In situ-Forming Pharmaceutical Organogels Based on the Self-Assembly of L-Alanine Derivatives

PURPOSE: To characterize novel pharmaceutical organogels based on the self-assembly of L-alanine derivatives in hydrophobic vehicles. METHODS: The gelation properties of N-lauroyl-L-alanine (LA) and N-lauroyl-L-alanine methyl ester (LAM) were investigated in the presence of various solvents. Gel-sol and sol-gel transitions were evaluated by the inverse flow method, and gelation kinetics were determined by turbidimetry. The in vitro release kinetics of labeled dextran physically dispersed in the oil-based organogel was assessed in phosphate-buffered saline. In situ formation of the implants was evaluated in rats by subcutaneously injecting a solution containing LAM, an oil, and a water-diffusible inhibitor of self-assembly (ethanol). RESULTS: The LAM-containing formulations showed a hysteretic gelling behavior with transition temperatures between 10 and 55 degrees C. Gelation kinetics exhibited a lag time of 10 and 30 min at 25 and 37 degrees C, respectively. In vitro, fluorescein isothiocyanate-dextran was released from the gel in a sustained manner with less than 6% released after 20 days. The addition of ethanol to the LAM/oil mixture inhibited gelation and allowed subcutaneous injection of the solution at room temperature. After injection, ethanol diffusion led to the formation of a solid implant. CONCLUSIONS: Low-molecular weight self-assembling organogelators may allow the preparation of novel in situ-forming hydrophobic implants.     

Detection and false-positive rates of maternal serum markers for Down syndrome screening according to maternal age in women over 35 years of age. A study of the agreement of eight dedicated software packages

Maternal serum markers for trisomy 21 screening (MSS) can be assayed in women > or =35 years in an attempt to reduce the need for invasive procedures and thereby avoid their side effects. Our objective was to compare, in women > or =35, eight different software packages dedicated to second trimester MSS, thus providing reliable data for patient counselling. A simulation study was carried out on 189 sera from women with Down syndrome fetuses and 11 962 sera from mothers of unaffected babies. The first step was to estimate the joint distribution of alpha-fetoprotein (AFP) and free beta-human chorionic gonadotrophin (beta-hCG). The second step was to calculate trisomy 21 detection and false-positive rates for each software according to maternal age (35-45 years), using the usual 1:250 risk threshold. Agreement between software packages was measured using 2 x 2 kappa coefficients. Detection rates and false-positive rates increased with maternal age. Depending on the software, 57-71% detection rates were achieved at 35 years with 12-18% false-positive rates. At 45 years, 61-100% detection rates were achieved with 66-95% false-positive rates. Up to 39 years, all softwares were concordant (kappa coefficients >0.75). In the range 35-45 years, false-positive and detection rates increased substantially with maternal age and differences between software packages are observed.     

Choroid plexectomy reduces neurosurgical intervention in patients with hydranencephaly

INTRODUCTION: The removal of the choroid plexus from the lateral ventricles was attempted by Dandy in the early 20th century but later discarded as complications arose and other methods of cerebrospinal fluid (CSF) diversion were introduced. We compare our experience with a variation of this operation to CSF diversion in patients with hydranencephaly or near hydranencephaly. METHODS: The hospital and office charts of patients with a diagnosis of hydranencephaly were reviewed from the two institutions spanning the career of the senior author. Thirteen patients were identified, of whom 9 underwent CSF diversionary procedures (group A) and 4 underwent choroid plexectomy (group B). RESULTS: The mean number of reoperations (2 in group A, 0 in group B), neurosurgical readmissions (1.5 in group A, 0 in group B) and days of hospitalization related to neurosurgical readmissions (43.5 in group A, 0 in group B) were all less in patients who underwent choroid plexectomy. The total incidence of complications related to surgery was also lower in this group (7 in group A, 0 in group B). CONCLUSION: In our experience, choroid plexectomy in patients with hydranencephaly reduces the incidence of reoperation and readmission, the number of days of hospitalization related to the surgical procedure and the total number of complications in comparison to patients undergoing CSF diversion. Further neurosurgical intervention is minimized as is the financial burden from multiple emergency department visits and radiological procedures for shunt evaluation. Choroid plexectomy is a viable alternative to CSF diversion in patients with hydranencephaly and a rapidly enlarging head. It avoids the chronic issues and complications surrounding CSF diversion in this difficult group of patients.     

Cerebrospinal fluid shunt survival and etiology of failures: a seven-year institutional experience

BACKGROUND: Innovations in shunt technology and neuroendoscopy have been increasingly applied to shunt management. However, the relative life span of shunts and the etiology of shunt failure have not been characterized recently. METHODS: We reviewed the records of all shunting procedures at our institution between January 1992 and December 1998. Independent predictors of shunt failure were analyzed via multivariate Cox regression analysis in 836 shunting procedures. Independent predictors of the etiology of failure (infection, proximal obstruction, distal malfunction) were analyzed via multivariate logistic regression analysis in the 383 shunts which failed. RESULTS: A total of 353 pediatric patients underwent 308 shunt placements and 528 revisions. The risk (hazard ratio; HR) of shunt failure decreased as a function of time in both primary placements and revised shunts. In failed shunts, the odds of infection decreased 4-fold per year of shunt function, while the odds of distal malfunction increased 1.45-fold per year. Increasing number of shunt revisions (HR 1.31, p < 0.05), decreasing patient age in years (HR 1.04, p < 0.001), gestational age <40 weeks (HR 2.15, p < 0.001) but not the etiology of hydrocephalus were associated with an increased risk of shunt failure. Revisions versus primary placements, Dandy-Walker cysts and gestational age <40 weeks were independently associated with proximal, distal and infectious causes of failure, respectively. CONCLUSIONS: The long-term shunt revision rates observed here are similar to those reported over the past 2 decades. Shunt life span remains poorer in shunt revisions and in younger patients. Patient characteristics may suggest a specific risk and mechanism of failure, aiding in the long-term management of shunted hydrocephalus.     

Biocompatibility of thermosensitive chitosan-based hydrogels: an in vivo experimental approach to injectable biomaterials

Chitosan, an amino-polysaccharide obtained from the alkaline deacetylation of chitin, presents an interest as a drug vehicle. Indeed, chitosan solutions containing glycerol-2-phosphate (beta-GP) undergo sol-gel transition at a temperature close to 37 degrees C, which make them suitable for the parenteral administration of drugs. However, before using these chitosan derivatives for biomedical applications, it is important to evaluate their biocompatibility, and particularly to test their inflammatory effects. When injected in the hindpaw of the rat, we have shown that: (i) four chitosan/beta-GP solutions tested triggered a non-specific response, with solutions prepared with chitosans of higher deacetylation degrees yielding a lesser inflammatory reaction and (ii) systemic pretreatment of animals with icatibant, apafant and diphenhydramine did not significantly diminish this response; dexamethasone practically abolished it for all solutions and ketanserine only slightly decreased it in one preparation at two different times. In conclusion, it appears that a higher degree of deacetylation of the chitin chain is desirable for superior biocompatibility.     

Facial appearance in persistent hyperinsulinemic hypoglycemia

Persistent hyperinsulinism is the most common cause of recurrent hypoglycemia in infancy because of inappropriate oversecretion of insulin by the pancreas. Pancreatic lesions can be either focal or diffuse, and they have distinct molecular bases. We have studied the facial features in 17 unrelated patients presenting with neonatal (n = 8) or infancy-onset (n = 9) hyperinsulinism. Hyperinsulinism was related to focal adenomatous hyperplasia (n = 7), diffuse hyperinsulinism (n = 5), non-operated hyperinsulinism (n = 2), and hyperinsulinism with hyperammonemia (n = 3). SUR1 or Kir6.2 mutations were found in six of seven focal adenomatous hyperplasia and three of five diffuse hyperinsulinism. A loss of the maternal allele from chromosome 11p15 in the lesion was found in all focal adenomatous hyperplasia. GLUD1 mutations were found in all patients with hyperammonemia. Large birth weight (mean > 3,800 g) was consistently observed (11/17) but protruding tongue, exomphalos, or visceromegaly were never noted and Wiedemann-Beckwith syndrome could always be ruled out. All patients presented with high forehead, small nasal tip, and short columella giving the impression that the nose is large and bulbous, smooth philtrum, and thin upper lip. A square appearance to the face was more obvious in younger patients. These specific facial features, observed in patients with hyperinsulinism of various molecular mechanisms, could be the consequence of fetal intoxication by insulin. However, to date, facial anomalies have not been noted in infants of diabetic mothers and inversely, malformations that are commonly reported in infants of diabetic mothers were not present in our hyperinsulinemic patients.     

Characterization of binary mixtures consisting of cross-linked high amylose starch and hydroxypropylmethylcellulose used in the preparation of controlled release tablets

Cross-linked amylose starch (CLA), hydroxypropylmethylcellulose (HPMC), and HPMC/CLA matrices were prepared by direct compression. HPMC was used to slow down the enzymatic degradation of CLA matrices. CLA was either granulated alone and mixed with HPMC or cogranulated with the latter. Compaction characteristics of the powder, hydration and mechanical properties of the resulting matrices, as well as the release profiles of three model drugs were investigated. The results showed that wet granulation of CLA in the presence of 10% HPMC improved significantly the flow properties of the powder without compromising its compactibility. Both CLA and HPMC deformed mainly by plastic flow (yield pressures are 75 and 124 MPa, respectively), but CLA exhibited a stronger elastic component (elastic recoveries are 18.4 and 11.5%, respectively). The values of yield pressure increased linearly with the concentration of HPMC. The addition of HPMC to CLA slightly decreased the resistance to consolidation but the crushing force of the final compacts was found to be proportional to the HPMC concentration. Mechanical studies on swollen matrices revealed that CLA formed a stronger gel than HPMC or CLA/HPMC mixture, and swelling and erosion of the tablets increased with HPMC content and incubation time. The in vitro release kinetics of three model drugs (pseudeoephedrine sulfate, sodium diclofenac, and prednisone) showed a clear effect of drug solubility and presence of alpha-amylase in the dissolution medium on the release rate. The addition of HPMC to CLA protected the tablets against alpha-amylase hydrolysis and reduced the release rate of prednisone and sodium diclofenac. The release of pseudoephedrine sulfate was fast and independent of HPMC and occurred mainly by diffusion.     

The focal form of persistent hyperinsulinemic hypoglycemia of infancy: morphological and molecular studies show structural and functional differences with insulinoma

Paternal mutation of ATP-sensitive K(+) (K(ATP)) channel genes and loss of heterozygosity (LOH) of the 11p15 region including the maternal alleles of ABCC8, IGF2, and CDKN1C characterize the focal form of persistent hyperinsulinemic hypoglycemia of infancy (FoPHHI). We aimed to understand the actual nature of FoPHHI in comparison with insulinoma. In FoPHHI, the lesion consists in clusters of beta-cells surrounded by non-beta-cells. Compared with adjacent islets, proinsulin mRNA is similar and proinsulin production higher (P < or = 0.02), indicating regulation at a translational level, with slightly lower insulin stock and lower ABCC8 peptide labeling (P<0.05). Insulinomas, composed of beta-cell nests or cords, have similar proinsulin mRNA compared with adjacent islets, highly variable proinsulin production, lower insulin stock (P < or = 0.02), and higher ABCC8 peptide labeling (P<0.05). Proinsulin mRNA is lower than in FoPHHI (P<0.001). Islets adjacent to FoPHHI appear to be resting, in contrast to those adjacent to insulinomas, evidencing intrapancreatic regulation of islet beta-cell activity. IGF2 peptide is present inside and outside both lesions, but IGF2 mRNA is restricted to the lesions. The 11p15 LOH and absence of CDKN1C peptide staining are demonstrated in all FoPHHI but also in three of eight insulinomas. Despite some molecular similarities, FoPHHI is thus fundamentally different from insulinoma.