Anti-Alpha-Toxin Monoclonal Antibody and Antibiotic Combination Therapy Improves Disease Outcome and Accelerates Healing in a Staphylococcus aureus Dermonecrosis Model

Alpha-toxin (AT) is a major virulence determinant in Staphylococcus aureus skin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), prevents S. aureus disease in a mouse dermonecrosis model by neutralizing AT-mediated tissue necrosis and immune evasion. In the present study, MEDI4893*, an affinity-optimized version of 2A3, was characterized for therapeutic activity in the dermonecrosis model as a single agent and in combination with two frontline antibiotics, vancomycin and linezolid. MEDI4893* postinfection therapy was found to exhibit a therapeutic treatment window similar to that for linezolid but longer than that for vancomycin. Additionally, when combined with either vancomycin or linezolid, MEDI4893* resulted in reduced tissue damage, increased neutrophil and macrophage infiltration and abscess formation, and accelerated healing relative to those with the antibiotic monotherapies. These data suggest that AT neutralization with a potent MAb holds promise for both prophylaxis and adjunctive therapy with antibiotics and may be a valuable addition to currently available options for the treatment of S. aureus skin and soft tissue infections.     

Review of Forty Years of Rehabilitation Issues in Spinal Cord Injury

Abstract

Context

Childhood laminectomy can lead to spinal deformity. This is a report of a case of paraplegia caused by rotokyphoscoliosis, a late complication of laminectomy.

Findings

A 55-year-old woman developed paraplegia due to post-laminectomy kyphoscoliosis. She had surgery for a spinal tumor at age 13 years. She developed kyphosis 2 years after the laminectomy, which has been gradually progressing over the years. She experienced weakness of lower limbs that progressed to paraplegia. There was no evidence for tumor recurrence. To our knowledge, this is the first reported case of post-laminectomy kyphoscoliosis causing late-onset paraplegia.

Conclusions/clinical relevance

This case highlights a possible long-term complication of laminectomy without stabilization or untreated kyphoscoliosis. Children should be followed closely after laminectomy because development of spinal deformity is very common. Without intervention, the kyphosis might progress and in the long term, serious neurological complications may result, including paraplegia.     

The cytoskeleton in Chediak-Higashi syndrome fibroblasts

The Chediak-Higashi syndrome (CHS) trait is expressed in cultured human skin fibroblasts as an abnormal perinuclear concentration of moderately enlarged lysosomes. The cytoskeleton of CHS fibroblasts appears intact. Microtubules are normal in number and morphology, as assessed by colchicine binding studies, antitubulin immunofluorescence, and electron microscopy. Deformability by shear force is unaltered and microfilaments are abundant. However, CHS lysosomes appear to interact abnormally with the cytoskeleton, since the perinculear aggregation partially disperses after depolymerization of cell microtubules with colchicine. These results suggest that CHS is associated with a defect of either the lysosomal membrane itself or of lysosomal membrane- microtubule interaction.     

Percutaneous Ultrasonic Tenotomy Reduces Insertional Achilles Tendinopathy Pain With High Patient Satisfaction and a Low Complication Rate

Due to the novelty of percutaneous ultrasonic tenotomy, the risks and benefits of this minimally invasive procedure for insertional Achilles tendinopathy pain have only been examined in case studies and retrospective chart reviews for other diagnoses. This retrospective chart review over a 3.5‐year period identified 34 patients with insertional Achilles tendinopathy who had percutaneous ultrasonic tenotomy (mean age ± SD, 52.2 ± 11.6 years; mean body mass index, 32.9 ± 7.5 kg/m²; 62% female). This procedure reduced the rate of moderate/severe pain from 68% at baseline to 15% at the long‐term follow‐up and had a satisfaction rate of 70%. There was 1 minor complication out of 40 procedures in 34 patients.     

Varicella exposure in a neonatal intensive care unit: case report and control measures

Forty-six infants in a neonatal intensive care unit and 138 health care workers were exposed to a pediatric medical resident during the prodromal period and the early days of unrecognized varicella. An attempt was made to prevent an outbreak of additional cases by the institution of emergency control measures. These measures included rapid identification of varicella antibody status in exposed neonates, varicella antibody testing of health care workers with unknown or uncertain history of varicella, prompt administration of varicella zoster immune globulin to potentially susceptible persons, and cohorting neonates on the basis of exposure and antibody status. Passive maternal antibody was detected in 44 of the neonates. Of 27 health care workers who reported either a negative or an uncertain history of varicella, 26 had detectable antibody. No overt cases of varicella occurred in exposed patients or personnel.     

IL-10-driven immunoglobulin production by B lymphocytes from IgA-deficient individuals correlates to infection proneness

In search for a possible explanation of the phenotypic heterogeneity in IgA deficiency, we studied the function of B cells from IgA-deficient (IgAd) individuals. Two groups of IgAd individuals, one frequently infected and one clinically apparently healthy, as well as normal controls, were studied. Peripheral blood mononuclear cells (PBMC) and B cells from IgAd individuals and controls were cultured with Staphylococcus aureus Cowan I strain and with anti-CD40 MoAb presented on the CD32-transfected fibroblast cell line in the presence of IL-10. In this experimental system PBMC and B cells from the infection-prone IgAd individuals produced only minute amounts of IgA. In contrast, PBMC and B cells from healthy IgAd subjects secreted significantly more IgA1 and IgA2 in comparison with infection-prone IgAd patients (P < 0.05). These data suggest that the abnormalities of B cell differentiation in IgAd could be of heterogeneous origin. Thus, whereas in healthy IgAd subjects IgA production may be efficiently up-regulated in vitro by addition of IL-10 to CD40-activated B cell culture, the corresponding B cell differentiation does not occur in infection-prone IgAd patients. These observations provide a conceptual framework for phenotypic heterogeneity in IgAd subjects.     

Spectral karyotyping combined with locus-specific FISH simultaneously defines genes and chromosomes involved in chromosomal translocations

Genes that play roles in malignant transformation have often been found proximate to cancer-associated chromosomal breakpoints. Identifying genes that flank chromosomal reconfigurations is thus essential for cancer cytogenetics. To simplify and expedite this identification, we have developed a novel approach, based on simultaneous spectral karyotyping and fluorescence in situ hybridization (FISH) which, in a single step, can identify gross chromosomal aberrations as well as detect the involvement of specific loci in these rearrangements. Signals for specifically queried genes (FISH probe) were easily detectable in metaphase cells, together with the signals from painted chromosomes (spectral karyotyping probes). The concentration and size of the FISH probes could cover a wide range and still be used successfully. Some of the nucleotide-bound dyes used for the labeling, as Cy3, Spectrum Orange, Alexa 594, Texas Red, and Rhodamine 110, were particularly efficient. More than one gene can be queried in the same metaphase, because multiple FISH probes could be hybridized simultaneously. To demonstrate this technique, we applied it to the myeloma cell line Karpas 620, which has numerous chromosomal rearrangements. The approach that we present here will be particularly useful for the analysis of complex karyotypes and for testing hypotheses arising from cancer gene expression studies. Published 2000 Wiley-Liss, Inc.