Holocephalan (Chondrichthyes) dental plates with hypermineralized dentine as a substitute for missing teeth through developmental plasticity.

All extant holocephalans (Chimaeroidei) have lost the ability to make individual teeth, as tooth germs are not part of the embryonic development of the dental plates or of their continuous growth. Instead, a hypermineralized dentine with a unique mineral, whitlockin, is specifically distributed within a dentine framework into structures that give the dental plates their distinctive, species-specific morphology. Control of the regulation of this distribution must be cellular, with a dental epithelium initiating the first outer dentine, and via contact with ectomesenchymal tissue as the only embryonic cell type that can make dentine. Chimaeroids have three pairs of dental plates within their mouth, two in the upper jaw and one in the lower. In the genera Chimaera, Hydrolagus and Harriotta, the morphology and distribution of this whitlockin within each dental plate differs both between different plates in the same species and between species. Whitlockin structures include ovoids, rods and tritoral pads, with substantial developmental changes between these. For example, rods appear before the ovoids and result from a change in the surrounding trabecular dentine. In Harriotta, ovoids form separately from the tritoral pads, but also contribute to tritor development, while in Chimaera and Hydrolagus, tritoral pads develop from rods that later are perforated to accommodate the vasculature. Nevertheless, the position of these structures, secreted by the specialized odontoblasts (whitloblasts), appears highly regulated in all three species. These distinct morphologies are established at the aboral margin of the dental plate, with proposed involvement of the outer dentine. We observe that this outer layer forms into serially added lingual ridges, occurring on the anterior plate only. We propose that positional, structural specificity must be contained within the ectomesenchymal populations, as stem cells below the dental epithelium, and a coincidental occurrence of each lingual, serial ridge with the whitlockin structures that contribute to the wear-resistant oral surface.

Cryoballoon versus Radiofrequency Catheter Ablation in Atrial Fibrillation: A Meta-Analysis.

INTRODUCTION: Radiofrequency (RF) and cryoballoon (CB) catheter ablation are effective for pulmonary vein isolation (PVI) in atrial fibrillation (AF). This report presents an updated meta-analysis comparing the efficacy and safety of CB versus RF ablations in AF. METHODS: Databases and conference abstracts were systematically searched for studies that directly compared CB and RF PVI, and reported safety or efficacy outcomes in follow-up ≥12 months. Recurrent atrial tachyarrhythmias (AT) were defined as AF, atrial flutter, or atrial tachycardia. RESULTS: Twenty-two studies and 8,668 patients were included. Freedom from AT was not significantly different between CB and RF ablations in the pooled population (OR 1.12; 95%CI 0.97-1.29; P = 0.13) and in randomized trials (OR 1.0; 95%CI 0.65-1.56; P = 0.99). Second-generation CB (CB2; 78.1%) and contact-force (CF) sensing RF (78.2%) have improved procedure success rate as compared to first-generation technology (57.9% CB, 58.1% RF). As compared to CF-RF, CB2 demonstrated similar freedom from recurrent AT (OR 1.04; 95%CI 0.71-1.51; P = 0.84). The incidence of pericardial effusions (OR 0.44; 95%CI 0.28-0.69; P < 0.01), tamponade (OR 0.31; 95%CI 0.15-0.64; P < 0.01), and non-AF AT (OR 0.46; 95%CI 0.26-0.83; P < 0.01) were significantly lower with CB ablation, whereas transient phrenic nerve palsy was more incident after CB (OR 7.40; 95%CI 2.56-21.34; P < 0.01). CONCLUSION: There was comparable freedom from AT between CB and RF in patients with AF undergoing PVI. Additionally, freedom from AT was similar between CB2 and CF-RF. However, CB was associated with a lower incidence of pericardial effusions or tamponade, albeit with a higher rate of transient phrenic nerve palsies.

Management of Ventricular Arrhythmias in Patients with Mechanical Ventricular Support Devices.

The use of mechanical ventricular support devices in the management of patients with advanced heart failure continues to increase. These devices have been shown to prolong life as a destination therapy and to increase survival when used as a bridge to transplantation. However, they are associated with a high rate of complications, including bleeding, infection, device malfunction, and ventricular arrhythmias (VAs). The mechanical support provided by the device typically allows for VAs to be well tolerated in the acute setting, though there are numerous long-term complications related to VAs such as ventricular remodeling, right ventricular failure in patients with left ventricular assist devices, and possibly increased mortality. Controversy exists as to the appropriate role of implantable cardioverter defibrillators in these patients. This review will focus on the management options available for patients with mechanical ventricular support devices and VAs.

ICD discrimination of SVT versus VT with 1:1 V-A conduction: A review of the literature.

Inappropriate ICD shocks are associated with increased mortality. They also impair patients' quality of life, increase hospitalizations, and raise health-care costs. Nearly 80% of inappropriate ICD shocks are caused by supraventricular tachycardia. Here we report the case of a patient who received a single-lead dual-chamber sensing ICD for primary prevention of sudden cardiac death and experienced inappropriate ICD shocks. V-A time, electrogram morphology, and response to antitachycardia pacing suggested atrioventricular nodal reentry tachycardia, which was confirmed in an electrophysiology study. Inspired by this case, we performed a literature review to discuss mechanisms for discrimination of supraventricular tachycardia with 1:1 A:V relationship from ventricular tachycardia with 1:1 retrograde conduction.

Familial atypical cold urticaria: description of a new hereditary disease.

BACKGROUND: Acquired cold urticaria (ACU) is usually a self-limited, sporadic, cutaneous disease diagnosed based on history and a positive cold stimulation time test (CSTT) result. We describe 3 unrelated families (A, B, and C) with lifelong atypical cold urticaria distinguished from ACU and familial cold autoinflammatory syndrome. OBJECTIVE: We sought to describe a new hereditary disease of cold urticaria and study its pathogenesis. METHODS: Questionnaires, interviews, physical examinations, skin testing, and biopsies were performed. Absolute values, means, and prevalence percentages of data are reported. RESULTS: Thirty-five subjects are described with familial atypical cold urticaria (FACU; family A, 17; family B, 8; and family C, 10) displaying an autosomal dominant pattern of inheritance. All tested subjects had negative CSTT results. Completed questionnaires from affected and unaffected members of families A and B (n = 35) revealed that all affected subjects had lifelong symptoms that began in early childhood with pruritus, erythema, and urticaria after cold exposure. Angioedema (family A, 23%; family B, 42%) and syncope, near syncope, or both (family A, 46%; family B, 86%) were also present. Triggers included cold atmosphere (100%), aquatic activities (family A, 92%; family B, 100%), handling cold objects (family A, 54%; family B, 71%), and ingestion of cold foods or beverages (family A, 69%; family B, 100%). Skin biopsy specimens demonstrated a mast cell infiltrate with the appearance of degranulation after cold challenge. CONCLUSIONS: FACU is a new cold-induced inherited disease that is different than ACU in its natural history, atmospheric cold elicitation, severity of systemic reactions, and CSTT results. FACU differs from familial cold autoinflammatory syndrome in symptom timing and the absence of fever, chills, and joint pain. The cause is suspected to be mast cell related. Treatment of reactions is similar to that for ACU. Further evaluation of pathogenesis and genetics is warranted.

Office surgery incidents: what seven years of Florida data show us.

BACKGROUND: In the wake of increased media attention focusing on human error in medicine, numerous state medical boards and legislatures have drafted, and are continuing to draft, regulations aimed at protecting patients undergoing procedures in the office setting. These regulations will have a considerable impact on patient access to medically necessary procedures, and any regulations should be based on good data. This report summarizes 7 years of prospective data from the state of Florida, the best data available on office surgery incidents. OBJECTIVE: The objective was to determine the nature and incidence of hospital transfers and deaths resulting from office procedures. METHODS: This study is a compilation of mandatory reporting by Florida physicians to a central agency of all in-office adverse incidents resulting in death, serious injury, or hospital transfer in the State of Florida from March 2000 to March 2007. Telephone and internet follow-up was conducted to determine reporting physician board certification, hospital privileges, and office accreditation. RESULTS: In 7 years there were 31 deaths and 143 procedure-related complications and hospital transfers. Liposuction and liposuction with abdominoplasty or another cosmetic procedure resulted in 24 complications and 8 deaths. Of the offices reporting adverse incidents, 38.5% were accredited by an independent accrediting agency, 92.5% of the physicians were board-certified, and 96.6% had hospital privileges. A total of 58% (18/31) of the deaths and 61% (87/143) of the complications were associated with nonmedically necessary (cosmetic) procedures. A total of 78% (14/18) of these deaths were in ASA Class 1 patients. Plastic surgeons were responsible for 48% of all deaths (83% of cosmetic surgery deaths) and for 52% of all hospital transfers (83% of cosmetic surgery complications and hospital transfers). CONCLUSION: Plastic surgeons were responsible for an inordinate number of deaths and hospital transfers. Requiring physician board certification and physician hospital privileges would not seem to increase safety, because most physicians already have these credentials, and physicians without these credentials were not responsible for a disproportionate share of incidents. These data do not show an emergent hazard to patients from medically necessary office surgery. Liposuction under general anesthesia deserves continued scrutiny because deaths due to this procedure continue to occur and this procedure can be performed with dilute local anesthesia, with which no deaths were reported. Mandatory reporting of office incidents should be strongly supported, as well as reporting of incidents that occur after surgery in the hospital outpatient department and ambulatory surgery center. These data should be available for analysis after protecting patient confidentiality. A national debate needs to occur to determine how many deaths and injuries are acceptable from cosmetic procedures performed under general and intravenous anesthesia.

Mohs micrographic surgery is accurate 95.1% of the time for melanoma in situ: a prospective study of 167 cases.

BACKGROUND: Mohs micrographic surgery (MMS) represents a promising option for treatment of melanoma in situ (MIS). However, interpretation of melanocytic lesions by fresh frozen sections may be difficult. OBJECTIVE: The objective of this study was to determine if margins called clear by MMS were clear by subsequent paraffin-embedded sections and to compare cure rate with available data for MMS and standard excision. MATERIALS AND METHODS: A total of 167 patients with MIS, including 116 patients with MIS in sun-exposed skin of lentigo maligna (LM) type, were treated by MMS with subsequent evaluation of the final margin with paraffin-embedded sections that were cut en face, over a period of 12 years. A total of 143 patients were available for follow-up from 6 months to 12 years (mean, 50 months; median 48 months; 594.5 patient-years), and 109 patients were available for follow-up from 2 to 12 years (mean, 63 months; median, 60 months; 569 patient-years). RESULTS: The clearance rate by MMS technique using frozen sections was 94.1% for MIS non-LM type, 95.7% for MIS LM type, and 95.1% for both. The cure rate was 97.8% for MIS non-LM type, 99.0% for MIS LM type, and 98.6% for both for mean follow-up of 50 months and 97.4% for MIS non-LM type, 98.6% for MIS LM type, and 98.2% for both for mean follow-up of 63 months. CONCLUSION: MMS is a viable option for treatment of MIS that may increase cure rate and reduce the size of the defect especially in cosmetically and functionally sensitive areas.

Radiographic and Clinical Assessment of Intramedullary Nail Fixation for the Treatment of Unstable Metacarpal Fractures.

BACKGROUND: The purpose of the article was to evaluate clinical and radiographic outcomes in a case series of unstable metacarpal fractures treated with flexible intramedullary nail (IMN) fixation. METHODS: A total of 55 patients with unstable metacarpal fractures between 2003 and 2010 were treated with IMN fixation and followed for a minimum of 1 year. The outcomes were assessed via a radiological study of longitudinal and angular collapse, Disabilities of the Arm, Shoulder, and Hand (DASH) score, total active range of motion (ROM) of the wrist, and grip strength testing. RESULTS: In the 55 patients, metacarpal fractures were healed by clinical and radiographic assessment at an average of 12.7 weeks. IMNs were removed in all cases at an average of 13.9 weeks. Patients regained full finger ROM at the final follow-up and were capable of 72.4% of motion at 2 weeks postoperatively. The mean DASH score at the final follow-up was 6.5. Complications included 3 cases of extensor tendon irritation that resolved without functional impairment and 2 cases of "backing out" that required reoperation to replace the pin. In one case, a bony exostosis formed on the affected metacarpal that led to tendon irritation and required operative excision. CONCLUSIONS: We found that this technique allowed for the stabilization of fractures, early ROM, resumption of usual activities, reduced immobilization, and minimal complications. A removable orthosis, instead of a cast, allowed for earlier mobilization of the wrist, metacarpophalangeal, and proximal interphalangeal joints.

Estimation of subject coregistration errors during multimodal preclinical imaging using separate instruments: origins and avoidance of artifacts.

We use high-resolution [Formula: see text] data in multiple experiments to estimate the sources of error during coregistration of images acquired on separate preclinical instruments. In combination with experiments with phantoms, we completed in vivo imaging on mice, aimed at identifying the possible sources of registration errors, caused either by transport of the animal, movement of the animal itself, or methods of coregistration. The same imaging cell was used as a holder for phantoms and animals. For all procedures, rigid coregistration was carried out using a common landmark coregistration system, placed inside the imaging cell. We used the fiducial registration error and the target registration error to analyze the coregistration accuracy. We found that moving an imaging cell between two preclinical devices during a multimodal procedure gives an error of about [Formula: see text] at most. Therefore, it could not be considered a source of coregistration errors. Errors linked to spontaneous movements of the animal increased with time, to nearly 1 mm at most, excepted for body parts that were properly restrained. This work highlights the importance of animal intrinsic movements during a multiacquisition procedure and demonstrates a simple method to identify and quantify the sources of error during coregistration.

Differences Between Access to Follow-Up Care and Inappropriate Shocks Based on Insurance Status of Implantable Cardioverter Defibrillator Recipients.

Differences in implantable cardioverter defibrillator (ICD) utilization based on insurance status have been described, but little is known about postimplant follow-up patterns associated with insurance status and outcomes. We collected demographic, clinical, and device data from 119 consecutive patients presenting with ICD shocks. Insurance status was classified as uninsured/Medicaid (uninsured) or private/Health Maintenance Organization /Medicare (insured). Shock frequencies were analyzed before and after a uniform follow-up pattern was implemented regardless of insurance profile. Uninsured patients were more likely to present with an inappropriate shock (63% vs 40%, p = 0.01), and they were more likely to present with atrial fibrillation (AF) as the shock trigger (37% vs 19%, p = 0.04). Uninsured patients had a longer interval between previous physician contact and index ICD shock (147 ± 167 vs 83 ± 124 days, p = 0.04). Patients were followed for a mean of 521 ± 458 days after being enrolled in a uniform follow-up protocol, and there were no differences in the rate of recurrent shocks based on insurance status. In conclusion, among patients presenting with an ICD shock, underinsured/uninsured patients had significantly longer intervals since previous physician contact and were more likely to present with inappropriate shocks and AF, compared to those with private/Medicare coverage. After the index shock, both groups were followed uniformly, and the differences in rates of inappropriate shocks were mitigated. This observation confirms the importance of regular postimplant follow-up as part of the overall ICD management standard.

Effects of Transendocardial Stem Cell Injection on Ventricular Proarrhythmia in Patients with Ischemic Cardiomyopathy: Results from the POSEIDON and TAC-HFT Trials.

Transendocardial stem cell injection in patients with ischemic cardiomyopathy (ICM) improves left ventricular function and structure but has ill-defined effects on ventricular arrhythmias. We hypothesized that mesenchymal stem cell (MSC) implantation is not proarrhythmic. Post hoc analyses were performed on ambulatory ECGs collected from the POSEIDON and TAC-HFT trials. Eighty-eight subjects (mean age 61 ± 10 years) with ICM (mean EF 32.2% ± 9.8%) received treatment with MSC (n = 48), Placebo (n = 21), or bone marrow mononuclear cells (BMC) (n = 19). Heart rate variability (HRV) and ventricular ectopy (VE) were evaluated over 12 months. VE did not change in any group following MSC implantation. However, in patients with ≥ 1 VE run (defined as ≥ 3 consecutive premature ventricular complexes in 24 hours) at baseline, there was a decrease in VE runs at 12 months in the MSC group (p = .01), but not in the placebo group (p = .07; intergroup comparison: p = .18). In a subset of the MSC group, HRV measures of standard deviation of normal intervals was 75 ± 30 msec at baseline and increased to 87 ± 32 msec (p =.02) at 12 months, and root mean square of intervals between successive complexes was 36 ± 30 msec and increased to 58.2 ± 50 msec (p = .01) at 12 months. In patients receiving MSCs, there was no evidence for ventricular proarrhythmia, manifested by sustained or nonsustained ventricular ectopy or worsened HRV. Signals of improvement in ventricular arrhythmias and HRV in the MSC group suggest a need for further studies of the antiarrhythmic potential of MSCs. Stem Cells Translational Medicine 2017;6:1366-1372.

Arrhythmias in chagasic cardiomyopathy.

Chagas disease, a chronic parasitosis caused by the protozoa Trypanosoma cruzi, is an increasing worldwide problem because of the number of cases in endemic areas and the migration of infected individuals to more developed regions. Chagas disease affects the heart through cardiac parasympathetic neuronal depopulation, immune-mediated myocardial injury, parasite persistence in cardiac tissue with secondary antigenic stimulation, and coronary microvascular abnormalities causing myocardial ischemia. A lack of knowledge exists for risk stratification, management, and prevention of ventricular arrhythmias in patients with chagasic cardiomyopathy. Catheter ablation can be effective for the management of recurrent ventricular tachycardia.

Activated WNT signaling in postnatal SOX2-positive dental stem cells can drive odontoma formation.

In common with most mammals, humans form only two dentitions during their lifetime. Occasionally, supernumerary teeth develop in addition to the normal complement. Odontoma represent a small group of malformations containing calcified dental tissues of both epithelial and mesenchymal origin, with varying levels of organization, including tooth-like structures. The specific cell type responsible for the induction of odontoma, which retains the capacity to re-initiate de novo tooth development in postnatal tissues, is not known. Here we demonstrate that aberrant activation of WNT signaling by expression of a non-degradable form of ß-catenin specifically in SOX2-positive postnatal dental epithelial stem cells is sufficient to generate odontoma containing multiple tooth-like structures complete with all dental tissue layers. Genetic lineage-tracing confirms that odontoma form in a similar manner to normal teeth, derived from both the mutation-sustaining epithelial stem cells and adjacent mesenchymal tissues. Activation of the WNT pathway in embryonic SOX2-positive progenitors results in ectopic expression of secreted signals that promote odontogenesis throughout the oral cavity. Significantly, the inductive potential of epithelial dental stem cells is retained in postnatal tissues, and up-regulation of WNT signaling specifically in these cells is sufficient to promote generation and growth of ectopic malformations faithfully resembling human odontoma.

Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis.

The extracellular signal-related kinases 1 and 2 (ERK1/2) are key proteins mediating mitogen-activated protein kinase signaling downstream of RAS: phosphorylation of ERK1/2 leads to nuclear uptake and modulation of multiple targets. Here, we show that reduced dosage of ERF, which encodes an inhibitory ETS transcription factor directly bound by ERK1/2 (refs. 2,3,4,5,6,7), causes complex craniosynostosis (premature fusion of the cranial sutures) in humans and mice. Features of this newly recognized clinical disorder include multiple-suture synostosis, craniofacial dysmorphism, Chiari malformation and language delay. Mice with functional Erf levels reduced to ∼30% of normal exhibit postnatal multiple-suture synostosis; by contrast, embryonic calvarial development appears mildly delayed. Using chromatin immunoprecipitation in mouse embryonic fibroblasts and high-throughput sequencing, we find that ERF binds preferentially to elements away from promoters that contain RUNX or AP-1 motifs. This work identifies ERF as a novel regulator of osteogenic stimulation by RAS-ERK signaling, potentially by competing with activating ETS factors in multifactor transcriptional complexes.

Skeletal analysis of the Fgfr3(P244R) mouse, a genetic model for the Muenke craniosynostosis syndrome.

Muenke syndrome, defined by heterozygosity for a Pro250Arg substitution in fibroblast growth factor receptor 3 (FGFR3), is the most common genetic cause of craniosynostosis in humans. We have used gene targeting to introduce the Muenke syndrome mutation (equivalent to P244R) into the murine Fgfr3 gene. A rounded skull and shortened snout (often skewed) with dental malocclusion was observed in a minority of heterozygotes and many homozygotes. Development of this incompletely penetrant skull phenotype was dependent on genetic background and sex, with males more often affected. However, these cranial abnormalities were rarely attributable to craniosynostosis, which was only present in 2/364 mutants; more commonly, we found fusion of the premaxillary and/or zygomatic sutures. We also found decreased cortical thickness and bone mineral densities in long bones. We conclude that although both cranial and long bone development is variably affected by the murine Fgfr3(P244R) mutation, coronal craniosynostosis is not reliably reproduced.

Sonic hedgehog in the pharyngeal endoderm controls arch pattern via regulation of Fgf8 in head ectoderm.

Fgf8 signalling is known to play an important role during patterning of the first pharyngeal arch, setting up the oral region of the head and then defining the rostral and proximal domains of the arch. The mechanisms that regulate the restricted expression of Fgf8 in the ectoderm of the developing first arch, however, are not well understood. It has become apparent that pharyngeal endoderm plays an important role in regulating craniofacial morphogenesis. Endoderm ablation in the developing chick embryo results in a loss of Fgf8 expression in presumptive first pharyngeal arch ectoderm. Shh is locally expressed in pharyngeal endoderm, adjacent to the Fgf8-expressing ectoderm, and is thus a candidate signal regulating ectodermal Fgf8 expression. We show that in cultured explants of presumptive first pharyngeal arch, loss of Shh signalling results in loss of Fgf8 expression, both at early stages before formation of the first arch, and during arch formation. Moreover, following removal of the endoderm, Shh protein can replace this tissue and restore Fgf8 expression. Overexpression of Shh in the non-oral ectoderm leads to an expansion of Fgf8, affecting the rostral-caudal axis of the developing first arch, and resulting in the formation of ectopic cartilage. Shh from the pharyngeal endoderm thus regulates Fgf8 in the ectoderm and the role of the endoderm in pharyngeal arch patterning may thus be indirectly mediated by the ectoderm.