Combination of Heel-strike like Mechanical Loading with Deproteinized Cancellous Bone Scaffold Implantation to Repair Segmental Bone Defects in Rabbits.

Under physiological conditions bone defects often occur at mechanical load bearing sites and bone substitutes used for regeneration should be similarly subjected to mechanical loading stress. In this study, we investigated whether a novel heel-strike like mechanical loading method can be used as a complementary therapy to promote bone regeneration following bone substitute grafting. To test this, three groups of rabbits with segmental bone defects in the tibia were implanted with bovine deproteinized cancellous bone scaffold (DCBS), with one group also receiving heel-strike like mechanical loading generated by a rap stress stimulator. From weeks 4-12 post-operation X-ray and micro-CT scanning showed that rabbits receiving combination therapy had significantly more callus at the bone defect. Moreover, bone defects in the combination group were completely replaced with new bone at week 12, while the DCBS implantation alone group healed only partially and rabbits receiving neither DCBS nor mechanical loading developed only small calluses throughout the observation period. Analysis of micro-CT scanning results demonstrated that new bone density in the combination group was significantly higher than the DCBS only group at weeks 4 and 12 (p<0.05). H&E staining results also indicated a significantly higher percentage of new bone in the bone defect area and a lower percentage of residual scaffold in the combination group compared to the DCBS only group (p<0.05). Thus, this heel-strike like mechanical loading method appears to accelerate bone regeneration following substitute implantation by restoring a local mechanical loading environment in segmental bone defects.

A biodegradable antibiotic-eluting PLGA nanofiber-loaded deproteinized bone for treatment of infected rabbit bone defects.

We fabricated a biodegradable antibiotic-eluting poly(d,l)-lactide-co-glycolide nanofiber-loaded deproteinized bone (ANDB) scaffold that provided sustained delivery of vancomycin to repair methicillin-resistant Staphylococcus aureus bone defects. To fabricate the biodegradable ANDB, poly(d,l)-lactide-co-glycolide and vancomycin were first dissolved in 1,1,1,3,3,3-hexafluoro-2-propano. The solution was then electrospun to produce biodegradable antibiotic-eluting membranes that were deposited on the surface of bovine deproteinized cancellous bone. We used scanning electron microscopy to determine the properties of the scaffold. Both elution and high-performance liquid chromatography assays were used to evaluate the in vitro vancomycin release rate from the ANDB scaffold. Three types of scaffolds were co-cultured with bacteria to confirm the in vitro antibacterial activity. The infected bone defect rabbit model was induced by injecting 10(7) colony forming units of a methicillin-resistant Staphylococcus aureus strain into the radial defect of rabbits. Animals were then separated into treatment groups and implanted according to the following scheme: ANDB scaffold in group A, poly(d,l)-lactide-co-glycolide nanofiber-loaded deproteinized bone (NDB) scaffold with intravenous (i.v.) vancomycin in group B, and NDB scaffold alone in group C. Treatment efficacy was evaluated after eight weeks using radiological, microbiological, and histological examinations. In vitro results revealed that biodegradable ANDB scaffolds released concentrations of vancomycin that were greater than the minimum inhibitory concentration for more than four weeks. Bacterial inhibition tests also confirmed antibacterial efficacy lasted for approximately four weeks. Radiological and histological scores obtained in vivo revealed significant differences between groups A, B and C. Importantly, group A had significantly lower bacterial load and better bone regeneration when compared to either group B or C. Collectively, these results show that our fabricated ANDB scaffolds possess: (1) effective bactericidal activity against methicillin-resistant Staphylococcus aureus, (2) the ability to promote site-specific bone regeneration, and (3) the potential for use in the treatment of infected bone defects.

Adjuvant chemoradiation plus intraoperative radiotherapy versus adjuvant chemoradiation alone in patients with locally advanced rectal cancer.

OBJECTIVES: To document the efficacy of intraoperative radiotherapy (IORT) followed by adjuvant chemoradiation in the management of locally advanced rectal cancer. MATERIALS AND METHODS: A total of 148 patients with pT4N0/T1-4N+ rectal adenocarcinoma were enrolled. Seventy-seven patients received total mesorectal excision surgery followed by adjuvant chemoradiation alone, 71 patients received total mesorectal excision surgery followed by IORT (range, 10 to 20 Gy) and adjuvant chemoradiation. RESULTS: The 5-year local control (LC) and disease-free survival were 79.2% versus 89.7% (P=0.032), 58.5% versus 69.0% (P=0.049) for external-beam radiation (EBRT) and IORT+EBRT groups, respectively. Multivariate analysis revealed that adjuvant IORT has a trend toward improvement of LC (P=0.079); 5 (3%) patients (EBRT n=2; IORT n=3) experienced incomplete intestinal obstruction and 3 patients had chronic diarrhea. There was no clinically relevant neuropathy or sacral osteoradionecrosis. Hydronephrosis occurred in 13 patients (EBRT n=8; IORT+EBRT n=5), 8 of whom had documented concomitant disease recurrence. CONCLUSIONS: For patients with locally advanced rectal cancer, higher radiation dose may contribute to the improvement of both LC and disease-free survival, without significantly increasing the incidence of acute and long-term complications compared with adjuvant chemoradiotherapy alone.

Pre-hospital emergency burn management in Shanghai: analysis of 1868 burn patients.

BACKGROUND: There are few studies reporting the level of pre-hospital emergency management of burn patients and related influencing factors in China. This study is a summary of our investigation on emergency education and people's awareness about pre-hospital emergency management of burn patients in Shanghai, China, and analyses key factors influencing pre-hospital emergency management of burn patients. METHODS: The survey was conducted by questionnaire in burn patients who sought initial clinical visits at the Burn Center of Changhai Hospital (Shanghai, China) between November 2009 and December 2010, including demographic data, burn conditions, pre-hospital emergency management and education about emergency burn management. Data were statistically treated by SPSS software. RESULTS: Altogether 1868 effective questionnaire forms were collected; 33.9% of these burn patients received cooling treatment before admission and 32.2% of them used 'folk remedies' or antibiotics to treat the wound surface. Only 12.2% of these burn patients had received education about the knowledge of emergency management, mainly through public media (38.2%), relatives and friends (24.6%), Internet (15.8%), workplace (11.4%) and schools (10.1%). The result of logistic regression analysis showed that emergency education, especially via Internet and workplace, played an important role in pre-hospital emergency management, and that different channels of emergency education affected different age groups of people: network and unit education mainly affected young adults, while relatives and friends mainly affected elderly people. In addition, educational level was an important factor favourably affecting 'cooling therapy'. CONCLUSIONS: The level of emergency burn management and related education is relatively low in China at present, and it is therefore necessary to intensify education about pre-hospital emergency management to raise the level of emergency burn management. At the same time, more attention should be paid to age- and population-specific education. Finally, universal emergency education should be included in the national basic education as a long-term strategy.

Development of a PET/SPECT agent for amyloid imaging in Alzheimer's disease.

In the search for a cure for Alzheimer's disease (AD), efforts have been focused on preventing or reversing amyloid deposition in the brain. Efficacy evaluation of these antiamyloid therapies would greatly benefit from development of a tool for the in vivo detection and quantitation of amyloid deposits in the brain. Toward this goal, we have developed a series of benzothiazole derivatives as amyloid-imaging agents for positron emission tomography (PET). To extend the potential of these amyloid-imaging agents for routine clinical studies, we also set out to develop iodinated benzothiazole derivatives that could be used as dual agents for either PET or the complementary single photon emission computed tomography (SPECT). Such dual agents would permit PET or SPECT studies using radiotracers with the same chemical identity but labeled with different radionuclides. This would facilitate the validation of clinical SPECT studies, based on quantitative PET studies. In this work we report the synthesis and biological evaluation of a potent, selective, and brain-permeable benzothiazole compound, 2-(3'-iodo-4'-methylaminophenyl)-6-hydroxy-benzothialzole, termed 6-OH-BTA-1-3'-I (4), which can be radiolabeled with either positron-emitting carbon-11 or single photon-emitting iodine-125/iodine-123. The synthesis and radiolabeling of [125I]4 or [11C]4 were achieved through direct iodination with sodium [125I]iodide in the presence of chloramine T or through radiomethylation with [11C]CH3I. In vitro amyloid binding assays indicated that [125I]4 bound to amyloid deposits in a saturable manner and exhibited affinities in the nanomolar concentration range. Binding studies of [125I]4 to postmortem human brain homogenates also showed preference of binding to frontal cortex in the AD homogenates relative to age-matched control homogenates or cerebellum from either AD or control. In vivo pharmacokinetic studies in normal mice following iv injection of [11C]4 indicated that the radioligand entered the brain readily at early time points and cleared from the brain rapidly at later time points with a 2- to 30-min ratio >3. These results suggest that the new radioiodinated benzothiazole ligand might be useful as a surrogate marker for the in vivo quantitation of amyloid deposition in human brain for use with either PET or SPECT.

Nanoparticles of biodegradable polymers for clinical administration of paclitaxel.

Paclitaxel is one of the best antineoplastic drugs found from nature in the past decades, which has been found effective against a wide spectrum of cancers including ovarian cancer, breast cancer, small and non small cell lung cancer, colon cancer, head and neck cancer, multiple myeloma, melanoma, and Kaposi's sarcoma. Like many other anticancer drugs, it has difficulties in clinical administration due to its poor solubility in water and most pharmaceutical reagents. In its current clinical application, an adjuvant called Cremophor EL has to be employed, which has been found to be responsible for many serious side effects. Nanoparticles of biodegradable polymers can provide an ideal solution to such an adjuvant problem and realize a controlled and targeted delivery of the drug with better efficacy and less side effects. With further development, such as particle size optimization and surface coating, nanoparticle formulation of paclitaxel can promote a new concept of chemotherapy to realize its full efficacy and to improve quality of life of the patients, which includes personalized chemotherapy, local chemotherapy, sustained chemotherapy, oral chemotherapy, chemotherapy across the blood-brain barrier, chemotherapy across the microcirculation barrier, etc. The present research proposes a novel formulation for fabrication of nanoparticles of poly(lactic-co-glycolic acid) (PLGA) by a modified solvent extraction/evaporation technique, in which natural emulsifiers, such as phospholipids, cholesterol and vitamin E TPGS are creatively applied to achieve high drug encapsulation efficiency, desired drug released kinetics, high cell uptake and high cytotoxicity. The nanoparticles composed of various recipes and manufactured under various conditions were characterized by laser light scattering (LLS) for size and size distribution, scanning electron microscopy (SEM) and atomic force microscopy (AFM) for morphological properties, X-ray photoelectron spectroscopy (XPS) and Fourier Transformation Infrared Spectroscopy (FTIR) for surface chemistry, zeta-potential for surface charge, and differential scanning calorimetry (DSC) for the thermogram properties. The drug encapsulation efficiency and the drug release kinetics under in vitro conditions were measured by high performance liquid chromatography (HPLC). It was found that these natural emulsifiers have great advantages for nanoparticle formulation of paclitaxel over the traditional macromolecular emulsifiers, such as polyvinyl alcohol (PVA). Nanoparticles of desired small size and narrow size distribution can be obtained. The drug encapsulation efficiency can be achieved as high as 100 %. The released kinetics can be made under control. The HT-29 cancer cell line experiment showed that after 24 hours of incubation, the cell mortality caused by the drug administered by such nanoparticle formulation could be more than 13 times higher than that caused by the free drug under similar conditions.