Local Heat Application for the Treatment of Buruli Ulcer: Results of a Phase II Open Label Single Center Non Comparative Clinical Trial.

BACKGROUND Buruli ulcer (BU) is a necrotizing skin disease most prevalent among West African children. The causative organism, Mycobacterium ulcerans, is sensitive to temperatures above 37°C. We investigated the safety and efficacy of a local heat application device based on phase change material. METHODS In a phase II open label single center noncomparative clinical trial (ISRCTN 72102977) under GCP standards in Cameroon, laboratory confirmed BU patients received up to 8 weeks of heat treatment. We assessed efficacy based on the endpoints 'absence of clinical BU specific features' or 'wound closure' within 6 months ("primary cure"), and 'absence of clinical recurrence within 24 month' ("definite cure"). RESULTS Of 53 patients 51 (96%) had ulcerative disease. 62% were classified as World Health Organization category II, 19% each as category I and III. The average lesion size was 45 cm(2). Within 6 months after completion of heat treatment 92.4% (49 of 53, 95% confidence interval [CI], 81.8% to 98.0%) achieved cure of their primary lesion. At 24 months follow-up 83.7% (41 of 49, 95% CI, 70.3% to 92.7%) of patients with primary cure remained free of recurrence. Heat treatment was well tolerated; adverse effects were occasional mild local skin reactions. CONCLUSIONS Local thermotherapy is a highly effective, simple, cheap and safe treatment for M. ulcerans disease. It has in particular potential as home-based remedy for BU suspicious lesions at community level where laboratory confirmation is not available. CLINICAL TRIALS REGISTRATION ISRCT 72102977.

Rituximab Maintenance for a Maximum of 5 Years After Single-Agent Rituximab Induction in Follicular Lymphoma: Results of the Randomized Controlled Phase III Trial SAKK 35/03.

PURPOSE Rituximab maintenance therapy has been shown to improve progression-free survival in patients with follicular lymphoma; however, the optimal duration of maintenance treatment remains unknown. PATIENTS AND METHODS Two hundred seventy patients with untreated, relapsed, stable, or chemotherapy-resistant follicular lymphoma were treated with four doses of rituximab monotherapy in weekly intervals (375 mg/m(2)). Patients achieving at least a partial response were randomly assigned to receive maintenance therapy with one infusion of rituximab every 2 months, either on a short-term schedule (four administrations) or a long-term schedule (maximum of 5 years or until disease progression or unacceptable toxicity). The primary end point was event-free survival (EFS). Progression-free survival, overall survival (OS), and toxicity were secondary end points. Comparisons between the two arms were performed using the log-rank test for survival end points. RESULTS One hundred sixty-five patients were randomly assigned to the short-term (n = 82) or long-term (n = 83) maintenance arms. Because of the low event rate, the final analysis was performed after 95 events had occurred, which was before the targeted event number of 99 had been reached. At a median follow-up period of 6.4 years, the median EFS was 3.4 years (95% CI, 2.1 to 5.3) in the short-term arm and 5.3 years (95% CI, 3.5 to not available) in the long-term arm (P = .14). Patients in the long-term arm experienced more adverse effects than did those in the short-term arm, with 76% v 50% of patients with at least one adverse event (P < .001), five versus one patient with grade 3 and 4 infections, and three versus zero patients discontinuing treatment because of unacceptable toxicity, respectively. There was no difference in OS between the two groups. CONCLUSION Long-term rituximab maintenance therapy does not improve EFS, which was the primary end point of this trial, or OS, and was associated with increased toxicity.

Stretching single-domain proteins: Phase diagram and kinetics of force-induced unfolding

Single-molecule force spectroscopy reveals unfolding of domains in titin on stretching. We provide a theoretical framework for these experiments by computing the phase diagrams for force-induced unfolding of single-domain proteins using lattice models. The results show that two-state folders (at zero force) unravel cooperatively, whereas stretching of non-two-state folders occurs through intermediates. The stretching rates of individual molecules show great variations reflecting the heterogeneity of force-induced unfolding pathways. The approach to the stretched state occurs in a stepwise “quantized” manner. Unfolding dynamics and forces required to stretch proteins depend sensitively on topology. The unfolding rates increase exponentially with force f till an optimum value, which is determined by the barrier to unfolding when f = 0. A mapping of these results to proteins shows qualitative agreement with force-induced unfolding of Ig-like domains in titin. We show that single-molecule force spectroscopy can be used to map the folding free energy landscape of proteins in the absence of denaturants.

Disruption of RB/E2F-1 interaction by single point mutations in E2F-1 enhances S-phase entry and apoptosis.

The retinoblastoma protein (RB) has been proposed to function as a negative regulator of cell proliferation by complexing with cellular proteins such as the transcription factor E2F. To study the biological consequences of the RB/E2F-1 interaction, point mutants of E2F-1 which fail to bind to RB were isolated by using the yeast two-hybrid system. Sequence analysis revealed that within the minimal 18-amino acid peptide of E2F-1 required for RB binding, five residues, Tyr (position 411), Glu (419), and Asp-Leu-Phe (423-425), are critical. These amino acids are conserved among the known E2F family members. While mutation of any of these five amino acids abolished binding to RB, all mutants retained their full transactivation potential. Expression of mutated E2F-1, when compared with that of wild-type, significantly accelerated entry into S phase and subsequent apoptosis. These results provide direct genetic evidence for the biological significance of the RB/E2F interaction and strongly suggest that the interplay between RB and E2F is critical for proper cell cycle progression.

Operator's and organizational maintenance manual : water purification unit, van-type, body mounted, electric driven, AC, 115, 208 V, single- and 3-phase, 60 hertz, 1/20 to 2 hp, 3000 gph (MET-PRO model 3000V), NSN 4610-00-168-1799.

"18 June 1980."

Organizational, direct support, and general support maintenance repair parts and special tools list : air conditioner, base mounted, air cooled, 208 VAC, 3-phase, 60 Hz, single package, 36,000 Btu/hr, model UAC 40-5/6-08, NSN 4120-01-122-0629, model 2643T100-1, NSN 4120-01-218-6912.

"10 October 1989."

Direct and general support and depot maintenance repair parts and special tools list : welding machine, arc, generator, electric motor driven, AC, 220V, 3 phrase [i.e. phase], 60HZ, single operator, remote control, 300 amp DC arc, wheel MTD ....

"December 1968."

Operator, organizational, field, and depot maintenance manual : welding machine, arc, generator, elec [sic] motor driven, AC, 220V, 3 phase, 60 cycle, single operator, remote control, 300 amp DC arc, wheel mounted ...

"August 1963."

Organizational, direct and general support, and depot maintenance repair parts and special tools list : air conditioner, base mounted, air cooled, 208V, 3 phase, 60 cycle, AC, single package, 36,000 BTU/HR, (York Corp model MA3-F23A), FSN 4120-926-1116.

Includes index.

Operator, organizational, direct and general support, and depot maintenance manual : air conditioner, base mounted, air cooled, 208 volt, 3-phase, 60 cycle, AC, single package, 36,000 BTU/hr, (York Corp model MA 3-F23A), FSN 4120-926-1116.

"October 1967."

Operator and organizational maintenance manual : water purification unit, van-type body mounted; electric driven, AC, 115, 208V single-and 3-phase, 60 hertz ... NS 4610-01-016-9964.

"5 March 1979."

Organizational maintenance repair parts and special tools lists : water purification unit, van-type, body mounted, electric driven, AC, 115/208 V, single and 3 phase, 60 hertz, 1/20 to 2 hp, 1500 GPH, model EMC-1500S, NSN 4610-01-037-8746.

"15 May 1980."

Operator's manual : water purification unit, base mounted, electric driven, AC, 115, 208 volt, single and 3 phase, 60 cycle, 3000 gallons per hour (MET-PRO model 3000-2700A), FSN 4610-857-0330).

"August 1963."

Direct support and general support maintenance manual : water purification unit, van type, body mounted, electric motor driven, AC, DC, 115, 208 V, single and 3 phase, 60 hertz, 1/20 to 2 hp, 1500 gph, model EMC-1500S, NSN 4610-01-037-8746, EMC Industries Inc., DAAKO1-76-C-5661.

"1 August 1979."

Direct support and general support maintenance repair parts and special tools lists (including depot maintenance repair parts and special tools) : water purification unit, van-type, body mounted, electric driven, AC, 115/208 V, single and 3 phase, 60 hertz, 1/20 to 2 hp, 1500 gph, model EMC-1500S, NSN 4610-01-037-8746.

"15 May 1980."