The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers.

Encapsulation of drugs within nanocarriers that selectively target malignant cells promises to mitigate side effects of conventional chemotherapy and to enable delivery of the unique drug combinations needed for personalized medicine. To realize this potential, however, targeted nanocarriers must simultaneously overcome multiple challenges, including specificity, stability and a high capacity for disparate cargos. Here we report porous nanoparticle-supported lipid bilayers (protocells) that synergistically combine properties of liposomes and nanoporous particles. Protocells modified with a targeting peptide that binds to human hepatocellular carcinoma exhibit a 10,000-fold greater affinity for human hepatocellular carcinoma than for hepatocytes, endothelial cells or immune cells. Furthermore, protocells can be loaded with combinations of therapeutic (drugs, small interfering RNA and toxins) and diagnostic (quantum dots) agents and modified to promote endosomal escape and nuclear accumulation of selected cargos. The enormous capacity of the high-surface-area nanoporous core combined with the enhanced targeting efficacy enabled by the fluid supported lipid bilayer enable a single protocell loaded with a drug cocktail to kill a drug-resistant human hepatocellular carcinoma cell, representing a 10(6)-fold improvement over comparable liposomes.

Interactions of endoglucanases with amorphous cellulose films resolved by neutron reflectometry and quartz crystal microbalance with dissipation monitoring.

A study of the interaction of four endoglucanases with amorphous cellulose films by neutron reflectometry (NR) and quartz crystal microbalance with dissipation monitoring (QCM-D) is reported. The endoglucanases include a mesophilic fungal endoglucanase (Cel45A from H. insolens), a processive endoglucanase from a marine bacterium (Cel5H from S. degradans ), and two from thermophilic bacteria (Cel9A from A. acidocaldarius and Cel5A from T. maritima ). The use of amorphous cellulose is motivated by the promise of ionic liquid pretreatment as a second generation technology that disrupts the native crystalline structure of cellulose. The endoglucanases displayed highly diverse behavior. Cel45A and Cel5H, which possess carbohydrate-binding modules (CBMs), penetrated and digested within the bulk of the films to a far greater extent than Cel9A and Cel5A, which lack CBMs. While both Cel45A and Cel5H were active within the bulk of the films, striking differences were observed. With Cel45A, substantial film expansion and interfacial broadening were observed, whereas for Cel5H the film thickness decreased with little interfacial broadening. These results are consistent with Cel45A digesting within the interior of cellulose chains as a classic endoglucanase, and Cel5H digesting predominantly at chain ends consistent with its designation as a processive endoglucanase.

Management of dental emergencies amongst Australian general medical practitioners - A case-vignette study.

BACKGROUND: In Australia, because of inequity in dental service accessibility and affordability, patients can see general medical practitioners (GPs) for acute dental conditions. METHODS: This cross-sectional study consisted of surveys distributed to the board registered GPs practising in Australia. The main outcome measures included statistical analysis of GPs managing different dental emergency scenarios and their confidence and expectations in managing dental emergencies. RESULTS: A total of 425 GPs participated in the study. The sample primarily consisted of GPs practising in metropolitan clinics (n = 315). Most participants reported that they would refer to the dentist for mobilized tooth (n = 402). There was a negative correlation between GPs with 5-29 years of experience and traumatized tooth management (P < 0.05). GPs aged between 40 and 49 years were more inclined to treat patients with mobilized teeth [Multivariate (MV): 0.42(0.09-0.74)]. However, GPs with 0-5 years of experience were less likely to manage patients with dental abscess [MV: -0.52(-0.80 to -0.24)]. CONCLUSION: Most GPs referred dental emergencies to dentists. GP management of dental emergencies were predominantly palliative. Therefore, opportunities for collaborative practice models amongst GPs and dentists may be needed to bridge the gap in the regional and remote locations.

Experience with a novel efalizumab-based immunosuppressive regimen to facilitate single donor islet cell transplantation.

Islet transplantation is an experimental therapy for selected patients with type 1 diabetes (T1DM). It remains limited by immunosuppressive drug toxicity, progressive loss of insulin independence, allosensitization and the need for multiple islet donors. We describe our experience with an efalizumab-based immunosuppressive regimen as compared to the prevailing standard regimen, the Edmonton protocol. Twelve patients with T1DM received islet transplants: eight were treated with the Edmonton protocol; four were treated with daclizumab induction, a 6-month course of tacrolimus, and maintenance with efalizumab and mycophenolate mofetil. The primary endpoint was insulin independence after one islet infusion. Only two Edmonton protocol treated patients achieved the primary endpoint; six required islets from multiple donors, and all experienced leukopenia, mouth ulcers, anemia, diarrhea and hypertransaminasemia. Four became allosensitized. All patients treated with the efalizumab-based regimen achieved insulin independence with normal hemoglobin A1c after a single islet cell infusion and remained insulin independent while on efalizumab. These patients experienced significantly fewer side effects and none became allosensitized. Trial continuation was terminated by withdrawal of efalizumab from the market. These data suggest that this efalizumab-based regimen prevents islet rejection, is well tolerated, and allows for single donor islet transplantation.

Excess NF-κB induces ectopic odontogenesis in embryonic incisor epithelium.

Nuclear factor kappa B (NF-κB) signaling plays critical roles in many physiological and pathological processes, including regulating organogenesis. Down-regulation of NF-κB signaling during development results in hypohidrotic ectodermal dysplasia. The roles of NF-κB signaling in tooth development, however, are not fully understood. We examined mice overexpressing IKKß, an essential component of the NF-κB pathway, under keratin 5 promoter (K5-Ikkß). K5-Ikkß mice showed supernumerary incisors whose formation was accompanied by up-regulation of canonical Wnt signaling. Apoptosis that is normally observed in wild-type incisor epithelium was reduced in K5-Ikkß mice. The supernumerary incisors in K5-Ikkß mice were found to phenocopy extra incisors in mice with mutations of Wnt inhibitor, Wise. Excess NF-κB activity thus induces an ectopic odontogenesis program that is usually suppressed under physiological conditions.

Immunodeficiency, xanthomas and obstructive liver disease.

Chronic obstructive liver disease and secondary hyperlipidemia developed in an immunodeficient boy. Sequential addition of cholestyramine and phenobarbital to his medical regimen, following an initial response to bile drainage, resulted in the disappearance of xanthomas and pruritus, and the restoration of normal serum concentrations of lipids and bile acids. This improvement may result from shifting the bile acid pool from the peripheral blood compartment to the enterohepatic circulation.

Thromboembolism from undersized Dacron grafts in the descending thoracic aorta.

Three patients were referred to our institution for major thromboembolic complications secondary to the use of undersized Dacron grafts (14, 16, and 18 mm) in the descending thoracic aorta. The progressive accumulation of thrombotic material in the prosthesis caused recurrent coarctation in 1 patient and peripheral embolisms in the other 2. With a 9-mm Gott shunt providing distal perfusion, excision of the clotted graft and its replacement with a 22-mm Dacron prosthesis was successfully achieved in each patient.

Spinal abscess of Haemophilus paraphrophilus. A case report.

STUDY DESIGN: A case of paraspinal abscess formation from Haemophilus paraphrophilus is presented. OBJECTIVES: To describe a case of paraspinal abscess formation from H. paraphrophilus, a fastidious commensal organism of the mouth and pharynx. A precise bacteriologic identification can be difficult; techniques for such identification are discussed. SUMMARY OF BACKGROUND DATA: Spinal abscess caused by H. paraphrophilus is unusual and can be very difficult to diagnose. METHODS: The etiology, clinical presentation, technical examinations, and treatment are reviewed. RESULTS: Prolonged antibiotic treatment was curative, although surgery was considered. CONCLUSIONS: Bacteriologic diagnoses in these rare infections are difficult. Antibiotic therapy was curative in the patient described.

[Antiarrhythmic action of disopyramide: a study of plasma levels]. / Action antiarythmique du disopyramide: etude des taux sanguins.

The action of dysopyramide was studied in 13 patients, 11 with ventricular and 2 with supraventricular arrhythmias. The drug was given parenterally at first and then by mouth. The patients were monitored with an arrhythmia counter and the plasma levels of disopyramide measured throughout the treatment period. The plasma level was stable at about 4 micrograms/ml during the different phases. Toxic levels of 10 microgram/ml were observed in 1 patient in renal failure. The antiarrhythmic action was very effective (70% success), especially on the ventricular arrhythmias. Two of the four patients who failed to respond to treatment had low, non-therapeutic plasma levels. The dosage should be adapted with respect to the patient's weight and renal function.

[Use of the Gott shunt in the prosthetic replacement of the aortic arch]. / Utilisation du shunt de Gott lors de remplacement prothétique de la crosse aortique.

Our previous experience in 272 consecutive cases of descending thoracic aortic aneurysms resected without paraplegia by using the 9 mm Gott shunt encouraged us to apply the same technique to more complex aortic surgery. Graft replacement of the transverse aortic arch with brachio-cephalic vessel reattachment was undertaken in 2 patients without the aid of extracorporeal circulation and without systemic heparinisation. Body perfusion was achieved with two 9 mm Gott shunts inserted between the ascending aorta and both femoral arteries. A 10 mm graft interposition between the shunts and the femoral arteries allowed for retrograde perfusion and distal leg irrigation. Blood supply to the brain was maintained with the cut halves of a 7 mm Gott shunt connected as side branches to one of the 9 mm shunts, allowing cannulation of the innominate ant the left carotid arteries. In 90 of the 272 patients treated for a descending aortic aneurysm, a mean shunt flow of 2526 ml/min. was recorded through the 9 mm Gott shunt and from there, we took for granted that the total cardiac output, in there 2 patients, could be propelled by using 2 shunts. During aortic cross clamping, there were no change in the filling pressure of either the right heart or the left heart, and no metabolic acidosis was observed. Both patients survived with normal physiological function of all organs including the brain and the spinal cord.

Cardiac troponin T forms a tetramer in vitro.

Cardiac troponin T (cTnT) is a myofibrillar protein essential for calcium-dependent contraction. This property has led to functional studies of developmentally expressed cTnT isoforms and mutants identified in patients with hypertrophic cardiomyopathy. The release of cTnT into the serum following myocardial infarction has led to the development of antibody-based assays for measuring cTnT serum concentration. We examined the behavior of cTnT in solution. Recombinant human cTnT3, the dominant isoform in the adult human heart, was used. The protein was pure and functional, as demonstrated by SDS-PAGE and surface plasmon resonance. cTnT3 was found to bind specifically and in a concentration-dependent manner to cTnC. Routine size exclusion chromatography suggested a higher-than-expected MW for cTnT. Using analytical ultracentrifugation, we found cTnT3 in solution to be mainly in the form of a tightly bound tetramer at concentrations as low as 4 micromol/L. Our sedimentation velocity and transmission electron microscopy results indicate that the tetramer's shape is elongated rather than globular. CTnT's self-association in solution is an important consideration in the design and interpretation of experiments with the aim of understanding the biochemical and biophysical properties of cTnT, its isoforms, and its mutants.

Homeless families and their children's health problems. A Utah urban experience.

Descriptive information was obtained about homeless families in the Intermountain West and their children's health care needs were defined to help professionals develop programs tailored to meet the unique needs of this population. We collected data during the well-child visits of 306 children in 161 families living at the Travelers Aid Society family shelter. The results reveal 2 types of homeless families, episodic and long term. Each requires different levels of assistance. This study's profile of mobile, predominantly white, 2-parent families with few children (mean of 1.2) differs considerably from that of studies conducted on the East and West coasts. The families' nomadic life-style (73.1% came from 32 states other than Utah) present important public health issues, especially because of the recent resurgence of tuberculosis and declining levels of childhood immunizations. The children's health problems were similar to those reported nationally: delayed immunizations, dental decay, anemia, and impaired vision.

Enhanced stability of uncemented canine femoral components by bone ingrowth into the porous coatings.

The following questions were answered in this study: (1) What is the initial stability of proximally porous-coated canine femoral components? (2) Does bone ingrowth occur under these conditions? (3) Is the stability enhanced by tissue ingrowth in vivo? The stability of proximally porous-coated femoral components of canine total hip arthroplasties after 6 months to 2 years of in vivo service in dogs was measured in vitro using displacement transducers under loads simulating canine midstance. This was compared with the stability of identical components under the same loading conditions immediately after implantation in vitro in the contralateral femurs. The femurs were then sectioned and bone ingrowth into the porous coatings was quantified. The results showed that immediately after implantation the implants can move as much as 50 microns, but that the bone ingrowth into porous coatings of canine femoral components can occur even under such conditions. These data also suggested that the relative motion existing at the time of insertion can be reduced to very small amounts (< 10 microns) by bone ingrowth.