Cleft Closure Research Articles

Simultaneous Alveolar Cleft Closure and Dental Midline Correction with Curvilinear Intraoral Distraction

This article describes a new method that enables vector control during alveolar distraction osteogenesis in the treatment of a cleft palate patient. The patient presented with unilateral complete cleft lip and palate, and the alveolar part of the defect was covered by a mobile buccal flap. The distraction was performed by sliding the surgically released tooth segment with the help of an intraoral distractor over 1.5-mm stainless steel archwires held by metal crowns. This vector-controlled method enabled new bone and attached gingiva formation in harmony with the proper alveolar shape.

Over 20-Year Follow-up of Miura Reconstruction of Cleft Hand

Several techniques have been described for cleft hand closure and web space reconstruction in patients with central deficiency; however, long-term documentation of results is rare. We present a 23-year follow-up of a patient who underwent the Miura procedure for a Manske type IIb cleft hand exhibiting long-term aesthetic and functional success. In addition, early skin flap necrosis and late web space contracture, which have been seen after the Snow-Littler procedure, did not occur in this case.

Anatomical study of the effects of five surgical maneuvers on palate movement

The anatomy of the palate has been extensively described, with a predominant focus on palatal musculature. There are no biomechanical studies investigating the effects of surgical maneuvers on the palate to aid cleft closure. This study aims to describe the soft tissue attachments at different zones and quantify the movement following their release. Fourteen adult cadaver heads were dissected. The palates were split in the midline and five maneuvers described: Step 1, over the hard palate; Step 2, around the greater palatine pedicle; Step 3, over the palatine aponeurosis; Step 4, over the hamulus; and Step 5, resulting in a hamulus fracture. The movements across the midline at the posterior nasal spine following each maneuver were measured. The age range of the 14 heads was between 60 -75 years. Completion of steps 1 and 2 over the hard palate obtained a mean release of 2.6 and 2.0 mm, respectively. The largest movements occurred at Step 3 (5.7 mm) and Step 4 (3.5 mm), after releasing attachments at the posterior hard palate and palatine aponeurosis. Steps 3 and 4 dissections exhibited cumulative release, with a maximum movement with Step 3 (p < 0.05). Isolated fracture of the hamulus (Step 5) yielded a mean movement of 1.4 mm. Individual steps of dissection are described with respect to releasing soft tissue attachments. Medial movement of the oral mucosa is quantified with each step of dissection. The greatest release occurred with dissection overlying the palatine aponeurosis posterior to the hard/soft palate junction. Additional dissection along the hamulus (without fracture) added significantly to this release.

The structures of the kinase domain and UBA domain of MPK38 suggest the activation mechanism for kinase activity.

Murine protein serine/threonine kinase 38 (MPK38) is the murine orthologue of human maternal embryonic leucine-zipper kinase (MELK), which belongs to the SNF1/AMPK family. MELK is considered to be a promising drug target for anticancer therapy because overexpression and hyperactivation of MELK is correlated with several human cancers. Activation of MPK38 requires the extended sequence (ExS) containing the ubiquitin-associated (UBA) linker and UBA domain and phosphorylation of the activation loop. However, the activation mechanism of MPK38 is unknown. This paper reports the crystal structure of MPK38 (T167E), which mimics a phosphorylated state of the activation loop, in complex with AMP-PNP. In the MPK38 structure, the UBA linker forces an inward movement of the αC helix. Phosphorylation of the activation loop then induces movement of the activation loop towards the C-lobe and results in interlobar cleft closure. These processes generate a fully active state of MPK38. This structure suggests that MPK38 has a similar molecular mechanism regulating activation as in other kinases of the SNF1/AMPK family.

The evaluation and surgical management of cyclodialysis clefts that have failed to respond to conservative management

PurposeTo investigate factors that may influence successful correction of hypotony in a consecutive series of patients with cyclodialysis clefts repaired surgically over a 10-year period.DesignRetrospective interventional case series.MethodsInterventional case series...

Single Molecule FRET Studies of the NMDA Receptor using Unnatural Amino Acids

The NMDA receptor is one class of ionotropic glutamate receptors, which are the primary mediators of excitatory neurotransmission in the central nervous system. As such, function and dysfunction of these receptors has been implicated in such physiological and pathological processes as learning and memory, strokes, Alzheimer disease, and Parkinson disease. Studies into the similarly structured AMPA-type glutamate receptor have revealed a relationship between the extent of closure of the agonist-binding domain cleft and activation of the channel, showing a structural mechanism for transduction of signal from binding of ligand to receptor activation. However, neither crystal structures nor more dynamics-based studies using ensemble FRET/LRET show such a correlation when examining the agonist-binding domain of the glycine-binding subunit of the NMDA receptor. Here, we use single molecule FRET to examine more closely the range of conformation states probed by the isolated agonist-binding domain. To perform this, we had to overcome the problem of immutable native cysteines, which resulted in non-specific labeling when using the conventional maleimide-conjugated fluorophores that are regularly used in protein-based FRET studies. Thus, we introduced the unnatural amino acid p-acetylphenylalanine, which contains a unique ketone functional group, at the sites which we wished to test, allowing for specific labeling of the protein. Doing this, we see that while the protein exhibits a peak probability around 33A when bound both to full agonist glycine and partial agonist ACPC, the protein bound to partial agonist probes a slightly broader range of states than full agonist. From these data, we can infer that while the agonist-binding domain may show similar average extents of cleft closure, irresolvable by crystallography or ensemble LRET, full agonists more narrowly restrict the range of conformational states probed to conformations that allow for channel activation.

Abrupt Laryngeal Engagement during Stop Plosive-Vowel Transitions in Children with Repaired Cleft Palate and Adequate Velopharyngeal Closure: Aerodynamic and Sound Pressure Level Evidence

To determine whether children with repaired cleft palate and adequate velopharyngeal closure exhibit abrupt laryngeal engagement during stop plosive-vowel transitions as compared with children without cleft palate. A prospective group design was used with convenience sampling of patients at a university craniofacial center. PARTICIPANTS were 25 children (15 boys, 10 girls) with repaired cleft palate (mean age = 10.9 years, standard deviation = 1.5 years) and 20 children (10 boys, 10 girls) without cleft palate (mean age = 10.8 years, standard deviation = 1.8 years). All children with cleft palate had adequate velopharyngeal closure as determined by aerodynamic testing. (1) Peak oral airflow was determined during the release of /t/ in the word "two" during a counting task. (2) An index of laryngeal engagement defined as the ratio of the maximum oral airflow declination to peak oral airflow was calculated during the release of /t/. (3) Sound pressure level was determined during the vowel of the word "two." Children with cleft palate exhibited significantly more negative laryngeal engagement ratios (i.e., more abrupt adduction) (P = .002) and greater sound pressure level (P = .049) than controls. There was a significant negative relationship between laryngeal engagement and sound pressure level for all children (r = -.428, P = .003). Children with repaired cleft palate and adequate velopharyngeal function appear to use a strategy of abrupt laryngeal adduction during stop plosive-vowel transitions. This strategy-perhaps learned even prior to palate surgery-may help to achieve either adequate sound pressure level and/or velopharyngeal closure.

Distraction osteogenesis for cleft palate closure: A finite element analysis

Distraction osteogenesis for cleft palate closure: A finite element analysis

Proton Mediated Conformational Changes in ACID Sensing Ion Channel1a

Acid sensing ion channels (ASIC) are cation channels, activated when there is a reduction in pH. They are involved in key functions including nociception, synaptic transmission and in the physiopathology of ischemic stroke. Previous crystal structures show a trimeric receptor, with each monomer having a large extracellular domain, shaped like a hand, with finger, palm and thumb domains which in turn connect to the transmembrane segments. Available structures indicate that there are three pairs of aspartate and glutamate residues located in the extracellular region, lining the thumb and finger domains. Previous studies have shown that mutating one or two pairs of the carboxylates leads to a shift in EC50 but not a loss in function, suggesting additional residues are involved in proton sensing. Our results from simulation studies indicate that neutralizing these two pairs alone is not sufficient to reduce the electrostatic potential. However, neutralizing all three pairs of carboxylates eliminates much of the negative electrostatic potential in this region, indicating the role of all three pairs in proton binding and gating of the ion channel. Electrophysiological studies with the triple mutant shows a loss of function, while surface biotinylation and pull down assays show expression of the receptors at the surface. To test the pH mediated structural changes and also the role of these residues in the same, we used Luminescence Resonance Energy Transfer to study the angstrom level changes that occur upon pH reduction from 8 to 6. We see that there is a cleft closure conformational change that occurs between the finger and thumb domain. This motion is lost in the triple carboxylate mutant protein, thus confirming that these residues play an important role in proton mediated conformational change in the receptor and ultimately gating of the receptor.

The early and mid-term results of mitral valve repair for mitral regurgitation in children

To review the surgical techniques and mid-term results of mitral valve repair in children with moderate or severe mitral regurgitation (MR). One hundred and seven children with moderate or severe MR, aged 19.6 ± 8.5 months, were enrolled in this study. The surgical techniques used for mitral valve repair varied according to the mitral valve morphology, and included annuloplasty, annuloplasty ring, cleft closure, reconstruction of the posterior leaflet, etc. The concomitant cardiac anomalies were treated simultaneously. The results of repair were evaluated by transesophageal echocardiography performed during the operation and by serial transthoracic echocardiography performed during the follow-up. One hundred and six cases had no more than mild regurgitation intraoperatively, whereas only one case had moderate regurgitation. This patient underwent redo repair immediately, and the subsequent regurgitation was trivial. The in-hospital mortality rate was 0.9 % (1/107). The average follow-up was 46.5 ± 8.2 months. One patient died of heart failure 10 months postoperatively. The freedom from moderate or severe regurgitation after mitral valve repair was 92.3 ± 3.3 %. Pediatric patients with moderate or severe MR require early surgical treatment. The early and mid-term results of mitral valve repair in pediatric patients were satisfactory.

Considerations Regarding Age at Surgery and Fistula Incidence Using One- and Two-stage Closure for Cleft Palate

Abstract Introduction: Although cleft lip and palate (CLP) is one of the most common congenital malformations, occurring in 1 in 700 live births, there is still no generally accepted treatment protocol. Numerous surgical techniques have been described for cleft palate repair; these techniques can be divided into one-stage (one operation) cleft palate repair and two-stage cleft palate closure. The aim of this study is to present our cleft palate team experience in using the two-stage cleft palate closure and the clinical outcomes in terms of oronasal fistula rate. Material and methods: A retrospective analysis was performed on medical records of 80 patients who underwent palate repair over a five-year period, from 2008 to 2012. All cleft palate patients were incorporated. Information on patient’s gender, cleft type, age at repair, one- or two-stage cleft palate repair were collected and analyzed. Results: Fifty-three (66%) and twenty-seven (34%) patients underwent two-stage and one-stage repair, respectively. According to Veau classification, more than 60% of them were Veau III and IV, associating cleft lip to cleft palate. Fistula occurred in 34% of the two-stage repairs versus 7% of one-stage repairs, with an overall incidence of 24%. Conclusions: Our study has shown that a two-stage cleft palate closure has a higher rate of fistula formation when compared with the one-stage repair. Two-stage repair is the protocol of choice in wide complete cleft lip and palate cases, while one-stage procedure is a good option for cleft palate alone, or some specific cleft lip and palate cases (narrow cleft palate, older age at surgery)

Role of Cross-Cleft Contacts in NMDA Receptor Gating

In response to brief glutamate exposure, NMDA receptors produce excitatory currents that have sub-maximal amplitudes and characteristically slow kinetics. The activation sequence starts when glutamate binds to residues located on the upper lobe of extracellularly located ligand-binding domains (LBDs) and then contacts lower lobe residues to bridge the cleft between the two hinged lobes. This event stabilizes a narrow-cleft LBD conformation and may facilitate subsequent inter-lobe contacts that further stabilize the closed cleft. Agonist efficacy has been traced to the degree of agonist-induced cleft-closure and may also depend on the stability of the closed-cleft conformation. To investigate how cross-cleft contacts contribute to the amplitude and kinetics of NMDA receptor response, we examined the activation reaction of GluN1/GluN2A receptors that had single-residue substitutions at the interface between LBD lobes. We found that side-chain truncations at residues of putative contact between lobes increased glutamate efficacy through independent additive mechanisms in GluN1 and GluN2A subunits. In contrast, removing side-chain charge with isosteric substitutions at the same sites decreased glutamate efficacy. These results support the view that in GluN1/GluN2A receptors’ natural interactions between residues on opposing sides of the ligand-binding cleft encode the stability of the glutamate-bound closed-cleft conformations and limit the degree of cleft closure, thus contributing to the sub-maximal response and emblematically slow NMDA receptor deactivation after brief stimulation.

Structural Interactions between Inhibitor and Substrate Docking Sites Give Insight into Mechanisms of Human PS1 Complexes

SummaryPresenilin-mediated endoproteolysis of transmembrane proteins plays a key role in physiological signaling and in the pathogenesis of Alzheimer disease and some cancers. Numerous inhibitors have been found via library screens, but their structural mechanisms remain unknown. We used several biophysical techniques to investigate the structure of human presenilin complexes and the effects of peptidomimetic γ-secretase inhibitors. The complexes are bilobed. The head contains nicastrin ectodomain. The membrane-embedded base has a central channel and a lateral cleft, which may represent the initial substrate docking site. Inhibitor binding induces widespread structural changes, including rotation of the head and closure of the lateral cleft. These changes block substrate access to the catalytic pocket and inhibit the enzyme. Intriguingly, peptide substrate docking has reciprocal effects on the inhibitor binding site. Similar reciprocal shifts may underlie the mechanisms of other inhibitors and of the “lateral gate” through which substrates access to the catalytic site.

Alveolar cleft closure with reinforcement from cyanoacrylate to the mucosal closure and cortical strut interposition in 28 patients and evaluation by CBCT

Methods: In our proposed technique of nasoalveolar cleft repair, nasal and oral mucosal flaps are elevated. Once nasal mucosa is sutured, cyanoacrylate is applied to nasalflap. Nose is irrigated to ensure a water-tight closure. Next, corticalstrut from iliac crest or allogeneic sheet is positioned by friction adaptation. Particulate cancellous marrow or BMP allogenic particulate mixture is compacted. Following advancement and flaps suturing, cyanoacrylate is applied to oral closure. We obtain presurgical Conebeam computed tomography (CBCT), which is compared to 6 months post-surgical study with assessment of grayscale Hounsfeld Units (HU).

Outcomes of repair of complete atrioventricular septal defect in the current era

We sought to evaluate the surgical outcomes of the repair of complete atrioventricular septal defects (cAVSDs) in our institution in the current era. From 2000 to 2011, 138 patients underwent definitive repair of cAVSD. Repair was performed using a two-patch technique in 92.0% of patients and one-patch technique in 2.2%, and the ventricular septal component was closed directly in 5.8% of patients. Operative mortality was 1.4% (2 of 138). Overall mortality was 5.8% (8 of 138). Follow-up was 96% complete. Freedom from reoperation was 84.3% (95% CI 77.1-91.5%) at 8 years. Age >6 months at repair was associated with higher rates of reoperation (P = 0.001; HR 6.85; 95% CI 2.30-20.44). However, operating at <6 months of age was associated with longer intensive care unit stay (P = 0.019; median 2.7 vs 1.4 days), mechanical ventilation (P = 0.001; median 1.7 vs 0.9 days) and postoperative hospital stay (P = 0.016; median 8 vs 5 days). Moderate or greater left atrioventricular valvular regurgitation (LAVVR) at discharge was a risk factor for reoperation (P < 0.001; HR 10.85; 95% CI 3.75-31.40). Repair of cAVSD carries low mortality, but a moderate reoperation rate. An optimal time for repair of the cAVSD is between 3 and 6 months of age. Repair prior to 3 months of age and the need for cleft closure were associated with a higher degree of LAVVR at discharge. Greater LAVVR at discharge is a risk factor for reoperation regardless of age at initial repair. In the current era, Down's syndrome is not a risk factor for reoperation.

Surgical Correction of Common Atrium without Noncardiac Congenital Anomalies

Common atrium (CA) is a rare congenital heart defect. We reviewed our experience of surgical treatment of CA and summarize the clinical features of CA and the key techniques for surgical correction. Between August 1984 and August 2010, 37 consecutive cases of CA underwent corrective surgery. There were no clinical findings of Down, asplenia-polysplenia or Ellis-van Creveld syndromes in all cases. Mitral valvuloplasty was performed in 34 cases, and tricuspid valvuloplasty in 20 cases. Complete closure of a mitral cleft was required in 32 cases. All new atrial septa were reconstructed using patches. Follow-up period ranged from 1 to 20 years. There were no hospital deaths or conduction system block. After surgery, mild mitral insufficiency was observed in only one case. Two cases had moderate-severe mitral insufficiency at postoperative years 1 and 3, respectively, that required mitral valve replacements. One patient died of low cardiac output syndrome after reoperation. Long-term survival after surgical correction of CA is good. Routine closure of a cleft in the mitral valve is very important for successful surgery.

Dynamics of Cleft Closure of the GluA2 Ligand-binding Domain in the Presence of Full and Partial Agonists Revealed by Hydrogen-Deuterium Exchange

The majority of excitatory neurotransmission in the CNS is mediated by tetrameric AMPA receptors. Channel activation begins with a series of interactions with an agonist that binds to the cleft between the two lobes of the ligand-binding domain of each subunit. Binding leads to a series of conformational transitions, including the closure of the two lobes of the binding domain around the ligand, culminating in ion channel opening. Although a great deal has been learned from crystal structures, determining the molecular details of channel activation, deactivation, and desensitization requires measures of dynamics and stabilities of hydrogen bonds that stabilize cleft closure. The use of hydrogen-deuterium exchange at low pH provides a measure of the variation of stability of specific hydrogen bonds among agonists of different efficacy. Here, we used NMR measurements of hydrogen-deuterium exchange to determine the stability of hydrogen bonds in the GluA2 (AMPA receptor) ligand-binding domain in the presence of several full and partial agonists. The results suggest that the stabilization of hydrogen bonds between the two lobes of the binding domain is weaker for partial than for full agonists, and efficacy is correlated with the stability of these hydrogen bonds. The closure of the lobes around the agonists leads to a destabilization of the hydrogen bonding in another portion of the lobe interface, and removing an electrostatic interaction in Lobe 2 can relieve the strain. These results provide new details of transitions in the binding domain that are associated with channel activation and desensitization.

Patch abscess after a closure of an atrial septal defect

Surgical atrial septal defect closure with a patch is one of the simplest interventions in cardiac surgery. However, patch infection could be a serious complication. A 34-year-old man was referred to our service 7 years after surgical closure with a Dacron patch of an ostium primum septal defect and mitral cleft closure. …

Technique of Alveolar Cleft Closure With Reinforcement From Cyanoacrylate to the Mucosal Closure and Cortical Strut Interposition

In 20 cases, we applied the use of cyanoacrylate glue as an adjunct to palatoplasty and fistula closure. We propose the following outlined technique as an adjunct to classic palatoplasty and fistula obliteration approach, to improve outcome of fistula development and bone graft success.

A Conformational Intermediate in Glutamate Receptor Activation

Ionotropic glutamate receptors (iGluRs) transduce the chemical signal of neurotransmitter release into membrane depolarization at excitatory synapses in the brain. The opening of the transmembrane ion channel of these ligand-gated receptors is driven by conformational transitions that are induced by the association of glutamate molecules to the ligand-binding domains (LBDs). Here, we describe the crystal structure of a GluA2 LBD tetramer in a configuration that involves an ∼30° rotation of the LBD dimers relative to the crystal structure of the full-length receptor. The configuration is stabilized by an engineered disulfide crosslink. Biochemical and electrophysiological studies on full-length receptors incorporating either this crosslink or an engineered metal bridge show that this LBD configuration corresponds to an intermediate state of receptor activation. GluA2 activation therefore involves a combination of both intra-LBD (cleft closure) and inter-LBD dimer conformational transitions. Overall, these results provide a comprehensive structural characterization of an iGluR intermediate state.