Potential of cannabinoids as treatments for autism spectrum disorders.

Current treatments for autism spectrum disorders (ASD) are limited in efficacy and are often associated with substantial side effects. These medications typically ameliorate problem behaviors associated with ASD, but do not target core symptom domains. As a result, there is a significant amount of research underway for development of novel experimental therapeutics. Endocannabinoids are arachidonic acid-derived lipid neuromodulators, which, in combination with their receptors and associated metabolic enzymes, constitute the endocannabinoid (EC) system. Cannabinoid signaling may be involved in the social impairment and repetitive behaviors observed in those with ASD. In this review, we discuss a possible role of the EC system in excitatory-inhibitory (E-I) imbalance and immune dysregulation in ASD. Novel treatments for the core symptom domains of ASD are needed and phytocannabinoids could be useful experimental therapeutics for core symptoms and associated domains.

A mass guide for the harvest of cortico-cancellous bone from the posterior iliac crest for mandibular reconstruction.

This study sought to find the mass of particulate cortico-cancellous bone graft required per 1 cm continuity defect of the mandible. Harvested bone was weighed, milled and maximally compressed in a syringe. The defect length (DL) was measured in centimetres, and the compressed bone volume (CBV) used was recorded. The wet bone mass (WBM) of bone required per centimetre of mandibular defect, and the mass of bone yielding 1cc of compressed bone was calculated. Results were analysed statistically to determine if clinically meaningful differences exist between male and female iliac crest. Forty three patient records were reviewed (28 female). Thirty patients had bilateral, and 13 patients had unilateral iliac crest harvest. Mean WBM used per centimetre of mandible defect was 6.9 g.WBM required to produce 1cc of CBV was 2.0g. For the bilateral harvest group the mean DL was 10.3 cm, the mean WBM was 66.7 g, and the mean CBV was 33.9cc. There was no significant difference in mean WBM between male (72.8 g) and female (62 g) patients. The mean CBV for males (39.7 g) was significantly higher than females (29.5 g). For patients who had unilateral harvest the mean DL was 7.7 cm, the mean WBM harvested was 59.1 g, and the mean CBV was 29.4cc. The mean wet bone mass of posterior iliac crest required to graft each centimetre of mandibular segmental defect is 6.9 grams. A unilateral posterior iliac crest harvest will yield on average 59.1 grams of bone whilst a bilateral posterior iliac crest harvest will yield on average 66.7 grams.

[Acute pulmonary edema and tocolytic therapy in pregnant women : clinical case and review of literature.] / Le cas clinique du mois. Œdème aigu du poumon et traitement par tocolytiques chez la femme enceinte.

We report the case of a pregnant woman, treated by nifedipine and next by atosiban for premature labour, who develop an acute pulmonary edema. The severity of symptoms and hypoxemia lead the patient to a cesarean and next to the intensive care hospitalization. This clinical case allow us to make a review of literature and reminds us the differential diagnosis to look for during an acute dyspnea in a pregnant woman and the treatment of acute pulmonary edema in these circumstances. The pathophysiological mechanisms which are at the origins of this condition and the implication of the tocolytic treatment will also be discussed.

Nous rapportons le cas d'une patiente traitée par nifédipine puis par atosiban pour une menace d'accouchement prématuré qui développe un œdème aigu du poumon non cardiogénique. La gravité des symptômes et de l'hypoxémie ont mené à une césarienne en urgence et une hospitalisation aux soins intensifs. Ce cas clinique nous permet de faire une revue de littérature et d'aborder les différents diagnostics différentiels à évoquer et rechercher face à une dyspnée aiguë survenant chez une femme enceinte et la prise en charge d'un œdème pulmonaire aigu dans de telles circonstances. Les mécanismes physiopathologiques qui sont à l'origine de cette affection et l'implication du traitement tocolytique seront également discutés.

New technique for endoscopically-assisted particulate graft reconstruction of the mandible.

The reconstruction of mandibular defects using particulate grafts is a proven technique that restores the osseous anatomy effectively. Secondary osseous reconstruction can be accomplished with endoscopic assistance and reduced-access incisions if an intermediate spacer is placed during resection. Two patients required reconstruction after resection of mandibular ameloblastomas. We used a modified protocol that involved the implantation of a graft of particulate corticocancellous bone after removal of the spacer, and prepared the recipient site under endoscopic guidance with small extraoral incisions. The grafts healed uneventfully and matured into ossicles suitable for the placement of osseointegrated implants.

The fine tuning of metabolism, autophagy and differentiation during in vitro myogenesis.

Although the mechanisms controlling skeletal muscle homeostasis have been identified, there is a lack of knowledge of the integrated dynamic processes occurring during myogenesis and their regulation. Here, metabolism, autophagy and differentiation were concomitantly analyzed in mouse muscle satellite cell (MSC)-derived myoblasts and their cross-talk addressed by drug and genetic manipulation. We show that increased mitochondrial biogenesis and activation of mammalian target of rapamycin complex 1 inactivation-independent basal autophagy characterize the conversion of myoblasts into myotubes. Notably, inhibition of autophagic flux halts cell fusion in the latest stages of differentiation and, conversely, when the fusion step of myocytes is impaired the biogenesis of autophagosomes is also impaired. By using myoblasts derived from p53 null mice, we show that in the absence of p53 glycolysis prevails and mitochondrial biogenesis is strongly impaired. P53 null myoblasts show defective terminal differentiation and attenuated basal autophagy when switched into differentiating culture conditions. In conclusion, we demonstrate that basal autophagy contributes to a correct execution of myogenesis and that physiological p53 activity is required for muscle homeostasis by regulating metabolism and by affecting autophagy and differentiation.

In vitro evaluation of mesenchymal stem cell isolation possibility from different intra-oral tissues.

Mesenchymal stem cells (MSCs) are of great interest for the regeneration of tissues and organs. Bone marrow is the first sources of MSCs, but in the recent years there has been interest in other tissues for the isolation of these pluripotent cells. In this study, we investigated the features of MSCs isolated from different oral regions in order to evaluate their potential application in the regeneration of damaged maxillofacial tissues. Sampling from human periodontal ligament, dental pulp, maxillary periosteum as well as bone marrow were collected in order to obtain different stem cell populations. Cells were morphologically and immunophenotipically characterized. Their proliferation potential and their ability to differentiate in osteoblasts were also assessed. All tested cell population showed a similar fibroblast-like morphology and superimposable immunophenotype. Slight differences were observed in proliferation and differentiation potential. Cells isolated from human periodontal ligament, dental pulp, maxillary periosteum had the characteristics of stem cells. Considering their peculiar feature they may alternatively represent interesting cell sources in stem cell-based bone/periodontal tissue regeneration approaches.

DNA damage response by single-strand breaks in terminally differentiated muscle cells and the control of muscle integrity.

DNA single-strand breaks (SSB) formation coordinates the myogenic program, and defects in SSB repair in post-mitotic cells have been associated with human diseases. However, the DNA damage response by SSB in terminally differentiated cells has not been explored yet. Here we show that mouse post-mitotic muscle cells accumulate SSB after alkylation damage, but they are extraordinarily resistant to the killing effects of a variety of SSB-inducers. We demonstrate that, upon SSB induction, phosphorylation of H2AX occurs in myotubes and is largely ataxia telangiectasia mutated (ATM)-dependent. However, the DNA damage signaling cascade downstream of ATM is defective as shown by lack of p53 increase and phosphorylation at serine 18 (human serine 15). The stabilization of p53 by nutlin-3 was ineffective in activating the cell death pathway, indicating that the resistance to SSB inducers is due to defective p53 downstream signaling. The induction of specific types of damage is required to activate the cell death program in myotubes. Besides the topoisomerase inhibitor doxorubicin known for its cardiotoxicity, we show that the mitochondria-specific inhibitor menadione is able to activate p53 and to kill effectively myotubes. Cell killing is p53-dependent as demonstrated by full protection of myotubes lacking p53, but there is a restriction of p53-activated genes. This new information may have important therapeutic implications in the prevention of muscle cell toxicity.

Human periosteum-derived stem cells for tissue engineering applications: the role of VEGF.

Mesenchymal stem cells (MSCs) are promising tools for studying the mechanisms of development and for the regeneration of injured tissues. Correct selection of the MSCs source is crucial in order to obtain a more efficient treatment and, in this respect Periosteum-Derived Cells (PDPCs) may represent an interesting alternative to bone marrow MSCs for osteochondral tissue regeneration. In the present study we have isolated and characterized a MSCs population from the periosteum of human adult donors. PDPCs were expanded under specific culture conditions that prevent fibroblast contamination and support the maintenance of their undifferentiated phenotype. We show, for the first time, that PDPCs expresses VEGF receptor (Flt1 and KDR/Flk1) proteins and that they were similar to bone marrow Multipotent Adult Progenitor Cells (MAPCs). Since the latter are able to differentiate into endothelial cells, we tested the possible PDPCs commitment toward an endothelial phenotype in view of bone tissue engineering approaches that takes into account not only bone formation but also vascularization. PDPCs were treated with two different VEGF concentrations for 7 and 15 days and, alternatively, with the supernatant of human primary osteoblasts. Differently from MAPCs our PDPCs were unable to differentiate into endothelial cells after their in vitro VEGF treatment. On the contrary, growth factor stimulation induces PDPCs differentiation toward osteoblasts. We concluded that in PDPCs the presence of VEGF receptors is related to different cross-talk between osteogenesis and angiogenesis that could involve in situ PDPCs recruitment.

The effects of pattern shape, subliminal stimulation, and voluntary control on multistable visual perception.

Spontaneous figure reversal of ambiguous patterns was analyzed in humans. A) With Necker-"cube"-like, or "drum"-like figures, having square or round shaped "front" and "rear" surfaces, and either large or small "depth", the perceptual intervals corresponding to both interpretations of "drum" were longer than those of "cube"; the perceived "depth" of the figures was less relevant for reversal timing (inter-reversal intervals were only slightly longer for the "deeper" figures). Although the shape of "front" and "rear" surfaces is not a crucial geometrical feature for figure reversal, it did influence its timing. More, or longer information-processing steps should probably be needed for perceptual representations of curvilinear patterns in comparison with rectangular ones. The underlying neural mechanisms are probably located at a relatively peripheral level in the visual system. B) With a modified Necker "cube"-like figure, having the two internal vertices coincident, and the long axis of the figure aligned horizontally, the effect of voluntary control on perception-reversal timing overcomes opposite effects due to either fixation-attention to pattern's focal zones, or subliminal stimulation by the pattern's biased versions, suggesting one or the other perception's possibility, while it is enhanced by concordant imagery. Voluntary control should intervene downward at a high-level processing, and should probably affect both a decision-making and a perception-stabilizing mechanism in the process of the pattern's unconscious interpretation. Results A and B are confronted with other results on both perceptual and binocular rivalry of up-to-date literature, in the frame of discussions on low-level bottom-up automatic stimulus-driven processing vs high-level top-down covert attention-driven processing.

A prospective trial of poly-L-lactic/polyglycolic acid co-polymer plates and screws for internal fixation of mandibular fractures.

The aim of this study was to test the performance of poly-L-lactic/polyglycolic acid (PLLA/PGA) co-polymer plates and screws in the fixation of mandibular fractures. Following clinical and radiographic examination, internal fixation was achieved with PLLA/PGA co-polymer plates and screws in 31 patients. Elastic maxillomandibular fixation was maintained for 4 weeks and a blenderized diet for 6 weeks. Patients were followed up at 1 week, 6 weeks, and 3, 6 and 12 months post surgery, and evaluated clinically for swelling, pain, mucosal discoloration and occlusal relation. Segment stability, fracture healing and screw-hole ossification were assessed radiographically. Of the 29 patients who completed the trial, 20 had an uncomplicated postoperative period, resulting in complete bone union. Radiographic evidence of screw-hole ossification was noted in several patients, with considerable site-dependent rate variation. Nine patients developed complications ranging from minor dehiscence (4 patients) to frank sepsis requiring plate removal (5 patients), resulting in a 22.5% complication rate. There were no cases of non-union at the end of the fixation period. The reported complication rate following titanium internal fixation of mandibular fractures is 13.7%-43%. PLLA/PGA co-polymer plate and screw fixation of mandibular fractures, although technically more challenging and costly, is a viable alternative to traditional metal devices in selected patients.

Optical coherence tomography findings of incomplete posterior vitreoschisis with vitreomacular traction syndrome and impending macular hole: a case report.

PURPOSE: Vitreomacular traction syndrome is a clinical entity characterized by partial posterior vitreous detachment in combination with persistent macular adherence. Recently, optical coherence tomography (OCT) allowed visualization of incomplete posterior vitreoschisis leading to vitreomacular traction. METHODS: The authors report on a 57-year-old woman with blurred vision in her left eye. RESULTS: OCT scan showed incomplete posterior vitreoschisis with vitreomacular traction syndrome and impending macular hole in her left eye. CONCLUSIONS: The intraoperative findings together with the evidence that the internal limiting membrane (ILM) thickness is thinner than the axial resolution of the Stratus OCT (8 micronm) and a spontaneous ILM detachment has never been demonstrated are likely to support the hypothesis that posterior vitreoschisis exists and can be associated with vitreomacular traction syndrome.

[Perioperative heart rate in patients taking beta-blockers: reality and efficiency of the treatment]. / Analyse des fréquences cardiaques durant la période péri-opératoire chez des patients prenant des bêtabloquants: réalité et efficacité du traitement.

OBJECTIVE: To compare perioperative heart rate (HR) control of patients chronically exposed to beta-blockers (BB) with those of patients whom BB treatment was initiated one week preoperatively. METHODS: HR was noticed at three successive time periods: the anaesthesia visit, just before induction of anaesthesia, and during surgery (maximum and minimum HR). HR, presented as mean+/-SD, was compared among 3 groups of patients: BB chronic treatment, preoperative BB, and a control group not taking BB. RESULTS: Four hundred (and) six patients were included: 181 chronic BB patients, 20 preoperative BB, and 205 control patients. As compared to the control group, HR of chronic BB patients were lower (P<0.05) than those of the control group at the three time period of the study. In the preoperative BB patient group, one week BB treatment resulted in a mean 30% reduction of HR. Just before induction of anaesthesia, HR of preoperative BB patients was lower than that of chronic BB patients (55+/-11 vs 67+/-13 b/min; P<0.05). CONCLUSION: Beta-blockers treatment initiated one week before surgery could be more effective on perioperative HR control than chronic BB treatment.

Effectiveness of the CRCAPRO program in identifying patients suspected for HNPCC.

Subjects affected by hereditary non-polyposis colorectal cancer exhibit a high susceptibility to colon and extracolonic tumours, due to MMR gene defects. Revised Bethesda criteria are used to select patients as candidates for genetic tests. Recently, the CRCAPRO model has been developed, based on family history of colorectal and endometrial cancers. Our study aims to evaluate the reliability of CRCAPRO in identifying mutation carriers. We used the CRCAPRO program to evaluate carrier probability risk in 99 patients fulfilling Amsterdam or Bethesda guidelines. MLH1 and MSH2 were studied by direct sequencing in all the 99 patients, and the study of microsatellite instability and of MMR proteins expression was performed. Nine MLH1 and nine MSH2 germline mutations were identified. Five out of the nine patients with MLH1 mutation showed a CRCAPRO risk evaluation of less than 20%. The same happened for four out of nine patients with MSH2 mutation. Of the 17 patients with an estimated risk of more than 80%, only four harboured a mutation, all in the MSH2 gene. The highest risk calculated by the CRCAPRO system in the nine carriers of a MLH1 mutation has been 31.7%. In our experience, the CRCAPRO program sensitivity and specificity appears to be low but needs to be further evaluated in larger samples.

Comparison of the effects of mepivacaine and lidocaine on rat myocardium.

BACKGROUND AND OBJECTIVE: To compare the inotropic and lusitropic effect of lidocaine and mepivacaine on rat papillary muscle. METHODS: Effects of lidocaine and mepivacaine (10-8-10-3 M) were studied in rat left ventricular papillary muscles in vitro at a calcium concentration of 1 mmol, under low (isotony) and high (isometric) loads. RESULTS: Lidocaine induced a significant negative inotropic effect in isotonic and isometric conditions whereas mepivacaine did not. Mepivacaine only induced a negative inotropic effect when added as a bolus for the highest concentration and this effect was significantly more pronounced with lidocaine than with mepivacaine (active force at 10-3 M: 63 +/- 10 vs. 84 +/- 10% of baseline, P < 0.05). Increasing calcium concentration resulted in a greater positive inotropic effect in the control (199 +/- 11% of baseline) and mepivacaine groups (197 +/- 22% of baseline) when compared to the lidocaine group (163 +/- 19% of baseline, P < 0.05 vs. lidocaine and control groups), suggesting an impairment on intracellular Ca2+ handling by lidocaine. A negative lusitropic effect under low load was observed only for mepivacaine and suggested an impairment of sarcoplasmic reticulum function. Lidocaine and mepivacaine did not modify post-rest potentiation but significantly depressed the force-frequency relationship. CONCLUSIONS: The negative inotropic and lusitropic effects induced by lidocaine were more important than that of mepivacaine and may involve an impairment of intracellular Ca2+ handling.

Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts.

Trophoblast research over the past decades has underlined the striking similarities between the proliferative, migratory and invasive properties of placental cells and those of cancer cells. This review recapitulates the numerous key molecules, proto-oncogenes, growth factors, receptors, enzymes, hormones, peptides and tumour-associated antigens (TAAs) expressed by both trophoblastic and cancer cells in an attempt to evaluate the genes and proteins forming molecular circuits and regulating the similar behaviours of these cells. Among the autocrine and paracrine loops that might be involved in the strong proliferative capacity of trophoblastic and cancer cells, epidermal growth factor (EGF)/EGF receptor (EGFR), hepatocyte growth factor (HGF)/HGF receptor (HGFR) (Met) and vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) loops may play a predominant role. Similar mechanisms of migration and invasion displayed by trophoblastic and malignant cells comprise alterations in the adhesion molecule phenotype, including the increased expression of alpha1beta1 and alphavbeta3 integrin receptors, whereas another critical molecular event is the down-regulation of the cell adhesion molecule E-cadherin. Among proteases that may play an active role in the invasive capacities of these cells, accumulating evidence suggests that matrix metalloproteinase-9 (MMP-9) expression/activation is a prerequisite. Finally, an overview of molecular circuitries shared by trophoblast and cancer cells reveals that the activation of the phosphatidylinositol 3'-kinase (PI3K)/AKT axis has recently emerged as a central feature of signalling pathways used by these cells to achieve their proliferative, migratory and invasive processes.

Soluble and insoluble signals and the induction of bone formation: molecular therapeutics recapitulating development.

The osteogenic molecular signals of the transforming growth factor-beta (TGF-beta) superfamily, the bone morphogenetic/osteogenic proteins (BMPs/OPs) and uniquely in primates the TGF-beta isoforms per se, pleiotropic members of the TGF-beta supergene family, induce de novo endochondral bone formation as a recapitulation of embryonic development. Naturally derived BMPs/OPs and gamma-irradiated human recombinant osteogenic protein-1 (hOP-1) delivered by allogeneic and xenogeneic insoluble collagenous matrices initiate de novo bone induction in heterotopic and orthotopic sites of the primate Papio ursinus, culminating in complete calvarial regeneration by day 90 and maintaining the regenerated structures by day 365. The induction of bone by hOP-1 in P. ursinus develops as a mosaic structure with distinct spatial and temporal patterns of gene expression of members of the TGF-beta superfamily that singly, synergistically and synchronously initiate and maintain tissue induction and morphogenesis. The temporal and spatial expressions of TGF-beta1 mRNA indicate a specific temporal transcriptional window during which expression of TGF-beta1 is mandatory for successful and optimal osteogenesis. Highly purified naturally derived bovine BMPs/OPs and hOP-1 delivered by human collagenous bone matrices and porous hydroxyapatite, respectively, induce bone formation in mandibular defects of human patients. By using healthy body sites as bioreactors it is possible to recapitulate embryonic developments by inducing selected biomaterials combined with recombinant proteins to transform into custom-made prefabricated bone grafts for human reconstruction. The osteogenic proteins of the TGF-beta superfamily, BMPs/OPs and TGF-betas, the last endowed with the striking prerogative of inducing endochondral bone formation in primates only, are helping to engineer skeletal reconstruction in molecular terms.

Photorefractive keratectomy in high myopic defects with or without intraoperative mitomycin C: 1-year results.

PURPOSE: To study the results of the prophylactic use of mitomycin C (MMC) to reduce haze formation and refractive regression after excimer laser photorefractive keratectomy (PRK) for high myopic defects (>5 diopters). METHODS: Prospective, consecutive, observational study. A total of 124 eyes of 62 patients were divided into two groups of 31 patients, 62 eyes each (Groups A and B). Only Group A was treated with MMC 0.02%. The data of the two groups of eyes, related to the best-corrected visual acuity (BCVA), to the difference of refraction pre- and post-treatment, and to the corneal haze, were analyzed through combined permutation tests by using the NPC Test software . RESULTS: BCVA of Group A, 1 year after treatment, was better than that of the control Group B (one-sided p value = 0.013): Group A - 3 eyes (4.8%) had a loss of a decimal fraction and no eyes > 1; Group B - 13 eyes (20.9%) had a loss of a decimal fraction and 1 eye (1.6%) of 2. There was a smaller difference between attempted and achieved SE correction in Group A with respect to Group B (one-sided p value = 0.068): Group A - 43 eyes (69.3%) within +/- 0.50 D; Group B - 31 eyes (50%) within +/- 0.50 D. there was a smaller incidence of corneal haze in the group for which MMC was used (one-sided p value = 0.005). CONCLUSIONS: In this study, the application of MMC 0.02% solution immediately after PRK produced lower haze rates and had better predictability and improved efficacy 1 year after treatment.

[Function recovery in patients with knee arthroplasty: role of proprioceptive rehabilitation]. / Il recupero funzionale del ginocchio artroprotesizzato: ruolo dell'allenamento propriocettivo.

This study evaluates the outcome of proprioceptive rehabilitation in 18 patients who underwent knee joint prosthetic replacement using the dynamic electronic plate Pro-kin_machine. The proprioceptive performance was determined by having the patients trace a set of three outlines (horizontal, vertical and circular) using the foot of the operated limb. The measures of outcome parameters were: 1) time taken to do the test; 2) score of accuracy of the test measured in percentage. Tests were performed on admission, half way through rehabilitation and on discharge. Each patient had 15 sittings of physiotherapy. Our results demonstrate a significant improvement of both parameters at the end of the treatment. After prosthetic knee joint replacement, not only is it important to re-establish mechanical stability but also dynamic stability. The latter can be achieved through active virtual taping by the stabilizer muscles. Prompt management of instability of the joint in the rehabilitation phase is extremely important in the re-activating of the control mechanisms that are compromised by the surgical operation.

Temporomandibular joint morphology following post-traumatic ankylosis in 26 patients.

This study evaluated the joint morphology on coronal computed tomography of ankylosed temporomandibular joints in 26 patients. All patients developed ankylosis following blunt trauma. Post-ankylosis joint morphology was assessed to determine if the precursor condylar fracture could be identified and this was compared to the condylar fracture prevalence to determine if any condylar fractures have an increased risk factor for ankylosis. Mean age at presentation was 20.9+/-14.41 years (range 6-58) and mean age at injury was 13.84+/-13.81 years (range 3-53). Thirty-seven joints were ankylosed in 26 patients (11 bilateral, 15 unilateral) with 27 joints in 19 patients showing vestiges of a medially dislocated condylar fracture (72.9% of joints). The prevalence of MDCF at our unit over a period of 6 months was 16.8% (16 of 95 condylar fractures). This suggests that a medially dislocated condylar fracture is more likely to ankylose than other condylar fractures. A hypothesis is proposed to explain this increased risk.