Cleft Space Research Articles

Impact of a new combined preoperative cleft assessment on dental implant success in patients with cleft and palate: a retrospective study

BackgroundBone height assessment alone is frequently used to guide rehabilitation choice, without consideration for soft tissues or adjacent teeth. This study aimed to evaluate the impact of different preoperative cleft assessments on implant success and patient satisfaction.MethodsThe study involved a retrospective assessment of records from 40 patients with cleft lip and palate (CLP). The alveolar cleft score (ACS; clinical criteria), interdental alveolar bone height (IABH) score (radiological criteria), patient compliance score (dental hygiene, medical visit observance, and smoking), and a novel combined score (IABH-ACS-Compliance) were assessed from patient records. Patients who required prosthetic tooth rehabilitation in the cleft dental arch space were included. Twenty-six patients (Group 1) were treated with dental implants, and 14 patients (Group 2) selected another prosthetic option (fixed prosthodontics, removal prosthesis), orthodontic space closure, or no rehabilitation. The main outcomes measured were relative implant success (no implant loss involving marginal bone loss ≤ 1.9 mm) for patients treated with dental implant therapy (Group 1) and patient satisfaction for all patients (Groups 1 and 2).ResultsForty dental implants were placed in the patients in Group 1. Four implants in four patients (Group 1 relative failure, RF) were lost (implant survival rate of 90%) after 36 (± 12.4) months of follow-up. Twenty-two patients who received implants belonged to the relative implant success group (Group 1 RS). The average “IABH-ACS-Compliance” scores were significantly different (p < 0.05): 16.90 ± 2.35 and 12.75 ± 0.43 for the Group 1 RS and RF groups, respectively.ConclusionsPreoperative cleft parameters have an impact on relative implant success and patient satisfaction. The new cleft assessment combined-score (“IABH-ACS-Compliance”) allows an accurate selection of cleft cases eligible for dental implants, thereby improving postoperative outcomes.

Mechanisms of arrhythmia termination during acute myocardial ischemia: Role of ephaptic coupling and complex geometry of border zone.

Myocardial ischemia occurs when blood flow to the heart is reduced, preventing the heart muscle from receiving enough oxygen required for survival. Several anatomical and electrophysiological changes occur at the ischemic core (IC) and border zone (BZ) during myocardial ischemia, for example, gap junctional remodeling, changes in ionic channel kinetics and electrophysiologic changes in cell excitability, which promote the development of cardiac arrhythmia. Ephaptic coupling (EpC), which is an electrical field effect developed in the shared cleft space between adjacent cells, has been suggested to rescue the conduction when gap junctions are impaired, such as myocardial ischemia. In this manuscript, we explored the impact of EpC, electrophysiological and anatomical components of myocardial ischemia on reentry termination during non-ischemic and ischemic condition. Our results indicated that EpC and BZ with complex geometry have opposite effects on the reentry termination. In particular, the presence of homogeneous EpC terminates reentry, whereas BZ with complex geometry alone facilitates reentry by producing wave break-up and alternating conduction block. The reentry is terminated in the presence of homogeneous or heterogeneous EpC despite the presence of complex geometry of the BZ, independent of the location of BZ. The inhibition of reentry can be attributed to a current-to-load mismatch. Our results points to an antiarrhythmic role of EpC and a pro-arrhythmic role of BZ with complex geometry.

Sodium channels and the intercalated disk - it is all about location, location, location.

Sodium channels and the intercalated disk - it is all about location, location, location.

Extracellular heparan sulfate proteoglycans and glycan-binding lectins orchestrate trans-synaptic signaling

The exceedingly narrow synaptic cleft (<20 nm) and adjacent perisynaptic extracellular space contain an astonishing array of secreted and membrane-anchored glycoproteins. A number of these extracellular molecules regulate intercellular trans-synaptic signaling by binding to ligands, acting as co-receptors or modulating ligand-receptor interactions. Recent work has greatly expanded our understanding of extracellular proteoglycan and glycan-binding lectin families as key regulators of intercellular signaling at the synapse. These secreted proteins act to regulate the compartmentalization of glycoprotein ligands and receptors, crosslink dynamic extracellular and cell surface lattices, modulate both exocytosis and endocytosis vesicle cycling, and control postsynaptic receptor trafficking. Here, we focus closely on the Drosophila glutamatergic neuromuscular junction (NMJ) as a model synapse for understanding extracellular roles of the many heparan sulfate proteoglycan (HSPG) and lectin proteins that help determine synaptic architecture and neurotransmission strength. We particularly concentrate on the roles of extracellular HSPGs and lectins in controlling trans-synaptic signaling, especially that mediated by the Wnt and BMP pathways. These signaling mechanisms are causally linked to a wide spectrum of neurological disease states that impair coordinated movement and cognitive functions.

Intercellular Sodium Regulates Repolarization in Cardiac Tissue with Sodium Channel Gain of Function

In cardiac myocytes, action potentials are initiated by an influx of sodium (Na+) ions via voltage-gated Na+ channels. Na+ channel gain of function (GOF), arising in both inherited conditions associated with mutation in the gene encoding the Na+ channel and acquired conditions associated with heart failure, ischemia, and atrial fibrillation, enhance Na+ influx, generating a late Na+ current that prolongs action potential duration (APD) and triggering proarrhythmic early afterdepolarizations (EADs). Recent studies have shown that Na+ channels are highly clustered at the myocyte intercalated disk, facilitating formation of Na+ nanodomains in the intercellular cleft between cells. Simulations from our group have recently predicted that narrowing the width of the intercellular cleft can suppress APD prolongation and EADs in the presence of Na+ channel mutations because of increased intercellular cleft Na+ ion depletion. In this study, we investigate the effects of modulating multiple extracellular spaces, specifically the intercellular cleft and bulk interstitial space, in a novel computational model and experimentally via osmotic agents albumin, dextran 70, and mannitol. We perform optical mapping and transmission electron microscopy in a drug-induced (sea anemone toxin, ATXII) Na+ channel GOF isolated heart model and modulate extracellular spaces via osmotic agents. Single-cell patch-clamp experiments confirmed that the osmotic agents individually do not enhance late Na+ current. Both experiments and simulations are consistent with the conclusion that intercellular cleft narrowing or expansion regulates APD prolongation; in contrast, modulating the bulk interstitial space has negligible effects on repolarization. Thus, we predict that intercellular cleft Na+ nanodomain formation and collapse critically regulates cardiac repolarization in the setting of Na+ channel GOF.

Quantitative analysis of the Ca2+ -dependent regulation of delayed rectifier K+ current IKs in rabbit ventricular myocytes.

[Ca2+ ]i enhanced rabbit ventricular slowly activating delayed rectifier K+ current (IKs ) by negatively shifting the voltage dependence of activation and slowing deactivation, similar to perfusion of isoproterenol. Rabbit ventricular rapidly activating delayed rectifier K+ current (IKr ) amplitude and voltage dependence were unaffected by high [Ca2+ ]i . When measuring or simulating IKs during an action potential, IKs was not different during a physiological Ca2+ transient or when [Ca2+ ]i was buffered to 500nm. The slowly activating delayed rectifier K+ current (IKs ) contributes to repolarization of the cardiac action potential (AP). Intracellular Ca2+ ([Ca2+ ]i ) and β-adrenergic receptor (β-AR) stimulation modulate IKs amplitude and kinetics, but details of these important IKs regulators and their interaction are limited. We assessed the [Ca2+ ]i dependence of IKs in steady-state conditions and with dynamically changing membrane potential and [Ca2+ ]i during an AP. IKs was recorded from freshly isolated rabbit ventricular myocytes using whole-cell patch clamp. With intracellular pipette solutions that controlled free [Ca2+ ]i , we found that raising [Ca2+ ]i from 100 to 600nm produced similar increases in IKs as did β-AR activation, and the effects appeared additive. Both β-AR activation and high [Ca2+ ]i increased maximally activated tail IKs , negatively shifted the voltage dependence of activation, and slowed deactivation kinetics. These data informed changes in our well-established mathematical model of the rabbit myocyte. In both AP-clamp experiments and simulations, IKs recorded during a normal physiological Ca2+ transient was similar to IKs measured with [Ca2+ ]i clamped at 500-600nm. Thus, our study provides novel quantitative data as to how physiological [Ca2+ ]i regulates IKs amplitude and kinetics during the normal rabbit AP. Our results suggest that micromolar [Ca2+ ]i , in the submembrane or junctional cleft space, is not required to maximize [Ca2+ ]i -dependent IKs activation during normal Ca2+ transients.

Role of Heterogeneous Macromolecular Crowding and Geometrical Irregularity at Central Excitatory Synapses in Shaping Synaptic Transmission.

Besides the geometrical tortousity due to the extrasynaptic structures, macromolecular crowding and geometrical irregularities constituting the cleft composition at central excitatory synapses has a major and direct role in retarding the glutamate diffusion within the cleft space. However, the cleft composition may not only coarsely reduce the overall diffusivity of the glutamate but may also lead to substantial spatial variation in the diffusivity across the cleft space. Decrease in the overall diffusivity of the glutamate may have straightforward consequences to the glutamate transients in the cleft. However, how spatial variation in the diffusivity may further affect glutamate transients is an intriguing aspect. Therefore, to understand the role of cleft heterogeneity, the present study adopts a novel approach of glutamate diffusion which considers a gamma statistical distribution of the diffusion coefficient of glutamate (Dglut) across the cleft space, such that its moments discernibly capture the dual impacts of the cleft composition, and further applies the framework of superstatistics. The findings reveal a power law behavior in the glutamate transients, akin to the long-range anomalous subdiffusion, which leads to slower decay profile of cleft glutamate at higher intensity of cleft heterogeneity. Moreover, increase in the cleft heterogeneity is seen to eventually cause slower-rising excitatory postsynaptic currents with higher amplitudes, lesser noise, and prolonged duration of charge transfer across the postsynaptic membrane. Further, with regard to the conventional standard diffusion approach, the study suggests that the effective Dglut essentially derives from the median of the Dglut distribution and does not necessarily need to be the mean Dglut. Together, the findings indicate a strong implication of cleft heterogeneity to the metabolically cost-effective tuning of synaptic response during the phenomenon of plasticity at individual synapses and also provide an additional factor of variability in transmission across identical synapses.

Age Associated Downregulation of Glutamate/GABA Transporters Expression in Rostral Ventral Lateral Medulla (RVLM)

Physiological function is altered with advancing age, including changes in sympathetic nervous system regulation. Studies focused on Glutamate/GABA ionotropic receptors using pharmacological agonists and antagonists in the rostral ventral lateral medulla (RVLM) indicates changes in medullary mechanisms regulating sympathetic nerve discharge (SND) in aged Fisher 344 rats. Identifying molecular mechanisms involved in this alteration is necessary to understand the regulation of central sympathetic neural circuits. Based on this rationale, we hypothesized that aging alters the basal regulation of RVLM Glutamate/GABA system‐associated genes. To test this hypothesis, the RVLM containing area was micro‐punched from young, middle‐aged and aged Fisher 344 rats. RNA level expression changes in RVLM GABA/Glutamate system‐associated genes were analyzed using RT2 profiler array and Taqman® real‐time PCR. Genes that showed &gt;2fold differences in expression were analyzed at protein level by using immunoblot analysis. Downregulation of RVLM glutamate (Slc1a6) and GABA (Slc6a13) transporter genes was observed in aged compared with young rats at the RNA level, with a similar trend at the protein level. Slc1a6 and Slc6a13 transporters are known to modulate the amount of Glutamate/GABA in synaptic cleft and extra synaptic space. Down regulation of these transporters suggests there may be an altered Glutamergic/GABAergic balance in the aged RVLM.Support or Funding InformationSupported by NIH AG‐041948.

The dual effect of ephaptic coupling on cardiac conduction with heterogeneous expression of connexin 43

Decreased and heterogeneous expression of connexin 43 (Cx43) are common features in animal heart failure models. Ephpatic coupling, which relies on the presence of junctional cleft space between the ends of adjacent cells, has been suggested to play a more active role in mediating intercellular electrical communication when gap junctions are reduced. To better understand the interplay of Cx43 expression and ephaptic coupling on cardiac conduction during heart failure, we performed numerical simulations on our model when Cx43 expression is reduced and heterogeneous. Under severely reduced Cx43 expression, we identified three new phenomena in the presence of ephaptic coupling: alternating conduction, in which ephaptic and gap junction-mediated mechanisms alternate; instability of planar fronts; and small amplitude action potential (SAP), which has a smaller potential amplitude than the normal action potential. In the presence of heterogeneous Cx43 expression, ephaptic coupling can either prevent or promote conduction block (CB) depending on the Cx43 knockout (Cx43KO) content. When Cx43KO content is relatively high, ephaptic coupling reduces the probabilities of CB. However, ephaptic coupling promotes CB when Cx43KO and wild type cells are mixed in roughly equal proportion, which can be attributed to an increase in current-to-load mismatch.

A Review of the Cleft Lip/Palate Literature Reveals That Differential Diagnosis of the Facial Skeleton and Musculature is Essential to Achieve All Treatment Goals.

After 40 years of monitoring cleft palate treatment results with extensive objective records of cephaloradiographs, dental casts, and photographs, it became apparent that patients with the same cleft type who received the same treatment at approximately the same age were obtaining different results. An extensive review of cleft palate surgical, orthodontic, facial, and palatal longitudinal growth studies was undertaken to determine the critical physical difference between these patients that determined why some treatments succeeded while others failed. Treatment should be based on performing staged palatal surgery between 18 and 24 months when the palatal surface area to cleft space size is approximately 15% to 20%. Presurgical orthopedics with a gingivoperiosteoplasty causes midfacial deformities. Even though patients have the same cleft type and have received the same surgical treatment, usually between 18 and 24 months, the ratio of cleft and palatal size of 15% to 20% is critical to obtain good palatal development.

Tympanosclerosis causing blockage of Middle Ear Cleft

Background: Middle ear cleft space starts from Eustachian tube, and includes middle ear, aditus & mastoid antrum. It develops from 1st visceral pouch. Blockage of middle ear cleft, particularly the aditus can result from a number of reasons. Tympanosclerosis creates obstruction in aeration of middle ear and mastoid antrum. Aims & Objective: To study effect of tympanosclerosis on blockage of middle ear cleft. Material and Methods: A retrospective study of all cases of cortical mastoidectomy surgeries done in a Tertiary care centre in Western U.P. was carried out. Relevant clinical data and histopathology reports were obtained from hospital records and the data was analysed. A total of 20 cases of cortical mastoidectomy were included in the study. Results: A total of 20 cases were included in the study, in the age group of 16 to 58 years. Tympanosclerosis was seen in 13 cases. In tympanosclerosis positive group, the mean age was 25-32years. The aditus was not patent in 10(50%) of patients in this group. Conclusion: Tympanosclerosis is a non-specific result of chronic inflammatory process and causes an increased risk for blockage of aditus through plaque formation. Clearance of these plaques and cortical mastoidectomy prevents recurrences. Key-Words: Tympanosclerosis, Mastoidectomy; Blockage; Middle Ear Cleft

Discovery of a subtype selective inhibitor of the human betaine/GABA transporter 1 (BGT-1) with a non-competitive pharmacological profile

The γ-aminobutyric acid (GABA) transporters (GATs) are essential regulators of the activity in the GABAergic system through their continuous uptake of the neurotransmitter from the synaptic cleft and extrasynaptic space. Four GAT subtypes have been identified to date, each displaying different pharmacological properties and expression patterns. The present study focus on the human betaine/GABA transporter 1 (BGT-1), which has recently emerged as a new target for treatment of epilepsy. However, the lack of selective inhibitors of this transporter has impaired the exploration of this potential considerably. With the objective of identifying novel compounds displaying selectivity for BGT-1, we performed a screening of a small compound library at cells expressing BGT-1 using a [3H]GABA uptake assay. The screening resulted in the identification of the compound N-(1-benzyl-4-piperidinyl)-2,4-dichlorobenzamide (BPDBA), a selective inhibitor of the human BGT-1 transporter with a non-competitive profile exhibiting no significant inhibitory activity at the other three human GAT subtypes. The selectivity profile of the compound was subsequently confirmed at cells expressing the four mouse GAT subtypes. Thus, BPDBA constitutes a potential useful pharmacological tool compound for future explorations of the function of the BGT-1 subtype.

Can the Sodium-Calcium Exchanger Initiate or Suppress Calcium Sparks in Cardiac Myocytes?

Positive feedback of Calcium (Ca)-induced Ca release is the mechanism of Ca spark formation in cardiac myocytes. To initiate this process, a certain amount of Ca in the cleft space is necessary. When the membrane potential becomes higher during excitation-contraction coupling, Ca can enter through both Ca current (ICaL) and sodium-calcium exchanger (NCX) and may activate ryanodine receptors to initiate a Ca spark. On the other hand, at the resting membrane potential (Vm ∼–80 mV), NCX removes Ca from the cell (forward mode). If Ca released from the sarcoplasmic reticulum is quickly removed via forward mode NCX before Ca-induced Ca release starts, the Ca release becomes nonspark Ca leak. This would also be influenced by the cleft/noncleft distribution of NCX, which is unknown. Using a physiologically detailed mathematical model of subcellular Ca cycling, we analyze how NCX strength and distribution alter Ca spark formation. During excitation-contraction coupling, most Ca sparks are induced by ICaL with very few due to NCX current. At the resting membrane potential if most NCX is localized to the cleft, spontaneous Ca sparks are significantly reduced.

How Does Stochastic Ryanodine Receptor-Mediated Ca Leak Fail to Initiate a Ca Spark?

Spontaneous calcium (Ca) sparks are initiated by single ryanodine receptor (RyR) opening. Once one RyR channel opens, it elevates local [Ca] in the cleft space ([Ca]Cleft), which opens other RyR channels in the same Ca release unit (CaRU) via Ca-induced Ca-release. Experiments by Zima et al. (J. Physiol. 588:4743–4757, 2010) demonstrate that spontaneous Ca sparks occur only when intrasarcoplasmic-reticulum (SR) [Ca] ([Ca]SR) is above a threshold level, but that RyR-mediated SR Ca leak exists without Ca sparks well below this threshold [Ca]SR. We examine here how single RyR opening at lower [Ca]SR can fail to recruit Ca sparks at a CaRU, while still contributing to SR Ca leak. We assess this using a physiologically detailed mathematical model of junctional SR Ca release in which RyR gating is regulated by [Ca]SR and [Ca]Cleft. We find that several factors contribute to the failure of Ca sparks as [Ca]SR declines: 1), lower [Ca]SR reduces driving force and thus limits local [Ca]Cleft achieved and the rate of rise during RyR opening; 2), low [Ca]SR limits RyR open time (τO), which further reduces local [Ca]Cleft attained; 3), low τO and fast [Ca]Cleft dissipation after RyR closure shorten the opportunity for neighboring RyR activation; 4), at low [Ca]SR, the RyR exhibits reduced [Ca]Cleft sensitivity. We conclude that all of these factors conspire to reduce the probability of Ca sparks as [Ca]SR declines, despite continued RyR-mediated Ca leak. In addition, these same factors explain the much lower efficacy of L-type Ca channel opening to trigger local SR Ca release at low [Ca]SR during excitation-contraction coupling. Conversely, all of these factors are fundamentally important for increasing the propensity for pro-arrhythmic Ca sparks and waves in cardiac myocytes at high [Ca]SR.

Use of Cone Beam Computed Tomography to Volumetrically Assess Alveolar Cleft Defects—Preliminary Results

The purpose of this study was to determine the utility of cone beam computed tomographic (CBCT) imaging in assessing the volume of alveolar cleft defects in patients undergoing secondary cleft repair. Fourteen patients with unilateral clefts were analyzed in a retrospective study. Preoperative CBCT imaging of patients preparing to undergo secondary repair of alveolar clefts was reviewed. Using anatomic landmarks, 3 measurements were collected from CBCT images for each patient: facial width (FW), facial height (FH), and facial-palatal length (FL). These values were used to calculate the estimated volume (EV) of the cleft and thus the amount of bone graft material that would be needed to fill the defect. The overall mean values of FW, FH, and FL were 9.7 ± 3.1, 14.07 ± 2.7, and 5.6 ± 0.8 mm, respectively. Mean EV was 489.0 ± 151.6 mm(3). The single (0.879) and average (0.956) measurements of the intraclass correlation coefficient for FH were very good to excellent. Similar data were observed for FH (single, 0.827; average, 0.935). For FL, a decreasing trend in the mean and variability over the 3 measurement times was reflected in low single (0.305) and moderate average (0.569) intraclass correlation coefficients. CBCT imaging can be used to reliably measure FW, FH, and FL and to calculate the EV of the cleft. These data can be used by oral and maxillofacial surgeons to quantitatively assess the volume of an alveolar cleft and aid in preoperative determination of the amount of bone that will be needed to adequately graft the cleft space. This will also aid in appropriate selection of an autogenous graft donor site before surgery.

How Does RyR2-Mediated SR Calcium Leak Fail to Cause Sparks?

Recent experiments have shown that Ca leak from the sarcoplasmic reticulum (SR) can occur via spontaneous Ca sparks, non spark ryanodine receptor (RyR) mediated leak, and RyR independent pathways (Zima et al. BJ, 94:104a, 2008). Opening of a single RyR is expected to increase local [Ca] in the cleft space rapidly (<< 1 ms) to levels that are expected to activate neighboring RyR in that cleft via Ca induced Ca release. Our question is how and why RyR-mediated SR Ca leak becomes mainly non-spark mediated at moderate to low SR Ca loads. To answer this question, we analyze Ca flux through RyRs using a physiologically detailed mathematical model of junctional SR Ca release in which RyR gating is regulated by intra SR and cleft [Ca] ([Ca]SR & [Ca]Cleft). In this model, there are one hundred RyR channels in one Ca release unit. Each RyR opens stochastically depending on [Ca]Cleft and [Ca]SR . We find that several factors contribute to the failure of one RyR channel opening to opens adjacent RyRs as [Ca]SR declines: 1) the lower [Ca]SR reduces driving force and thus limits local [Ca]Cleft (both absolute level and rate of rise), 2) low [Ca]SR can inhibit RyR open time (τO) which further reduces local [Ca]Cleft attained, 3) the low τO and fast [Ca]Cleft dissipation after closure shorten the opportunity for neighboring RyR activation, 4) at low [Ca]SR the RyR2 exhibits reduced [Ca]Cleft sensitivity. We conclude that all of these factors conspire to reduce the probability of Ca sparks as [Ca]SR declines, despite continued RyR-mediated SR Ca leak.

Histidine 562 on S5 is a pH Sensor for HERG Gating

In the HERG channel there are at least two binding sites for extracellular protons. One site alters gating, and the other alters conductance. One of these sites shifts activation and inactivation voltage dependence. The only two histidines on the extracellular loops of the channel have been shown to be uninvolved in the pH sensitivity of gating. We hypothesized that a histidine residue located at nearly the midpoint of S5 (H562) could be the pH sensor for gating kinetics. We substituted a glutamine at this point and produced a HERG current with kinetics shifted nearly 20 mV negative and rendered gating pHo-insensitive. This analysis was extended to a HERG construct with all three histidines removed. Although removal of the histidine from S5 in HERG resulted in reduced pH sensitivity of deactivation time constants, this disruption could occur via several mechanisms. Therefore, we tested whether inserting a histidine into the middle of the S5 region of the Kv1.4 channel would confer pH sensitivity. Because of an intrinsic pH sensitivity, we made the S5 mutation in a double construct in which the external pH sensing histidine at position 508 in Kv1.4 was mutated to a glutamine. Introduction of a histidine at position G489 on the S5 voltage sensor of the H508Q mutant channel induced pH dependent gating. Changing pHo from 7.8 to 6.2 caused an approximate −15 mV shift in the threshold for activation of Kv1.4[G489H][H508Q]. The half activation time was pHo dependent for a shift from pH 7.4 to 6.2. The G489H mutation restored the coupling between extracellular pH and N-terminal binding that was disrupted by the H508Q mutation. These studies suggest that an important pH sensitivity of gating is conferred by an S5 cleft space histidine in HERG.

Modeling electrical activity of myocardial cells incorporating the effects of ephaptic coupling.

Existing models of electrical activity in myocardial tissue are unable to easily capture the effects of ephaptic coupling. Homogenized models do not account for cellular geometry, while detailed spatial models are too complicated to simulate in three dimensions. Here we propose a unique model that accurately captures the geometric effects while being computationally efficient. We use this model to provide an initial study of the effects of changes in extracellular geometry, gap junctional coupling, and sodium ion channel distribution on propagation velocity in a single 1D strand of cells. In agreement with previous studies, we find that ephaptic coupling increases propagation velocity at low gap junctional conductivity while it decreases propagation at higher conductivities. We also find that conduction velocity is relatively insensitive to gap junctional coupling when sodium ion channels are located entirely on the cell ends and cleft space is small. The numerical efficiency of this model, verified by comparison with more detailed simulations, allows a thorough study in parameter variation and shows that cellular structure and geometry has a nontrivial impact on propagation velocity. This model can be relatively easily extended to higher dimensions while maintaining numerical efficiency and incorporating ephaptic effects through modeling of complex, irregular cellular geometry.

A Computer Model of Engineered Cardiac Monolayers

Engineered monolayers created using microabrasion and micropatterning methods have provided a simplified in vitro system to study the effects of anisotropy and fiber direction on electrical propagation. Interpreting the behavior in these culture systems has often been performed using classical computer models with continuous properties. However, such models do not account for the effects of random cell shapes, cell orientations, and cleft spaces inherent in these monolayers on the resulting wavefront conduction. This work presents a novel methodology for modeling a monolayer of cardiac tissue in which the factors governing cell shape, cell-to-cell coupling, and degree of cleft space are not constant but rather are treated as spatially random with assigned distributions. This modeling approach makes it possible to simulate wavefront propagation in a manner analogous to performing experiments on engineered monolayer tissues. Simulated results are compared to previously published measured data from monolayers used to investigate the role of cellular architecture on conduction velocities and anisotropy ratios. We also present an estimate for obtaining the electrical properties from these networks and demonstrate how variations in the discrete cellular architecture affect the macroscopic conductivities. The simulations support the common assumption that under normal ranges of coupling strength, tissues with relatively uniform distributions of cell shapes and connectivity can be represented using continuous models with conductivities derived from random discrete cellular architecture using either global or local estimates. The results also reveal that in the presence of abrupt changes in cell orientation, local estimates of tissue properties predict smoother changes in conductivity that may not adequately predict the discrete nature of propagation at the transition sites.

Ｌｅ Ｆｏｒｔ Ｉ型骨切り術により幅の広い顎裂を閉鎖した成人片側性口唇口蓋裂の１症例

The residual wide alveolar cleft often causes potential risk in bone grafting and prosthodontic treatment for cleft lip and palate patients. While performing cleft reduction, maxillary advancement is required because closure of the cleft space itself with orthodontic/orthognathic treatment will result in a crossbite. In this paper, we report the case of a 21-year 4-month old male with left cleft lip and palate. The patient had undergone orthodontic treatment once at another institute, and he visited our Orthodontic Clinic at the University Hospital of Dentistry, Tokyo Medical and Dental University with a chief complaint of residual cleft space. Overjet and overbite were both 2.0 mm and the intercuspation of the buccal segments was optimal. However, the residual cleft space was 14.5 mm with no history of bone grafting. The right maxillary lateral incisor lacked congenitally, and the left lateral incisor was a lingually malpositioned conical tooth. The midline of the maxillary had right deviation of 6.5 mm. A multibracket appliance was used for the presurgical orthodontic treatment and a Le Fort I osteotomy was performed when the patient was 22-years and 4-months old. During the operation, the left maxillary lateral incisor in the cleft area was extracted. A Twin-Track device was placed along with the maxillary dental arch to guide the surgical movement of the alveolar segments into place. After complete cleft closure was achieved along this splint, maxillary segments were fixed using mini-plates and bone grafting was simultaneously performed. After 2 years of post-surgical orthodontic treatment, acceptable occlusion was achieved and no further prosthetic treatment was required.