Oral and topical boswellic acid attenuates mouse osteoarthritis.

OBJECTIVE: Boswellic acid is a plant-derived molecule with putative anti-inflammatory effects. This study was performed to determine whether oral or topical administration of boswellic acid can attenuate joint damage in a mouse model of osteoarthritis (OA). METHODS: Levels of boswellic acid were measured in the blood and synovium of mice treated with oral or topical boswellic acid. OA was generated by surgical destabilization of the medial meniscus (DMM). Therapy with oral or topical boswellic acid was initiated one day after surgery and continued for 12 weeks, when knees were harvested and scored histologically for degree of cartilage loss, osteophyte formation, and synovitis. Microdissected OA synovium was stimulated with IL-1ß or lipopolysaccharide (LPS) in the presence or absence of boswellic acid and cytokine production by quantitative polymerase chain reaction (PCR) or multiplex enzyme linked immunoabsorbant assay (ELISA). RESULTS: Topical treatment resulted in synovial concentrations of boswellic acid 2-6-fold higher than that measured in plasma. Cartilage loss was significantly reduced in mice treated with oral or topical boswellic acid compared with vehicle control (P < 0.01 for both oral and topical therapies). Likewise, treatment with either oral boswellic acid or boswellic acid ointment reduced of synovitis (P = 0.006 and 0.025, respectively) and osteophyte formation (P = 0.009 and 0.030, respectively). In vitro, boswellic acid was able to inhibit IL-1ß and TLR4 mediated induction of several inflammatory mediators from OA synovial explant tissue. CONCLUSIONS: Significant synovial concentration and therapeutic efficacy can be achieved with topical boswellic acid treatment. These findings suggest that boswellic acid has potential as a disease-modifying agent in OA.

Idiopathic pulmonary arteriovenous malformations: clinical and imaging characteristics.

Pulmonary arteriovenous malformations (PAVMs) can cause stroke, brain abscess or life-threatening haemorrhage. Most PAVMs are associated with hereditary haemorrhagic telangiectasia (HHT). The aim of the present study was to describe the clinical presentation and treatment outcomes of those with idiopathic PAVMs, which has not previously been described in the literature. Patients with idiopathic PAVMs were identified at our HHT centre. Retrospective review of charts and imaging were performed. 20 patients were identified with idiopathic PAVMs. The most common symptoms reported were dyspnoea and migraines (50 and 30% of patients, respectively). Previous complications of PAVMs included haemoptysis (20%), stroke (20%) and brain abscess (5%). A total of 28 focal PAVMs were identified. Most patients (80%) had a solitary PAVM. 13 out of 28 PAVMs (46%) were located in the lower lobes. Most were simple and fistulous rather than complex and plexiform. Transcatheter embolotherapy was performed in 17 patients and was successful in improving oxygenation in all cases. The clinical manifestations and complications of idiopathic PAVMs are similar to those associated with HHT. Idiopathic PAVMs are anatomically similar to HHT-related PAVMs except for a greater number of solitary PAVMs and a lack of lower lobe predominance. Transcatheter embolotherapy is a safe and effective method for treating idiopathic PAVMs.

Targeted therapies for pancreatic cancer.

INTRODUCTION: Pancreatic cancer is a devastating malignancy and a leading cause of cancer mortality. Furthermore, early diagnosis represents a serious hurdle for clinicians, as symptoms are non-specific and usually manifest in advanced, treatment-resistant stages of the disease. SOURCES OF DATA: Here, we review the rationale and progress of targeted therapies currently under investigation. AREAS OF AGREEMENT: At present, chemoradiation regimes are administered palliatively, and produce only marginal survival benefits, underscoring a desperate need for more effective treatment modalities. AREAS OF CONTROVERSY: Questions have been raised as to whether erlotinib, the only targeted therapy to attain a statistically significant increase in median survival, is cost-effective. GROWING POINTS: The last decade of research has provided us with a wealth of information regarding the molecular nature of pancreatic cancer, leading to the identification of signalling pathways and their respective components which are critical for the maintenance of the malignant phenotype. AREAS TIMELY FOR DEVELOPING RESEARCH: These proteins thus represent ideal targets for novel molecular therapies which embody an urgently needed novel treatment strategy.

Surgical resection of a massive primary mediastinal liposarcoma with cervical extension.

A 73-year-old man was referred for surgical excision of a massive mediastinal and cervical liposarcoma following neoadjuvant chemotherapy. Surgery was performed via a cervical incision, sternotomy and right posterolateral thoracotomy. The tumour arose from the oesophagus, which underwent extensive dissection and was oversewn with pleura after tumour resection. Histology confirmed a completely excised grade 2 de-differentiated liposarcoma with complete macroscopic excision. The patient made an excellent recovery. Oesophageal liposarcomas are rare and, unlike in this case, often extend intraluminally, necessitating oesophagectomy. To our knowledge, this is the largest such tumour found in the literature.

Nonprescription bronchodilator medication use in asthma.

STUDY OBJECTIVE: Many persons with asthma self-medicate with widely available and potentially hazardous nonprescription medicines. This study assessed the demographic and clinical covariates of self-treatment with over-the-counter asthma medications (OTCs). DESIGN AND SETTING: We conducted an analytical investigation using questionnaires and measures of lung function, comparing OTC and prescription medication users. We recruited adults with asthma by public advertisement. SUBJECTS: We studied 22 exclusive prescription asthma medication users, 15 exclusive OTC users, and 13 other subjects who combined prescription medication use with self-treatment with asthma OTCs. All but one OTC user self-medicated with a nonselective, sympathomimetic metered-dose inhaler. RESULTS: Taking income, access to care, and self-assessed disease severity into account, male gender was strongly associated with exclusive OTC use alone (odds ratio [OR]=8.9, 95% confidence interval [CI]= 1.3 to 61) and mixed OTC-prescription medication use (OR=9.7, 95% CI=1.1 to 83). The covariates of income, access to care, and self-assessed disease severity provided significant additional explanatory power to the model of exclusive OTC use (model chi2 difference 11.3, 5 df, p<0.05). Pulmonary function was similar among OTC and prescription medication users. However, prescription medication users' self-assessed asthma severity (mild compared to more severe) was associated with postbronchodilator reversibility of FEV1 obstruction (6% vs 18% reversibility, p<0.05) while exclusive OTC users' self-assessed severity showed the reverse pattern (19% vs 8%, p=0.2). CONCLUSION: Asthma education programs attempting to discourage unregulated bronchodilator use should give consideration to this profile of the "asthmatic-at-risk."

Penicillinase-producing Neisseria gonorrhoeae: epidemiology, antimicrobial susceptibility and plasmid types.

Between 1976 and 1984 204 infections by penicillinase-producing Neisseria gonorrhoeae (PPNG) were seen in the Whitechapel Clinic. In 1984 PPNG were isolated from 4.7% of all patients attending with gonorrhoea. Three infections were homosexually acquired; 140 infections (68%) were acquired in the U.K. Strains that were tested were fully sensitive to spectinomycin (190), cefuroxime (177), kanamycin (170), amoxycillin combined with clavulanic acid (24) and rosoxacin (18). Of 135 strains 61% were resistant to co-trimoxazole, 69% of 169 to tetracycline (MIC greater than or equal to I mg/l) and 32% of 75 to streptomycin. Of 109 strains subjected to plasmid typing, 72(66%) were Asian strains. Of these, 55 (50% of the total) were without and 17 (16% of the total) possessed the 24.5 Mdal transfer plasmid; 27 (25%) were African strains without and 10 (9%) with the transfer plasmid. Of the Asian strains 10 were acquired in Africa. All four plasmid-containing strains are now endemic in the U.K. On the basis of the sensitivity tests, spectinomycin, cefuroxime and kanamycin should be effective in treatment, but not co-trimoxazole and tetracycline.

Recent advances in polyhydroxyalkanoate production by bacterial fermentation: mini-review.

Poly(3-hydroxybutyrate) [P(3HB)] and other polyhydroxyalkanoates (PHAs) have been drawing much attention as biodegradable substitutes for conventional nondegradable plastics. For the economical production of P(3HB), various bacterial strains, either wild-type or recombinant, and new fermentation strategies were developed for the production of P(3HB) with high concentration and productivity. To reduce the cost of carbon substrate, several processes for P(3HB) production from cheap carbon sources were also developed. P(3HB) can now be produced to a content of 80% of cell dry weight with the productivity greater than 4 g/l per h. Fermentation strategy was also developed for the efficient production of medium chain length PHA by high cell density culture. With all these advances, P(3HB) and PHAs can be produced by bacterial fermentation at a cost (ca. $2/kg) similar to that of other biodegradable polymers under development.

Abdominal wall abscess secondary to spilled gallstones: late complication of laparoscopic cholecystectomy and preventive measures.

Spilled gallstones left in the abdominal cavity or trapped at trocar sites may cause considerable morbidity. We saw a patient with an abdominal wall abscess 2 years after laparoscopic cholecystectomy secondary to spilled stones. After we reviewed the operative procedure in addition to the accumulated experience in laparoscopic surgery, we believe that retrieval of specimens and their contents is of paramount importance, especially when the gallbladder is infected, contains several stones, or may harbor malignancy. Therefore, we made use of a simple surgical glove with a long pursestring suture surrounding the opening to collect the specimen. This method proved to be simple and quite convenient, with the needed materials readily available. It can collect the spilled stones within the abdominal cavity as well as the gallbladder and can transport these stones out of the abdominal cavity with ease and safety. It also protects the specimen in contact with the wound and cuts short the operating time. The technique and advantages are described.

Liberal use of a bag made from a surgical glove during laparoscopic surgery for specimens retrieval.

Laparoscopic surgery has been gaining wide acceptance in recent years. Tissue removal from the abdominal cavity becomes a paramount issue, especially when the specimen is infected, contains several fragments, or potentially contains a malignancy. Several sophisticated instruments and devices have been designed for this purpose. However, most of these are expensive, difficult to handle, and come in a fixed size. Condoms, glove fingers, and zipper-type plastic bags have been tried also, but with limited success. The authors report use of a simple bag made from a surgical glove to collect specimens; a long purse-string suture surrounds the opening or the base of the glove finger to secure material during retrieval. This method has been found to be simple and convenient, and necessary construction material is readily available. The bag not only protects the specimen from contact with the wound but also cuts short the operating time. The technique and advantages are described.

Laparosopic removal of large gastric phytobezoars.

Large gastric bezoars are difficult to remove endoscopically. A 78-year-old man presenting with abdominal pain and loss of appetite for 4 months was admitted and evaluated. Gastroscopy disclosed two large phytobezoars within the stomach. Laparoscopic removal was undertaken. The bezoars were removed via a gastrotomy using the three-trocar technique. They were successfully retrieved from the abdominal cavity using an improvised "endobag" made from a simple surgical glove. Such an endobag presents several advantages; they are easy to make, sterile, economical, readily available, disposable, there is ample space to manipulate the specimen within, and there is minimal risk of contamination throughout the procedure. The authors recommend this approach for the treatment of patients with large gastric bezoars in whom laparotomy is indicated.

Laparoscopic resection of an omental cyst with pedicle torsion.

Omental cysts are the least-common variety of all types of intra-abdominal cystic lesions. In the past, transabdominal laparotomy with excision of the cyst was the treatment of choice. With the advent of laparoscopic surgery, it has become possible to resect the cyst without the need for a large incision in the abdomen. We report a case of a 15-year-old girl who underwent diagnostic laparoscopy for recurring abdominal pain of 2 years' duration. The procedure revealed a huge cyst lying above the omentum with its pedicle rising from the greater curvature of the stomach. The pedicle was noted to have twisted eight times in a clockwise direction. The cyst was resected by laparoscopic means using three trocars. The postoperative course was uneventful. As presented in this case, we believe that a laparoscopic approach is an attractive alternative for the management of omental cystic lesions.

Pediatric transplantation in the United States, 1995-2004.

This article reviews trends in pediatric solid organ transplantation over the last decade, as reflected in OPTN/SRTR data. In 2004, children younger than 18 years made up nearly 3% of the 86,378 candidates for organ transplantation and nearly 7% of the 27,031 organ transplant recipients. Children accounted for nearly 14% of the 7152 deceased organ donors. The transplant community recognizes important differences between pediatric and adult organ transplant recipients, including different etiologies of organ failure, surgical procedures that are more complex or technically challenging, effects of development on the pharmacokinetic properties of common immunosuppressants, unique immunological aspects of transplant in the developing immune system and increased susceptibility to posttransplant complications, particularly infectious diseases. For these reasons, and because of the impact of end-stage organ failure on growth and development, the transplant community has generally provided pediatric candidates with special consideration in the allocation of deceased donor organs. Outcomes following kidney, liver and heart transplantation in children often rank among the best. This article emphasizes that the prospects for solid organ transplantation in children, especially those aged 1-10 years are excellent. It also identifies themes warranting further consideration, including organ availability, adolescent survival and challenges facing pediatric transplant clinical research.

SRTR center-specific reporting tools: Posttransplant outcomes.

Measuring and monitoring performance--be it waiting list and posttransplant outcomes by a transplant center, or organ donation success by an organ procurement organization and its partnering hospitals--is an important component of ensuring good care for people with end-stage organ failure. Many parties have an interest in examining these outcomes, from patients and their families to payers such as insurance companies or the Centers for Medicare and Medicaid Services; from primary caregivers providing patient counseling to government agencies charged with protecting patients. The Scientific Registry of Transplant Recipients produces regular, public reports on the performance of transplant centers and organ procurement organizations. This article explains the statistical tools used to prepare these reports, with a focus on graft survival and patient survival rates of transplant centers--especially the methods used to fairly and usefully compare outcomes of centers that serve different populations. The article concludes with a practical application of these statistics--their use in screening transplant center performance to identify centers that may need remedial action by the OPTN/UNOS Membership and Professional Standards Committee.

Structural changes to airway smooth muscle in cystic fibrosis.

BACKGROUND: Chronic airway obstruction is characteristic of cystic fibrosis (CF) but there are few studies of airway smooth muscle remodelling in CF. METHODS: Airway smooth muscle content and mean airway smooth muscle cell size were measured by applying design-based stereology to bronchoscopic biopsy specimens obtained from seven subjects with CF and 15 healthy controls. RESULTS: The smooth muscle content increased by 63% in subjects with CF (mean (SD) 0.173 (0.08) v 0.106 (0.042) mm(3) smooth muscle/mm(3) submucosa, mean difference -0.067; 95% CI -0.12 to -0.013, p = 0.017) but there was no increase in mean cell size (2705 (351) v 2654 (757) microm(3), mean difference -51; 95% CI -687 to 585, p = 0.87). CONCLUSIONS: These findings indicate hyperplasia of airway smooth muscle cells without hypertrophy and suggest that accumulation of airway smooth muscle cells may contribute to airway narrowing and bronchial hyperresponsiveness in CF.

Risk management. Recommendations for the freestanding oncology center. Part two.

Risk management is an active ongoing process for identification and management of possible losses. It is no longer possible, in this day of escalating numbers of suits and escalating dollar amounts for damages, to solely manage this by transfer of liability through insurance. An active program, in order to reduce the potential for liability, needs to be implemented and needs to be continued on an active ongoing basis, even in the freestanding radiation oncology center. This will require expenditure of time and dollars for periodic review by consultants, but will pay handsome rewards by reducing the potential for loss.

Safety of one method of sputum induction in asthmatic subjects.

To assess the safety of sputum induction in asthmatic subjects, we conducted a retrospective review of data from 351 sputum inductions in 78 subjects from our institution. The sputum induction protcol consisted of baseline FEV1, pretreatment with albuterol 180 micrograms, postbronchodilator spirometry 15 min later, the induction procedure itself (inhalation of 3% saline for 20 min), and postsputum induction spirometry. We found that sputum induction was usually well tolerated, although some subjects developed wheeze and dyspnea. Overall, 11 of the 78 subjects (14%) had a fall in FEV1 of > or = 20% from the postbronchodilator baseline ("excessive bronchoconstriction") during their first sputum induction (range: -20 to -69%); no subject developed refractory bronchoconstriction requiring hospitalization or emergency room treatment. Only one of the 54 subjects (1.9%) with a baseline prebronchodilator FEV1 > 80% had excessive bronchoconstriction, whereas 10 of the 24 subjects (42%) whose baseline FEV1 was < or = 80% predicted did so. The change in FEV1 during sputum induction was significantly correlated with the baseline prebronchodilator FEV1% predicted, the baseline postbronchodilator FEV1% predicted, the PC20 for methacholine, and the percentage of eosinophils in induced sputum. We conclude that 180 micrograms albuterol does not prevent excessive bronchoconstriction in all asthmatic subjects undergoing sputum induction, especially in asthmatic subjects with a low baseline FEV1. Pulmonary function should be monitored regularly during sputum induction in asthmatic subjects to monitor for excessive bronchoconstriction.

Poly-(3-hydroxybutyrate) production from whey by high-density cultivation of recombinant Escherichia coli.

Recombinant Escherichia coli strain GCSC 6576, harboring a high-copy-number plasmid containing the Ralstonia eutropha genes for polyhydroxyalkanoate (PHA) synthesis and the E. coli ftsZ gene, was employed to produce poly-(3-hydroxybutyrate) (PHB) from whey, pH-stat fed-batch fermentation, using whey powder as the nutrient feed, produced cellular dry weight and PHB concentrations of 109 g l-1 and 50 g l-1 respectively in 47 h. When concentrated whey solution containing 210 g l-1 lactose was used as the nutrient feed, cellular dry weight and PHB concentrations of 87 g l-1 and 69 g l-1 respectively could be obtained in 49 h by pH-stat fed-batch culture. The PHB content was as high as 80% of the cellular dry weight. These results suggest that cost-effective production of PHB is possible by fed-batch culture of recombinant E. coli using concentrated whey solution as a substrate.

Defining the binding site of Xenopus transcription factor IIIA on 5S RNA using truncated and chimeric 5S RNA molecules.

The interaction of TFIIIA with deletion fragments of Xenopus 5S RNA has been quantified using a nitrocellulose filter binding assay. TFIIIA binding was found to be more sensitive to the deletion of nucleotides from the 5' terminus of the 5S RNA as opposed to the 3' terminus. These effects have been correlated to the changes in RNA secondary structure resulting from the deletions. Nucleotides 11-108 of the intact 5S RNA provide the necessary sequence and conformational information required for the binding of TFIIIA. Synthetic 5S RNA genes have been constructed so that in vitro transcription with T7 RNA polymerase yields mature 5S RNA. The transcription factor has a higher affinity for somatic vs. oocyte 5S RNA, similar to the differential affinity of TFIIIA for the two genes. Binding studies with chimeric 5S RNA molecules indicated that the increased binding strength of somatic 5S RNA is conferred by nucleotide substitutions in the 5' half of the molecule.

Analysis of induced sputum after air and ozone exposures in healthy subjects.

Exposure of healthy subjects to ozone is associated with increases in cellular and biochemical markers of inflammation in bronchoalveolar lavage fluid. To determine if analysis of induced sputum might similarly reveal the pulmonary inflammatory effects of ozone exposure, we performed cellular and biochemical analysis of induced sputum collected 4 hr after air and ozone (0.4 ppm for 2 hr) exposures from 10 healthy subjects (age 30.0 +/- 5.0 years; 5 females) in a randomized crossover study in which exposures were separated by 2 weeks. We found that the total number of nonsquamous cells was significantly higher after ozone exposure than after air exposure (7.4 vs 3.9 x 10(5)/ml, P < 0.05) as was the percentage of the nonsquamous cells that were neutrophils (80.0 +/- 7.0% vs 51.0 +/- 20.0%, P < 0.05) and the levels of myeloperoxidase in the sputum fluid phase (1.6 +/- 0.6 vs 1.3 +/- 0.6 microg/ml, P < 0.05). In addition, IL-6 and IL-8 levels were higher after ozone than after air exposures, but not significantly so (44.5 +/- 32.4 pg/ml vs 26.8 +/- 30.7 pg/ml, P = 0.11; 1.5 +/- 0.5 ng/ml vs 1.1 +/- 0.6 ng/ml, P = 0.09). Mucin-like glycoprotein levels were also not significantly different between exposures (1.6 +/- 0.9 mg/ml vs 1.3 +/- 1.0 mg/ml, P = 0.26). We conclude that analysis of induced sputum is a useful noninvasive method for studying the pulmonary response to ozone exposure in healthy subjects.

Centrifugal recovery and dissolution of recombinant Gly-IGF-II inclusion-bodies: the impact of feedrate and re-centrifugation on protein yield.

The impact of centrifuge feedrate and multiple centrifuge passes on protein yield following recombinant Gly-Insulin-like Growth Factor II (Gly-IGF-II) inclusion-body dissolution has been investigated. Altering centrifuge feedrate did not significantly improve the overall protein yield following dissolution. Improved centrifuge recovery at a low feedrate was offset by poorer inclusion body paste purity. This reduced purity resulted in a significant loss of protein during inclusion-body dissolution due to proteolysis. Multiple centrifuge passes improved the inclusion-body paste purity. This resulted in a net improvement in the overall protein yield following dissolution. This work demonstrates that a strong interaction exists between centrifuge performance and inclusion-body dissolution for protease-sensitive products such as Gly-IGF-II.