Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity.

Histone variants, which can be expressed outside of S-phase and deposited DNA synthesis-independently, provide long-term histone replacement in postmitotic cells, including neurons. Beyond replenishment, histone variants also play active roles in gene regulation by modulating chromatin states or enabling nucleosome turnover. Here, we uncover crucial roles for the histone H3 variant H3.3 in neuronal development. We find that newborn cortical excitatory neurons, which have only just completed replication-coupled deposition of canonical H3.1 and H3.2, substantially accumulate H3.3 immediately postmitosis. Codeletion of H3.3-encoding genes H3f3a and H3f3b from newly postmitotic neurons abrogates H3.3 accumulation, markedly alters the histone posttranslational modification landscape, and causes widespread disruptions to the establishment of the neuronal transcriptome. These changes coincide with developmental phenotypes in neuronal identities and axon projections. Thus, preexisting, replication-dependent histones are insufficient for establishing neuronal chromatin and transcriptome; de novo H3.3 is required. Stage-dependent deletion of H3f3a and H3f3b from 1) cycling neural progenitor cells, 2) neurons immediately postmitosis, or 3) several days later, reveals the first postmitotic days to be a critical window for de novo H3.3. After H3.3 accumulation within this developmental window, codeletion of H3f3a and H3f3b does not lead to immediate H3.3 loss, but causes progressive H3.3 depletion over several months without widespread transcriptional disruptions or cellular phenotypes. Our study thus uncovers key developmental roles for de novo H3.3 in establishing neuronal chromatin, transcriptome, identity, and connectivity immediately postmitosis that are distinct from its role in maintaining total histone H3 levels over the neuronal lifespan.

Chromatin remodeler Arid1a regulates subplate neuron identity and wiring of cortical connectivity.

Loss-of-function mutations in chromatin remodeler gene ARID1A are a cause of Coffin-Siris syndrome, a developmental disorder characterized by dysgenesis of corpus callosum. Here, we characterize Arid1a function during cortical development and find unexpectedly selective roles for Arid1a in subplate neurons (SPNs). SPNs, strategically positioned at the interface of cortical gray and white matter, orchestrate multiple developmental processes indispensable for neural circuit wiring. We find that pancortical deletion of Arid1a leads to extensive mistargeting of intracortical axons and agenesis of corpus callosum. Sparse Arid1a deletion, however, does not autonomously misroute callosal axons, implicating noncell-autonomous Arid1a functions in axon guidance. Supporting this possibility, the ascending axons of thalamocortical neurons, which are not autonomously affected by cortical Arid1a deletion, are also disrupted in their pathfinding into cortex and innervation of whisker barrels. Coincident with these miswiring phenotypes, which are reminiscent of subplate ablation, we unbiasedly find a selective loss of SPN gene expression following Arid1a deletion. In addition, multiple characteristics of SPNs crucial to their wiring functions, including subplate organization, subplate axon-thalamocortical axon cofasciculation ("handshake"), and extracellular matrix, are severely disrupted. To empirically test Arid1a sufficiency in subplate, we generate a cortical plate deletion of Arid1a that spares SPNs. In this model, subplate Arid1a expression is sufficient for subplate organization, subplate axon-thalamocortical axon cofasciculation, and subplate extracellular matrix. Consistent with these wiring functions, subplate Arid1a sufficiently enables normal callosum formation, thalamocortical axon targeting, and whisker barrel development. Thus, Arid1a is a multifunctional regulator of subplate-dependent guidance mechanisms essential to cortical circuit wiring.

Medically actionable comorbidities in adults with Costello syndrome.

Costello syndrome (CS) is an autosomal-dominant condition caused by activating missense mutations in HRAS. There is little literature describing health concerns specific to adults with CS. Parents of individuals with CS need to know what to anticipate as their children age. We surveyed a group of 20 adults and older adolescents with CS regarding their medical concerns and lifestyle characteristics. We identified several previously undescribed actionable medical concerns in adults with CS. First, the high prevalence of anxiety in this cohort indicates that screening for anxiety is warranted since this is a treatable condition that can have a significant impact on quality of life. Second, adults with CS should be monitored for progressive contractures or other problems that could decrease mobility. This is especially important in a population that seems to have increased risk for osteopenia. Finally, the lack of cancer diagnoses in adulthood is of interest, although the cohort is too small to draw definitive conclusions about cancer risk in adults with CS. Ongoing follow-up of the current cohort of adults with CS is necessary to delineate progressive medical and physical problems, which is essential for providing targeted management recommendations and anticipatory guidance to families.

Telehealth in the time of Corona: 'doctor in the house'.

The COVID-19 pandemic has led to many physicians working from home whenever possible. Although the concept of 'remote' patient care has been around for decades, present circumstances have provided a grand impetus in that direction with a view to protecting both patient and caregiver. In this article, we discuss some of the various challenges to moving forward with telemedicine, drawing in part on our own experiences in dealing with the COVID-19 pandemic. Clinical, technical, financial and cultural barriers to telemedicine are identified, along with a discussion concerning anticipated benefits. We conclude that the COVID-19 pandemic will likely forever change how healthcare is conducted as telemedicine figures increasingly prominently in the clinical landscape.

Costello syndrome: Clinical phenotype, genotype, and management guidelines.

Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues; however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are based on expert opinion and do not represent evidence-based guidelines due to the lack of data for this rare condition.

Significant mitral regurgitation in patients undergoing TAVR: Mechanisms and imaging variables associated with improvement.

BACKGROUND: Significant mitral regurgitation (MR) is associated with poorer outcomes in patients undergoing transcatheter aortic valve replacement (TAVR). Factors associated with MR improvement have not been studied thoroughly. METHODS: Retrospective analysis of consecutive patients treated with TAVR with more than mild MR at baseline. MR evolution was assessed at 1-3 and 6-12 months after intervention. MR severity and mechanisms were assessed by echocardiography. Mitral annulus calcification (MAC) was quantified using preoperative cardiac CT. RESULTS: From 674 consecutive TAVR recipients, 78 with more than mild MR had a 6-12 months follow-up. Following TAVR, MR improved in 34 patients (43%), remained stable in 38 (49%) and worsened in 6 (8%). Patients with MR improvement had greater tenting area (141 ± 56 vs. 99 ± 40 mm2 , P < 0.01), tenting height (7.2 ± 1.9 vs. 5.6 ± 1.9 mm, P < 0.01) and lower ejection fraction (43 ± 16 vs. 52 ± 14%, P = 0.01). MAC was frequent (87.7% of patients) and a trend in greater MAC was observed in patients without MR improvement (3560 ± 5587 vs. 2053 ± 2800, P = 0.16). In multivariable analysis, tenting area (OR per 10 mm2 increase: 1.012, 95% CI, 1.001-1.024 P = 0.039) and annulus calcifications associated with leaflet restriction (OR = 0.108, 95% CI, 0.012-0.956, P = 0.045) were independently associated with MR outcome after TAVR. CONCLUSION: Larger mitral valve tenting area was associated with more improvement of MR after TAVR whereas extensive MAC associated with leaflet restriction was associated with less improvement. This may help in the clinical decision-making process of TAVR candidates with concomitant MR.

Predictors and Association With Clinical Outcomes of the Changes in Exercise Capacity After Transcatheter Aortic Valve Replacement.

BACKGROUND: At present, there are no objective data specifically examining the clinical impact of variations in exercise capacity post-transcatheter aortic valve replacement (TAVR). We describe the changes in exercise capacity between baseline and 6 months post-TAVR, and ascertain factors associated with and clinical implications of a lack of improvement in exercise capacity post-TAVR. METHODS: A total of 305 patients (mean age, 79±9 years; 44% men; Society of Thoracic Surgeons predicted risk mortality score, 6.7±4.2%) undergoing TAVR completed both baseline and follow-up exercise capacity assessments at 6 months post-TAVR. Exercise capacity was evaluated by the 6-minute walk test (6MWT). Clinical outcomes were compared between patients displaying greater than (n=152; improving group) versus less than (n=153; nonimproving group) the median percentage change in distance walked between baseline and 6-month follow-up examinations. The primary outcome measure was clinical event rates, measured from the 6-month post-TAVR period onward. Further dichotomization according to baseline 6MWT distance (less than versus more than median walking distance, or slow walker versus fast walker) was also assessed. RESULTS: The mean overall distances walked pre- and post-TAVR (6 months post-TAVR) were 204±119 and 263±116 m, respectively (Δ6MWT=60±106 m), with 219 (72%) patients demonstrating an increase in their walking distance (median percentage increase of the entire population was 20% [interquartile range, 0%-80%]). Factors independently correlated with reduced exercise capacity improvement included a range of baseline clinical characteristics (older age, female sex, chronic obstructive pulmonary disease; P<0.05 for all), periprocedural major or life-threatening bleeding (P=0.009) and new-onset anemia at 6 months post-TAVR (P=0.009). Failure to improve the 6MWT distance by at least 20% was independently associated with all-cause mortality (P=0.002) and cardiovascular death or rehospitalization for cardiovascular causes (P=0.001). Baseline slow walkers who were able to improve the 6MWT distance presented with significantly better outcomes than nonimprovers (P=0.01 for all-cause mortality; P=0.001 for cardiovascular end point). CONCLUSIONS: Approximately one-third of patients undergoing TAVR did not improve their exercise capacity postprocedure. The lack of functional improvement post-TAVR was predicted by a mix of baseline and periprocedural factors translating into poorer clinical outcomes. These results suggest that systematically implementing exercise capacity assessment pre- and post-TAVR may help to improve patient risk stratification.

Phenotypic spectrum of Costello syndrome individuals harboring the rare HRAS mutation p.Gly13Asp.

Costello syndrome is part of the RASopathies, a group of neurocardiofaciocutaneous syndromes caused by deregulation of the RAS mitogen-activated protein kinase pathway. Heterozygous mutations in HRAS are responsible for Costello syndrome, with more than 80% of the patients harboring the specific p.Gly12Ser variant. These individuals show a homogeneous phenotype. The clinical characteristics of the Costello syndrome individuals harboring rarer HRAS mutations are less understood, due to the small number of reported cases. Here, we describe the phenotypic spectrum of five additional individuals with HRAS c.38G>A; p.Gly13Asp, including one with somatic mosaicism, and review five previously described cases. The facial and hair abnormalities of the HRAS p.Gly13Asp individuals differ from the typical pattern observed in those showing the common HRAS (p.Gly12Ser) mutation, with less coarse facial features and slow growing, sparse hair with abnormal texture, the latter resembling the pattern observed in Noonan syndrome-like disorder with loose anagen hair and individuals harboring another amino acid substitution in HRAS (p.Gly13Cys). Although some individuals with HRAS p.Gly13Asp developed papillomata and vascular proliferation lesions, no malignant tumors occurred, similar to what was reported for individuals harboring the HRAS p.Gly13Cys. The fact that no malignant tumors were described in these individuals does not allow definitive conclusions about the risk for cancer development. It remains to be determined if substitutions of amino acid 13 in HRAS (p.Gly13Asp and p.Gly13Cys) increase the risk of tumor development.

Paternal uniparental disomy 11p15.5 in the pancreatic nodule of an infant with Costello syndrome: Shared mechanism for hyperinsulinemic hypoglycemia in neonates with Costello and Beckwith-Wiedemann syndrome and somatic loss of heterozygosity in Costello syndrome driving clonal expansion.

Costello syndrome (CS) entails a cancer predisposition and is caused by activating HRAS mutations, typically arising de novo in the paternal germline. Hypoglycemia is common in CS neonates. A previously reported individual with the rare HRAS p.Gln22Lys had hyperinsulinemic hypoglycemia. Autopsy showed a discrete pancreatic nodule. The morphologic and immunohistochemistry findings, including loss of p57(Kip2) protein, were identical to a focal lesion of congenital hyperinsulinism, however, no KCNJ11 or ABCC8 mutation was identified and germline derived DNA showed no alternation of the maternal or paternal 11p15 alleles. Here we report paternal uniparental disomy (pUPD) within the lesion, similar to the pUPD11p15.5 in Beckwith-Wiedemann syndrome (BWS). The similar extent of the pUPD suggests a similar mechanism driving hyperinsulinemia in both conditions. After coincidental somatic LOH and pUPD, the growth promoting effects of the paternally derived HRAS mutation, in combination with the increased function of the adjacent paternally expressed IGF2, may together result in clonal expansion. Although this somatic LOH within pancreatic tissue resulted in hyperinsulinism, similar LOH in mesenchymal cells may drive embryonal rhabdomyosarcoma (ERMS). Interestingly, biallelic IGF2 expression has been linked to rhabdomyosarcoma tumorigenesis and pUPD11 occurred in all 8 ERMS samples from CS individuals. Somatic KRAS and HRAS mutations occur with comparable frequency in isolated malignancies. Yet, the malignancy risk in CS is notably higher than in Noonan syndrome with a KRAS mutation. It is conceivable that HRAS co-localization with IGF2 and the combined effect of pUPD 11p15.5 on both genes contributes to the oncogenic potential.

Embolic protection in patients undergoing transaortic transcatheter aortic valve replacement: initial experience with the TriGuard HDH embolic deflection device.

BACKGROUND: Stroke remains one of the most worrisome complications following transcatheter aortic valve replacement (TAVR). This pilot study evaluates the safety, feasibility, and exploratory efficacy of the TriGuard HDH embolic deflection device (Keystone Heart Ltd., Caesarea, Israel) in patients undergoing transaortic TAVR. METHODS: A total of 10 patients (median age: 81 years, STS score: 9.6 ± 5.6%) undergoing transaortic TAVR were included. All 30-day events were recorded and defined according to Valve Academic Research Consortium-2 criteria. Cerebral diffusion-weighted magnetic resonance imaging exams were planned preprocedure and within 10 days post-TAVR. The results of the magnetic resonances were analyzed in an independent core laboratory blinded to clinical data. Neurocognitive evaluation tests (Montreal Cognitive Assessment, Cogstate, Digit Symbol Substitution Test, Word Fluency Test, and Trailmaking tests) were performed at baseline, and within 10 and 30 days post-TAVR. RESULTS: The TriGuard HDH device was successfully deployed in all patients without complications. There was one procedural major vascular complication unrelated to the study device, and no clinically apparent stroke events were observed at 30-day follow-up. Cerebral diffusion weighted magnetic resonance imaging exams were performed in six patients at 7.5 ± 1.9 days post-TAVR showing the presence of new ischemic lesions in five patients (83.3%), which were single lesions in 60% of these individuals. Paired neurocognitive evaluation tests demonstrated no significant changes in neurocognitive parameters over time. CONCLUSIONS: This study shows the safety and feasibility of using the TriGuard HDH embolic protection device in transaortic TAVR. Further studies are warranted to determine the efficacy of embolic protection in this population.

The CATCH My Breath Vaping Prevention Curriculum: An Evaluation of Impacts in Central Appalachian Middle and High Schools, 2019-2023.

INTRODUCTION/OBJECTIVES: Since 2015, the rise in e-cigarette use among youth has concerned public health authorities. After peaking in 2019, usage rates have declined but remain high. In 2023, 10% of high school and 4.6% of middle school students reported current use. This report describes the implementation and evaluation of a school-based e-cigarette prevention program, CATCH My Breath (CMB), in 8 central Appalachian counties. These counties have some of the highest rates of tobacco use, poor health, and premature death in the United States. METHODS: A total of 6217 students across 25 middle and high schools in West Virginia and Kentucky received the CMB program from 2019 to 2023. Lists of participating counties, schools, and teachers were maintained on a rolling basis over the 4 years of the project. Program reach and impact on e-cigarette knowledge and use are reported. Thirteen-item pre- and post-tests were completed electronically by students before and after each course delivery. Questions assessed knowledge about e-cigarettes, current (past 30-day) e-cigarette use, and interest in future use. RESULTS: From 2019 to 2023, there were 9399 deliveries of the 4-session CMB course, primarily to middle school students. Approximately 84% reported being less likely to use e-cigarettes following the program. Significant improvements in e-cigarette knowledge and beliefs on 5 of 8 items were observed, including a significant increase in knowledge composite score (4.15-4.75, P < .001). From pre- to post-test, declines in current e-cigarette use (5.1% to 4.4%; P = .005) and peer influence (4.9% to 4.0%; P = .025) were also observed. CONCLUSIONS: CMB was feasible, effective, and well-received in a convenience sample of central Appalachian counties and schools. This curriculum, combined with other policy initiatives, offers hope for curbing the growing epidemic of youth e-cigarette use and nicotine dependence. The success of this project contributed to a decision by the West Virginia Bureau for Public Health and the West Virginia Department of Education to launch a joint effort to bring CMB to middle schools in all 55 counties during the next 3 school years of 2023-2026.

A quasi-experimental analysis comparing antimicrobial usage on COVID-19 and non-COVID-19 wards.

Objective: To describe antimicrobial usage (AMU) trends before and during the coronavirus disease 2019 (COVID-19) pandemic, between COVID-19 and non-COVID-19 wards, and if there was any association with a COVID-19 order set. Design: Quasi-experimental retrospective interrupted time series analysis of AMU rates with a contemporaneous comparison of COVID-19 versus non-COVID-19 control wards. Analysis using incidence rate ratios (IRR) was conducted using a Poisson regression generalized linear model. Setting: Five COVID-19 and 4 comparable non-COVID-19 wards and 6 intensive care units (ICUs) at 4 hospitals during pandemic waves 1-4. Participants: All inpatients receiving systemic antimicrobials. Intervention: The COVID-19 checkbox antimicrobial order set was implemented in March 2020, to be used only if considered clinically indicated with modification in August 2021. Main Outcomes and Measures: The primary outcome was a change in AMU rates (defined daily dose per 100 patient days per month) comparing pre- versus peri-pandemic periods and COVID-19 versus control non-COVID-19 wards. Secondary outcomes included antifungal usage rate in ICUs and assessing AMUs following implementation and modification of a COVID-19 order set. Results: Significantly greater rates of AMU (IRR[95%CI]) were observed on COVID-19 wards versus non-COVID-19 wards during waves 1-4 for all systemic antimicrobials (1.76[1.71-1.81], 1.10[1.07-1.13], 1.48[1.43-1.53], and 1.06[1.03-1.09]); for azithromycin (11.76[9.80-14.23], 10.96[9.49-12.74], 12.41[10.73-14.45], and 4.88[4.31-5.55]); and for ceftriaxone (2.39[2.16-2.65], 3.64[3.29-4.03], 2.94[2.67-3.23], and 1.62[1.49-1.76]). Conclusions: We observed significantly increased AMU rates of all systemic agents during the first 4 waves of the pandemic and on COVID-19 wards compared with control wards for azithromycin and ceftriaxone. These agents saw a twofold reduction following order-set removal, suggesting that the clinical decision-support tool order set, as utilized, had influenced prescribing behavior.

Long-term clinical and echocardiographic follow-up of the Freestyle stentless aortic bioprosthesis.

BACKGROUND: Stentless aortic bioprostheses were designed to provide enhanced hemodynamic performance and potentially greater longevity. The present report describes the outcomes of patients with the Freestyle stentless bioprosthesis followed for ≤18 years. METHODS AND RESULTS: Between 1993 and 2011, 430 patients underwent primary aortic valve replacement with a Freestyle bioprosthesis in the subcoronary position. Mean age was 68.2 ± 8.2 years. All of the clinical and echocardiographic data were collected prospectively. Mean overall follow-up was 9.1 ± 4.4 years and was complete in all of the patients. In-hospital mortality was 3.5% (n=15). Overall, 10- and 15-year survival were 60.7% and 35.0%, respectively. Fifty-one patients required reoperation during follow-up, including 27 for structural valve deterioration (SVD). Overall, freedom from reoperation was 91.0% and 75.0% at 10 and 15 years, whereas freedom from reoperation for SVD was 95.9% and 82.3%, respectively. At 10 and 15 years, freedom from reoperation for SVD was 94.0% and 62.6% for patients <60 years of age and 96.3% and 88.4% for patients ≥60 years of age (P=0.002). The median time to explant for SVD was 10.7 years. SVD presented mostly as acute, severe aortic insufficiency attributed to leaflet tear (77.8%). The independent risk factors for reoperation for SVD were age <60 years (P=0.001) and dyslipidemia (P=0.02). CONCLUSIONS: Aortic valve replacement with the Freestyle bioprosthesis in a subcoronary position provides good long-term clinical and echocardiographic outcomes for patients >60 years of age. Severe aortic insufficiency with leaflet tear is the major mode of SVD leading to reoperation in these patients.

Timing, predictive factors, and prognostic value of cerebrovascular events in a large cohort of patients undergoing transcatheter aortic valve implantation.

BACKGROUND: The objective of this study was to evaluate the timing, predictive factors, and prognostic value of cerebrovascular events (CVEs) after transcatheter aortic valve implantation. METHODS AND RESULTS: The study included 1061 consecutive patients who underwent transcatheter aortic valve implantation with a balloon-expandable (64%) or self-expandable (36%) valve. CVEs were classified as acute (≤24 hours), subacute (1-30 days), or late (>30 days). CVEs occurred in 54 patients (5.1%; stroke, 4.2%) within 30 days after transcatheter aortic valve implantation (acute in 54% of cases). The predictors of acute CVEs were balloon postdilation of the valve prosthesis (odds ratio, 2.46; 95% confidence interval,1.07-5.67) and valve dislodgment/embolization (odds ratio, 4.36; 95% CI, 1.21-15.69); new-onset atrial fibrillation (odds ratio, 2.76; 95% CI, 1.11-6.83) was a predictor of subacute CVEs. Late CVEs occurred in 35 patients (3.3%; stroke, 2.1%) at a median follow-up of 12 months (3-23 months). The predictors of late CVEs were chronic atrial fibrillation (2.84; 95% CI, 1.46-5.53), peripheral vascular disease (hazard ratio, 2.02; 95% CI, 1.02-3.97), and prior cerebrovascular disease (hazard ratio, 2.04; 95% CI, 1.01-4.15). Major stroke was associated with 30-day (odds ratio, 7.43; 95% CI, 2.45-22.53) and late (hazard ratio, 1.75; 95% CI, 1.01-3.04) mortality. CONCLUSIONS: In a large cohort of patients undergoing transcatheter aortic valve implantation, the rates of acute and subacute CVEs were 2.7% and 2.4%, respectively. While balloon postdilation and valve dislodgment/embolization were the predictors of acute CVEs, new-onset atrial fibrillation determined a higher risk for subacute events. Late events were determined mainly by a history of chronic atrial fibrillation and peripheral and cerebrovascular disease. The occurrence of major stroke was associated with increased early and late mortality. These results provide important insights for the implementation of preventive measures for CVEs after transcatheter aortic valve implantation.

Clinical and prognostic implications of existing and new-onset atrial fibrillation in patients undergoing transcatheter aortic valve implantation.

Atrial fibrillation (AF) is a common co-morbidity among patients undergoing Transcatheter Aortic Valve Implantation (TAVI). Only recently have the clinical outcomes of patients with chronic or new-onset AF after TAVI been reported. The absence of clinical trials focusing on this cohort of patients has resulted in the lack of evidence based clinical guidelines. We aim to review and discuss the current literature on AF in TAVI, its clinical implications and future perspectives.

Transapical implantation of the SAPIEN 3 valve.

We report two cases of high-risk aortic stenosis treated with the SAPIEN 3 valve. This is the first procedure performed with this type of valve through the transapical approach. This new balloon-expandable valve incorporates a lower profile cobalt-chromium stent and an additional outer skirt to enhance paravalvular sealing. The procedure was performed without complications and no paravalvular leak was detected in control echocardiogram at follow-up.

A novel mutation in the GCM2 gene causing severe congenital isolated hypoparathyroidism.

OBJECTIVE: To investigate the GCM2 gene in three siblings with congenital hypoparathyroidism and perform functional analysis. MATERIALS AND METHODS: We sequenced the GCM2 gene by PCR and analyzed the functional consequence of the mutation by transient transfection studies. Haplotype analysis was performed. RESULTS: We identified a nucleotide change, c.408C>A, in exon 3 that is predicted to truncate the Gcm2 protein (p.Tyr136Ter). All three affected siblings were homozygous and both parents were heterozygous for the mutation. Transfection studies revealed the mutant mRNA but not expression of the Gcm2 protein. Haplotype analysis revealed that the two mutant GCM2 alleles shared genotypes on chromosome 6p24.2. CONCLUSIONS: We describe the first GCM2 mutation in exon 3 in patients with severe congenital hypoparathyroidism. Informative genetic markers could not exclude identity by descent for the mutant alleles. Gcm2 protein was not detected after transfection, suggesting that complete lack of Gcm2 action accounts for severe hypoparathyroidism.

Transcatheter aortic valve implantation using the slow balloon inflation technique: making balloon-expandable valves partially repositionable.

In transcatheter aortic valve implantation procedures using balloon-expandable valves, the valve is deployed by rapid balloon inflation within a short period of rapid ventricular pacing. This system and deployment technique is generally considered to be nonrepositionable. We illustrate with two cases (transapical and transfemoral) the possibility to partially reposition the valve during its deployment if a slow balloon inflation technique were employed-a technique that may minimize the risk of valve mal-positioning and its attendant complications.

Prominent septal hypertrophy: a contra-indication for transapical aortic valve implantation?

We report a case of transapical aortic valve implantation in a patient with severe left ventricular hypertrophy. The valve was deployed but failed to attain stable seating because of a hypertrophied septal ridge encroaching on the landing zone. Moderate perivalvar insufficiency was also noted. A second valve was deployed in an attempt to achieve stable seating and correct the perivalvar leak. This was unsuccessful and the two-valve complex embolized into the ascending aorta. The valves were moved and seated in the proximal descending thoracic aorta. The technical issues of transapical aortic valve implantation in patients with severe left ventricular hypertrophy are reviewed.