Targeting Alpha Toxin and ClfA with a Multimechanistic Monoclonal-Antibody-Based Approach for Prophylaxis of Serious Staphylococcus aureus Disease.

UNLABELLED: Staphylococcus aureus produces numerous virulence factors, each contributing different mechanisms to bacterial pathogenesis in a spectrum of diseases. Alpha toxin (AT), a cytolytic pore-forming toxin, plays a key role in skin and soft tissue infections and pneumonia, and a human anti-AT monoclonal antibody (MAb), MEDI4893*, has been shown to reduce disease severity in dermonecrosis and pneumonia infection models. However, interstrain diversity and the complex pathogenesis of S. aureus bloodstream infections suggests that MEDI4893* alone may not provide adequate protection against S. aureus sepsis. Clumping factor A (ClfA), a fibrinogen binding protein, is an important virulence factor facilitating S. aureus bloodstream infections. Herein, we report on the identification of a high-affinity anti-ClfA MAb, 11H10, that inhibits ClfA binding to fibrinogen, prevents bacterial agglutination in human plasma, and promotes opsonophagocytic bacterial killing (OPK). 11H10 prophylaxis reduced disease severity in a mouse bacteremia model and was dependent on Fc effector function and OPK. Additionally, prophylaxis with 11H10 in combination with MEDI4893* provided enhanced strain coverage in this model and increased survival compared to that obtained with the individual MAbs. The MAb combination also reduced disease severity in murine dermonecrosis and pneumonia models, with activity similar to that of MEDI4893* alone. These results indicate that an MAb combination targeting multiple virulence factors provides benefit over a single MAb neutralizing one virulence mechanism by providing improved efficacy, broader strain coverage, and protection against multiple infection pathologies. IMPORTANCE: Alternative strategies to broad-spectrum antibiotics are required to combat the antibiotic resistance epidemic. Previous attempts at active or passive immunization against Staphylococcus aureus targeting single antigens have failed in clinical trials despite positive preclinical data. To provide broad disease and isolate coverage, an effective immunization strategy likely must target multiple virulence mechanisms of the pathogen. Herein, we tested a multimechanistic MAb combination targeting alpha toxin (AT) and clumping factor A (ClfA) that neutralizes AT-mediated cytotoxicity, blocks fibrinogen binding by ClfA, prevents bacterial agglutination, targets the bacteria for opsonophagocytic killing, and provides broad isolate coverage in a lethal-bacteremia model. Although each MAb alone was effective in bacteremia against some individual isolates, the MAb combination provided improved protection against other isolates. These results illustrate the importance of targeting multiple virulence mechanisms and highlight the potential for an MAb combination targeting AT and ClfA to effectively prevent S. aureus disease.

Laser hair removal update.

Laser hair removal has made possible the permanent reduction of unwanted hair. However, this technology remains far from perfect. Many advances have occurred in the past several years to improve laser hair removal, including lengthening pulse widths and adding mechanisms to cool the skin during treatment. These advances have improved results and broadened the scope of patients who are candidates for this procedure. This article reviews the latest advances as well as the various laser hair removal systems currently available.

A successful 15-year experience in double-dome tip surgery via endonasal approach: nuances and pitfalls.

BACKGROUND: Endonasal double-dome techniques provide a reliable method to approach the nasal tip. OBJECTIVES: To review one surgeon's 15-year experience using a graduated method of endonasal double-dome tip surgery including patient selection, intraoperative techniques, and postoperative complications and to emphasize the nuances to achieve symmetry and consistent results. PATIENTS AND METHODS: Three hundred eighty-six patients who had adequate follow-up after undergoing endonasal double-dome tip rhinoplasty. RESULTS: Results at 1 year showed high rates of supratip (94%), dome (96%), and nostril (88%) symmetry. There was a high rate of patient satisfaction with a low rate of revision (7%). CONCLUSION: Endonasal double-dome tip surgery provides the surgeon the ability to achieve consistent results with high patient satisfaction and a low rate of revision.

Optimal sample preparation conditions for the determination of uranium in biological samples by kinetic phosphorescence analysis (KPA).

Kinetic phosphorescence analysis (KPA) is a proven technique for rapid, precise, and accurate determination of uranium in aqueous solutions. Uranium analysis of biological samples require dry-ashing in a muffle furnace between 400 and 600 degrees C followed by wet-ashing with concentrated nitric acid and hydrogen peroxide to digest the organic component in the sample that interferes with uranium determination by KPA. The optimal dry-ashing temperature was determined to be 450 degrees C. At dry-ashing temperatures greater than 450 degrees C, uranium loss was attributed to vaporization. High temperatures also caused increased background values that were attributed to uranium leaching from the glass vials. Dry-ashing temperatures less than 450 degrees C result in the samples needing additional wet-ashing steps. The recovery of uranium in urine samples was 99.2+/-4.02% between spiked concentrations of 1.98-1980 ng (0.198-198 microg l(-1)) uranium, whereas the recovery in whole blood was 89.9+/-7.33% between the same spiked concentrations. The limit of quantification in which uranium in urine and blood could be accurately measured above the background was determined to be 0.05 and 0.6 microg l(-1), respectively.

Determination of the isotopic composition of uranium in urine by inductively coupled plasma mass spectrometry.

A simple method based on inductively coupled plasma mass spectrometry (ICP-MS) was developed to identify exposure to depleted uranium by measuring the isotopic composition of uranium in urine. Exposure to depleted uranium results in a decreased percentage of 235U in urine samples causing measurements to vary between natural uranium's 0.72% and depleted uranium's 0.2%. Urine samples from a non-depleted uranium exposed group and a suspected depleted uranium exposed group were processed and analyzed by ICP-MS to determine whether depleted uranium was present in the urine. Sample preparation involved dry-ashing the urine at 450 degrees C followed by wet-ashing with a series of additions of concentrated nitric acid and 30% hydrogen peroxide. The ash from the urine was dissolved in 1 M nitric acid, and the intensity of 235U and 238U ions were measured by ICP-MS. After the samples were ashed, the ICP-MS measurements required less than 5 min. The 235U percentage in individuals from the depleted uranium exposed group with urine uranium concentrations greater than 150 ng L(-1) was between 0.20%-0.33%, correctly identifying depleted uranium exposure. Samples from the non-depleted uranium exposed individuals had urine uranium concentration less than 50 ng L(-1) and 235U percentages consistent with natural uranium (0.7%-1.0%). A minimum concentration of 14 ng L(-1) uranium was required to obtain sufficient 235U to allow calculating a valid isotopic ratio. Therefore, the percent 235U in urine samples measured by this method can be used to identify low-level exposure to depleted uranium.

Mersilene mesh chin augmentation. A 14-year experience.

During the past 20 years, a variety of alloplastic materials have been introduced for chin augmentation. Mersilene mesh (Ethicon, Sommerville, NJ), introduced in 1950, demonstrates many qualities that make it an ideal implant. This article reviews the senior author's (S.W.P.) successful 14-year experience using Mersilene mesh chin implants. Between 1983 and 1997, 264 patients underwent chin implantation procedures. The results show a low rate of infection (0.8%) and displacement (1.5%). There were 14 temporary paresthesias and no cases of permanent anesthesia. There were no incidences of absorption, rejection, or extrusion. Mersilene provides a soft, natural appearance to the chin, and it continues to be our choice for chin implantation.

Transformation of human osteoblast cells to the tumorigenic phenotype by depleted uranium-uranyl chloride.

Depleted uranium (DU) is a dense heavy metal used primarily in military applications. Although the health effects of occupational uranium exposure are well known, limited data exist regarding the long-term health effects of internalized DU in humans. We established an in vitro cellular model to study DU exposure. Microdosimetric assessment, determined using a Monte Carlo computer simulation based on measured intracellular and extracellular uranium levels, showed that few (0.0014%) cell nuclei were hit by alpha particles. We report the ability of DU-uranyl chloride to transform immortalized human osteoblastic cells (HOS) to the tumorigenic phenotype. DU-uranyl chloride-transformants are characterized by anchorage-independent growth, tumor formation in nude mice, expression of high levels of the k-ras oncogene, reduced production of the Rb tumor-suppressor protein, and elevated levels of sister chromatid exchanges per cell. DU-uranyl chloride treatment resulted in a 9.6 (+/- 2.8)-fold increase in transformation frequency compared to untreated cells. In comparison, nickel sulfate resulted in a 7.1 (+/- 2.1)-fold increase in transformation frequency. This is the first report showing that a DU compound caused human cell transformation to the neoplastic phenotype. Although additional studies are needed to determine if protracted DU exposure produces tumors in vivo, the implication from these in vitro results is that the risk of cancer induction from internalized DU exposure may be comparable to other biologically reactive and carcinogenic heavy-metal compounds (e.g., nickel).

Concepts in lip reconstruction.

Reconstruction of defects of the lip presents a significant challenge to the facial plastic surgeon. Both functional and aesthetic considerations exist. Each defect should be evaluated in terms of its location, size, and depth. Using these three factors, the appropriate reconstructive options can be chosen in a systematic fashion.

Endoscopic excision of a forehead mass.

Endoscopic applications in facial plastic surgery have recently increased with the advent of new instrumentation and as surgeons have become more accustomed to their use. We report the first case (to our knowledge) of an endoscopic removal of a forehead soft tissue mass. The endoscopic approach allows the surgeon access to the forehead area with placement of a skin incision in the hair-bearing scalp. This type of approach is especially of value in patients with a predisposition to unusual scar formation or in those with smooth skin in which a direct incision would yield a noticeable scar.

A comparison of ibuprofen versus acetaminophen with codeine in the young tonsillectomy patient.

OBJECTIVE: To compare the use of ibuprofen with the use of acetaminophen with codeine for posttonsillectomy management. BACKGROUND: We were not satisfied with our traditional pain-management practice for tonsillectomy patients. We hoped to find a new approach for improved patient comfort and avoid scheduled, abusable drugs such as codeine. DESIGN: Intervention, prospective, randomized control trial. Follow-up was 1 month. SETTING: University referral center; institutional pediatric practice, ambulatory. PATIENTS: 110 children undergoing tonsillectomy with or without other procedures. Consecutive patients were offered participation. Enrollees were randomly assigned to one of two classes and analyzed with the initial assignment. No patients withdrew for adverse effects, although 12 in group 2 used codeine and 5 of those used acetaminophen, whereas 2 in group 1 received ibuprofen. INTERVENTIONS: Patients received either acetaminophen with codeine (group 1) or ibuprofen (group 2) for postoperative pain control. MAIN OUTCOME MEASURES: The main outcomes, determined before initiation of the study, were assessment of (1) postoperative bleeding, (2) pain, (3) efficacy of relief of pain by drug, (4) nausea, (5) emesis, (6) readmission to hospital, (7) average temperature, and (8) highest temperature after surgery. RESULTS: The only statistically significant difference is less nausea in patients receiving ibuprofen (p = 0.0049). Of note, no difference existed in postoperative bleeding, pain, or temperature control. CONCLUSIONS: Ibuprofen is at least as effective as acetaminophen with codeine for postoperative pain control in children after tonsillectomy.