MAP kinase phosphatase activity sets the threshold for thymocyte positive selection

Phosphorylation of MAP kinases is important for proper translation of T cell antigen receptor (TCR) signals into thymocyte cell fates, but the role of MAP kinase phosphatase (MKP) activity in thymocyte development has not been characterized. To explore the role of MKP in thymocytes, we constructed a double mutant MKP-3 (DM-MKP3) that acts as a dominant-negative inhibitor of ERK- and JNK-specific MKP. Thymocytes developing in the presence of DM-MKP3 have enhanced frequencies of both CD4 and CD8 mature, single-positive cells and no increase in apoptosis. Expression of DM-MKP3 also results in an increased proportion of thymocytes with high levels of both CD69 and TCRbeta, suggesting that the increased proportion of mature thymocytes is the result of an increased probability that CD4(+)CD8(+) cells will be positively selected. Thus, MKP activity controls thymocyte cell fate by regulating the threshold of TCR signaling that is able to induce positive selection.     

Long-term outcomes of surgical resection of the jaws in cancer patients with bisphosphonate-related osteonecrosis

Surgical treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is controversial. Current recommendations contraindicate aggressive surgery because its results are unpredictable and may trigger disease progression. In this prospective study, we assessed the effectiveness of surgical resection of the jaws in cancer patients with BRONJ. Between June 2004 and July 2009, 30 cancer patients with refractory BRONJ underwent surgical resection of the jaws at our Units. They were followed-up weekly for the first month, at 3-month intervals up to 1 year, and at 6-month intervals up to 2 years. Panoramic radiographs and CT-scan were obtained at 3, 6, 12, 18 and 24 months. Primary outcomes were the 24-month recurrence rate of BRONJ and the 24-month mortality rate. Secondary outcomes were post-operative complications, duration of hospital stay after surgery, time to return to oral diet, and degree of oral pain. The 30 patients had a median age of 66 years and were mostly females (80%). Twenty-eight underwent a single resection and two had both jaws resected, for a total of 32 resected jaws. The cumulative recurrence rate of BRONJ in resected jaws 3.1% and 9.4% at 3 and 6 months, respectively. All the jaws with recurrent BRONJ had osteomyelitis at the margins of bone resection. The cumulative incidence of death was 3%, 12% and 16% at 12, 18 and 24 months. Surgical resection of BRONJ was highly effective, with few post-operative complications and were not associated with long-term mortality.     

Novel Platforms for Oral Drug Delivery

The aim of this review is to provide the reader general and inspiring prospects on recent and promising fields of innovation in oral drug delivery. Nowadays, inventive drug delivery systems vary from geometrically modified and modular matrices, more close to “classic” pharmaceutical manufacturing processes, to futuristic bio micro-electro-mechanical systems (bioMEMS), based on manufacturing techniques borrowed from electronics and other fields. In these technologies new materials and creative solutions are essential designing intelligent drug delivery systems able to release the required drug at the proper body location with the correct release rate. In particular, oral drug delivery systems of the future are expected to have a significant impact on the treatment of diseases, such as AIDS, cancer, malaria, diabetes requiring complex and multi-drug therapies, as well as on the life of patients, whose age and/or health status make necessary a multiple pharmacological approach.     

Solid-state chemistry of ambroxol theophylline-7-acetate

Ambroxol theophylline-7-acetate (ACE) is the salt obtained by reaction of equimolar amounts of ambroxol (AMB), a drug showing mucolytic and expectorant properties, and theophylline-7-acetic acid (TAA), a xanthine derivative with specific bronchodilator activity. ACE is used for the treatment of bronchial and pulmonary diseases (bronchitis, asthma, emphysema, chronic obstructive disease). Recrystallization experiments of ACE resulted in the isolation of two polymorphs (monotropically related) and four solvated forms. X-ray diffractometry, DSC, TGA, and HSM techniques were used to investigate the forms that are obtained by thermal desolvation of the solvates. The phase diagram of the TAA-AMB binary system was constructed by performing thermal analyses on mixtures of TAA-AMB and of each component plus the interaction compound (TAA-ACE and ACE-AMB). The Schroeder-Van Laar equation proved to be a very useful tool for checking the consistency between the experimental data and the theoretical model related to the general system, showing complete miscibility in the liquid phase and complete immiscibility in the solid phase.     

Intraoperative ultrasonography imaging in spinal surgery (technique and indications).

Intraoperative ultrasonography was conducted in 20 patients; the technique of intraoperative ultrasonography for use in spinal surgery is described. The authors emphasize that this non-invasive method obtains real time images of considerable diagnostic importance, allowing for a significantly minor use of image intensifier, with a consequent reduction in doses for both the patient and the staff.     

Evaluation of conservative treatment of non specific spondylodiscitis

The objective of this study was to analyse the presentation, aetiology, conservative management, and outcome of non-tuberculous pyogenic spinal infection in adults. We performed a retrospective review of 56 patients (35 women and 21 men) of pyogenic spinal infection presenting over a 7-year period (1999–2006) to the Department of Spinal Surgery of Hesperia Hospital. The medical records, radiologic imaging, bacteriology results, treatment, and complications of all patients were reviewed. The mean age at presentation was 47.8 years (age range 35–72 years), the mean follow-up duration was 12.5 months. The most common site of infection was lumbar spine (n: 48), followed by the thoracic spine (n: 8). Most patients were symptomatic for between 4 and 10 weeks before presenting to hospital. The frequently isolated pathogen was Staphylococcus aureus in 31 of 56 cases (57.6%). Percutaneous biopsies were diagnostic in 57% of patients; the open biopsy was indicated if closed biopsy failed and when the infection was not accessible by percutaneous technique. The patients were managed by conservative measures alone, including antibiotic therapy and spinal bracing. The mean period of antibiotic therapy was 8.5 weeks (range 6–9 weeks), followed by oral antibiotics for 6 weeks. All patients had a supportive spinal brace for mean 8 weeks (range 6–10 weeks). The duration of the administration of oral antibiotics was dependent on clinical and laboratory evidence (white cell count, erythrocyte sedimentation rate, C-reactive protein) that the infection was resolved. The follow-up MR gadolinium scans were essential to monitor the response to medical treatment. The diagnosis of pyogenic spinal infection should be considered in any patient presenting with severe localised unremitting back and neck pain, especially when accompanied with systemic features, such as fever and weight loss and in the presence of elevated inflammatory markers. The conservative management of infection with antibiotic therapy and spinal bracing was very successful.

     

Prognostic value of the staging system proposed by Merlini, Waldenstr?m and Jayakar for multiple myeloma

We have reviewed a series of 90 consecutive patients with multiple myeloma (MM) diagnosed in the period 1.1.1971-31.12.1980 and subsequently treated with an intermittent administration of melphalan and prednisone (62 IgG MM, 20 IgA MM and 8 Bence-Jones (BJ) MM). Unfavorable prognostic factors were: presence of micromolecular M component (K or lambda), serum creatinine greater than or equal to 2 mg/dl, serum calcium greater than or equal to 12 mg/dl, presence of BJ proteinuria, Hb less than 10 g/dl, diffuse osteolytic lesions, bone marrow plasma cell percentage greater than or equal to 30%. In particular, according to the recent staging system proposed by Merlini et al. [Blood 55: 1011, 1980], the most important prognostic parameters for IgG and BJ MM were: serum creatinine, BMPC % and serum calcium; for IgA MM the most important were: serum hemoglobin, calcium and M component levels. We have compared the survival curve of 45 patients who died, with the predicted survival curve according to the multivariate regression analysis of Merlini and co-workers; the prediction was equally precise for all the three types of MM considered, thus showing the high sensibility of this new staging system.     

Malignant ventricular hyperkinetic arrhythmias. Classificational criteria: review of Lown's classification. Polycentric study

Although Lown grading system of ventricular premature complexes (VPCs) has important conceptual shortcomings and has shown severe limitations in either cross-sectional or longitudinal studies, this classification is still the most well-known and used method to characterize the arrhythmologic ventricular pattern of the individual patient. We have looked at a modification of VPCs Lown grading scheme to correct the defects and to make the use of the classification more accurate. Our proposal is based on maintenance of 5 classes--similar to those of Lown original classification--to which we have assigned a score from 0 to 60. We have also introduced many sub-classes, each with a definite score, to better characterize the type of arrhythmic event. The sum of the score of the highest class and the score of every subclass furnishes the final score. This score is a direct index of the importance of the ventricular arrhythmias and seems to be useful for statistical evaluation of the anti-arrhythmic therapy and for follow-up studies, as confirmed by preliminary clinical results obtained through the use of this new VPCs classification.