High regioselectivity in the amination reaction of isoquinolinequinone derivatives using conceptual DFT and NCI analysis.

DFT-derived reactivity descriptors and Non-Covalent interaction (NCI) analysis were performed to rationalize the regioselectivity in the amination reaction of some isoquinolinequinone derivatives. Statistical analysis was performed to assess robustness of atomic charges to the basis set. Various electronic population schemes including Mulliken population analysis (MPA), electrostatic method (ChelpG), Hirshfeld population analysis (HPA) and Natural population analysis (NPA) have been considered. The results revealed that NPA was the most efficient for this purpose. NCI study using the reduced density gradient (RDG) was performed for revealing weak interactions. Domains defined by isosurfaces of RDG have been integrated to quantitatively study the strength of weak interactions and their stabilities have also been examined. Steric hindrance caused by coordination of ethanol with the neighboring carbonyl prevents the nucleophilic attack on C-6 and therefore leads to preferential C-7 substitution. The quantitative study of NCI clearly demonstrates that the hydrogen bond of carbonyl (2) is more stabilizing. Consequently, the high polarity of hydrogen bond on this carbonyl may explain the high electrophilicity of C-5 compared to C-8. Our work proved that the difference in local reactivity, as well as the steric hindrance are the key elements explaining the high regioselectivity exhibited by the amination reaction.

A genome-wide association study of pulmonary tuberculosis in Morocco.

Although epidemiological evidence suggests a human genetic basis of pulmonary tuberculosis (PTB) susceptibility, the identification of specific genes and alleles influencing PTB risk has proven to be difficult. Previous genome-wide association (GWA) studies have identified only three novel loci with modest effect sizes in sub-Saharan African and Russian populations. We performed a GWA study of 550,352 autosomal SNPs in a family-based discovery Moroccan sample (on the full population and on the subset with PTB diagnosis at <25 years), which identified 143 SNPs with p < 1 × 10(-4). The replication study in an independent case/control sample identified four SNPs displaying a p < 0.01 implicating the same risk allele. In the combined sample including 556 PTB subjects and 650 controls these four SNPs showed suggestive association (2 × 10(-6) < p < 4 × 10(-5)): rs358793 and rs17590261 were intergenic, while rs6786408 and rs916943 were located in introns of FOXP1 and AGMO, respectively. Both genes are involved in the function of macrophages, which are the site of latency and reactivation of Mycobacterium tuberculosis. The most significant finding (p = 2 × 10(-6)) was obtained for the AGMO SNP in an early (<25 years) age-at-onset subset, confirming the importance of considering age-at-onset to decipher the genetic basis of PTB. Although only suggestive, these findings highlight several avenues for future research in the human genetics of PTB.

[Surgical treatment of chronic mallet finger by shortening--suture of the tendon scar. Sixty six cases]. / Traitement chirurgical du doigt en maillet invétéré par accourcissement--suture du cal tendineux. A propos de 66 cas.

Acute mallet fingers are commonly treated by splinting. Treatment of chronic injuries is more debated. Since 1989, a "shortening and suture" technique have been used for such chronic injuries on the elongated tendon scar. Sixty six of 77 patients treated on a 10 years period were reviewed with a mean follow-up of 21 months. The mean active extension lag at the distal interphalangeal (DIP) joint was 4.5 degrees (41 degrees of improvement) with 52% of fingers which recovered a full extension, representing 77% of good and excellent results according to Abouna's and Brown's modified criteria. There were two failures which lead to reoperation, and no complication (2 painful scars and 20% of cold intolerance). We propose this safe and simple technique for chronic mallet fingers if deformity exceeds 30 degrees, for patients untreated (after the second month), or when splinting has failed. "Swan-neck" deformities were improved by an associated Fowler procedure. In case of failure, a new "shortening and suture" or a DIP arthrodesis can be discussed.

Maturation of fetal human neural xenografts in the adult rat brain.

Transplantation of human fetal neural cells has been used for several years as a treatment for Parkinson's disease. These therapeutic trials were based on a large number of rat allografts studies, and the species to species extrapolation appeared valid in many respects. One major difference between neurons of various species, however, is their rate of maturation; indeed, human neurons have been proven to grow much more slowly than rat neurons. This has been studied mostly, up to now, at the light microscope level. In an attempt to determine the fine structural correlates of this protracted development and to detail the schedule of morphogenesis and synaptogenesis, human fetal brain stem tissue (at 8 weeks of gestation) was transplanted into a previously lesioned brain area of immunosuppressed adult rats. Transplants, which were allowed to develop for 15 days to 3 months, were analyzed using the electron microscope. At 15 days, small cells containing a large nucleus were surrounded by wide extracellular spaces. At 1 month, grafted neurons displayed a thin rim of cytoplasm and few thin processes. At 2 months, extracellular spaces tended to diminish. Thin processes formed bundles and large processes extended from enlarged neurons. Major changes were observed at 3 months survival as the neuropile filled up with cells and processes and synaptogenesis began. Comparison with a similar ultrastructural study of thalamic rat allografts shows that human cells develop following a pattern similar to that in rat cells but that the duration of each maturation step is largely extended.

Microglial chimaerism in human xenografts to the rat brain.

Neural tissue from human fetuses is currently used for intracerebral transplantation to treat patients with Parkinson's disease. The development of the human fetal tissue following grafting has been considered mostly, up to now, from the neuronal point of view in xenografts. Very little is known, in contrast, about nonneuronal, glial, or vascular cells in the grafts. Comparison of the data gathered on the development of grafted human neurons with those obtained in comparable studies using rat transplants has demonstrated species-specific features. We have therefore undertaken a series of studies dealing with nonneuronal cells in human-to-rat transplants to reveal other possible species-specificity of the human tissue. This study has, accordingly, been devoted to the immunohistochemical analysis of microglia of host and donor origins in a human to rat xenograft paradigm allowing clear distinction of the origin of the cells. Human neural tissue was transplanted as a cell suspension into the thalamus of adult rats. Amoeboid human microglia were observed in 1-, 2-, and 3-month-old transplants, but their density, already relatively low at the first stage, decreased further over time. Ramified human microglia were only occasional. In sharp contrast, host rat microglia rapidly invaded the transplant in the absence of any sign of necrosis. The rat cells exhibited first an amoeboid morphology but progressed at the later stages toward a more mature, ramified morphology. These results indicate that donor microglia are quite few in number at first and, at least, do not proliferate actively after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term delayed vascularization of human neural transplants to the rat brain.

Human neural transplants are being developed to treat Parkinson's disease. Previous characterization of human transplants focused on neuronal development, while little is known of the interaction between the transplant and its environment, among which blood is of prime importance. We evaluated here the formation of blood vessels in human neural xenografts placed into the brain of rats immunosuppressed with cyclosporin A. Using capillary wall markers, we found that human transplants remain virtually nonvascularized for more than 1 month. Angiogenesis takes place very slowly and the density of blood vessels is still quite poor after 3 months, the fine structure of these capillaries, when they form, is apparently normal. Functional studies indicate that the vascular network formed in the transplant allows blood circulation and exhibits a working barrier to macromolecules. Glucose uptake and consumption and cytochrome oxidase activity are almost undetectable up to 3 months after grafting. These results demonstrate that vascularization is much delayed in human xenografts into the rat brain. This delay is likely to be dependent on the maturation of the transplanted tissue. A dedifferentiation of human endothelial cells cotransplanted with neural cells occurs since histochemical and immunocytochemical markers revealing endothelial cells in the human fetus are not present up to 1 month in the transplant. The origin of this phenomenon is a matter of speculation. How neural cells survive and mature in such conditions are issues of prime interest for the future of human neural grafting.