathologie de la croissance relative ostéo-neurale.

     

Heart development in the spotted dolphin (Stenella attenuata)

Marine mammals show many deviations from typical mammalian characteristics due to their high degree of specialization to the aquatic environment. In Cetaceans, some of the features of limbs and dentition resemble very ancestral patterns. In some species, hearts with a clearly bifid apex (a feature normally present during mammalian embryogenesis prior to completion of ventricular septation) have been described. However, there is a scant amount of data regarding heart development in Cetaceans, and it is not clear whether the bifid apex is the rule or the exception. We examined samples from a unique collection of embryonic dolphin specimens macroscopically and histologically to learn more about normal cardiac development in the spotted dolphin. It was found that during the dolphin's 280 days of gestation, the heart completes septation at about 35 days. However, substantial trabecular compaction, which normally occurs in chicks, mice, and humans at around that time period, was delayed until day 60, when coronary circulation became established. At that time, the apex still appeared bifid, similarly to early fetal mouse or rat hearts. By day 80, however, the heart gained a compacted, characteristic shape, with a single apex. It thus appears that the bifid apex in the adult Cetacean heart is probably particular to certain species, and its significance remains unclear.