Prenatal alcohol exposure and white matter microstructural changes across the first 6-7 years of life: A longitudinal diffusion tensor imaging study of a South African birth cohort.

Prenatal alcohol exposure (PAE) can affect brain development in early life, but few studies have investigated the effects of PAE on trajectories of white matter tract maturation in young children. Here we used diffusion weighted imaging (DWI) repeated over three time points, to measure the effects of PAE on patterns of white matter microstructural development during the pre-school years. Participants were drawn from the Drakenstein Child Health Study (DCHS), an ongoing birth cohort study conducted in a peri-urban community in the Western Cape, South Africa. A total of 342 scans acquired from 237 children as neonates (N = 82 scans: 30 PAE; 52 controls) and at ages 2-3 (N = 121 scans: 27 PAE; 94 controls) and 6-7 years (N = 139 scans: 45 PAE; 94 controls) were included. Maternal alcohol use during pregnancy and other antenatal covariates were collected from 28 to 32 weeks' gestation. Linear mixed effects models with restricted maxium likelihood to accommodate missing data were implemented to investigate the effects of PAE on fractional anisotropy (FA) and mean diffusivity (MD) in specific white matter tracts over time, while adjusting for child sex and maternal education. We found significant PAE-by-time effects on trajectories of FA development in the left superior cerebellar peduncle (SCP-L: p = 0.001; survived FDR correction) and right superior longitudinal fasciculus (SLF-R: p = 0.046), suggesting altered white matter development among children with PAE. Compared with controls, children with PAE demonstrated a more rapid change in FA in these tracts from the neonatal period to 2-3 years of age, followed by a more tapered trajectory for the period from 2-3 to 6-7 years of age, with these trajectories differing from unexposed control children. Given their supporting roles in various aspects of neurocognitive functioning (i.e., motor regulation, learning, memory, language), altered patterns of maturation in the SCP and SLF may contribute to a spectrum of physical, social, emotional, and cognitive difficulties often experienced by children with PAE. This study highlights the value of repeated early imaging in longitudinal studies of PAE, and focus for early childhood as a critical window of potential susceptibility as well as an opportunity for early intervention.

Heterotopic ossification prophylaxis with indomethacin increases the risk of long-bone nonunion.

Indomethacin is commonly administered for the prophylaxis of heterotopic ossification (HO) after the surgical treatment of acetabular fractures. Non-steroidal anti-inflammatory drugs such as indomethacin, have been associated with delayed healing of fractures and mechanically weaker callus. Our aim was to determine if patients with an acetabular fracture, who received indomethacin for prophylaxis against HO, were at risk of delayed healing or nonunion of any associated fractures of long bones. We reviewed 282 patients who had had open reduction and internal fixation of an acetabular fracture. Patients at risk of HO were randomised to receive either radiation therapy (XRT) or indomethacin. Of these patients, 112 had sustained at least one concomitant fracture of a long bone; 36 needed no prophylaxis, 38 received focal radiation and 38 received indomethacin. Fifteen patients developed 16 nonunions. When comparing patients who received indomethacin with those who did not, a significant difference was noted in the rate of nonunion (26% v 7%; p = 0.004). Patients with concurrent fractures of the acetabulum and long bones who receive indomethacin have a significantly greater risk of nonunion of the fractures of the long bones when compared with those who receive XRT or no prophylaxis.

Indomethacin compared with localized irradiation for the prevention of heterotopic ossification following surgical treatment of acetabular fractures.

BACKGROUND: There is controversy surrounding the relative effectiveness of local irradiation and oral indomethacin for prophylaxis against heterotopic ossification following surgical treatment of acetabular fractures. The purpose of this study was to compare the efficacy of these two commonly used methods in a prospective, randomized trial. METHODS: From July 1992 to June 1999, 166 patients in whom a fracture of the acetabulum was treated surgically through a posterior, extensile, or combination approach were randomized to receive either indomethacin or radiation therapy postoperatively. Seventy-eight patients received 800 cGy of local radiation therapy within seventy-two hours after surgery, and seventy-two patients received a six-week course of indomethacin (25 mg three times a day) beginning within twenty-four hours after surgery. Sixteen additional patients were randomized but did not receive treatment with either prophylactic regimen. At an average of fourteen months, the extent of heterotopic ossification was assessed on plain radiographs with use of the classification of Brooker et al. The grade of ossification was correlated with hip motion. RESULTS: There was no significant difference between treatment groups with regard to patient age, gender, Glasgow Coma Scale, operative time, estimated operative blood loss, duration of follow-up, or presence of closed head injury. The Injury Severity Score appeared to be the only covariate that was significantly different between the groups (p = 0.019). Grade-III or IV ossification developed in eight (11%) of the patients in the indomethacin group and three (4%) in the radiation therapy group. The difference was not significant (p = 0.22; 95% confidence interval, -1.1%, +15.7%). No complications related to the prophylaxis were noted in either group. Heterotopic ossification developed in all sixteen patients who did not receive prophylaxis, with six demonstrating grade-III or IV changes. The overall prevalence of grade-III or IV heterotopic ossification was 7% (eleven of 150) in the treated groups and 38% (six of sixteen) in the untreated group. We did not find any association between the prevalence of heterotopic ossification and fracture type (p = 0.296) or posterior hip dislocation (p = 0.306). Grade-I, II, and III heterotopic ossification did not decrease the range of motion of the hip except in flexion. CONCLUSIONS: Both local radiation therapy and indomethacin were found to provide effective prophylaxis against heterotopic ossification following surgical treatment of acetabular fractures through a posterior or extensile approach. We detected no significant difference in efficacy between the two prophylactic regimens.

Elution characteristics of tobramycin from polycaprolactone in a rabbit model.

This study investigated the elution characteristics of tobramycin from polycaprolactone, a bioabsorbable polymer, in a rabbit model. Sixty rabbits were divided into two groups. Group 1 had polycaprolactone rods impregnated with 6% tobramycin surgically implanted into the proximal femoral intramedullary canal. Group 2 received polymethylmethacrylate rods of like size, shape, and antibiotic concentration. Serum and urine samples were obtained, and tobramycin levels were determined via fluorescent immunosorbent assay. Rabbits were sacrificed as long as 56 days after surgery. Local bone tobramycin concentration was determined using the agar diffusion method. Polycaprolactone delivered a significantly higher peak bone concentration of tobramycin (22.4 microg/mL) than did polymethylmethacrylate (13.59 microg/mL). Polycaprolactone also had a more gradual decrease in local tobramycin concentration than did polymethylmethacrylate. Neither polycaprolactone nor polymethylmethacrylate yielded consistently detectable (> 0.1 microg/mL) serum tobramycin levels. Urine concentrations mirrored those seen in bone, with polycaprolactone achieving significantly higher tobramycin concentrations than did polymethylmethacrylate. Polycaprolactone had superior elution characteristics compared with polymethylmethacrylate in this lapine model, suggesting that polycaprolactone might be a promising local antibiotic delivery vehicle for the treatment of osteomyelitis.

In vitro elution of tobramycin from bioabsorbable polycaprolactone beads.

OBJECTIVES: To compare the in vitro elution characteristics of tobramycin impregnated beads made of polycaprolactone (PCL) and polymethylmethacrylate (PMMA). DESIGN: Six-millimeter PCL and PMMA beads with 6% tobramycin were formed and placed in phosphate-buffered saline or newborn calf serum and incubated at room temperature or 37 degrees C. Aliquots were taken at intervals for eight weeks. Tobramycin levels were determined by fluorescent assay and antibacterial efficacy was assessed by measuring the zones of inhibition against Staphylococcus aureus and Pseudomonas aeruginosa on agar diffusion plates. RESULTS: Tobramycin elution rates at room temperature were similar up to three weeks. At three weeks, elution rates from PCL beads were twice those from PMMA beads, and at eight weeks, elution from PCL was quadruple that from PMMA. At 37 degrees C, tobramycin elution rates from PCL were eight times greater than those from PMMA by eight weeks. Total tobramycin eluted from PCL beads was 38.9% and 20% in PMMA beads. All samples showed bacteriostatic activity against S. aureus and P. aeruginosa at eight weeks. CONCLUSIONS: These in vitro results show that PCL has superior antibiotic elution characteristics compared with PMMA, and this may translate into a more effective antibiotic delivery vehicle. In addition, PCL is a bioabsorbable polymer, which may decrease the need for a second surgical procedure to remove retained beads.

Postoperative pain control using epidural catheters after anterior spinal fusion for adolescent scoliosis.

STUDY DESIGN: A prospective review of patients undergoing epidural catheter placement after anterior spinal fusion and instrumentation for adolescent scoliosis was performed. Data were collected using visual analog pain scores reflecting the patients' perception of their pain control. OBJECTIVES: To present the authors' technique for epidural catheter placement and dosing protocol, and to demonstrate the results from postoperative pain control after anterior spinal instrumented fusion for 10 consecutive patients. SUMMARY OF BACKGROUND DATA: The literature regarding the benefits of epidural catheters after spinal surgery is contradictory, even with controlled studies comparing epidural catheters with intravenous morphine patient-controlled anesthesia. The authors believe that this lack of consensus stems from varied epidural dosing protocols and techniques in catheter placement, which they have witnessed anecdotally at their own institution. This prompted the authors to develop and refine a standardized dosing and catheter placement protocol for pain control after spinal surgery. METHODS: Epidural catheters were placed intraoperatively before wound closure, then removed on postoperative Day 5. Dosing consisted of fentanyl (1 microg/kg) and hydromorphone (5 microg/kg) diluted in preservative-free saline (0.2 mL/kg). After surgery, dosing consisted of 0.1% ropivacaine and hydromorphone (10 microg/ml) continuously infused at 0.2 mL/kg/hour. Postoperative pain control was assessed on each postoperative day using a visual analog pain scale with choices ranging from 0 to 10. RESULTS: The arithmetic mean of the median pain scores after surgery was 2.1. The mean of the maximum pain scores for the 5 days was 4.1. Three patients required an epidural bolus and a 20% increase in the epidural infusion rate. One patient was judged to be excessively sleepy, so the epidural infusion rate was decreased by 20%. Pruritus requiring diphenhydramine developed in three patients. No other adverse effects related to epidural analgesia were noted. No catheters were accidentally pulled out or disconnected. CONCLUSION: By following the dosing protocol described, epidural catheters can be used safely and effectively to control postoperative pain after anterior instrumentation and spinal fusion for adolescent scoliosis.

Synergy between Staphylococcus aureus and Pseudomonas aeruginosa in a rat model of complex orthopaedic wounds.

BACKGROUND: We observed an interaction in animals inoculated concomitantly with Staphylococcus aureus and Pseudomonas aeruginosa during a study of the efficacy of surfactants for disinfection of orthopaedic wounds. This led us to investigate whether synergy could be demonstrated between Staphylococcus aureus and Pseudomonas aeruginosa in a rat model of complex orthopaedic wounds. METHODS: A wire was implanted into the spinous process of a lumbar vertebra of Sprague-Dawley rats through a dorsal incision. Animals were divided into two groups: group one was inoculated with either Staphylococcus aureus or Pseudomonas aeruginosa, and group two received a polymicrobial inoculation with both test organisms in varying concentrations. After inoculation, the wounds were irrigated and closed. On postoperative day 14, all animals were killed and specimens from the wounds were cultured. The number of colony-forming units (CFU) of Staphylococcus aureus or Pseudomonas aeruginosa needed to cause infection in 50% of the animals (ID50) was determined with use of the Reed-Muench method. The infection rate associated with each inoculum combination was calculated, and the two groups were compared. RESULTS: The ID50 was 2.8 x 10(4) CFU for Staphylococcus aureus and 4.8 x 10(5) CFU for Pseudomonas aeruginosa. The combination of 10(3) CFU of Staphylococcus aureus with low concentrations (10(2), 10(3), or 10(4) CFU) of Pseudomonas aeruginosa yielded infection rates that were higher than those found with either organism alone at the same concentrations. The combination of 10(3) CFU of Staphylococcus aureus and 10(3) CFU of Pseudomonas aeruginosa yielded a 75% infection rate, which was significantly higher (p = 0.004) than that associated with 10(3) CFU of either organism alone. As the Pseudomonas aeruginosa concentration was increased (to 10(5), 10(6), and 10(7) CFU), this trend reversed, and the infection rate decreased to 33% (p = 0.004). Low concentrations of Pseudomonas aeruginosa (0 to 10(5) CFU) combined with 10(6) CFU of Staphylococcus aureus yielded infection rates ranging from 83% to 100%. At the higher concentrations of Pseudomonas aeruginosa (10(6) and 10(7) CFU), however, the infection rate again decreased, to 33% (p = 0.005). Only Staphylococcus aureus was isolated from the cultures of the specimens from the animals that had received a polymicrobial inoculum. CONCLUSIONS: Synergy between Staphylococcus aureus and Pseudomonas aeruginosa was demonstrated when low levels of each organism were present in the wound. As the Pseudomonas aeruginosa concentration was increased, the infection rates fell well below what would be anticipated, suggesting that low concentrations of Pseudomonas aeruginosa enhance the ability of Staphylococcus aureus to cause infection in this orthopaedic wound model. At the same time, the presence of Staphylococcus aureus in the ratios tested decreased the rate of infection by Pseudomonas aeruginosa. CLINICAL RELEVANCE: Staphylococcus aureus is a pathogen commonly seen in orthopaedic patients. The pathogenicity of Staphylococcus aureus was shown to be increased in the presence of anaerobic bacteria. This study is the first one that we are aware of that demonstrated synergy between Staphylococcus aureus and Pseudomonas aeruginosa, at low concentrations, in a wound model while at the same time showing that Staphylococcus aureus lowers the rate of Pseudomonas aeruginosa infection.

The effects of chlorhexidine irrigation solution on contaminated bone-tendon allografts.

The purpose of this study was to determine an expedient and effective method for disinfecting contaminated human bone-tendon allografts. The first part of this study used beef muscle and cadaveric human tissues to determine the most effective solution and volume to decontaminate tissues inoculated with four different organisms: Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Of the solutions tested (benzalkonium chloride, castile soap, castile soap followed by benzalkonium chloride, triple antibiotic, chlorhexidine gluconate, and chlorhexidine gluconate/triple antibiotic), only the 4% chlorhexidine power irrigation solution and 4% chlorhexidine/triple antibiotic bath completely disinfected all tissues. Work in part 2 revealed that a 2% chlorhexidine irrigation solution was equally effective as the 4% solutions. Part 3 of the study involved human Achilles tendon-calcaneus allografts. We found similar results: 3 liters of 2% chlorhexidine power irrigation solution thoroughly removed all microorganisms from the contaminated tissues. All control allografts irrigated with normal saline solution alone revealed positive bacterial growth for all four organisms after 72 hours' growth on sheep blood agar. Total decontamination time was 10 to 12 minutes. Two percent chlorhexidine irrigation solution may be an effective method for decontaminating human bone-tendon allografts challenged with a polymicrobial inoculum. This method of disinfecting bone-tendon allografts is at least five times more expeditious than methods in previously reported studies.

Sequential irrigation with common detergents: a promising new method for decontaminating orthopedic wounds.

This investigation sought to determine the capacity of irrigation solutions in decontaminating orthopedic wounds challenged with a polymicrobial inoculum. Rats were divided into two groups, a control group and a treatment group. After creation of a dorsolumbar incision and placement of a wire through the spinous process, rats were inoculated with Staphylococcus aureus and Pseudomonas aeruginosa. Wounds were irrigated with control or treated solutions. At 2 weeks, cultures were obtained. There were statistically significant differences between groups regarding total number of culture positive sites (P < 0.001), culture-positive animals (P = 0.02), and quantitative cultures (P < 0.02). Sequential irrigation with surfactants lowers bacteria counts recovered from polymicrobial wounds.

Centrifugation and capillarity integrated into a multiple analyte whole blood analyser.

A unique clinical chemistry analyser is described which processes 90 mul of whole blood (fingerstick or venous) into multiple aliquots of diluted plasma and reports the results of 12 tests in 14 min. To perform a panel of tests, the operator applies the unmetered sample directly into a single use, 8 cm diameter plastic rotor which contains the required liquid diluent and dry reagents. Using centrifugal and capillary forces, the rotor meters the required amount of blood, separates the red cells, meters the plasma, meters the diluent, mixes the fluids, distributes the fluid to the reaction cuvettes and mixes the reagents and the diluted plasma in the cuvettes. The instrument monitors the reagent reactions simultaneously using nine wavelengths, calculates the results from the absorbance data, and reports the results.

Activation of a distinct subpopulation of pulmonary macrophages following exposure to biological response modifiers.

A distinct subpopulation of tissue-associated pulmonary macrophages (TAPM) displayed tumoricidal activity towards syngeneic and xenogeneic targets following in vitro incubation with N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP). This subpopulation, as well as, the predominant population of freely lavagable alveolar macrophages destroyed allogeneic targets following a similar incubation with either 6-0-stearoyl MDP (S-MDP) or recombinant interferon-gamma (IFN-gamma). IFN-gamma-induced in vivo tumoricidal activation of both populations of pulmonary macrophage was most effective when delivered either intravenously or via osmotic minipump infusion and least effective when administered by direct intratracheal instillation. The separate populations also displayed in vivo activation in response to liposome-encapsulated i.v. administered S-MDP. Under comparable conditions, IFN-alpha was not nearly as effective. Metabolic activation of TAPM, assessed by the release of increased levels of superoxide free radicals during phagocytosis, occurred following 24 hr exposure to S-MDP or lipopolysaccharide. Incorporation of these agents into multilamellar vesicle liposomes further augmented the release of superoxide observed at 24 hrs. Our results collectively demonstrated that a subpopulation of lung macrophage, a tissue-associated pulmonary macrophage, may be activated to a tumoricidal state and to release pronounced levels of oxygen free radicals following either in vitro or in situ treatment with several biological response modifiers.

Portable simultaneous multiple analyte whole-blood analyzer for point-of-care testing.

We describe a portable clinical chemistry analyzer for point-of-care measurements of multiple analytes in less than 10 min from approximately 40 microL of whole blood (fingerstick or venous). Whole blood is applied directly to a 7.9-cm-diameter, single-use plastic rotor containing liquid diluent and greater than or equal to 4-12 tests in the form of 1- to 2-mm-diameter dry reagent beads. The reagent/rotor is immediately placed in a portable instrument along with a ticket/label results card. As the instrument spins the rotor, capillary and rotational forces process the blood into diluted plasma, distribute the patient's diluted sample to cuvettes containing the reagent beads, and mix the diluted sample with the reagents. The instrument monitors the chemical reactions optically at nine wavelengths; sample volume and temperature are also measured optically. The calibration data for each reagent are read from a bar code on the periphery of each rotor. The instrument processes all the measurements to calculate, store, print, and communicate the results. Each reagent/rotor contains an enzymatic control that must be within a defined range before the results from that analysis are reported.

Patient-side immunoassay system with a single-use cartridge for measuring analytes in blood.

We describe an immunoassay system suited to patient-side assay of therapeutic drugs and blood proteins. The system consists of an electronic monitor and single-use plastic cartridges containing dry reagents and liquid diluents. The monitor is turned on by insertion of a cartridge. To run the test, the user applies an unmeasured drop of blood to the cartridge when prompted by the monitor. All subsequent steps are performed without further user intervention and results are provided in less than 3 min. The system hemolyzes and precisely dilutes the blood. Hemoglobin concentration is measured, then the diluted blood is precisely diluted further and mixed with two dry reagents. The drug concentration is measured by a turbidimetric latex agglutination inhibition reaction. Theophylline and hemoglobin assay results for clinical samples correlate well with results of widely used comparison methods.