Soft-Tissue Simulation for Cranio-Maxillofacial Surgery: Clinical Needs and Technical Aspects

Computerized soft-tissue simulation can provide unprecedented means for predicting facial outlook pre-operatively. Surgeons can virtually perform several surgical plans to have the best surgical results for their patients while considering corresponding soft-tissue outcome. It could be used as an interactive communication tool with their patients as well. There has been comprehensive amount of works for simulating soft-tissue for cranio-maxillofacial surgery. Although some of them have been realized as commercial products, none of them has been fully integrated into clinical practice due to the lack of accuracy and excessive amount of processing time. In this chapter, state-of-the-art and general workflow in facial soft-tissue simulation will be presented, along with an example of patient-specific facial soft-tissue simulation method.

Coupling biomechanics to a cellular level model: An approach to patient-specific image driven multi-scale and multi-physics tumor simulation

Modeling of tumor growth has been performed according to various approaches addressing different biocomplexity levels and spatiotemporal scales. Mathematical treatments range from partial differential equation based diffusion models to rule-based cellular level simulators, aiming at both improving our quantitative understanding of the underlying biological processes and, in the mid- and long term, constructing reliable multi-scale predictive platforms to support patient-individualized treatment planning and optimization. The aim of this paper is to establish a multi-scale and multi-physics approach to tumor modeling taking into account both the cellular and the macroscopic mechanical level. Therefore, an already developed biomodel of clinical tumor growth and response to treatment is self-consistently coupled with a biomechanical model. Results are presented for the free growth case of the imageable component of an initially point-like glioblastoma multiforme tumor. The composite model leads to significant tumor shape corrections that are achieved through the utilization of environmental pressure information and the application of biomechanical principles. Using the ratio of smallest to largest moment of inertia of the tumor material to quantify the effect of our coupled approach, we have found a tumor shape correction of 20\% by coupling biomechanics to the cellular simulator as compared to a cellular simulation without preferred growth directions. We conclude that the integration of the two models provides additional morphological insight into realistic tumor growth behavior. Therefore, it might be used for the development of an advanced oncosimulator focusing on tumor types for which morphology plays an important role in surgical and/or radio-therapeutic treatment planning.

Intradermal injection of heat-killed Mycobacterium vaccae in dogs with atopic dermatitis: a multicentre pilot study

Canine atopic dermatitis (cAD) is a common disease with a multifactorial aetiology associated with impaired immunoregulation. The immunopathogenesis has similarities to that of human atopic dermatitis. Clinical signs of allergic disease in humans and mice are reduced by administration of saprophytic mycobacteria that amplify regulatory cytokines and hence the effect of Mycobacterium vaccae on the clinical severity of cAD was investigated. Sixty-two dogs with cAD, selected according to strict criteria, were treated with a single intradermal injection and evaluated monthly for 3 months in a placebo-controlled double-blind clinical trial. Clinical severity was quantified using standardized scores and by owner assessment of pruritus. A single injection of a heat-killed suspension of M. vaccae was found to be well tolerated and effective in treating mild to moderate cases of cAD demonstrable for 3 months, but was insignificant in more severely affected dogs.

Adiponectin as a marker of success in intracytoplasmic sperm injection/embryo transfer cycles

Adiponectin (Acrp30) is an adipose tissue-derived protein whose serum concentrations, in contrast to leptin, are reported to be negatively correlated to body mass. In spite of the comparatively high circulating adiponectin concentrations, this protein has not been studied in the context of assisted reproduction to date. The aim of this preliminary project was thus to examine the potential of adiponectin to serve as a marker for fertility. We compared adiponectin levels in serum before and after controlled ovarian hyperstimulation, as well as in follicular fluid (FF), between two groups: those with successful outcome (clinical pregnancies) and those with implantation failure. In the former, adiponectin concentrations were higher than in the negative outcome group; this difference was statistically significant (p < 0.05) in serum on the day of oocyte pick-up (OPU) as well as two or three days before OPU, but not in FF or in serum at the beginning of the stimulation phase. This finding adds a new perspective to the suggested but still controversial reduction in FF leptin concentrations in the positive outcome group, and may become a useful tool for early prediction of success of in vitro fertilization treatment for a given patient.

Effects of non-ionic iodinated contrast media on patient heart rate and pressures during intra-cardiac or intra-arterial injection

PURPOSE: To compare the effects on heart rate (HR), on left ventricular (LV) or arterial pressures, and the general safety of a non-ionic low-osmolar contrast medium (CM) and a non-ionic iso-osmolar CM in patients undergoing cardiac angiography (CA) or peripheral intra-arterial digital subtraction angiography (IA-DSA). MATERIALS AND METHODS: Two double-blind, randomized studies were conducted in 216 patients who underwent CA (n=120) or peripheral IA-DSA (n=96). Patients referred for CA received a low-osmolar monomeric CM (iomeprol-350, n=60) or an iso-osmolar dimeric CM (iodixanol-320; n=60). HR and LV peak systolic and end-diastolic pressures were determined before and after the first injection during left and right coronary arteriography and left ventriculography. Monitoring for all types of adverse event (AE) was performed for 24 h following the procedure. t-tests were performed to compare CM for effects on HR. Patients referred for IA-DSA received iomeprol-300 (n=49) or iodixanol-320 (n=47). HR and arterial blood pressure (BP) were evaluated before and after the first 4 injections. Monitoring for AE was performed for 4 h following the procedure. Repeated-measures ANOVA was used to compare mean HR changes across the first 4 injections, whereas changes after the first injection were compared using t-tests. RESULTS: No significant differences were noted between iomeprol and iodixanol in terms of mean changes in HR during left coronary arteriography (p=0.8), right coronary arteriography (p=0.9), and left ventriculography (p=0.8). In patients undergoing IA-DSA, no differences between CM were noted for effects on mean HR after the first injection (p=0.6) or across the first 4 injections (p=0.2). No significant differences (p>0.05) were noted in terms of effects on arterial BP in either study or on LV pressures in patients undergoing CA. Non-serious AE considered possibly CM-related (primarily headache and events affecting the cardiovascular and digestive systems) were reported more frequently by patients undergoing CA and more frequently after iodixanol (14/60 [23.3%] and 2/47 [4.3%]; CA and IA-DSA, respectively) than iomeprol (10/60 [16.7%] and 1/49 [2%], respectively). CONCLUSIONS: Iomeprol and iodixanol are safe and have equally negligible effects on HR and LV pressures or arterial BP during and after selective intra-cardiac injection and peripheral IA-DSA. CLINICAL APPLICATION: Iomeprol and iodixanol are safe and equally well tolerated with regard to cardiac rhythm and clinical preference should be based on diagnostic image quality alone.

Rotational atherectomy followed by drug-eluting stent implantation (Rota-DES): a rational approach for complex calcified coronary lesions

Rotational atherectomy has been regaining interest over the last couple of years after it almost has disappeared from most interventional catheterization laboratories for several years due to failure to prove its original concept of improving long term results of percutaneous coronary interventions (PCI) as was repeatedly shown in studies in the 1990s. Its revival coupled the introduction of drug-eluting stents (DES); these devices have led to treating much more complex lesions and high-risk patients by PCI. However, real-world experience suggested that off-label use of DES is associated with a higher rate of early and late stent thrombosis. Therefore, more attention is now being paid to the initial implantation technique of DES including aggressive lesion preparation to facilitate stent delivery and expansion. The limited studies with rot-ablation and DES showed promising results with no long term safety concerns. In these studies, a subtle observation was made suggesting that rot-ablation prior to DES implantation in such lesions may have an add-on effect on long term outcome compared to DES alone. An ongoing multicenter study is investigating such effect among complex calcified coronary lesions. Even if this additive benefit does not prove true, rot-ablation remains an efficient tool for preparing certain lesions to facilitate effective and safe DES implantation. Therefore, interventional training programs should focus on this difficult technique to bridge the gap of experience which resulted from neglecting it for several years. In this regard, dedicated courses at experienced sites as well as medical simulation may be appropriate.

Colonization history of the Swiss Rhine basin by the bullhead (Cottus gobio): inference under a Bayesian spatially explicit framework

The present distribution of freshwater fish in the Alpine region has been strongly affected by colonization events occurring after the last glacial maximum (LGM), some 20,000 years ago. We use here a spatially explicit simulation framework to model and better understand their colonization dynamics in the Swiss Rhine basin. This approach is applied to the European bullhead (Cottus gobio), which is an ideal model organism to study fish past demographic processes since it has not been managed by humans. The molecular diversity of eight sampled populations is simulated and compared to observed data at six microsatellite loci under an approximate Bayesian computation framework to estimate the parameters of the colonization process. Our demographic estimates fit well with current knowledge about the biology of this species, but they suggest that the Swiss Rhine basin was colonized very recently, after the Younger Dryas some 6600 years ago. We discuss the implication of this result, as well as the strengths and limits of the spatially explicit approach coupled to the approximate Bayesian computation framework.

High-resolution computer simulation of the dynamics of isoelectric focusing: in quest of more realistic input parameters for carrier ampholytes

The impact of the systematic variation of either DeltapK(a) or mobility of 140 biprotic carrier ampholytes on the conductivity profile of a pH 3-10 gradient was studied by dynamic computer simulation. A configuration with the greatest DeltapK(a) in the pH 6-7 range and uniform mobilities produced a conductivity profile consistent with that which is experimentally observed. A similar result was observed when the neutral (pI = 7) ampholyte is assigned the lowest mobility and mobilities of the other carriers are systematically increased as their pI's recede from 7. When equal DeltapK(a) values and mobilities are assigned to all ampholytes a conductivity plateau in the pH 5-9 region is produced which does not reflect what is seen experimentally. The variation in DeltapK(a) values is considered to most accurately reflect the electrochemical parameters of commercially available mixtures of carrier ampholytes. Simulations with unequal mobilities of the cationic and anionic species of the carrier ampholytes show either cathodic (greater mobility of the cationic species) or anodic (greater mobility of the anionic species) drifts of the pH gradient. The simulated cationic drifts compare well to those observed experimentally in a capillary in which the focusing of three dyes was followed by whole column optical imaging. The cathodic drift flattens the acidic portion of the gradient and steepens the basic part. This phenomenon is an additional argument against the notion that focused zones of carrier ampholytes have no electrophoretic flux.

Alternative splicing of pre-mRNA in cancer: focus on G protein-coupled peptide hormone receptors

Through alternative splicing, multiple different transcripts can be generated from a single gene. Alternative splicing represents an important molecular mechanism of gene regulation in physiological processes such as developmental programming as well as in disease. In cancer, splicing is significantly altered. Tumors express a different collection of alternative spliceoforms than normal tissues. Many tumor-associated splice variants arise from genes with an established role in carcinogenesis or tumor progression, and their functions can be oncogenic. This raises the possibility that products of alternative splicing play a pathogenic role in cancer. Moreover, cancer-associated spliceoforms represent potential diagnostic biomarkers and therapeutic targets. G protein-coupled peptide hormone receptors provide a good illustration of alternative splicing in cancer. The wild-type forms of these receptors have long been known to be expressed in cancer and to modulate tumor cell functions. They are also recognized as attractive clinical targets. Recently, splice variants of these receptors have been increasingly identified in various types of cancer. In particular, alternative cholecystokinin type 2, secretin, and growth hormone-releasing hormone receptor spliceoforms are expressed in tumors. Peptide hormone receptor splice variants can fundamentally differ from their wild-type receptor counterparts in pharmacological and functional characteristics, in their distribution in normal and malignant tissues, and in their potential use for clinical applications.

The effect of pulsed jet lavage in vertebroplasty on injection forces of PMMA bone cement: an animal study

Percutaneous vertebroplasty, comprising of the injection of polymethylmethacrylate (PMMA) into vertebral bodies, is an efficient procedure to stabilize osteoporotic compression fractures as well as other weakening lesions. Besides fat embolism, cement leakage is considered to be one of the major and most severe complications during percutaneous vertebroplasty. The viscosity of the PMMA during injection plays a key role in this context. It was shown in vitro that the best way to lower the risk of cement leakage is to inject the cement at higher viscosity, which is requires high injection forces. Injection forces can be reduced by applying a newly developed lavage technique as it was shown in vitro using human cadaver vertebrae. The purpose of this study was to prove the in vitro results in an in vivo model. The investigation was incorporated in an animal study that was performed to evaluate the cardiovascular reaction on cement augmentation using the lavage technique. Injection forces were measured with instrumentation for 1 cc syringes, additionally acquiring plunger displacement. Averaged injection forces measured, ranged from 12 to 130 N and from 28 to 140 N for the lavage group and the control group, respectively. Normalized injection forces (by viscosity and injection speed) showed a trend to be lower for the lavage group in comparison to the control group (P = 0.073). In conclusion, the clinical relevance on the investigated lavage technique concerning lowering injection forces was only shown by trend in the performed animal study. However, it might well be that the effect is more pronounced for osteoporotic vertebral bodies.

Clinical investigations of polymethylmethacrylate cement viscosity during vertebroplasty and related in vitro measurements

Percutaneous vertebroplasty, comprising an injection of polymethylmethacrylate (PMMA) into vertebral bodies, is a practical procedure for the stabilization of osteoporotic compression fractures as well as other weakening lesions. Cement leakage is considered to be one of the major and most severe complications during percutaneous vertebroplasty. The viscosity of the material plays a key role in this context. In order to enhance the safety for the patient, a rheometer system was developed to measure the cement viscosity intraoperatively. For this development, it is of great importance to know the proper viscosity to start the procedure determined by experienced surgeons and the relation between the time period when different injection devices are used and the cement viscosity. The purpose of the study was to investigate the viscosity ranges for different injection systems during conventional vertebroplasty. Clinically observed viscosity values and related time periods showed high scattering. In order to get a better understanding of the clinical observations, cement viscosity during hardening at different ambient temperatures and by simulation of the body temperature was investigated in vitro. It could be concluded, that the direct viscosity assessment with a rheometer during vertebroplasty can help clinicians to define a lower threshold viscosity and thereby decrease the risk of leakage and make adjustments to their injection technique in real time. Secondly, the acceleration in hardening of PMMA-based cements at body temperature can be useful in minimizing leakages by addressing them with a short injection break.

Modeling of human P450 oxidoreductase structure by in silico mutagenesis and MD simulation

P450 oxidoreductase (POR) is the obligate electron donor for microsomal cytochrome P450s and mutations in POR cause several metabolic disorders. We have modeled the structure of human P450 oxidoreductase by in silico amino acid replacements in the rat POR crystal structure. The rat POR has 94% homology with human POR and 38 amino acids were replaced to make its sequence identical to human POR. Several rounds of molecular dynamic simulations refined the model and removed structural clashes from side chain alterations of replaced amino acids. This approach has the advantage of keeping the cofactor contacts and structural features of the core enzyme intact which could not be achieved by homology based approaches. The final model from our approach was of high quality and compared well with experimentally determined structures of other PORs. This model will be used for analyzing the structural implications of mutations and polymorphisms in human POR.

Modifying peripheral IV catheters with side holes and side slits results in favorable changes in fluid dynamic properties during the injection of iodinated contrast material

OBJECTIVE: The purpose of this study was to compare a standard peripheral end-hole angiocatheter with those modified with side holes or side slits using experimental optical techniques to qualitatively compare the contrast material exit jets and using numeric techniques to provide flow visualization and quantitative comparisons. MATERIALS AND METHODS: A Schlieren imaging system was used to visualize the angiocatheter exit jet fluid dynamics at two different flow rates. Catheters were modified by drilling through-and-through side holes or by cutting slits into the catheters. A commercial computational fluid dynamics package was used to calculate numeric results for various vessel diameters and catheter orientations. RESULTS: Experimental images showed that modifying standard peripheral IV angiocatheters with side holes or side slits qualitatively changed the overall flow field and caused the exiting jet to become less well defined. Numeric calculations showed that the addition of side holes or slits resulted in a 9-30% reduction of the velocity of contrast material exiting the end hole of the angiocatheter. With the catheter tip directed obliquely to the wall, the maximum wall shear stress was always highest for the unmodified catheter and was always lowest for the four-side-slit catheter. CONCLUSION: Modified angiocatheters may have the potential to reduce extravasation events in patients by reducing vessel wall shear stress.

Central venous catheter integrity during mechanical power injection of iodinated contrast medium

PURPOSE: To evaluate a widely used nontunneled triple-lumen central venous catheter in order to determine whether the largest of the three lumina (16 gauge) can tolerate high flow rates, such as those required for computed tomographic angiography. MATERIALS AND METHODS: Forty-two catheters were tested in vitro, including 10 new and 32 used catheters (median indwelling time, 5 days). Injection pressures were continuously monitored at the site of the 16-gauge central venous catheter hub. Catheters were injected with 300 and 370 mg of iodine per milliliter of iopamidol by using a mechanical injector at increasing flow rates until the catheter failed. The infusion rate, hub pressure, and location were documented for each failure event. The catheter pressures generated during hand injection by five operators were also analyzed. Mean flow rates and pressures at failure were compared by means of two-tailed Student t test, with differences considered significant at P < .05. RESULTS: Injections of iopamidol with 370 mg of iodine per milliliter generate more pressure than injections of iopamidol with 300 mg of iodine per milliliter at the same injection rate. All catheters failed in the tubing external to the patient. The lowest flow rate at which catheter failure occurred was 9 mL/sec. The lowest hub pressure at failure was 262 pounds per square inch gauge (psig) for new and 213 psig for used catheters. Hand injection of iopamidol with 300 mg of iodine per milliliter generated peak hub pressures ranging from 35 to 72 psig, corresponding to flow rates ranging from 2.5 to 5.0 mL/sec. CONCLUSION: Indwelling use has an effect on catheter material property, but even for used catheters there is a substantial safety margin for power injection with the particular triple-lumen central venous catheter tested in this study, as the manufacturer's recommendation for maximum pressure is 15 psig.

Effect of urinary tract infection on reservoir function in patients with ileal bladder substitute

PURPOSE: We determined the functional consequences of urinary tract infection in patients with an ileal bladder substitute in terms of urinary continence, post-void residual and urinary retention. MATERIALS AND METHODS: A total of 48 patients with culture documented urinary tract infection (single organism, 10(5) or greater cfu) were retrospectively evaluated before, during and after the infection for changes in continence, post-void residual and urinary retention as well as for resolution of symptomatology after appropriate antibiotic therapy. RESULTS: Of the 48 patients 40 had a single infection while the remaining 8 had multiple urinary tract infection episodes. During daytime 27 of the 44 patients with previously good daytime continence experienced deterioration in their baseline voiding status while infected. Of the 40 patients who were previously continent at night 20 had incontinence while infected. There were 15 patients with documented post-void residual and urinary retention developed in 4 during the urinary tract infection. All patients returned to baseline continence status and reservoir function after appropriate antibiotic treatment based on objective and subjective assessments. CONCLUSIONS: Urinary tract infection may cause urinary incontinence in patients with ileal bladder substitutes. Therefore, when there are complaints of de novo urinary incontinence, a finding of post-void residual or an acute presentation of urinary retention, a urinary tract infection should be excluded. When the urinary tract infection is appropriately treated urinary continence and reservoir function return to their baseline status.