Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes

Macrolide antibiotics are known to have a different proarrhythmic potential in the presence of comparable QT prolongation in the surface ECG. Because the extent of QT prolongation has been used as a surrogate marker for cardiotoxicity, we aimed to study the different electrophysiological effects of the macrolide antibiotics erythromycin, clarithromycin, and azithromycin in a previously developed experimental model of proarrhythmia. In 37 Langendorff-perfused rabbit hearts, erythromycin (150-300 microM, n = 13) clarithromycin (150-300 microM, n = 13), and azithromycin (150-300 microM, n = 11) led to similar increases in QT interval and monophasic action potential (MAP) duration. In bradycardic (atrioventricular-blocked) hearts, eight simultaneously recorded epi- and endocardial MAPs demonstrated increased dispersion of repolarization in the presence of all three antibiotics. Erythromycin and clarithromycin led to early afterdepolarizations (EADs) and torsade de pointes (TdP) after lowering of potassium concentration. In the presence of azithromycin, no EAD or TdP occurred. Erythromycin and clarithromycin changed the MAP configuration to a triangular pattern, whereas azithromycin caused a rectangular pattern of MAP prolongation. In 13 additional hearts, 150 microM azithromycin was administered after previous treatment with 300 microM erythromycin and suppressed TdP provoked by erythromycin. In conclusion, macrolide antibiotics lead to similar prolongation of repolarization but show a different proarrhythmic potential (erythromycin > clarithromycin > azithromycin). In the presence of azithromycin, neither EAD nor TdP occur. This effect may be related to a rectangular pattern of action potential prolongation, whereas erythromycin and clarithromycin cause triangular action potential prolongation and induce TdP.     

Extracorporeal shockwave lithotripsy for treatment of sialolithiasis of salivary glands

BACKGROUND: Following the clinical introduction of extracorporeal shockwave lithotripsy in the 1980s for the treatment of sialolithiasis of salivary glands this method has been widely used and replaced surgical interventions in selected patients. PATIENTS: Between 1/1995 and 1/1999 35 patients were treated by extracorporeal shockwave lithotripsy (ESWL) with the "Minilith SL-1" lithotripter on an outpatient basis. Radiography and sonography were performed to verify sialolithiasis and scintigraphic investigation was done to control sufficient gland function. Treatment was performed in a fractionated manner with up to 3000 shockwaves per session, normally without anesthesia or analgosedation. RESULTS: After treatment 45.4 % of the patients with sialolithiasis of the parotid gland (n = 11) were stone-free and in 36.3 % an adequate desintegration of the stones was achieved. These patients underwent 2.6 sessions on average for sufficient stone-destruction. 41.6 % of the patients with sialolithiasis of the submandibular gland (n = 24) were stone-free and 3.1 sessions were necessary on average. Desintegration of the stones was achieved in 25 %. Mild pain, swelling, bleeding out of the intraoral orifice of the affected gland and skin petechia were the only complications. All patients were symptom-free after lithotripsy, although fragmented stones persisted in the parotid gland (18.3 %) and the submandibular gland (33.4 %). CONCLUSIONS: The advantages of ESWL are the relatively painless treatment and the elimination of the need for an operation with its surgical risks.     

Anemia and erythropoietin in critically ill patients

The transfusion of red blood cells is still associated with possible adverse effects and a residual risk of transmission of viral and nonviral diseases. In addition, there is an increasing shortage of blood supply worldwide. These two facts together with the success experienced in the treatment of various types of anemia with recombinant human EPO, have recently led to an increasing interest in the anemia of critically ill patients. As in the anemia of chronic diseases there are several reasons that contribute to the development of anemia in patients on intensive care units: pre-existing anemia, blood loss, reduced red cell life span, impaired iron availability and a direct inhibition of erythropoiesis by inflammatory cytokines. The implications of anemia for the progression and prognosis of critical illness are still unclear and the optimal treatment, including optimal "transfusion triggers" remains controversial. Recombinant human EPO has been proven to be effective in ameliorating the anemia of critical illness in several pilot studies and is currently being tested in larger trials.     

High-grade extremity soft tissue sarcomas: factors predictive of local recurrence and its effect on morbidity and mortality

OBJECTIVE: To identify patient characteristics associated with the development of local recurrence and the effect of local recurrence on subsequent morbidity and mortality in patients with intermediate- to high-grade extremity soft tissue sarcomas. SUMMARY BACKGROUND DATA: Numerous studies on extremity soft tissue sarcomas have consistently shown that presentation with locally recurrent disease is associated with the development of subsequent local recurrences and that large tumor size and high histologic grade are significant factors associated with decreased survival. However, the effect of local recurrence on patient survival remains unclear. METHODS: From 1975 to 1997, 753 patients with intermediate- to high-grade extremity soft tissue sarcomas were treated at UCLA. Treatment outcomes and patient characteristics were analyzed to identify factors associated with both local recurrence and survival. RESULTS: Patients with locally recurrent disease were at a significantly increased risk of developing a subsequent local recurrence. Local recurrence was a morbid event requiring amputation in 38% of the cases. The development of a local recurrence was the most significant factor associated with decreased survival. Once a patient developed a local recurrence, he or she was about three times more likely to die of disease compared to similar patients who had not developed a local recurrence. CONCLUSIONS: Local recurrence in patients with intermediate- to high-grade extremity soft tissue sarcomas is associated with the development of subsequent local recurrences, a morbid event decreasing functional outcomes and the most significant factor associated with decreased survival. Although 85% to 90% of patients with high-grade extremity soft tissue sarcomas are treatable with a limb salvage approach, patients who develop a local recurrence need aggressive treatment and should be considered for trials of adjuvant systemic therapy.     

Biological fixation of hydroxyapatite-coated versus grit-blasted titanium hip stems: a canine study

BACKGROUND: The purpose of the study was to evaluate the influence of a proximal hydroxyapatite (HA) coating in comparison with a grit-blasted titanium surface of an anatomic hip stem in an animal model over a maximum duration of 2 years. METHODS: Thirty adult dogs underwent implantation of either a proximally HA-coated or a grit-blasted anatomic titanium stem. The animals were clinically evaluated for their walking ability, and serial radiographs were taken. The femora were assessed histomorphologically at set time points from 6 weeks to 2 years postoperatively. Undecalcified thin section specimens through the proximal and distal portion of the coating or grit blasting were prepared. The percentage of implant surface with direct bone contact without connective tissue involvement was determined. RESULTS: Radiographically, animals with uncoated prostheses showed characteristic signs of loosening more frequently. Histomorphometrically, an average of 65% of the surface of HA-coated implants had bone contact, but only 14.7% of the surface of grit-blasted prostheses ( p=0.0001). There was no relationship between bone contact and the duration of implantation of the prosthesis, either for the coated or for the uncoated prostheses. HA coating enhances osseointegration of an anatomic hip stem. CONCLUSION: Anatomic stems with rounded design require a surface coating or surface structure, since the mere grit-blasting of the titanium surface does not ensure osseointegration in this animal model.     

Options for first- and second-line therapy in small cell lung cancer--a workshop discussion

In a case study-based workshop, physicians were asked to discuss various aspects of patient management in small cell lung cancer (SCLC). For first-line chemotherapy, most investigators recommended treatment with etoposide/cisplatin, with possible dosing variations according to tolerability and convenience. In France (but not elsewhere), medical oncologists tend to use a four-drug regimen (etoposide/cisplatin/cyclophosphamide/epirubicin), based on the results of an extensive-stage SCLC trial. Alternative first-line regimens, such as vincristine/ifosfamide/carboplatin/etoposide (VICE) and topotecan/platinum, are currently being explored. Options for therapy in patients with recurrent disease are more varied, although there was consensus that active treatment at relapse should be considered. Regimens include topotecan (alone or in combination), cyclophosphamide/doxorubicin/vincristine (CAV) and re-induction with the earlier first-line agents. Studies are also investigating the potential benefits of other combinations, including topotecan/vinorelbine and paclitaxel/carboplatin. For patients with relapsed extensive-stage SCLC and brain metastases, whole brain radiation therapy was considered appropriate for both palliative and therapeutic reasons. The potential role of combination therapy with topotecan/temozolomide, both of which cross the blood-brain barrier, is currently being investigated.     

Second-line treatment of small-cell lung cancer. The case for systemic chemotherapy

Small-cell lung cancer is an aggressive tumor associated with high rates of regional or distant metastases at diagnosis. Although highly chemosensitive to agents given in the first-line setting (e.g., etoposide and cisplatin), most patients relapse and have a poor prognosis. Treatment options for relapsed patients include radiotherapy for limited-stage disease and chemotherapy or combined modalities for advanced-stage disease. In clinical practice, however, some oncologists maintain that chemotherapy provides an insufficient survival benefit to justify the sometimes debilitating toxicity associated with the more active regimens in particular. Other potential barriers to further treatment include patient comorbidities, performance status, site(s) of progression, progression-free interval, and previous treatments. However, numerous clinical trials demonstrate that some patients benefit from treatment, achieving prolonged survival, symptom palliation, improved quality of life, and the opportunity, albeit rare, for durable remission. Additionally, several novel chemotherapeutics are available that alone or in combination help patients lead an improved quality of life. Finally, alternative routes and schedules--oral formulations, weekly administration, and prolonged treatment vacations--have been developed to deliver chemotherapy to patients with poor performance status or multiple comorbidities. This article reviews the advantages and disadvantages of treating recurrent small-cell lung cancer and summarizes the utility of several active agents.     

Macular translocation: unifying concepts, terminology, and classification

PURPOSE: To describe some unifying concepts, terminology, and classification of macular translocation so as to facilitate communication within the scientific community. METHODS: A panel of ophthalmologists with expertise in macular translocation reviewed available data and developed some unifying concepts, terminology, and classification of macular translocation. RESULTS: Macular translocation may be defined as any surgery that has a primary goal of relocating the central neurosensory retina or fovea intraoperatively or postoperatively specifically for the management of macular disease. It may be classified according to the size of the retinotomy and, where applicable, the technique of chorioscleral shortening used. The direction of macular translocation is denoted by the movement of the neurosensory macula relative to the underlying tissues. Effective macular translocation may be defined as successful intraoperative or postoperative relocation of the fovea overlying a subfoveal lesion to an area outside the border of the lesion. The concepts of minimum desired translocation and median postoperative foveal displacement can give some useful idea of the likelihood of effective macular translocation before surgery. CONCLUSIONS: Use of a common standardized terminology for macular translocation will facilitate communication within the scientific community and enhance further research in this area. However, the definitions, terms, classification, and concepts concerning macular translocation are likely to continue to evolve as macular translocation undergoes further modifications and refinements.