A preliminary study on the enhancement of the osteointegration of a novel synthetic hydroxyapatite scaffold in vivo

Synthetic hydroxyapatite, a bioactive calcium phosphate, is clinically used as a bone replacement bioceramic because of its similarity in composition to bone mineral, biocompatibility, and osteoconductive nature. The aim of this study was to evaluate the bioactivity of a novel synthetic porous hydroxyapatite (PHA) in vivo in rabbit and to investigate the enhancement of its bioactivity and osteointegration. In the investigation reported here, insulin-like growth factor-I (IGF-I) has been used to enhance the bioactivity of PHA. Cylindrical PHA implants with or without IGF-I were implanted bilaterally in rabbit femurs. Fluorochrome bone markers were administered at 7-day intervals. The implants with the attached bone were retrieved at postmortem, 1 and 3 weeks after implantation, for histological and histomorphometric analysis. Undecalcified sections stained with toluidine blue showed new bone formation. Mineralization of the new bone formed in the interface, surrounding trabecular bone, and within the pores of the implants was studied. Lamellar bone mineral apposition rate (MAR) was assessed and compared among treatment groups, sham, PHA alone, and PHA with IGF-I (500 ng/implant), by fluorochrome label incorporation using UVL microscopy. We report for the first time, that the supplementation of PHA implants with IGF-I significantly increased new bone formation and MAR (6.58 +/- 0.08 microm/day) compared with implantation of PHA alone (4.08 +/- 0.05 microm/day) or sham operation (3.11 +/- 0.12 microm/day). These results suggest that synthetic PHA might provide a delivery system for bioactive agents to accelerate bone healing in orthopedic procedures.     

Clinical and molecular overlap in overgrowth syndromes

Here, we report the clinical and molecular analysis of 75 patients with overgrowth and mental retardation, including 45 previously reported cases [Rio et al., 2003; Baujat et al., 2004]. Two groups are distinguished: group I corresponding to patients with recognizable overgrowth syndromes (Sotos syndrome (SS), Weaver syndrome (WS), Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome (SGBS), and del(22)(qter) syndrome) (60 cases) and group II corresponding to unclassified cases (15 patients). We investigated NSD1 and GPC3 deletions or mutations, 11p15 abnormalities, and 22qter deletions. Surprisingly, in Group I, two SS patients had 11p15 abnormalities and two patients with Beckwith-Wiedemann syndrome had NSD1 aberrations. In group II, two cases of del(22)(qter) were identified but neither NSD1, 11p15, nor GPC3 abnormalities were detected. These results emphasize the clinical and molecular overlap in overgrowth conditions.     

Plasmodium falciparum merozoite surface protein 8 is a ring-stage membrane protein that localizes to the parasitophorous vacuole of infected erythrocytes

To date, the following seven glycosylphosphatidylinositol (GPI)-anchored merozoite antigens have been described in Plasmodium falciparum: merozoite-associated surface protein 1 (MSP-1), MSP-2, MSP-4, MSP-5, MSP-8, MSP-10, and the rhoptry-associated membrane antigen. Of these, MSP-1, MSP-8, and MSP-10 possess a double epidermal growth factor (EGF)-like domain at the C terminus, and these modules are considered potential targets of protective immunity. In this study, we found that surprisingly, P. falciparum MSP-8 is transcribed and translated in the ring stage and is absent from the surface of merozoites. MSP-8 is the only GPI-anchored protein known to be expressed at this time. It is synthesized as a mature 80-kDa protein which is rapidly processed to a C-terminal 17-kDa species that contains the double EGF module. As determined by a combination of immunofluorescence and membrane purification approaches, it appears likely that MSP-8 initially localizes to the parasite plasma membrane in the ring stage. Although the C-terminal 17-kDa fragment is present in more mature stages, at these times it is found in the food vacuole. We successfully disrupted the MSP-8 gene in P. falciparum, a process that validated the specificity of the antibodies used in this study and also demonstrated that MSP-8 does not play a role essential to maintenance of the erythrocyte cycle. This finding, together with the observation that MSP-8 is exclusively intracellular, casts doubt over the viability of this antigen as a vaccine. However, it is still possible that MSP-8 is involved in an early parasitophorous vacuole function that is significant for pathogenesis in the human host.     

Evaluation of an Ileorectostomised Rat Model for Resistant Starch Determination

The human ileostomy model, widely considered the benchmark for determining in vivo starch digestibility, has disadvantages. The ileorectostomised rat model (IRM) is a possible surrogate but evidence as to its validity is scant. In this preliminary study, the resistant starch (RS) content of test breads made from refined low (LAW-R) and high amylose wheat (HAW-R) flours was established in a randomised cross-over trial involving six human ileostomy participants. Starch digestibility of refined breads and diets made from these flours was then evaluated in ileorectostomised rats using a similar experimental format. Physical performance measures and other data were also collected for the rat model. The amount of RS in the low- and high-amylose breads as measured using the human model was 0.8 ± 0.1 and 6.5 ± 0.3 g/100 g, respectively. The RS level of HAW-R bread determined using ileorectostomised rats was 5.5 ± 0.8 g/100 g, about 15% less than that recorded in the human study, whereas for conventional wheat breads the models produced similar RS values. While offering promise, further validation using a wide variety of starchy food products is needed before the IRM can be considered an acceptable alternative for RS determination.     

1p36 deletion syndrome: Review and mapping with further characterization of the phenotype,a new cohort of 86 patients

Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype–phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients.     

Schizanthines N, O, and P, tropane alkaloids from the aerial parts of Schizanthus tricolor

Three tropane alkaloids, named schizanthines N, O, and P (1-3), have been isolated from the crude alkaloid extract of the endemic Chilean plant Schizanthus tricolor. On the basis of extensive NMR studies and MS fragmentation analysis, their structures were determined to be 3α-(E)-4-hydroxysenecioyloxy-6β-angeloyloxytropane (1), 3α-(E)-4-hydroxysenecioyloxy-6β-senecioyloxytropane (2), and 3α-mesaconyloxy-6β-senecioyloxytropane (3). Compounds 1 and 2 are the first isomeric alkaloids in the tropane series possessing a hydroxysenecioyl substituent as an esterifying moiety.     

Baseline Brain Metabolism in Resistant Depression and Response to Transcranial Magnetic Stimulation

Neuroimaging studies of patients with treatment-resistant depression (TRD) have reported abnormalities in the frontal and temporal regions. We sought to determine whether metabolism in these regions might be related to response to repetitive transcranial magnetic stimulation (TMS) in patients with TRD. Magnetic resonance images and baseline resting-state cerebral glucose uptake index (gluMI) obtained using ¹⁸F-fluorodeoxyglucose positron emission tomography were analyzed in TRD patients who had participated in a double-blind, randomized, sham-controlled trial of prefrontal 10 Hz TMS. Among the patients randomized to active TMS, 17 responders, defined as having 50% depression score decrease, and 14 nonresponders were investigated for prestimulation glucose metabolism and compared with 39 healthy subjects using a voxel-based analysis. In nonresponders relative to responders, gluMI was lower in left lateral orbitofrontal cortex (OFC), and higher in left amygdala and uncinate fasciculus. OFC and amygdala gluMI negatively correlated in nonresponders, positively correlated in responders, and did not correlate in healthy subjects. Relative to healthy subjects, both responders and nonresponders displayed lower gluMI in right dorsolateral prefrontal (DLPFC), right anterior cingulate (ACC), and left ventrolateral prefrontal cortices. Additionally, nonresponders had lower gluMI in left DLPFC, ACC, left and right insula, and higher gluMI in left amygdala and uncus. Hypometabolisms were partly explained by gray matter reductions, whereas hypermetabolisms were unrelated to structural changes. The findings suggest that different patterns of frontal–temporal–limbic abnormalities may distinguish responders and nonresponders to prefrontal magnetic stimulation. Both preserved OFC volume and amygdala metabolism might precondition response to TMS.