Regulations on excipients used in 3D printing of pediatric oral forms.

A promising solution to customize oral drug formulations for the pediatric population has been found in the use of 3D printing, in particular Fused Deposition Modeling (FDM) and Semi-Solid Extrusion (SSE). Although formulation development is currently limited to research studies, the rapid advances in 3D printing warn of the need for regulation. Indeed, even if the developed formulations include pharmaceutical excipients used to produce traditional oral forms such as tablets, the quantities of excipients used must be adapted to the process. Therefore, the aim of this literature review is to provide a synthesis of the available safety data on excipients mainly used in extrusion-based 3D printing for the pediatric population. A total of 39 relevant articles were identified through two scientific databases (PubMed and Science Direct). Then, groups of the main excipients were listed including their general information (name, chemical structure and pharmaceutical use) and a synthesis of the available safety data extracted from several databases. Finally, the role of the excipients in 3D printing, the amount used in formulations and the oral dose administered per form are presented.

Experimental Evidence of the Collective Brillouin Scattering of Multiple Laser Beams Sharing Acoustic Waves.

The indirect-drive scheme to inertial confinement fusion uses a large number of laser beams arranged in a symmetric angular distribution. Collective laser plasma instabilities can therefore develop that couple all the incident laser waves located in a cone to the daughter wave growing along the cone symmetry axis [D. F. DuBois et al., Phys. Fluids B 4, 241 (1992)]. With complementary diagnostics of Thomson scattering and of the scattered light, we demonstrate the occurrence of collective stimulated Brillouin sidescattering driving collective acoustic waves in indirect-drive experiments.

Synthesis of novel polymerizable molecules bearing bisphosphonate.

In recent years, bisphosphonate chemistry has undergone an exponential growth due to the potential applications of these compounds in medicine and nanobiomaterial research. In this paper we describe the synthesis methods of different families of methacrylic monomers bearing a bisphosphonate with varying lengths of the chain, PEG linkers and more or less hydrolysable functions such as ester, carbamate or amide.

Superparamagnetic bifunctional bisphosphonates nanoparticles: a potential MRI contrast agent for osteoporosis therapy and diagnostic.

A bone targeting nanosystem is reported here which combined magnetic contrast agent for Magnetic Resonance Imaging (MRI) and a therapeutic agent (bisphosphonates) into one drug delivery system. This new targeting nanoplatform consists of superparamagnetic γFe(2)O(3) nanoparticles conjugated to 1,5-dihydroxy-1,5,5-tris-phosphono-pentyl-phosphonic acid (di-HMBPs) molecules with a bisphosphonate function at the outer of the nanoparticle surface for bone targeting. The as-synthesized nanoparticles were evaluated as a specific MRI contrast agent by adsorption study onto hydroxyapatite and MRI measurment. The strong adsorption of the bisphosphonates nanoparticles to hydroxyapatite and their use as MRI T2(∗) contrast agent were demonstrated. Cellular tests performed on human osteosarcoma cells (MG63) show that γFe(2)O(3)@di-HMBP hybrid nanomaterial has no citoxity effect in cell viability and may act as a diagnostic and therapeutic system.

Experimental demonstration of X-ray drive enhancement with rugby-shaped hohlraums.

Rugby-shaped hohlraums have been suggested as a way to enhance x-ray drive in the indirect drive approach to inertial confinement fusion. This Letter presents an experimental comparison of rugby-shaped and cylinder hohlraums used for D2 and D3He-filled capsules implosions on the Omega laser facility, demonstrating an increase of x-ray flux by 18% in rugby-shaped hohlraums. The highest yields to date for deuterium gas implosions in indirect drive on Omega (1.5x10{10} neutrons) were obtained, allowing for the first time the measurement of a DD burn history. Proton spectra measurements provide additional validation of the higher drive in rugby-shaped hohlraums.

[Surgical management of traumatic ear amputations: literature review]. / Prise en charge des amputations traumatiques de l'oreille : revue de la littérature.

Traumatic ear amputation (TEA) is a complete avulsion of a part or of the total auricular tissue. TEA are rare (only 74 cases have been described in the literature) and their handling is complex. The surgeon's objective is to obtain the best cosmetic result without demolishing the auricular area in order to allow future ear reconstruction in case of replantation failure. Many techniques of ear replantation have been described in the literature during the last 30 years: microsurgical replantation, pocket techniques and reattachment techniques. Microsurgical replantation should be achieved every time it is possible. When it is not possible, the surgeon can choose between ear reattachment and a pocket technique according to two clinical features: the size of the amputated part and the involvement of the ear lobe. Ear reattachment can be achieved when the amputated part is smaller than 15 mm or when amputation involves the earlobe. Pocket techniques, which are appropriate for the replantation of the auricular cartilage, can be used when the amputated part is bigger than 15 mm and does not comprise the earlobe.

[Perilunate dislocations and fracture-dislocations of the wrist, a review of 14 cases]. / Luxations et fractures-luxations périlunaires du carpe, étude rétrospective d'une série de 14 cas.

OBJECTIVES: We report a retrospective series of 14 dislocations or perilunate fracture-dislocations. The results of our series are compared with the data of the literature and we discuss epidemiology, types of lesions, surgical treatment, complications and prognosis of this pathology. METHODS: The series included seven pure dislocations and seven fracture-dislocations including three trans-scapho-lunate forms (including one Fenton's syndrome). The displacement of all these lesions was posterior. The mean age was 35 years. Sixty-four percent were manual workers. All 14 patients had undergone surgical treatment through a dorsal approach in the first seven days following the injury. They were reviewed clinically and radiologically with a mean follow-up of 25 months. RESULTS: The average Cooney functional score was 72/100 with two excellent, six good, four fair and two poor results. Average flexion-extension motion arc was 74%, the grip strength was 77% compared to the other wrist. Persistent wrist pain was almost constant. One carpal instability was observed and one patient required a four-corner arthrodesis for SLAC wrist. Eighty-five percent of all patients were employed at least. CONCLUSIONS: Early diagnosis and anatomical reduction can provide satisfactory functional results. Emergency surgical treatment is required. We prefer a dorsal approach and we do not perform primary closed reductions.

[Traumatic pseudo-boutonniere of the metacarpophalangeal joint of the little finger. Case report and review of the literature]. / Pseudoboutonnière traumatique de l'articulation métacarpophalangienne du cinquième doigt: a propos d'un cas et revue de la littérature.

Dislocation of the extensor tendon over the metacarpophalangeal joint is common among patients with rheumatoid arthritis. Patients without arthritis are exceptionally involved. The authors describe a new case of traumatic boutonniere-like of the metacarpophalangeal joint of the little finger. This lesion is a rarely, only eleven cases are described in literature. Patients are usually young adults and dislocation is related to a direct axial trauma on their fifth metacarpophalangeal joint. Diagnosis is clinical and relies on an incomplete active extension of the metacarpophalangeal joint, secondary to the dislocation of the extensor apparatus. Diagnosis is often delayed the lesion remaining unnoticed with the occurrence of others hand lesions. Proper treatment is surgery, based on suturing side to side both extensor digiti minimi and common extensor tendon over the fifth metacarpophalangeal joint. Results are excellent, with a complete range of motion and the absence of recurrence.

Anti-IgE for chronic asthma in adults and children.

BACKGROUND: Omalizumab is a recombinant humanised monoclonal antibody directed against immunoglobulin E (anti-IgE) to inhibit the immune system's response to allergen exposure. Omalizumab is directed against the binding site of IgE for its high affinity Fc receptor. It prevents free serum IgE from attaching to mast cells and other effector cells and prevents IgE mediated inflammatory changes. OBJECTIVES: To determine the efficacy of anti-IgE compared with placebo in patients with allergic asthma SEARCH STRATEGY: We searched the Cochrane Airways Group Asthma trials register for potentially relevant studies (February 2006). SELECTION CRITERIA: Randomised controlled trials examining anti-IgE administered in any manner for any duration. Trials with co-interventions were included as long as they were the same in each arm. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed study quality and extracted and entered data. Three modes of administration were identified from the published literature (inhaled, intravenous and subcutaneous injection). Subgroup analysis was performed by asthma severity. Data were extracted from published and unpublished sources. MAIN RESULTS: Fourteen trials (15 group comparisons) were included in the review, contributing a total of 3143 mild to severe allergic asthmatic participants with high levels of IgE. Treatment with intravenous and subcutaneous Omalizumab significantly reduced free IgE compared with placebo. Omalizumab led to a significant reduction in inhaled steroid (ICS) consumption compared with placebo (-119 mcg/day (95% CI -154 to -83, three trials)). There were significant increases in the number of participants who were able to reduce ICS by over 50% (odds ratio (OR) 2.50, 95% confidence interval (CI) 2.02 to 3.10 (four trials)); or completely withdraw their daily ICS intake (OR 2.50 (95%CI 2.00 to 3.13; four trials)). Participants treated with Omalizumab were less likely to suffer an asthma exacerbation with treatment as an adjunct to ICS (OR 0.52, 95%CI 0.41 to 0.65, five trials), or as an ICS tapering agent (OR 0.47, 95% CI 0.37 to 0.60, four trials). AUTHORS' CONCLUSIONS: Omalizumab was significantly more effective than placebo at increasing the numbers of patients who were able to reduce or withdraw their inhaled steroids, but the clinical value of the reduction in steroid consumption has be considered in the light of the high cost of Omalizumab. The impressive placebo effects observed in control groups bring into question the true effect of Omalizumab. Omalizumab was effective in reducing asthma exacerbations as an adjunctive therapy to inhaled steroids, and during steroid tapering phases of clinical trials. Omalizumab was generally well tolerated, although there were more injection site reactions with Omalizumab. Patient and physician assessments of the drug were positive. Further assessment in paediatric populations is necessary, as is direct double-dummy comparison with ICS.

African dust clouds are associated with increased paediatric asthma accident and emergency admissions on the Caribbean island of Trinidad.

A retrospective ecological study of paediatric asthma patients who attended the Accident and Emergency (A and E) department of the Paediatric Priority Care Facility at the Eric Williams Medical Sciences Complex in relation to Saharan dust visibility and other climatic variables for the period 23 May 2001 to 13 May 2002 was undertaken to determine if there is an association between paediatric A and E asthma visits and Saharan dust cloud cover. A Poisson regression model was used to determine the statistical relationship between acute paediatric asthma A and E visits and Saharan dust cover with and without other variables such as climatic parameters and month. During the study period, there were 2,655 A and E visits for acute asthma. There was an association between increased paediatric asthma admissions and increased Saharan dust cover. The best fitting model estimated that in one month, such as June, a deterioration of visibility due to increased Saharan dust cover from no dust (visibility =16 km) to very dusty (visibility =7 km) would increase a daily admission rate of 7.8 patients to 9.25 when climate variables such as barometric pressure and humidity were kept constant.

[Right bundle branch block: electrocardiographic and prognostic features]. / Bloc de branche droit: aspects electrocardiographiques et pronostiques.

The electrocardiographic appearances and the significance of right bundle branch block were described at the beginning of the 20th century. Typical appearances include prolongation > 0.12 s of the QRS complex, RR' or rR' or Rr' appearances in V1 and widened S waves in the leads exploring the left ventricle (SI, aVL, V5 and V6). A delay in the appearance of the intrinsic deflection > 0.08 s may also be observed in the right precordial leads and negative T waves with ST depression may be seen in V1 and sometimes in V2. Left axis deviation of the QRS complex greater than - 45 degrees suggests associated left anterior hemiblock. Right axis deviation beyond + 120 degrees is equivocal. The principal differential ECG diagnosis is the Brugada syndrome, a familial arrhythmogenic autosomal dominant cardiomyopathy of variable penetration. This diagnosis is suggested when ECG abnormalities are observed in patients with a personal or family history of sudden death. Right bundle branch block only seems to have haemodynamic consequences in cardiac failure with associated asynchrony of the left ventricle or in certain cases of right ventricular dilatation encountered in congenital heart disease. The prognosis of right bundle branch block in the absence of underlying cardiac disease is good but it may be poor in other cases, particularly coronary artery disease. Moreover, the prognosis of right bundle branch block to complete atrioventricular block is rare in the absence of associated cardiac disease.

Anti-IgE for chronic asthma in adults and children.

BACKGROUND: Omalizumab is a recombinant humanised monoclonal antibody directed against immunoglobulin E (IgE) to inhibit the immune system's response to allergen exposure. Omalizumab is directed against the binding site of IgE for its high affinity Fc receptor. It prevents free serum IgE from attaching to mast cells and other effector cells and prevents IgE mediated inflammatory changes. OBJECTIVES: To determine the efficacy of anti-IgE in patients with allergic asthma SEARCH STRATEGY: We searched the Cochrane Airways Group Asthma trials register (February 2003) for potentially relevant studies. SELECTION CRITERIA: Randomised controlled trials examining anti-IgE administered in any manner for any duration. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed study quality and extracted and entered data. Three modes of administration were identified from the published literature (inhaled, intravenous and subcutaneous injection). Subgroup analysis was performed by asthma severity. Data were extracted from published and unpublished sources. MAIN RESULTS: Eight trials were included in the review, contributing a total of 2037 mild to severe allergic asthmatic participants with high levels of IgE. Treatment with intravenous and subcutaneous Omalizumab significantly reduced free IgE compared with placebo. Omalizumab led to a significant reduction in inhaled steroid consumption compared with placebo: -114 mcg/day (95% CI -150 to -78.13, two trials). There were significant increases in the number of participants who were able to reduce steroids by over 50%: odds ratio (OR) 2.50, 95% confidence interval (CI) 2.02 to 3.10 (four trials); or completely withdraw their daily steroid intake: OR 2.50, 95%CI 2.00 to 3.13 (four trials). Participants treated with Omalizumab were less likely to suffer an asthma exacerbation with treatment as an adjunct to steroids (OR 0.49, 95%CI 0.38 to 0.64, four trials), or as a steroid tapering agent (OR 0.47, 95% CI 0.37 to 0.60, four trials). REVIEWERS' CONCLUSIONS: Omalizumab was significantly more effective than placebo at increasing the numbers of patients who were able to reduce or withdraw their inhaled steroids, but the mean difference in steroid consumption achieved with Omalizumab was of debatable clinical value. The impressive effects observed in control groups bring into question the true effect of Omalizumab. Omalizumab was effective in reducing asthma exacerbations as an adjunctive therapy to inhaled steroids. Omalizumab was well tolerated, although the safety profile requires longer term assessment. Patient and physician assessment of the drug was positive. Further assessment in paediatric and severe adult populations is necessary, as is double-dummy comparison with inhaled corticosteroids.

Adenovirus fibre exchange alters cell tropism in vitro but not transgene-specific T CD8+ immune responses in vivo.

Gene transfer with recombinant adenoviruses (rAds) is a powerful means of inducing an immune response against a transgene product. However, little is known about the mechanisms that underlie the induction of the immune response after intramuscular inoculation of adenovirus and, in particular, the relative role of the different cell types transduced. Several studies have suggested that CD8+ cytotoxic T lymphocyte responses elicited after inoculation of adenoviruses (Ads) are induced both by direct transduction of antigen presenting cells (APCs) and by cross-priming. In the present study, a library of fibre-chimeric rAds was screened in order to identify rAds with distinct capacities to express transgene product in murine cell types naturally found in muscle, i.e. myoblasts, endothelial cells (both representing non-APCs) and dendritic cells (representing APCs). Four selected pseudotypes, differing in their ability to infect muscular cells were used to immunize C57BL/6 mice. The relationship between the capacity to transduce non-APC or APC in vitro and the ability to induce humoral and cellular responses against the beta-galactosidase antigen after intramuscular inoculation were studied. Results indicate that CD8+ T cell responses against the beta-galactosidase antigen were similar after inoculation of the four viruses, thus revealing no direct relationship with their ability to transduce myoblasts, endothelial cells or dendritic cells in vitro.

Climatic variables are associated with seasonal acute asthma admissions to accident and emergency room facilities in Trinidad, West Indies.

OBJECTIVES: To determine if there is seasonal variation in acute asthmatic visits to accident and emergency (A&E) facilities in Trinidad and to identify the climatic variables associated with such visits. DESIGN AND METHODS: A retrospective census of patients with asthma, defined as those who required emergency bronchodilator nebulization, was taken at two A&E facilities in Trinidad from 1 January 1997 to 31 December 1999. The study included patients aged 64 years and under. Patient demographic data were obtained from the A&E records. Climate variables were taken from the island's sole Meteorological Office. Multiple regression was used to identify climate variables that were independent predictors of A&E asthma visits. RESULTS: There were a total of 45 842 asthma admissions to the two facilities during the study period. Visits exhibited a cyclic pattern over the 3 years that varied according to the island's dry (January-May) and wet (June-December) seasons. There were more visits during the wet season than the dry (40 [SD=2] vs. 32 [SD=2] visits/day; P<0.001). The results of multiple regression indicated that season (P<0.001), barometric pressure (P<0.001), temperature difference (P<0.001), minimum temperature2 (P<0.001) and wind speed2 (P=0.032) were predictors of paediatric visits. Independent predictors of adult visits were season (P<0.001), relative humidity (P<0.001), minimum temperature (P=0.01), temperature difference2 (P<0.001) and minimum temperature2 (P=0.004). Season and climatic variables explained 18% of the variance of the total A&E asthma admissions. CONCLUSION: There is seasonal variation in acute asthma visits to A&E facilities in Trinidad, which remains significant after controlling for climate variables. However, while climate has a role, there are other factors that may also be responsible for increased visits during the wet season. More research is needed to identify these factors.

Anti-IgE for chronic asthma.

BACKGROUND: Omalizumab is a recombinant humanised monoclonal antibody directed against immunoglobulin E (IgE) to inhibit the immune system's response to allergen exposure. Omalizumab is directed against the binding site of IgE for its high affinity Fc receptor. It prevents free serum IgE from attaching to mast cells and other effector cells and prevents IgE mediated inflammatory changes. The complexes of Omalizumab and IgE formed as a result of treatment are small and not thought to be able to trigger complement activation or give rise to immune complex mediated pathology. OBJECTIVES: To determine the efficacy of anti-IgE in patients with allergic asthma. SEARCH STRATEGY: We searched the Cochrane Airways Group Asthma trials register (February 2003) for potentially relevant studies. SELECTION CRITERIA: Randomised control trials examining anti-IgE administered in any manner for any duration. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed study quality and extracted and entered data. Three modes of administration were identified from the published literature (inhaled, intravenous and subcutaneous injection). Subgroup analysis was performed by asthma severity. Data were extracted from published and unpublished sources. MAIN RESULTS: Eight trials were included in the review, contributing a total of 2037 mild to severe allergic asthmatic participants with high levels of IgE. Treatment with intravenous and subcutaneous Omalizumab resulted in a 98 to 99% reduction in free IgE, reductions which were not observed following placebo treatment. Significant increases in the number of participants who were able to reduce (> 50% reduction in daily corticosteroid usage (four trials): odds ratio (OR) 2.50, 95% confidence interval (CI) 2.02 to 3.10; or completely withdraw their daily steroid intake (four trials): OR 2.50, 95%CI 2.00 to 3.13, were observed. Participants treated with Omalizumab were less likely to suffer an asthma exacerbation (stable steroid phase (three trials): OR 0.46, 95%CI 0.35 to 0.61; steroid reduction phase (three trials) OR 0.46, 95% CI 0.36 to 0.59). REVIEWER'S CONCLUSIONS: Omalizumab was significantly more effective than placebo at increasing the numbers of patients who were able to reduce or withdraw their inhaled steroids and was effective in reducing asthma exacerbations. Omalizumab was well tolerated, although the safety profile requires longer term assessment. Patient and physician assessment of the drug was positive. Further assessment in paediatric and severe adult populations is necessary, as is comparison with inhaled corticosteroids.

Immunoreactive domains and integrin-binding motifs in adenovirus penton base capsomer.

A panel of nine independent mouse monoclonal antibodies (MAbs) against penton base capsomers of subgenus C adenovirus serotypes 2 (Ad2) and 5 (Ad5) were isolated and characterized. Two of them (1D2 and 5A5), raised against Ad5 virion as the immunogen, bound to sodium dodecyl sulfate (SDS)-resistant and subgenus C-specific epitopes that were not present in subgenus B Ad3 penton base. The 1D2 and 5A5 epitopes were mapped to two distinct regions that did not belong to the main variable region carrying the integrin-binding RGD motif at position 340. For the other seven MAbs, raised against recombinant Ad2 penton base protein (9S-pentamers), the epitopes were sensitive to SDS-denaturation, but reacted with native Ad2, Ad5, and Ad3 penton base. The epitopes recognized by the nine MAbs and by polyclonal antipenton base antibodies defined three major immunoreactive regions. One (I) mapped to the N-terminal domain (residues 116-165); the other two regions were almost symmetrically disposed on both sides of the integrin-binding RGD motif at position 340, within residues 248-270 (II), and within residues 368-427 (III) in the C-terminal domain. Region II overlapped the fiber-binding site in penton base (residues 254-260). None of the MAbs showed any detectable virus neutralization effect, but they all slightly augmented the efficiency of Ad-mediated gene transfer. Although none of their epitopes included the RGD-340 tripeptide, substitutions of the arginine residue in the RGD motif abolished the reactivity of six individual and distant epitopes, suggesting a major conformational role for the RGD-containing domain.

A retrospective analysis of invasive Streptococcus pneumoniae infections in Trinidad.

A retrospective analysis of culture-positive cases of S pneumoniae from normally sterile body fluids is reported. Over 40% of patients were 5 years old or less while 28% of patients were 50 years old or more. Meningitis (44%) was the commonest clinical presentation followed closely by pneumonia (31%). The commonest predisposing disorder was human immunodeficiency virus infection though there were no identifiable risk factors in the majority of patients. Mortality from invasive pneumococcal disease was significantly higher in elderly patients compared with other age groups (p = 0.0003). In this study, all S pneumoniae isolates, for which there were antibiotic sensitivity data, were penicillin and/or amoxycillin sensitive.

Single inoculation of replication-defective adenovirus-vectored vaccines at birth in piglets with maternal antibodies induces high level of antibodies and protection against pseudorabies.

In neonates, one limitation of vaccination is its inhibition by maternal antibodies. We show that piglets vaccinated intramuscularly once at birth with recombinant replication-defective adenoviruses developed comparable neutralizing antibody response against pseudorabies virus, independently of the presence or absence of maternal antibodies, and were partially protected against challenge 16 weeks later.