Clinically apparent adverse reactions to intra-wound vancomycin powder in early onset scoliosis are rare.

PURPOSE: Spine surgeons have increasingly used intraoperative application of topical vancomycin powder (TVP) to prevent surgical site infections (SSIs). The goals of this study were to define the rate of pharmacological adverse reaction to TVP in young patients undergoing posterior spinal surgery and to summarise institutional variation in TVP dosing. METHODS: This retrospective observational study included ten spine centres in the United States and one in Europe. Patients with early onset scoliosis who underwent posterior spine surgery were eligible for inclusion. Age, weight, TVP dose and surgery type were recorded. Surgeries where patient age was > 12 years were excluded. Pharmacological adverse reactions were defined as clinical instances of Red Man Syndrome, rash, nephrotoxicity, proteinuria, hepatotoxicity or ototoxicity. The rate of pharmacological adverse reaction to TVP was calculated. Dosing practices were summarised. RESULTS: Patient age was in the range of seven months to 12 years (median ten years). Of 1398 observations, there was one possible pharmacological adverse reaction. This was in a ten-year-old, 20.4-kg female patient with neuromuscular sco-liosis undergoing growing rod implantation. She was dosed with 1500 mg of TVP and immediately developed a transient rash without systemic symptoms. This abated over minutes without any medical intervention. There were no other adverse reactions in the sample. The population rate of pharmacological adverse reaction was 0.072% (95% confidence interval 0 to 0.4). Significant variability in dosing practices existed between centres. CONCLUSION: Pharmacological adverse reactions to TVP are rare. Future work may establish evidence-based guidelines for TVP dosing based on patient weight and other variables.

Skeletal muscle and plasma concentrations of cefazolin during complex paediatric spinal surgery.

BACKGROUND: Surgical site infections (SSIs) can have devastating consequences for children who undergo spinal instrumentation. Prospective evaluations of prophylactic cefazolin in this population are limited. The purpose of this study was to describe the pharmacokinetics and skeletal muscle disposition of prophylactic cefazolin in a paediatric population undergoing complex spinal surgery. METHODS: This prospective pharmacokinetic study included 17 children with adolescent idiopathic scoliosis undergoing posterior spinal fusion, with a median age of 13.8 [interquartile range (IQR) 13.4-15.4] yr and a median weight of 60.6 (IQR 50.8-66.0) kg. A dosing strategy consistent with published guidelines was used. Serial plasma and skeletal muscle microdialysis samples were obtained during the operative procedure and unbound cefazolin concentrations measured. Non-compartmental pharmacokinetic analyses were performed. The amount of time that the concentration of unbound cefazolin exceeded the minimal inhibitory concentration for bacterial growth for selected SSI pathogens was calculated. RESULTS: Skeletal muscle concentrations peaked at a median of 37.6 (IQR 26.8-40.0) µg ml(-1) within 30-60 min after the first cefazolin 30 mg kg(-1) dose. For patients who received a second 30 mg kg(-1) dose, the peak concentrations reached a median of 40.5 (IQR 30.8-45.7) µg ml(-1) within 30-60 min. The target cefazolin concentrations for SSI prophylaxis for meticillin-sensitive Staphylococcus aureus (MSSA) and Gram-negative pathogens were exceeded in skeletal muscle 98.9 and 58.3% of the intraoperative time, respectively. CONCLUSIONS: For children with adolescent idiopathic scoliosis undergoing posterior spinal fusion, the cefazolin dosing strategy used in this study resulted in skeletal muscle concentrations that were likely not to be effective for intraoperative SSI prophylaxis against Gram-negative pathogens.

Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is frequently complicated by secondary autoimmune cytopenias (AICs). Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase approved for the treatment of relapsed CLL and CLL with del(17p). The effect of ibrutinib treatment on the incidence of AIC is currently unknown. We reviewed medical records of 301 patients treated with ibrutinib, as participants in therapeutic clinical trials at The Ohio State University Comprehensive Cancer Center between July 2010 and July 2014. Subjects were reviewed with respect to past history of AIC, and treatment-emergent AIC cases were identified. Before starting ibrutinib treatment, 26% of patients had experienced AIC. Information was available for a total of 468 patient-years of ibrutinib exposure, during which there were six cases of treatment-emergent AIC. This corresponds to an estimated incidence rate of 13 episodes for every 1000 patient-years of ibrutinib treatment. We further identified 22 patients receiving therapy for AIC at the time ibrutinib was started. Of these 22 patients, 19 were able to discontinue AIC therapy. We found that ibrutinib treatment is associated with a low rate of treatment-emergent AIC. Patients with an existing AIC have been successfully treated with ibrutinib and subsequently discontinued AIC therapy.

The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model.

Therapeutic regimens for chronic lymphocytic leukemia (CLL) have increasingly utilized monoclonal antibodies since the chimeric anti-CD20 antibody rituximab was introduced. Despite improved clinical outcomes, current CLL therapies are not curative. Therefore, antibodies with greater efficacy and novel targets are desirable. One promising target is CD37, a tetraspanin protein highly expressed on malignant B-cells in CLL and non-Hodgkin lymphoma. Although several novel CD37-directed therapeutics are emerging, detailed preclinical evaluation of these agents is limited by lack of appropriate animal models with spontaneous leukemia expressing the human CD37 (hCD37) target. To address this, we generated a murine CLL model that develops transplantable hCD37+ leukemia. Subsequently, we engrafted healthy mice with this leukemia to evaluate IMGN529, a novel hCD37-targeting antibody-drug conjugate. IMGN529 rapidly eliminated peripheral blood leukemia and improved overall survival. In contrast, the antibody component of IMGN529 could not alter disease course despite exhibiting substantial in vitro cytotoxicity. Furthermore, IMGN529 is directly cytotoxic to human CLL in vitro, depletes B-cells in patient whole blood and promotes killing by macrophages and natural killer cells. Our results demonstrate the utility of a novel mouse model for evaluating anti-human CD37 therapeutics and highlight the potential of IMGN529 for treatment of CLL and other CD37-positive B-cell malignancies.

Risk factors for tumor lysis syndrome in patients with chronic lymphocytic leukemia treated with the cyclin-dependent kinase inhibitor, flavopiridol.

Tumor lysis syndrome (TLS) has been described in over 40% of patients with chronic lymphocytic leukemia treated with the cyclin-dependent kinase inhibitor, flavopiridol. We conducted a retrospective analysis to determine predictive factors for TLS. In 116 patients, the incidence of TLS was 46% (95% CI: 36-55%). In univariable analysis, female gender, greater number of prior therapies, Rai stages III-IV, adenopathy ≥ 10 cm, splenomegaly, del(11q), decreased albumin and increased absolute lymphocyte count, white blood cell count (WBC), ß2-microglobulin, and lactate dehydrogenase were associated (P < 0.05) with TLS. In multivariable analysis, female gender, adenopathy ≥ 10 cm, elevated WBC, increased ß2-microglobulin, and decreased albumin were associated with TLS (P < 0.05). With respect to patient outcomes, 49 and 44% of patients with and without TLS, respectively, responded to flavopiridol (P = 0.71). In a multivariable analysis, controlling for number of prior therapies, cytogenetics, Rai stage, age and gender, progression-free survival (PFS) was inferior in patients with TLS (P = 0.01). Female patients and patients with elevated ß2-microglobulin, increased WBC, adenopathy ≥ 10 cm and decreased albumin were at highest risk and should be monitored for TLS with flavopiridol. TLS does not appear to be predictive of response or improved PFS in patients receiving flavopiridol.

Concomitant hypertension, bradycardia, and loss of transcranial electric motor evoked potentials during pedicle hook removal: report of a case.

Neurophysiologic monitors in the form of transcranial electric motor evoked potentials (tceMEPs) and somatosensory evoked potentials (SSEPs) have become widely used modalities to monitor spinal cord function during major orthopedic spine procedures. In combination with invasive and non-invasive clinical monitoring and an anesthesia information management system (AIMS), we promptly recognized an acute change in hemodynamic and neurophysiologic parameters, managed intraoperative spinal cord contusion, and successfully minimized iatrogenic injury to the spinal cord during corrective spine surgery.

Fractures of the odontoid in children with an open basilar synchondrosis.

Fractures of the odontoid in children with an open basilar synchondrosis differ from those which occur in older children and adults. We have reviewed the morphology of these fractures and present a classification system for them. There were four distinct patterns of fracture (types IA to IC and type II) which were distinguished by the site of the fracture, the degree of displacement and the presence or absence of atlantoaxial dislocation. Children with a closed synchondrosis were classified using the system devised by Anderson and D'Alonzo. Those with an open synchondrosis had a comparatively lower incidence of traumatic brain injury, a higher rate of missed diagnosis and a shorter mean stay in hospital. Certain subtypes (type IA and type II) are likely to be missed on plain radiographs and therefore more advanced imaging is recommended. We suggest staged treatment with initial stabilisation in a Halo body jacket and early fusion for those with unstable injuries, severe displacement or neurological involvement.

Role of wild-type estrogen receptor-beta in mitochondrial cytoprotection of cultured normal male and female human lens epithelial cells.

The influence of sexual category as a modifier of cellular function is underinvestigated. Whether sex differences affect estrogen-mediated mitochondrial cytoprotection was determined using cell cultures of normal human lens epithelia (nHLE) from postmortem male and female donors. Experimental indicators assessed included differences in estrogen receptor-beta (ERbeta) isoform expression, receptor localization in mitochondria, and estrogen-mediated prevention of loss of mitochondrial membrane potential using the potentiometric fluorescent compound JC-1 after nHLE were exposed to peroxide. The impact of wild-type ERbeta (wtERbeta1) was also assessed using wtERbeta1 siRNA to suppress expression. A triple-primer PCR assay was employed to determine the proportional distribution of the receptor isoforms (wtERbeta1, -beta2, and -beta5) from the total ERbeta message pool in male and female cell cultures. Irrespective of sex, nHLE express wtERbeta1 and the ERbeta2 and ERbeta5 splice variants in similar ratios. Confocal microscopy and immunofluorescence revealed localization of the wild-type receptor in peripheral mitochondrial arrays and perinuclear mitochondria as well as nuclear staining in both cell populations. The ERbeta2 and ERbeta5 isoforms were distributed primarily in the nucleus and cytosol, respectively; no association with the mitochondria was detected. Both male and female nHLE treated with E(2) (1 muM) displayed similar levels of protection against peroxide-induced oxidative stress. In conjunction with acute oxidative insult, RNA suppression of wtERbeta1 elicited the collapse of mitochondrial membrane potential and markedly diminished the otherwise protective effects of E(2). Thus, whereas the estrogen-mediated prevention of mitochondrial membrane permeability transition is sex independent, the mechanism of estrogen-induced mitochondrial cytoprotection is wtERbeta1 dependent.

An international parentage and identification panel for the domestic cat (Felis catus).

Seventeen commercial and research laboratories participated in two comparison tests under the auspices of the International Society for Animal Genetics to develop an internationally tested, microsatellite-based parentage and identification panel for the domestic cat (Felis catus). Genetic marker selection was based on the polymorphism information content and allele ranges from seven random-bred populations (n = 261) from the USA, Europe and Brazil and eight breeds (n = 200) from the USA. Nineteen microsatellite markers were included in the comparison test and genotyped across the samples. Based on robustness and efficiency, nine autosomal microsatellite markers were ultimately selected as a single multiplex 'core' panel for cat identification and parentage testing. Most markers contained dinucleotide repeats. In addition to the autosomal markers, the panel included two gender-specific markers, amelogenin and zinc-finger XY, which produced genotypes for both the X and Y chromosomes. This international cat parentage and identification panel has a power of exclusion comparable to panels used in other species, ranging from 90.08% to 99.79% across breeds and 99.47% to 99.87% in random-bred cat populations.

Titanium elastic nailing of fractures of the femur in children. Predictors of complications and poor outcome.

Between 1996 and 2003 six institutions in the United States and France contributed a consecutive series of 234 fractures of the femur in 229 children which were treated by titanium elastic nailing. Minor or major complications occurred in 80 fractures. Full information was available concerning 230 fractures, of which the outcome was excellent in 150 (65%), satisfactory in 57 (25%), and poor in 23 (10%). Poor outcomes were due to leg-length discrepancy in five fractures, unacceptable angulation in 17, and failure of fixation in one. There was a statistically significant relationship (p = 0.003) between age and outcome, and the odds ratio for poor outcome was 3.86 for children aged 11 years and older compared with those below this age. The difference between the weight of children with a poor outcome and those with an excellent or satisfactory outcome was statistically significant (54 kg vs 39 kg; p = 0.003). A poor outcome was five times more likely in children who weighed more than 49 kg.

Displaced fractures of the hip in children. Management by early operation and immobilisation in a hip spica cast.

Fractures of the hip in children have been associated with a very high rate of serious complications including avascular necrosis (up to 47%) and coxa vara (up to 32%). Over a period of 20 years, we have treated displaced fractures by early anatomical reduction, internal fixation and immobilisation in a spica cast to try to reduce these complications. We have reviewed 18 patients who had a displaced non-pathological fracture of the hip when under 16 years of age. Their mean age at the time of the injury was eight years (2 to 13). They returned for examination and radiography at a mean follow-up of eight years (2 to 17). Each patient had been treated by early (" 24 hours) closed or open reduction with internal fixation and 16 had immobilisation in a spica cast. By Delbet's classification, there was one type-I, eight type-II, eight type-III, and one type-IV fractures. There were no complications in 15 patients. Avascular necrosis occurred in one patient (type-III), nonunion in one (type-II, one of the two patients who did not have a cast) and premature physeal closure in one (type-I). There were no cases of infection or complications as a result of the cast. Our treatment of displaced hip fractures in children by early reduction, internal fixation, and immobilisation in a spica cast gave reduced rates of complications compared with that of large published series in the literature.

Investigation of primary cell-biomaterial interactions using silver nitrate staining of nucleolar organising regions.

The quantification of silver nitrate staining of nucleolar organising regions (AgNORs) within the nucleus of the cell has been shown to give a relative measure of the metabolic activity of the cell. In the present study, silver nitrate staining was utilised to identify metabolic variations in cells cultured on different surfaces and compared with proliferative activity assessed using bromodeoxyuridine (BrdU) uptake. Primary osteoblast and periosteal cells, isolated from the calvaria of neonate rats, were cultured on tissue culture-grade (TCPS) and bacteriological-grade (BACPS) polystyrene petri dishes for 3, 5, 7 and 9 days (silver nitrate) or 14 days (BrdU). The phenotype of the cells was examined using RT-PCR of the mRNA for osteocalcin, collagen 1a, alkaline phosphatase and osteopontin. The number and area of AgNORs and the proportion of BrdU positive cells were statistically different in cells cultured on TCPS compared with BACPS at each culture period tested. The results suggest that the metabolic activity and proliferation of cells were affected by the substrate which they colonise.

Surgical treatment of congenital kyphosis.

STUDY DESIGN: In this study, 26 cases of congenital kyphosis and kyphoscoliosis treated surgically were retrospectively reviewed. OBJECTIVE: To assess the clinical outcomes and surgical indications for posterior only versus anteroposterior surgery in the child. SUMMARY OF BACKGROUND DATA: Congenital kyphosis usually is progressive without surgical intervention. Current recommended treatment includes posterior arthrodesis for deformities of less than 50 degrees to 60 degrees, and anterior release or decompression, anterior fusion, and posterior instrumented arthrodesis for large deformities and cord compression. METHODS: Cases involving myelodysplasia, spinal dysgenesis, and skeletal dysplasia were excluded from the study. Kyphoscoliosis was included if the kyphotic deformity was greater than the scoliotic deformity. Patients were grouped by age and surgical technique. The patients in group P1 underwent posterior arthrodesis at an age younger than 3 years, and those in group P2 underwent the procedure at an age older than 3 years. The patients in group AP1 underwent anterior and posterior procedures at an age younger than 3 years, and those in group AP2 underwent the procedures at an age older than 3 years. The preoperative deformity, complications, and postoperative deformity correction were analyzed. There were nine Type 1 (failure of formation), nine Type 2 (failure of segmentation), and eight Type 3 (mixed) deformities. Four patients had associated spinal dysraphism. Three patients with Type 1 deformities had clinical or radiographic evidence of cord compression. RESULTS: In Group P1, five patients at an average age of 16 months underwent posterior arthrodesis alone for an average kyphotic deformity of 49 degrees. The immediate postoperative correction improved over a period of 6 years and 9 months by an additional 10 degrees, resulting in a final deformity of 26 degrees. Pseudarthrosis developed in two patients, requiring fusion mass augmentation or anterior arthrodesis. Neither patient was instrumented. In Group P2, five patients at an average age of 13 years and 7 months underwent posterior arthrodesis with instrumentation for kyphotic deformity of 59 degrees. Approximately 30 degrees of intraoperative correction was achieved safely using compression instrumentation and positioning. No further correction occurred with growth. The final residual kyphotic deformity was 29 degrees after a follow-up period of 4 years and 5 months. In Group AP1, seven patients underwent anterior release or vertebra resection for deformity correction and posterior arthrodesis for an average kyphotic deformity of 48 degrees at the age of 16 months. There were no iatrogenic neurologic injuries. The final residual kyphotic deformity was 22 degrees after a follow-up period of 6 years and 3 months. In Group AP2, nine patients underwent anterior release or decompression with posterior arthrodesis for kyphotic deformity of 77 degrees at the age of 11 years and 6 months. The deformity was corrected to 37 degrees, with no significant loss over a follow-up period of 5 years and 2 months. There were two postoperative neurologic complications. CONCLUSIONS: After reviewing their experience, the authors made the following observations: 1) The pseudarthrosis rate was low even without routine augmentation of fusion mass if instrumentation was used; 2) gradual correction of kyphosis may occur with growth in patients younger than 3 years with Types 2 and 3 deformities after posterior fusion, but appears to be unpredictable; 3) the risk of neurologic injury with anterior and posterior fusion for kyphotic deformity was associated with greater age, more severe deformity, and preexisting spinal cord compromise.

The orthopedists' perspective: bone tumors, scoliosis, and trauma.

Although a detailed, comprehensive look at pediatric orthopedists' use of imaging is beyond the scope of this article, we offer an orthopedist's perspective of the role imaging plays in the care of children with tumors, scoliosis, and trauma. Given the growing, dynamic state of a child's skeleton, the long-term consequences of injury must always be considered.

Overlapping recognition determinants within the ssrA degradation tag allow modulation of proteolysis.

The ssrA tag, an 11-aa peptide added to the C terminus of proteins stalled during translation, targets proteins for degradation by ClpXP and ClpAP. Mutational analysis of the ssrA tag reveals independent, but overlapping determinants for its interactions with ClpX, ClpA, and SspB, a specificity-enhancing factor for ClpX. ClpX interacts with residues 9-11 at the C terminus of the tag, whereas ClpA recognizes positions 8-10 in addition to residues 1-2 at the N terminus. SspB interacts with residues 1-4 and 7, N-terminal to the ClpX-binding determinants, but overlapping the ClpA determinants. As a result, SspB and ClpX work together to recognize ssrA-tagged substrates efficiently, whereas SspB inhibits recognition of these substrates by ClpA. Thus, dissection of the recognition signals within the ssrA tag provides insight into how multiple proteins function in concert to modulate proteolysis.

Analysis of the cause, classification, and associated injuries of 166 consecutive pediatric pelvic fractures.

SUMMARY: Pediatric pelvic fractures are serious injuries. Anatomical differences exist between pediatric and adult populations, leading to different causes and rates of death, fracture patterns, and associated injuries. This study is the largest consecutive series of pediatric pelvic fractures from one institution emphasizing the unique aspects seen in pediatrics. One hundred sixty-six children were included. Plain radiography and computed tomography scans were used to classify pelvic fractures. Multisystem injuries occurred in 60%, and 50% sustained additional skeletal injuries. The death rate was 3.6%. Head and/or visceral injuries were the causes of all deaths. Life-threatening hemorrhage did not occur. Urethral injury was not seen as often as in adults. Anterior ring fractures were the most common type, dominated by pedestrian versus motor vehicle trauma. Anatomical differences and mechanism of injury may play a role in these contrasting findings.