Accretion of a giant planet onto a white dwarf star.

The detection1 of a dust disk around the white dwarf star G29-38 and transits from debris orbiting the white dwarf WD 1145+017 (ref. 2) confirmed that the photospheric trace metals found in many white dwarfs3 arise from the accretion of tidally disrupted planetesimals4. The composition of these planetesimals is similar to that of rocky bodies in the inner Solar System5. Gravitational scattering of planetesimals towards the white dwarf requires the presence of more massive bodies6, yet no planet has so far been detected at a white dwarf. Here we report optical spectroscopy of a hot (about 27,750 kelvin) white dwarf, WD J091405.30+191412.25, that is accreting from a circumstellar gaseous disk composed of hydrogen, oxygen and sulfur at a rate of about 3.3 × 109 grams per second. The composition of this disk is unlike all other known planetary debris around white dwarfs7, but resembles predictions for the makeup of deeper atmospheric layers of icy giant planets, with H2O and H2S being major constituents. A giant planet orbiting a hot white dwarf with a semi-major axis of around 15 solar radii will undergo substantial evaporation with expected mass loss rates comparable to the accretion rate that we observe onto the white dwarf. The orbit of the planet is most probably the result of gravitational interactions, indicating the presence of additional planets in the system. We infer an occurrence rate of approximately 1 in 10,000 for spectroscopically detectable giant planets in close orbits around white dwarfs.

Imaging the water snow-line during a protostellar outburst.

A snow-line is the region of a protoplanetary disk at which a major volatile, such as water or carbon monoxide, reaches its condensation temperature. Snow-lines play a crucial role in disk evolution by promoting the rapid growth of ice-covered grains. Signatures of the carbon monoxide snow-line (at temperatures of around 20 kelvin) have recently been imaged in the disks surrounding the pre-main-sequence stars TW Hydra and HD163296 (refs 3, 10), at distances of about 30 astronomical units (au) from the star. But the water snow-line of a protoplanetary disk (at temperatures of more than 100 kelvin) has not hitherto been seen, as it generally lies very close to the star (less than 5 au away for solar-type stars). Water-ice is important because it regulates the efficiency of dust and planetesimal coagulation, and the formation of comets, ice giants and the cores of gas giants. Here we report images at 0.03-arcsec resolution (12 au) of the protoplanetary disk around V883 Ori, a protostar of 1.3 solar masses that is undergoing an outburst in luminosity arising from a temporary increase in the accretion rate. We find an intensity break corresponding to an abrupt change in the optical depth at about 42 au, where the elevated disk temperature approaches the condensation point of water, from which we conclude that the outburst has moved the water snow-line. The spectral behaviour across the snow-line confirms recent model predictions: dust fragmentation and the inhibition of grain growth at higher temperatures results in soaring grain number densities and optical depths. As most planetary systems are expected to experience outbursts caused by accretion during their formation, our results imply that highly dynamical water snow-lines must be considered when developing models of disk evolution and planet formation.

Drug-coated balloons for small coronary artery disease (BASKET-SMALL 2): an open-label randomised non-inferiority trial.

BACKGROUND: Drug-coated balloons (DCB) are a novel therapeutic strategy for small native coronary artery disease. However, their safety and efficacy is poorly defined in comparison with drug-eluting stents (DES). METHODS: BASKET-SMALL 2 was a multicentre, open-label, randomised non-inferiority trial. 758 patients with de-novo lesions (<3 mm in diameter) in coronary vessels and an indication for percutaneous coronary intervention were randomly allocated (1:1) to receive angioplasty with DCB versus implantation of a second-generation DES after successful predilatation via an interactive internet-based response system. Dual antiplatelet therapy was given according to current guidelines. The primary objective was to show non-inferiority of DCB versus DES regarding major adverse cardiac events (MACE; ie, cardiac death, non-fatal myocardial infarction, and target-vessel revascularisation) after 12 months. The non-inferiority margin was an absolute difference of 4% in MACE. This trial is registered with ClinicalTrials.gov, number NCT01574534. FINDINGS: Between April 10, 2012, and February 1, 2017, 382 patients were randomly assigned to the DCB group and 376 to DES group. Non-inferiority of DCB versus DES was shown because the 95% CI of the absolute difference in MACE in the per-protocol population was below the predefined margin (-3·83 to 3·93%, p=0·0217). After 12 months, the proportions of MACE were similar in both groups of the full-analysis population (MACE was 7·5% for the DCB group vs 7·3% for the DES group; hazard ratio [HR] 0·97 [95% CI 0·58-1·64], p=0·9180). There were five (1·3%) cardiac-related deaths in the DES group and 12 (3·1%) in the DCB group (full analysis population). Probable or definite stent thrombosis (three [0·8%] in the DCB group vs four [1·1%] in the DES group; HR 0·73 [0·16-3·26]) and major bleeding (four [1·1%] in the DCB group vs nine [2·4%] in the DES group; HR 0·45 [0·14-1·46]) were the most common adverse events. INTERPRETATION: In small native coronary artery disease, DCB was non-inferior to DES regarding MACE up to 12 months, with similar event rates for both treatment groups. FUNDING: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Basel Cardiovascular Research Foundation, and B Braun Medical AG.

Flows of gas through a protoplanetary gap.

The formation of gaseous giant planets is thought to occur in the first few million years after stellar birth. Models predict that the process produces a deep gap in the dust component (shallower in the gas). Infrared observations of the disk around the young star HD 142527 (at a distance of about 140 parsecs from Earth) found an inner disk about 10 astronomical units (AU) in radius (1 AU is the Earth-Sun distance), surrounded by a particularly large gap and a disrupted outer disk beyond 140 AU. This disruption is indicative of a perturbing planetary-mass body at about 90 AU. Radio observations indicate that the bulk mass is molecular and lies in the outer disk, whose continuum emission has a horseshoe morphology. The high stellar accretion rate would deplete the inner disk in less than one year, and to sustain the observed accretion matter must therefore flow from the outer disk and cross the gap. In dynamical models, the putative protoplanets channel outer-disk material into gap-crossing bridges that feed stellar accretion through the inner disk. Here we report observations of diffuse CO gas inside the gap, with denser HCO(+) gas along gap-crossing filaments. The estimated flow rate of the gas is in the range of 7 × 10(-9) to 2 × 10(-7) solar masses per year, which is sufficient to maintain accretion onto the star at the present rate.

Transcatheter Aortic Valve Implantation: Addressing the Subsequent Risk of Permanent Pacemaker Implantation.

Transcatheter aortic valve implantation (TAVI) is now a commonly used therapy in patients with severe aortic stenosis, even in those patients at low surgical risk. The indications for TAVI have broadened as the therapy has proven to be safe and effective. Most challenges associated with TAVI after its initial introduction have been impressively reduced; however, the possible need for post-TAVI permanent pacemaker implantation (PPI) secondary to conduction disturbances continues to be on the radar. Conduction abnormalities post-TAVI are always of concern given that the aortic valve lies in close proximity to critical components of the cardiac conduction system. This review will present a summary of noteworthy pre-and post-procedural conduction blocks, the best use of telemetry and ambulatory device monitoring to avoid unnecessary PPI or to recognize the need for late PPI due to delayed high-grade conduction blocks, predictors to identify those patients at greatest risk of requiring PPI, important CT measurements and considerations to optimize TAVI planning, and the utility of the MInimizing Depth According to the membranous Septum (MIDAS) technique and the cusp-overlap technique. It is stressed that careful membranous septal (MS) length measurement by MDCT during pre-TAVI planning is necessary to establish the optimal implantation depth before the procedure to reduce the risk of compression of the MS and consequent damage to the cardiac conduction system.

Influence of the anatomic characteristics of the pulmonary vein ostium, the learning curve, and the use of a steerable sheath on success of pulmonary vein isolation with a novel multielectrode ablation catheter.

AIMS: Anatomic variability of the pulmonary vein (PV) ostium may adversely affect isolation rates with the circular fixed-size pulmonary vein ablation catheter (PVAC). We wanted to assess the influence on PV isolation rates of anatomic characteristics of the ostium, increasing experience of four different operators, and additional use of a steerable sheath. METHODS AND RESULTS: In the first 190 patients (pts) undergoing PVAC ablation, minimum/maximum diameter, area and shape of the PV ostia, and the length of a common ostium were analysed from computed tomography 3D reconstructions of the left atrium and related to isolation rates. In addition, a comparison was drawn between pts at the beginning and after completion (isolation of all PVs in ≥ 85% of pts) of the learning curve, and the effect of a steerable sheath was assessed. Pulmonary vein isolation was achieved with the PVAC alone in 85% of pts and in 94% of veins after a median procedure and ablation time of 154 [interquartile ranges (IQR): 120, 200] and 51 (IQR: 38, 70) min. An increase in isolation rates was observed after the first 60 pts (73 vs. 90% of pts; P< 0.01; 88 vs. 96% of PVs; P< 0.001), coincident with routine use of a steerable sheath. Anatomic characteristics (larger minimum diameter and area) identified unsuccessful isolation only of the left inferior PV at the beginning of the learning curve. CONCLUSIONS: Pulmonary vein isolation rates using this catheter are high. Anatomic variability of PV ostia modestly affects PV isolation rates. Standard use of a steerable sheath plays a major role in increasing isolation rates and overcoming 'difficult' anatomies.

Multicentre propensity-matched comparison of transcatheter aortic valve implantation using the ACURATE TA/neo self-expanding versus the SAPIEN 3 balloon-expandable prosthesis.

AIMS: In the absence of randomised data, we aimed to compare the transapical ACURATE and transfemoral ACURATE neo with the SAPIEN 3 prosthesis using propensity matching. METHODS AND RESULTS: From 2012 to 2016, 1,306 patients at three German centres received either the ACURATE/ACURATE neo prosthesis (n=591) or the SAPIEN 3 prosthesis (n=715). Through nearest neighbour matching with exact allocation for access route and centre, pairs of 329 patients (250 transfemoral, 79 transapical) per group were determined. Patients were 81 years old on average and had a logistic EuroSCORE I of 19%. Predilatation and post-dilatation were more frequent in the ACURATE group (97.6% versus 52.1%, p<0.001 for predilatation and 40.4% versus 11.6%, p<0.001 for post-dilatation), but rapid pacing for implantation was used less frequently (37.1% versus 98.2%, p<0.001). More-than-mild aortic regurgitation at postoperative echocardiography was 12.0% for the ACURATE group and 3.1% for the SAPIEN group, p≤0.001). More-than-mild aortic regurgitation in the ACURATE group differed amongst the centres with 6.0% (3/50) in centre A, 34.1% (29/85) in centre B and 3.4% (6/181) in centre C. Patients in the ACURATE group less frequently had pacemaker implantation compared to the SAPIEN 3 group (11.9% versus 18.5%, p=0.020), 30-day mortality was 4.6% versus 2.1%, respectively, p=0.134, and one-year survival was 83.1% (95% CI: 77.6-87.4) versus 88.8% (95% CI: 84.0-92.2). CONCLUSIONS: In this propensity score analysis, patients treated with the transapical ACURATE or transfemoral ACURATE neo prosthesis less frequently had pacemakers at 30 days but had more aortic regurgitation and lower one-year survival.

A planetesimal orbiting within the debris disc around a white dwarf star.

Many white dwarf stars show signs of having accreted smaller bodies, implying that they may host planetary systems. A small number of these systems contain gaseous debris discs, visible through emission lines. We report a stable 123.4-minute periodic variation in the strength and shape of the Ca ii emission line profiles originating from the debris disc around the white dwarf SDSS J122859.93+104032.9. We interpret this short-period signal as the signature of a solid-body planetesimal held together by its internal strength.

Percutaneous closure of an iatrogenic ventricular septal defect following transcatheter aortic valve implantation.

Transcatheter aortic valve implantation (TAVI) has been increasingly used in symptomatic patients with severe aortic stenosis who are at high risk for conventional open heart surgery. However, it might be associated with serious complications. We report a case with an iatrogenic ventricular septal defect as a rare complication following TAVI procedure. .

Therapeutic effect of immunoadsorption and subsequent immunoglobulin substitution in patients with dilated cardiomyopathy: Results from the observational prospective Bad Berka Registry.

BACKGROUND: Elimination of cardiac autoantibodies, frequently detected in patients with dilated cardiomyopathy (DCM), with immunoadsorption (IA) improves functional capacity and left ventricular (LV) function. This study aimed to prospectively address this issue in a large cohort of unselected patients. METHODS: Consecutive patients undergoing IA followed by IgG substitution were included. Clinical and echocardiographic parameters were assessed at baseline (BL) and 12-month follow-up (FU). Patients were classified as IA responders when ≥2 of the following criteria were achieved: improvement in the Minnesota Living with Heart Failure Questionnaire (MLHFQ) ≥5 points, symptoms [≥1 New York Heart Association (NYHA) class], LV ejection fraction (EF) ≥10% or decrease in LV end-diastolic diameter (EDD) ≥10%, or N-terminal pro B-type natriuretic peptide (NT-pro-BNP) ≥50%. RESULTS: 93 patients (median age 61 years, LVEF 30%, duration of symptoms 14 months, 87% in NYHA class III/IV, >90% treated with ß-blocker/angiotensin-converting enzyme inhibitor) were included. When the entire cohort was analyzed, a significant improvement in MLHFQ (50 vs. 26 points), NYHA-class (median 3.0 vs. 2.0), LVEF (30% vs. 38%), LVEDD (62 vs. 59mm), NT-pro-BNP (892 vs. 523pg/ml) was observed at FU (p<0.05 for all). 48% (n=43) were classified as responders. Those were characterized by a shorter disease duration (11 vs. 22 months), larger BL LVEDD (64 vs. 60mm), presence of >1 viral genome, and higher values of mononuclear inflammatory cells at endomyocardial biopsy. Sixteen (17.2%) patients experienced IA related complications. CONCLUSIONS: A positive response is observed in 48% of inflammatory DCM patients undergoing IA, and this translates into a significant improvement in clinical and echocardiographic parameters.

[Prevention of pocket-related complications following heart rhythm device implantation. D-Stat Hemostat™ versus vacuum drainage]. / Prävention von Taschenkomplikationen nach Implantation von Herzrhythmusdevices. D-Stat Hemostat™ im Vergleich mit konventioneller Vakuumdrainage.

BACKGROUND: Pocket hematoma is a common complication after heart rhythm device implantation (HRD) in patients receiving anticoagulation and/or dual antiplatelet therapy (DAPT). METHODS: We conducted a prospective case-control study and enrolled all patients admitted for HRD receiving anticoagulation or DAPT. Participants received D-Stat (a mixture of collagen and thrombin) into the pectoral pocket and were compared with an age- and gender-matched group receiving a vacuum drainage system. The primary endpoint was a composite of hematoma needing evacuation and pocket infection. RESULTS: We included a total of 164 patients (mean age 73 ± 10.7 years; 118 [72 %] men). In all, 82 patients (50 %) received D-stat and 82 (50 %) vacuum drainage. There were 83 (51 %) patients who were treated with anticoagulation, 69 (42 %) patients received DAPT, and 11 (7 %) patients both. The primary endpoint occurred in 14.5 % (12/82) of patients in the D-Stat group and 0 % (0/82) of patients in the drainage group (p < 0.01). The use of D-Stat solution was associated with an increased incidence of pocket hematoma requiring evacuation (8.5 % versus 0 %; p = 0.01), and tended to an increased rate of pocket infections (6.1 % versus 0 %; p = 0.06). Postoperative immunoglobulin E levels (106 ± 219 IU/ml [D-Stat] versus 117 ± 189 IU/ml [drainage]) and increase of C-reactive protein (D-Stat: ∆19 mg/l versus drainage: ∆21 mg/l) were similar in both groups (p = 0.7 and p = 0.5, respectively). CONCLUSIONS: Administration of D-Stat solution is associated with a higher rate of pocket hematoma requiring reoperation in a high risk population receiving anticoagulation and/or DAPT. The observed rate of pocket infections in the D-Stat group is a matter of concern.

Novel intronic polymorphisms in the RET proto-oncogene and their association with Hirschsprung disease.

Germline mutations of the RET proto-oncogene have been found in familial and sporadic forms of Hirschsprung disease (HSCR), but also in the autosomal dominantly inherited multiple endocrine neoplasia type 2 (MEN2) syndromes, which comprise the medullary thyroid carcinoma (MTC) as an obligatory feature. Besides mutations various polymorphisms of the RET proto-oncogene are associated with the HSCR. In this study, we have characterized seven intronic RET polymorphisms (IVS2+9G>A, IVS4+48A>G, IVS12+47C>T, IVS14-24G>A, IVS19+47T>C, IVS20+96C>T, 3'UTR+124A>G) and investigated these variants by DNA sequencing in populations of 76 HSCR patients and 40 sporadic MTC patients as well as in a control population. Variants of four of these seven polymorphisms have a strong association with the HSCR phenotype. In contrast, none of the investigated polymorphisms show a significant difference in the genotype distribution and the allele frequencies in patients with sporadic MTC when compared to controls. These findings support the hypothesis that specific RET haplotypes cause or modify the HSCR phenotype.

Pocket related complications in 163 patients receiving anticoagulation or dual antiplatelet therapy: D-Stat Hemostat versus standard of care.

BACKGROUND: Pocket hematoma is a common complication after cardiac rhythm device implantation (CRDI) in patients receiving anticoagulation or dual antiplatelet therapy (DAPT). We sought to assess the safety and effectiveness of D-Stat Flowable Hemostat ([D-Stat]-a mixture of thrombin and collagen) in these patients. METHODS: We conducted a prospective case control study and enrolled all patients admitted for CRDI receiving anticoagulation or DAPT. Participants received either D-Stat into the pectoral pocket as an adjunct to standard of care versus the standard of care (UC) alone. The primary endpoint was a composite of hematoma needing evacuation, and pocket infection. RESULTS: We included a total of 163 patients (mean age 72 ± 8 years). 119 (73%) were male. 82 patients (50%) received D-stat and 81 (50%) usual care; 82 patients (50%) were treated with anticoagulation, 62 patients (38%) received DAPT, and 19 patients (12%) both. The primary endpoint occurred in 12/82 patients from the D-Stat group and 3/81 patients of the control group (14.6% versus 3.7%; p=0.03). The use of D-Stat tended for a higher incidence of pocket hematoma requiring evacuation (8.5% versus 2.4%; p=0.12), and an increased rate of pocket infections (6.1% versus 1.2%; p=0.21). Postoperative Immunoglobulin E levels (86 ± 147 IU/ml (D-Stat) versus 120 ± 231 IU/ml (UC)) and increase of C-reactive protein (D-Stat: ∆19 mg/l versus UC: 14 mg/l) were similar in both groups (p=0.26 and p=0.4, respectively). CONCLUSIONS: Administration of D-Stat does not decrease the frequency of clinically relevant pocket hematomas. The observed rate of pocket infections in the D-Stat group is a matter of concern.

Prognostic implications of netrin-1 expression and its receptors in patients with adenocarcinoma of the pancreas.

BACKGROUND: To assess the interaction between the expression of netrin-1 or of its receptors to the prognosis of ductal adenocarcinoma of the pancreas. METHODS: In 82 patients with resectable pancreatic adenocarcinoma who underwent curative operation, the expression patterns of netrin-1, deleted in colorectal carcinomas (DCC), UNC5H3, and neogenin were determined by immunohistochemical staining. Kaplan-Meier analysis was performed to assess the prognostic relevance of the examined expression patterns. RESULTS: Median follow-up was 15 +/- 19.9 months (range, 4-108 months). Patients suffering from tumors with no or little expression of netrin-1 (n = 67) had a median recurrence-free survival of 10 months (95% CI, 7-13 months), while a middle to strong expression (n = 15) was associated with a significantly worse median recurrence-free survival of only four months (95% CI, three to five months, p = 0.0165). Overall and recurrence-free survival showed no significant differences between the different expression patterns of DCC, UNC5H3 or neogenin. Netrin-1 expression had significant impact (p = 0.001) on overall survival of patients suffering from poorly differentiated tumors. Stratification according to the nodal status revealed significant influence (p = 0.007) of UNC5H3 expression on the overall survival of patients with pN1 status. CONCLUSION: Expression of netrin-1 has significant impact on time to tumor relapse in adenocarcinoma of the pancreas. Netrin-1 expression is associated with worse outcome in poorly differentiated pancreatic adenocarcinomas. Risk-stratification according to the UNC5H3 receptor expression pattern shows that node positive patients (pN1) with no to little UNC5H3 expression carry a significantly worse prognosis than those with middle to strong UNC5H3 expression.

Impact of the variability of cyclosporin A trough levels on long-term renal allograft function.

BACKGROUND: Among renal allograft recipients, there is a considerable variability in cyclosporin A (CsA) trough levels. Some of the CsA metabolites are pharmacologically active. The variability of polyclonal CsA trough levels may contribute to the fact that long-term renal allograft survival is still not satisfactory. In a retrospective, single-centre study, we investigated the influence of the variability of polyclonal CsA trough levels on long-term renal allograft function. METHODS: Patients (n=381) received double immunosuppression consisting of CsA and methylprednisolone (MP). For each patient the CsA coefficient of variation (CCV) and the mean CsA trough level during the observation period (5 years) were calculated. Based on receiver operating characteristic (ROC) analysis, patients were divided into two groups: group I, CCV <28.05%, n=231; group II, CCV >28.05%, n=150. Additionally, patients were divided into three groups according to their mean CsA trough level: group A, <270 ng/ml, n=50; group B, 270-370 ng/ml, n=282; group C: >370 ng/ml, n=49. RESULTS: Compared to group I, patients in group II experienced a higher incidence of acute rejection episodes (40.7% vs 29.4%, P=0.02), reduced 5-year graft survival (81.1% vs 93.3%, P=0.002), and higher serum creatinine levels (1.7+/-1.2 mg/dl vs 1.4+/-0.5 mg/dl, P=0.03). In patients with low mean CsA trough levels, the incidence of acute rejection episodes was elevated (group A vs B, 50.0% vs 30.9%, P=0.008) and 5-year graft survival was reduced (group A vs B, 79.8% vs 89.5%, P=0.005). Multiple logistic regression analysis confirmed that the risk of graft failure within 5 years after transplantation was markedly elevated in group II (RR: 6.2, P=0.013) and in group A (RR: 8.9, P=0.008). Whereas the effect of CCV on 5-year graft survival was still evident in patients with normal or high mean CsA trough levels (>270 ng/ml, 81.9% vs 94.8%, P=0.0005), graft survival was independent from CCV in patients with low mean CsA trough levels (<270 ng/ml, 77.0% vs 81.7%, P=NS). CONCLUSIONS: Both, the intra-individual variability and the mean of polyclonal CsA trough levels influence long-term renal allograft survival. Targeting at sufficiently high mean CsA levels with a low intra-individual variability may help to further improve long-term renal allograft survival.

Association between c135G/A genotype and RET proto-oncogene germline mutations and phenotype of Hirschsprung's disease.

BACKGROUND: Several genes, including the major susceptibility gene RET, have roles in development of Hirschsprung's disease. Results of genetic-linkage analysis of patients with familial disease with both long-segment and short-segment phenotypes have shown close linkage with the RET locus. We aimed to investigate whether both RET mutations and polymorphisms contribute to phenotype of Hirschsprung's disease. METHODS: We looked at the coding region of all 21 exons of the RET proto-oncogene, including the flanking intronic sequences, by direct DNA sequencing in 76 caucasians from Germany with Hirschsprung's disease. FINDINGS: 20 different mutations were detected in 18 patients. Mutations were under-represented in patients with a homozygous RET c135A/A genotype in association with short-segment phenotype. Short-segment phenotype also arose if the RET mutation was on the c135A allele; conversely, a RET germline mutation on the c135G allele resulted in long-segment phenotype, particularly in heterozygous c135G/A patients. INTERPRETATION: These observations lend support to the idea that both RET alleles have a role in pathogenesis of Hirschsprung's disease, in a dose-dependent fashion. We also showed that the c135G/A polymorphism modifies the phenotype by a within-gene interaction between the c135A variant and a mutation.

Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR).

The activation of the RET signaling pathway during embryogenesis is a crucial prerequisite for a directional migration of enteric nervous system progenitor cells. Loss-of-function germline mutations of the RET proto-oncogene are reported in familial and sporadic cases of Hirschsprung disease (HSCR) with a variable frequency. Furthermore, variants of several RET polymorphisms are over- or under-represented in HSCR populations. Specifically, the c.135A RET variant has been previously shown to be strongly associated with the HSCR phenotype. We have reported an HSCR-phenotype modifying effect of the RET c.135G>A polymorphism due to a within-gene interaction in patients harboring RET germline mutations, yet the function of the c.135G>A variant is unknown. The basic RET promoter region was investigated by DNA sequencing approach in 80 HSCR patients. Identified polymorphisms were genotyped in the HSCR and in a control population and haplotypes were reconstructed. The dual-luciferase assay was used to evaluate the activity of different RET promoter haplotypes. We demonstrate that variants of two RET promoter polymorphisms -5G>A and -1C>A from the transcription start site are associated with HSCR. Furthermore, the -5G>A polymorphism is in strong linkage disequilibrium with the c.135G>A polymorphism. The promoter haplotype -5/-1AC associated with HSCR has a significantly lower activity in an in vitro dual-luciferase expression assay compared with those haplotypes identified in the majority of normal controls. These data suggest a role for RET haplotypes containing the -5A promoter variant in the etiology of HSCR.