Pediatric Mandibular Fracture Management: Intraoperative Thermoplastic Splint Fabrication and Circummandibular Wires, without Maxillomandibular Fixation.

Management of mandibular fractures often involves the use of maxillomandibular fixation (MMF) to attain immobility of the fractured segments. This can be used as a primary treatment modality or as an adjunct in fracture management. This technique, however, has its drawbacks due to the great burden of care imposed on patients. In the following case, fixation of a pediatric open mandibular body fracture was attained without the use of MMF, and bone union was achieved. Due to age, safety concerns, long-distance travel, and parent's preference, the routine management of this type of fracture with MMF using piriform aperture drop wires and circummandibular wires was not done. Instead, the fracture was reduced, and an intraoral mandibular impression was taken in the operating room, which was used to create a stone model. A 2-mm acrylic splint was designed and fabricated from the stone model, and two circummandibular wires were placed. The wires were tightened over the acrylic splint to achieve stabilization of the mandibular reduction. At 4 weeks postoperatively, the splint was removed, and the patient was maintained on a soft diet. At 6 weeks, bone union was appreciated clinically by immobility of the mandibular segments, and the patient was advanced to a regular diet. Occlusion was corrected to premorbid state by clinical findings and 6 months postoperative imaging. This technique represents an effective approach in managing pediatric mandibular fractures when MMF cannot be used.

3D spatially-adaptive canonical correlation analysis: Local and global methods.

Local spatially-adaptive canonical correlation analysis (local CCA) with spatial constraints has been introduced to fMRI multivariate analysis for improved modeling of activation patterns. However, current algorithms require complicated spatial constraints that have only been applied to 2D local neighborhoods because the computational time would be exponentially increased if the same method is applied to 3D spatial neighborhoods. In this study, an efficient and accurate line search sequential quadratic programming (SQP) algorithm has been developed to efficiently solve the 3D local CCA problem with spatial constraints. In addition, a spatially-adaptive kernel CCA (KCCA) method is proposed to increase accuracy of fMRI activation maps. With oriented 3D spatial filters anisotropic shapes can be estimated during the KCCA analysis of fMRI time courses. These filters are orientation-adaptive leading to rotational invariance to better match arbitrary oriented fMRI activation patterns, resulting in improved sensitivity of activation detection while significantly reducing spatial blurring artifacts. The kernel method in its basic form does not require any spatial constraints and analyzes the whole-brain fMRI time series to construct an activation map. Finally, we have developed a penalized kernel CCA model that involves spatial low-pass filter constraints to increase the specificity of the method. The kernel CCA methods are compared with the standard univariate method and with two different local CCA methods that were solved by the SQP algorithm. Results show that SQP is the most efficient algorithm to solve the local constrained CCA problem, and the proposed kernel CCA methods outperformed univariate and local CCA methods in detecting activations for both simulated and real fMRI episodic memory data.

Nonclinical pharmacology and toxicology of the first biosimilar insulin glargine drug product (BASAGLAR®/ABASAGLAR®) approved in the European Union.

Basaglar®/Abasaglar® (Lilly insulin glargine [LY IGlar]) is a long-acting human insulin analogue drug product granted marketing authorisation as a biosimilar to Lantus® (Sanofi insulin glargine [SA IGlar]) by the European Medicines Agency. We assessed the similarity of LY IGlar to the reference drug product, European Union-sourced SA IGlar (EU-SA IGlar), using nonclinical in vitro and in vivo studies. No biologically relevant differences were observed for receptor binding affinity at either the insulin or insulin-like growth factor-1 (IGF-1) receptors, or in assays of functional or de novo lipogenic activity. The mitogenic potential of LY IGlar and EU-SA IGlar was similar when tested in both insulin- and IGF-1 receptor dominant cell systems. Repeated subcutaneous daily dosing of rats for 4 weeks with 0, 0.3, 1.0, or 2.0 mg/kg LY IGlar and EU-SA IGlar produced mortalities and clinical signs consistent with severe hypoglycaemia. Glucodynamic profiles of LY IGlar and EU-SA IGlar in satellite animals showed comparable dose-related hypoglycaemia. Severe hypoglycaemia was associated with axonal degeneration of the sciatic nerve; the incidence and severity were low and did not differ between LY IGlar and EU-SA IGlar. These results demonstrated no biologically relevant differences in toxicity between LY IGlar and EU-SA IGlar.

Chronic Toxicology Studies of Basal Insulin Peglispro in Rats and Dogs: A Novel, PEGylated Insulin Lispro Analog with a Prolonged Duration of Action.

Basal insulin peglispro (BIL) consists of insulin lispro with a 20-kDa polyethylene glycol (PEG) moiety covalently attached to lysine B28. Because chronic parenteral administration of PEGylated proteins to animals has sometimes resulted in PEG vacuolation of tissue macrophages, renal tubular cells, and choroid plexus ependymal cells, we investigated whether chronic subcutaneous (sc) injection of BIL in rats (52 weeks) and dogs (39 weeks) was associated with systemic toxicities or other changes, including vacuolation of tissue macrophages, renal tubular cells, and ependymal cells. Rats and dogs received daily sc injections of BIL (rats: 0.17, 0.45, or 1.15 mg/kg/d and dogs: 0.025, 0.10, or 0.20 mg/kg/d) and the reference compound, HUMULIN N® (neutral protamine Hagedorn [NPH] human insulin; rats: 0.15 mg/kg/d and dogs: 0.02-0.03 mg/kg/d). Animals were evaluated for standard end points including mortality, clinical signs, body weights, toxicokinetics, glucodynamics, clinical pathology, and morphological pathology. Nonadverse injection site lipohypertrophy occurred for all BIL and NPH doses but more frequently with BIL. No BIL-related hyperplasia or neoplasia was observed. There was no vacuolation of tissue macrophages, renal tubular cells, or ependymal cells attributable to PEG. These studies demonstrate BIL is not associated with tissue vacuolation attributable to PEG at 4- to 6-fold multiple of the median clinical exposure in patients with diabetes.

A family of locally constrained CCA models for detecting activation patterns in fMRI.

Canonical correlation analysis (CCA) has been used in Functional Magnetic Resonance Imaging (fMRI) for improved detection of activation by incorporating time series from multiple voxels in a local neighborhood. To improve the specificity of local CCA methods, spatial constraints were previously proposed. In this study, constraints are generalized by introducing a family model of spatial constraints for CCA to further increase both sensitivity and specificity in fMRI activation detection. The proposed locally-constrained CCA (cCCA) model is formulated in terms of a multivariate constrained optimization problem and solved efficiently with numerical optimization techniques. To evaluate the performance of this cCCA model, simulated data are generated with a Signal-To-Noise Ratio of 0.25, which is realistic to the noise level contained in episodic memory fMRI data. Receiver operating characteristic (ROC) methods are used to compare the performance of different models. The cCCA model with optimum parameters (called optimum-cCCA) obtains the largest area under the ROC curve. Furthermore, a novel validation method is proposed to validate the selected optimum-cCCA parameters based on ROC from simulated data and real fMRI data. Results for optimum-cCCA are then compared with conventional fMRI analysis methods using data from an episodic memory task. Wavelet-resampled resting-state data are used to obtain the null distribution of activation. For simulated data, accuracy in detecting activation increases for the optimum-cCCA model by about 43% as compared to the single voxel analysis with comparable Gaussian smoothing. Results from the real fMRI data set indicate a significant increase in activation detection, particularly in hippocampus, para-hippocampal area and nearby medial temporal lobe regions with the proposed method.

An Investigative Study of Pancreatic Exocrine Biomarkers, Histology, and Histomorphometry in Male Zucker Diabetic Fatty (ZDF) Rats Given Dulaglutide by Subcutaneous Injection Twice Weekly for 13 Weeks.

Glucagon-like peptide-1 (GLP-1) receptor agonist therapy has been implicated as a possible risk factor for acute pancreatitis in patients with type 2 diabetes. Dulaglutide is a long-acting GLP-1 receptor agonist in development for treatment of type 2 diabetes. The effects of dulaglutide were evaluated in male Zucker diabetic fatty (ZDF) rats to examine whether dulaglutide may induce or modulate pancreatitis. Rats were randomized to dose groups receiving twice-weekly subcutaneously administered dulaglutide 0.5, 1.5, and 5.0 mg/kg/dose (corresponding human plasma exposures following twice-weekly dosing are 3-, 8-, and 30-fold, respectively) for 13 weeks or to vehicle control. Following termination, serially trimmed sections of pancreases were stained with hematoxylin and eosin or co-stained with an epithelial marker and a marker of either proliferation or apoptosis. Efficacious reductions in glucose and hemoglobin A1c occurred at all dulaglutide doses. Lipase activity was unaffected, and there were modest increases in total and pancreatic amylase activities at all doses without individual microscopic inflammatory correlates. Microscopic dulaglutide-related pancreatic changes included increased interlobular ductal epithelium without ductal cell proliferation (≥0.5 mg/kg), increased acinar atrophy with/without inflammation (≥1.5 mg/kg), and increased incidence/severity of neutrophilic acinar pancreatic inflammation (5.0 mg/kg). In summary, dulaglutide treatment was associated with mild alterations in ductal epithelium and modest exacerbation of spontaneous lesions of the exocrine pancreas typically found in the ZDF rat model.

Effects of the GLP-1 Receptor Agonist Dulaglutide on the Structure of the Exocrine Pancreas of Cynomolgus Monkeys.

Clinical and nonclinical studies have implicated glucagon-like peptide-1 (GLP-1) receptor agonist therapy as a risk factor for acute pancreatitis in patients with type 2 diabetes. Therefore, it is critical to understand the effect that dulaglutide, an approved GLP-1 receptor agonist, has on the exocrine pancreas. Dulaglutide 8.15 mg/kg (approximately 500 times the maximum recommended human dose based on plasma exposure) was administered twice weekly for 12 months to cynomolgus monkeys. Serum amylase and lipase activities were measured and 6 sections of each pancreas were examined microscopically. Ductal epithelial cell proliferation was estimated using Ki67 labeling. Dulaglutide administration did not alter serum amylase or lipase activities measured at the end of treatment compared to control values. An extensive histologic evaluation of the pancreas revealed no changes in the acinar or endocrine portions and no evidence of pancreatitis, necrosis, or pancreatic intraepithelial neoplasia. An increase in goblet cells noted in 4 of the 19 treated monkeys was considered an effect of dulaglutide but was not associated with dilation, blockage, or accumulation of mucin in the pancreatic duct. There was no difference in cell proliferation in ductal epithelium between control and dulaglutide-treated monkeys. These data reveal that chronic dosing of nondiabetic primates with dulaglutide does not induce inflammatory or preneoplastic changes in exocrine pancreas.

Effects of Dulaglutide on Thyroid C Cells and Serum Calcitonin in Male Monkeys.

Glucagon-like peptide-1 (GLP-1) receptor agonists, used for the treatment of type 2 diabetes, have caused hyperplasia/neoplasia of thyroid C cells in rodent carcinogenicity studies. Studies in monkeys have not identified an effect of GLP-1 receptor agonists on thyroid C cells; however, group sizes were small. Dulaglutide is a once-weekly, long-acting human GLP-1 receptor agonist recently approved in the United States and the European Union. The objective of this study was to determine whether dulaglutide altered C-cell mass in monkeys. Male cynomolgus monkeys (20 per group) were sc injected with dulaglutide 8.15 mg/kg (∼500-fold maximum human plasma exposure) or a vehicle control twice weekly for 52 weeks. Basal and calcium gluconate-stimulated serum calcitonin concentrations were obtained at 3, 6, 9, and 12 months. Thyroid glands were weighed, fixed, and sectioned at 500-µm intervals. C-cell volumes were measured using an automated image analysis. C-cell proliferation was estimated using Ki67/calcitonin colabeling and cell counting. Administration of dulaglutide 8.15 mg/kg twice weekly for 52 weeks did not increase serum calcitonin in monkeys or affect thyroid weight, histology, C-cell proliferation, or absolute/relative C-cell volume. This study represents a comprehensive evaluation of the monkey thyroid C cells after dosing with a GLP-1 receptor agonist, with a large group size, and measurement of multiple relevant parameters. The lack of effect of dulaglutide on C cells is consistent with other studies in monkeys using GLP-1 receptor agonists and suggests that nonhuman primates are less sensitive than rodents to the induction of proliferative changes in thyroid C cells by GLP-1 receptor agonists.

Chronic Toxicity and Carcinogenicity Studies of the Long-Acting GLP-1 Receptor Agonist Dulaglutide in Rodents.

The tumorigenic potential of dulaglutide was evaluated in rats and transgenic mice. Rats were injected sc twice weekly for 93 weeks with dulaglutide 0, 0.05, 0.5, 1.5, or 5 mg/kg corresponding to 0, 0.5, 7, 20, and 58 times, respectively, the maximum recommended human dose based on plasma area under the curve. Transgenic mice were dosed sc twice weekly with dulaglutide 0, 0.3, 1, or 3 mg/kg for 26 weeks. Dulaglutide effects were limited to the thyroid C-cells. In rats, diffuse C-cell hyperplasia and adenomas were statistically increased at 0.5 mg/kg or greater (P ≤ .01 at 5 mg/kg), and C-cell carcinomas were numerically increased at 5 mg/kg. Focal C-cell hyperplasia was higher compared with controls in females given 0.5, 1.5, and 5 mg/kg. In transgenic mice, no dulaglutide-related C-cell hyperplasia or neoplasia was observed at any dose; however, minimal cytoplasmic hypertrophy of C cells was observed in all dulaglutide groups. Systemic exposures decreased over time in mice, possibly due to an antidrug antibody response. In a 52-week study designed to quantitate C-cell mass and plasma calcitonin responses, rats received twice-weekly sc injections of dulaglutide 0 or 5 mg/kg. Dulaglutide increased focal C-cell hyperplasia; however, quantitative increases in C-cell mass did not occur. Consistent with the lack of morphometric changes in C-cell mass, dulaglutide did not affect the incidence of diffuse C-cell hyperplasia or basal or calcium-stimulated plasma calcitonin, suggesting that diffuse increases in C-cell mass did not occur during the initial 52 weeks of the rat carcinogenicity study.

Unusual infections due to Listeria monocytogenes in the Southern California Desert.

BACKGROUND: During the past 22 years, 14 patients have been hospitalized with infection due to Listeria monocytogenes at the Eisenhower Medical Center, a regional 300-bed hospital in the desert southwest of Southern California. A large number of patients are retired, elderly, and have underlying and often systemic disease. METHODS: Blood agar and routine media were inoculated with liquid from a sterile site such as blood, cerebrospinal fluid, or joint fluid and observed daily for growth. Appropriate biochemical studies were used to speciate the organism. RESULTS: While bacteremia and meningitis constitute 75% of infections in most studies, they made up only 36% of patients in the current study. Listeriosis occurred mostly in patients with infected aortic aneurysms and brain abscesses, and in prosthetic joint infections. While mortality is generally stated to be around 45% in patients with listeriosis, it was 35% in this study. However, there were no deaths in five patients with bacteremia or meningitis inferring that organ involvement poses a greater hazard for survival. CONCLUSIONS: Listeriosis usually presents as a bacteremia or meningitis due to a food-borne invasive infection. In the desert of Southern California most cases are seen in older patients with underlying disease and present with infected aortic aneurysms, prosthetic joints, and brain abscesses. They represent a greater threat to survival due to organ involvement.

A line integral reaction path approximation for large systems via nonlinear constrained optimization: application to alanine dipeptide and the beta hairpin of protein G.

A variation of the line integral method of Elber with self-avoiding walk has been implemented using a state of the art nonlinear constrained optimization procedure. The new implementation appears to be robust in finding approximate reaction paths for small and large systems. Exact transition states and intermediates for the resulting paths can easily be pinpointed with subsequent application of the conjugate peak refinement method [S. Fischer and M. Karplus, Chem. Phys. Lett. 194, 252 (1992)] and unconstrained minimization, respectively. Unlike previous implementations utilizing a penalty function approach, the present implementation generates an exact solution of the underlying problem. Most importantly, this formulation does not require an initial guess for the path, which makes it particularly useful for studying complex molecular rearrangements. The method has been applied to conformational rearrangements of the alanine dipeptide in the gas phase and in water, and folding of the beta hairpin of protein G in water. In the latter case a procedure was developed to systematically sample the potential energy surface underlying folding and reconstruct folding pathways within the nearest-neighbor hopping approximation.

Diagnosis and treatment of Candida vertebral osteomyelitis: clinical experience with a short course therapy of amphotericin B lipid complex.

BACKGROUND: Musculoskeletal candidiasis occurs in some patients with candidemia resulting from organ infection, IV drug use, or indwelling central venous catheters. Diagnosis is often difficult because of vague symptomatology and a frequent afebrile course. CASE DESCRIPTION: Three patients with Candida vertebral osteomyelitis are presented. All followed the use of indwelling central venous access catheters and antimicrobial therapy between 6 months and 3 years earlier. In 2, fungemia with the same Candida spp. preceded the spondylodiskitis. These 3 patients bring to nearly 75 the number of reported individuals with what was once quite rare. Although IV amphotericin B doxycholate and fluconazole have usually been effective therapy over prolonged periods of time, we used liposomal amphotericin B to treat 2 of our 3 patients. Both received 5 mg/kg daily for 18-42 days that resulted in total disappearance of signs and symptoms. CONCLUSION: This relatively brief duration of therapy reduces treatment time and is cost-effective.

Multiple cerebral abscesses because of Listeria monocytogenes: three case reports and a literature review of supratentorial listerial brain abscess(es).

BACKGROUND: Central nervous system involvement often follows bacteremia because of Listeria monocytogenes. Meningitis is clinically the most common manifestation, while brain abscess occurs in about 1% of patients. Brain abscess is usually solitary but in recent years, probably in part because of the availability of computerized tomography and magnetic resonance imaging, several reports have described two or more separate supratentorial abscesses. METHODS: We have described three patients with listerial brain abscesses and reviewed the North American and European literature of brain abscess(es) because of L. monocytogenes through December 2001. We have evaluated the role of underlying diseases and therapeutic immunosuppression on the development of solitary or greater than one brain abscess. RESULTS: In contrast to meningitis, where immunosuppression does not predispose either to disease incidence or to higher mortality, patients with solitary and particularly those with more than one supratentorial abscess usually are immunosuppressed either by disease or by therapy. Corticosteroids in particular are significant predisposing factors, especially in those patients with two or more brain abscesses. Mortality resulting from listerial brain abscess, whether solitary or multiple, is nearly three times higher than nonlisterial brain abscess, probably in part because of both underlying diseases and immunosuppressive therapy. CONCLUSIONS: Therapy with high-dose ampicillin in combination with gentamicin appear to be the drugs of choice, followed by trimethoprim/sufamethoxazole and vancomycin. In general, antimicrobial therapy appears to be satisfactory treatment without surgical intervention.

A physical approach to protein structure prediction.

We describe our global optimization method called Stochastic Perturbation with Soft Constraints (SPSC), which uses information from known proteins to predict secondary structure, but not in the tertiary structure predictions or in generating the terms of the physics-based energy function. Our approach is also characterized by the use of an all atom energy function that includes a novel hydrophobic solvation function derived from experiments that shows promising ability for energy discrimination against misfolded structures. We present the results obtained using our SPSC method and energy function for blind prediction in the 4th Critical Assessment of Techniques for Protein Structure Prediction competition, and show that our approach is more effective on targets for which less information from known proteins is available. In fact our SPSC method produced the best prediction for one of the most difficult targets of the competition, a new fold protein of 240 amino acids.