Cowries derived aragonite as raw biomaterials for bone regenerative medicine.

Carbonate apatites are sought as a bone substitute due to their biocompatibility and excellent resorbability. The present study deals with Cowrie's shell derived powder (CSDP) as natural biomaterial for bone regenerative medicine. Structural and physicochemical analysis showed that Cowrie's shells, presenting brick and mortar microstructures, were mainly composed of aragonite crystals, which were converted into poorly crystalline B-type carbonate apatite once soaked, at 37 °C, in simulated body fluid for 7 days, reflecting bioactive features. Cytotoxic assays showed that CSDP boosted human stem cell proliferation over the study time compared to nacre derived powder (NDP), used as positive control. Human stem cells adopted a flattened morphology and established physical contact with CSDP, signature of a good biocompatibility. Thus, these results suggested that CSDP presents a great interest for bone regenerative medicine, and could be a useful and versatile carrier/scaffold for bone tissue engineering or a raw material for 3D printed orthopedic devices.

Inhaled nitric oxide for acute chest syndrome in adult sickle cell patients: a randomized controlled study.

PURPOSE: Previous clinical trials suggested that inhaled nitric oxide (iNO) could have beneficial effects in sickle cell disease (SCD) patients with acute chest syndrome (ACS). METHODS: To determine whether iNO reduces treatment failure rate in adult patients with ACS, we conducted a prospective, double-blind, randomized, placebo-controlled clinical trial. iNO (80 ppm, N = 50) gas or inhaled nitrogen placebo (N = 50) was delivered for 3 days. The primary end point was the number of patients with treatment failure at day 3, defined as any one of the following: (1) death from any cause, (2) need for endotracheal intubation, (3) decrease of PaO2/FiO2 ≥ 15 mmHg between days 1 and 3, (4) augmented therapy defined as new transfusion or phlebotomy. RESULTS: The two groups did not differ in age, gender, genotype, or baseline characteristics and biological parameters. iNO was well tolerated, although a transient decrease in nitric oxide concentration was mandated in one patient. There was no significant difference in the primary end point between the iNO and placebo groups [23 (46 %) and 29 (58 %); odds ratio (OR), 0.8; 95 % CI, 0.54-1.16; p = 0.23]. A post hoc analysis of the 45 patients with hypoxemia showed that those in the iNO group were less likely to experience treatment failure at day 3 [7 (33.3 %) vs 18 (72 %); OR = 0.19; 95 % CI, 0.06-0.68; p = 0.009]. CONCLUSIONS: iNO did not reduce the rate of treatment failure in adult SCD patients with mild to moderate ACS. Future trials should target more severely ill ACS patients with hypoxemia. CLINICAL TRIAL REGISTRATION: NCT00748423.

Gene screening of Wharton's jelly derived stem cells.

Stem cells are the most powerful candidate for the treatment of various diseases. Suitable stem cell source should be harvested with minimal invasive procedure, found in great quantity, and transplanted with no risk of immune response and tumor formation. Fetal derived stem cells have been introduced as an excellent alternative to adult and embryonic stem cells use, but unfortunately, their degree of "stemness" and molecular characterization is still unclear. Several studies have been performed deciphering whether fetal stem cells meet the needs of regenerative medicine. We believe that a transcriptomic screening of Wharton's jelly stem cells will bring insights on cell population features.

Molecular characterization of 39 de novo sSMC: contribution to prognosis and genetic counselling, a prospective study.

Small supernumerary marker chromosomes (sSMCs) are structurally abnormal chromosomes that cannot be characterized by karyotype. In many prenatal cases of de novo sSMC, the outcome of pregnancy is difficult to predict because the euchromatin content is unclear. This study aimed to determine the presence or absence of euchromatin material of 39 de novo prenatally ascertained sSMC by array-comparative genomic hybridization (array-CGH) or single nucleotide polymorphism (SNP) array. Cases were prospectively ascertained from the study of 65,000 prenatal samples [0.060%; 95% confidence interval (CI), 0.042-0.082]. Array-CGH showed that 22 markers were derived from non-acrocentric markers (56.4%) and 7 from acrocentic markers (18%). The 10 additional cases remained unidentified (25.6%), but 7 of 10 could be further identified using fluorescence in situ hybridization; 69% of de novo sSMC contained euchromatin material, 95.4% of which for non-acrocentric markers. Some sSMC containing euchromatin had a normal phenotype (31% for non-acrocentric and 75% for acrocentric markers). Statistical differences between normal and abnormal phenotypes were shown for the size of the euchromatin material (more or less than 1 Mb, p = 0.0006) and number of genes (more or less than 10, p = 0.0009). This study is the largest to date and shows the utility of array-CGH or SNP array in the detection and characterization of de novo sSMC in a prenatal context.

[Epidemiology of orofacial clefts (1995-2006) in France (Congenital Malformations of Alsace Registry)]. / Épidémiologie des fentes labio-palatines : expérience du Registre de malformations congénitales d'Alsace entre 1995 et 2006.

OBJECTIVES: To review clinical and epidemiologic data of orofacial clefts and to evaluate the efficacy and the impact of prenatal diagnosis. MATERIAL AND METHODS: A population-based retrospective study was carried out on data from the Congenital Malformations of Alsace Registry (France) between 1995 and 2006. RESULTS: A total of 321 orofacial clefts were recorded (overall prevalence, 2.1 per 1000), divided into cleft lip (CL) or cleft lip palate (CLP) (204 cases) and cleft palate (117 cases). The cleft lip and cleft lip palate CL±P sex-ratio was 1.87, whereas the CP sex-ratio was 1. CLs were more often unilateral than CLPs (79% versus 59%). CLs were unilateral in 79% of the cases (60/76), bilateral in 20% of the cases (15/76), and median in 1% (1/76); 55% of the unilateral CLs were right and 45% were left. CLPs were unilateral in 59% of the cases (76/128), bilateral in 39% of the cases (50/128), and median in 2% (2/128); 45% of the unilateral CLPs were right and 55% were left. The 117 CPs were divided into 50 clefts of the total palate (43%) and 67 clefts of the posterior palate (57%); 25 cases (21%) of Pierre Robin sequence were collected. Sixty-six percent of CL±P (134/204) were associated with other congenital anomalies, including chromosome abnormality in 31 cases and identified monogenic syndrome or association in 12 cases. The most frequent chromosome abnormalities were 16 cases of trisomy 13 and 7 cases of trisomy 18. No cases of 22q11.2 microdeletion or duplication were detected among CL±P. Monogenic syndromes were identified in 6% (12/204) of CL±P cases: Van der Woude syndrome (2 cases); CHARGE syndrome (2 cases); ectrodactyly, ectodermal dysplasia, and cleft/lip palate (EEC) syndrome (2 cases); branchiooculofacial (BOF) syndrome (1 case); Treacher-Collins syndrome (1 case); Nager syndrome (1 case); Goldenhar syndrome (1 case); holoprosencephaly spectrum (1 case); and Meckel syndrome (1 case). Forty-two percent of CPs (49/117) were associated with other congenital anomalies; chromosome abnormality was identified in 12 cases and monogenic syndrome was diagnosed in 14 cases. The most frequent chromosome abnormality was 22q11 microdeletion (5 cases). Monogenic syndromes were recognized in 12% of the CP cases (14/117): fragile X syndrome (2 cases), Meckel syndrome (2 cases), Orofaciodigital syndrome type I (OFD1) (1 case), Stickler syndrome (1 case), Larsen syndrome (1 case), Kniest syndrome (1 case), Cornelia de Lange syndrome (1 case), thanatophoric dysplasia (1 case), other unknown bone chondrodysplasia (1 case), Fryns syndrome (1 case), fetal akinesia sequence (1 case), and Silver-Russel syndrome (1 case). Fifty-two percent of CL cases (106/204) were prenatally diagnosed. An increasing tendency was observed between the 1995-2000 and 2001-2006 periods with a detection rate increasing from 47% to 56%. During the whole period, only 1 case of CP was prenatally diagnosed. Eighty-two percent of all cases (263/321) were livebirths; 8 stillbirths were reported (2%); 50 syndromic or associated cases (16%) led to medical abortion (no termination of pregnancy was performed for isolated cleft). CONCLUSION: Orofacial clefts are a frequent malformation with a total prevalence of 2.1 per 1000 total births. Sonbographic prenatal diagnosis of orofacial clefts remains difficult with a mean detection rate about 50% for CL±P and is extremely rare for CP. Associated malformations and genetic syndromes are frequent and require a systematic survey. This study also highlights the different pathogenic background of CL±P compared to CP, regarding the sex-ratio and the proportion and type of associated malformations.

Brute force meets Bruno force in parameter optimisation: introduction of novel constraints for parameter accuracy improvement by symbolic computation.

Recent remarkable advances in computer performance have enabled us to estimate parameter values by the huge power of numerical computation, the so-called 'Brute force', resulting in the high-speed simultaneous estimation of a large number of parameter values. However, these advancements have not been fully utilised to improve the accuracy of parameter estimation. Here the authors review a novel method for parameter estimation using symbolic computation power, 'Bruno force', named after Bruno Buchberger, who found the Gröbner base. In the method, the objective functions combining the symbolic computation techniques are formulated. First, the authors utilise a symbolic computation technique, differential elimination, which symbolically reduces an equivalent system of differential equations to a system in a given model. Second, since its equivalent system is frequently composed of large equations, the system is further simplified by another symbolic computation. The performance of the authors' method for parameter accuracy improvement is illustrated by two representative models in biology, a simple cascade model and a negative feedback model in comparison with the previous numerical methods. Finally, the limits and extensions of the authors' method are discussed, in terms of the possible power of 'Bruno force' for the development of a new horizon in parameter estimation.

External or internal lateral osteotomy: why I choose the external percutaneous approach.

The authors present their surgical experience with the management of patients with dorsum deformities using a precise technique: the external percutaneous approach. The indications for this technique have still not been set out very clearly in the rhinological textbooks or manuals, and so novices (and not only novices) have difficulty in understanding and applying it. We therefore try to systematise and clarify these indications in brief, together with the technical details, providing a comparison with another technique that is in very widespread use at present: the internal lateral osteotomy. Although the external percutaneous approach is not used very often--in our experience in 30% of cases only--we find the results very satisfactory and we recommend it when it is required by the anatomic conditions.

Feasibility, limits and problems of clinical studies in Intensive Care Unit.

In critical care medicine there is still a paucity of evidence on how to manage most of the clinical problems commonly encountered in critically ill patients. Randomized controlled trials (RCTs) are the most powerful instruments to evaluate the efficacy of a therapeutic intervention and to generate evidence for clinical practice. Unfortunately, the design and conduct of RCTs in our field are particularly complicated, because of some intrinsic and structural problems (e.g. lack of reliable nosography, concomitant use of different therapies, problems in the definition of end-points besides mortality) that will be discussed in this review. Further challenges are represented by the lack of tradition of large ICU networks, difficulties in linking or integrating physiologic and therapeutic objectives in designing clinical protocols, scarcity of independent or non-profit funds. A particularly stimulating opportunity of development is represented also by the relationship of critical care to EBM. Because of the above problems, metanalyses could be less informative than in other areas of medicine, as they are based on few trials which are often contradictory and of unsatisfactory quality. Few suggestions are formulated which could help looking forwards.

Phenotype in X chromosome rearrangements: pitfalls of X inactivation study.

OBJECTIVE: X inactivation pattern in X chromosome rearrangements usually favor the less unbalanced cells. It is correlated to a normal phenotype, small size or infertility. We studied the correlation between phenotype and X inactivation ratio in patients with X structural anomalies. PATIENTS AND METHODS: During the 1999-2005 period, 12 X chromosome rearrangements, including three prenatal cases, were diagnosed in the Laboratoire de Cytogénétique of Strasbourg. In seven cases, X inactivation ratio could be assessed by late replication or methylation assay. RESULTS: In three of seven cases (del Xp, dup Xp, t(X;A)), X inactivation ratio and phenotype were consistent. The four other cases showed discrepancies between phenotype and X inactivation pattern: mental retardation and dysmorphism in a case of balanced X-autosome translocation, schizophrenia and autism in two cases of XX maleness and MLS syndrome (microphthalmia with linear skin defects) in a case of Xp(21.3-pter) deletion. CONCLUSION: Discrepancies between X inactivation ratio and phenotype are not rare and can be due to gene disruption, position effect, complex microrearrangements, variable pattern of X inactivation in different tissues or fortuitous association. In this context, the prognostic value of X inactivation study in prenatal diagnosis will be discussed.

Participation of French general practitioners in end-of-life decisions for their hospitalised patients.

BACKGROUND AND OBJECTIVE: Assuming the hypothesis that the general practitioner (GP) can and should be a key player in making end-of-life decisions for hospitalised patients, perceptions of GPs' role assigned to them by hospital doctors in making withdrawal decisions for such patients were surveyed. DESIGN: Questionnaire survey. SETTING: Urban (districts located near Paris) and rural (southern France) areas. PARTICIPANTS: GPs. RESULTS: The response rate was 32.2% (161/500), and it was observed that 70.8% of respondents believed that their participation in withdrawal decisions for their hospitalised patients was essential, whereas 42.1% believed that the hospital doctors were sufficiently skilled to make withdrawal decisions without input from the GPs. Most respondents were found to believe that they had the necessary skills (91.9%) and enough time (87.6%) to participate in withdrawal decisions. The last case of treatment withdrawal in hospital for one of their patients was described by 40% (65/161) of respondents, of whom only 40.0% (26/65) believed that they had participated actively in the decision process. The major factors in the multivariate analysis were the GP's strong belief that his or her participation was essential (p = 0.01), information on admission of the patient given to the GP by the hospital department (p = 0.007), rural practice (p = 0.03), visit to the patient dying in hospital (p = 0.02) and a request by the family to be kept informed about the patient (p = 0.003). CONCLUSION: Strong interest was evinced among GPs regarding end-of-life issues, as well as considerable experience of patients dying at home. As GPs are more closely corrected to patients' families, they may be a good choice for third-party intervention in making end-of-life decisions for hospitalised patients.

Head and neck squamous cell carcinoma transcriptome analysis by comprehensive validated differential display.

Head and neck squamous cell carcinoma (HNSCC) is common worldwide and is associated with a poor rate of survival. Identification of new markers and therapeutic targets, and understanding the complex transformation process, will require a comprehensive description of genome expression, that can only be achieved by combining different methodologies. We report here the HNSCC transcriptome that was determined by exhaustive differential display (DD) analysis coupled with validation by different methods on the same patient samples. The resulting 820 nonredundant sequences were analysed by high throughput bioinformatics analysis. Human proteins were identified for 73% (596) of the DD sequences. A large proportion (>50%) of the remaining unassigned sequences match ESTs (expressed sequence tags) from human tumours. For the functionally annotated proteins, there is significant enrichment for relevant biological processes, including cell motility, protein biosynthesis, stress and immune responses, cell death, cell cycle, cell proliferation and/or maintenance and transport. Three of the novel proteins (TMEM16A, PHLDB2 and ARHGAP21) were analysed further to show that they have the potential to be developed as therapeutic targets.

[The project of a law concerning patients' rights at the end of life]. / Le projet de loi relative aux droits des malades et à la fin de vie.

A bill about Patients' rights and the end of life was adopted unanimously by the National Assembly on November 30, 2004. Article 1 provides that the physician is not obligated to continue treatment "when the latter appears futile, disproportional and has no effect other than artificially maintaining the patient's life". Article 2 recognizes that painkillers administered at high doses to terminally ill patients may as a side effect "shorten the patient's life". Conscious patients and the families of unconscious patients must be so informed, and the discussion must be mentioned in the patient's file. Physicians must respect their patients' refusal of treatment, even in life-threatening situations. On the other hand, patients who are not terminally ill must await the expiration of a mandatory waiting period before the physicians must comply with their wishes to refuse care. Article 3 specifies that any treatment can be withheld or withdrawn, including artificial nutrition. The law specifies that it is applicable in 4 different sets of situations: for patients who are or are not terminally and for those who are or are not conscious. Article 9 makes clear that futile treatment of unconscious patients can be withheld or withdrawn. Article 7 specifies that adults may draw up advance directives to indicate their wishes for their end of life and their desires regarding the withholding or withdrawal of treatment. Withholding or withdrawing active treatment is authorized under 3 conditions: the consent from the patient, or if he or she is unconscious, the approval of the health-care proxy, or a family member or close friend if the patient is unconscious; the inclusion of the decision in the patient's medical file, and a group decision-making process.

Loss of HOP tumour suppressor expression in head and neck squamous cell carcinoma.

We report that homeodomain-only protein (HOP) is expressed in the suprabasal layer of normal upper aerodigestive tract epithelium and expression strongly decreases in hypopharyngeal carcinoma. Interestingly, HOP has very recently been shown to be a tumour suppressor involved in differentiation, suggesting that HOP may have a similar role in head and neck squamous cell carcinoma (HNSSC).

Successful weaning from mechanical ventilation after coronary angioplasty.

Weaning failure can be caused by myocardial ischaemia during the switch from mechanical to spontaneous ventilation. We report ischaemic left ventricular failure and ischaemic mitral insufficiency during weaning. Angiography showed that the coronary vessels were stenosed. Transluminal angioplasty made weaning possible. We conclude that acute ischaemic mitral insufficiency may contribute to cardiac failure during weaning and that angioplasty, by reversing it, can allow successful weaning.

Prenatal diagnosis of a true fetal tetraploidy in direct and cultured chorionic villi.

Prenatal diagnosis of a true fetal tetraploidy in direct and cultured chorionic villi: Tetraploidy is characterized by four complete sets of chromosomes (4n= 92). Although it has been frequently reported in spontaneous abortions, tetraploidy is extremely rare in term pregnancy. Most of late surviving patients are diploid/tetraploid mosaics and present severe mental and physical impairment. Up to date, only five tetraploidies were ascertained in the prenatal stage in amniocytes and/or fetal blood lymphocytes. No one has been reported in chorionic villi probably because tetraploidy is generally considered in this tissue as a false positive result due to confined placental mosaicism (CPM) or placental culture artefacts. We report here on a case of tetraploidy detected in chorionic villi because of fetal cystic hygroma. We discuss the reliability of this diagnosis and propose guidelines in the follow-up of tetraploidies detected after chorionic villus sampling (CVS). Thus a misdiagnosis of this poor condition will be avoided at best and an appropriate genetic counseling will be given to the parents.