The application of massively parallel sequencing technology to the field of skeletal disorders has boosted the discovery of the underlying genetic defect for many of these diseases. It has also ...resulted in the delineation of new clinical entities and the identification of genes and pathways that had not previously been associated with skeletal disorders. These rapid advances have prompted the Nosology Committee of the International Skeletal Dysplasia Society to revise and update the last (2015) version of the Nosology and Classification of Genetic Skeletal Disorders. This newest and tenth version of the Nosology comprises 461 different diseases that are classified into 42 groups based on their clinical, radiographic, and/or molecular phenotypes. Remarkably, pathogenic variants affecting 437 different genes have been found in 425/461 (92%) of these disorders. By providing a reference list of recognized entities and their causal genes, the Nosology should help clinicians achieve accurate diagnoses for their patients and help scientists advance research in skeletal biology.
The acrofacial dysostoses (AFD) are a genetically heterogeneous group of inherited disorders with craniofacial and limb abnormalities. Rodriguez syndrome is a severe, usually perinatal lethal AFD, ...characterized by severe retrognathia, oligodactyly and lower limb abnormalities. Rodriguez syndrome has been proposed to be a severe form of Nager syndrome, a non-lethal AFD that results from mutations in SF3B4, a component of the U2 small nuclear ribonucleoprotein particle (U2 snRNP). Furthermore, a case with a phenotype intermediate between Rodriguez and Nager syndromes has been shown to have an SF3B4 mutation. We identified heterozygosity for SF3B4 mutations in Rodriguez syndrome, confirming that the phenotype is a dominant disorder that is allelic with Nager syndrome. The mutations led to reduced SF3B4 synthesis and defects in mRNA splicing, primarily exon skipping. The mutations also led to reduced expression in growth plate chondrocytes of target genes, including the DLX5, DLX6, SOX9, and SOX6 transcription factor genes, which are known to be important for skeletal development. These data provide mechanistic insight toward understanding how SF3B4 mutations lead to the skeletal abnormalities observed in the acrofacial dysostoses.
Ulcerative colitis and Crohn's disease are chronic inflammatory bowel diseases for which there are no cures. These diseases are immunopathogenic, and medical treatment is centered on the temperance ...of a dysregulated immune response to allow mucosal healing and prevent the sequelae of fistulation and stenosis. Accordingly, the armamentarium of medications, which has expanded immensely in recent history, is not without significant infectious and neoplastic risks. Many of these untoward effects can be mitigated by screening and avoidance of contraindicated medications. This review seeks to highlight the cautions for use of immunomodulators, anticytokine, and α4-integrin antagonists. The potential adverse events are further complicated by substantial heterogeneity in disease phenotype in the inflammatory bowel disease population. Large patient registries and databases provide considerable experience and knowledge to calculate the incidence of safety outcomes. To identify rarer outcomes after prolonged therapy, more prospective studies and continued adverse event reporting will aid safe application and minimize potential harms.
Pulmonary embolectomy is often indicated for central pulmonary embolism (PE) with hemodynamic instability, but remains controversial for hemodynamically stable patients with signs of right ...ventricular dysfunction. Because thrombolytic therapy is often contraindicated postoperatively, we reviewed risk factors and outcomes of pulmonary embolectomy for stable and unstable central PE, particularly in the early postoperative period.
Between October 1999 and September 2013, 115 patients underwent pulmonary embolectomy for central, hemodynamically unstable PE (49 of 115, 43%) or hemodynamically stable PE (56 of 115, 49%). Ten operations for alternate indications (right atrial mass, endocarditis) were excluded for comparison analysis, leaving 105 patients.
Mean age was 59 ± 13 years; 46 of 105 patients (44%) had recent surgery (within 5 weeks): orthopedic (12 of 46, 25%), neurosurgery (11 of 46, 24%), or general surgery (10 of 46, 22%). Preoperative demographics did not differ between groups, except for the frequency of cardiopulmonary resuscitation among unstable patients (11 of 49, 22%) versus stable patients (0 of 56, 0%; p < 0.001). Operative mortality for the combined groups was 6.6% (7 of 105): unstable 10.2% (5 of 49) versus stable 3.6% (2 of 56; p = 0.247). Of 11 patients requiring preoperative cardiopulmonary resuscitation, 4 died. Six-month, 1-year, and 3-year survival rates were, respectively, 75%, 68.4%, and 65.8% for unstable PE, and 92.6%, 86.7%, and 80.4% for stable PE (p = 0.018).
This large series of pulmonary embolectomies demonstrates excellent early and late survival rates for patients with stable PE and unstable PE. These findings confirm pulmonary embolectomy as a beneficial therapeutic option for central PE, especially during the postoperative period when thrombolytic therapy is often contraindicated.
Minimally-Invasive Valve Surgery Schmitto, Jan D., MD, PhD; Mokashi, Suyog A., MD; Cohn, Lawrence H., MD
Journal of the American College of Cardiology,
08/2010, Letnik:
56, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Minimally-invasive approaches have become increasingly important in cardiac valve surgery. Smaller incisions have become commonplace in many major centers. We reviewed the existing literature and ...present the current state-of-the-art of minimally-invasive valve operations in this paper.
We have discovered a new transient low-mass X-ray binary, NGC 6440 X-2, with Chandra/ACIS, RXTE/PCA, and Swift/XRT observations of the globular cluster NGC 6440. The discovery outburst (2009 July ...28-31) peaked at L{sub X} {approx} 1.5 x 10{sup 36} erg s{sup -1} and lasted for <4 days above L{sub X} = 10{sup 35} erg s{sup -1}. Four other outbursts (2009 May 29-June 4, August 29-September 1, October 1-3, and October 28-31) have been observed with RXTE/PCA (identifying millisecond pulsations) and Swift/XRT (confirming a positional association with NGC 6440 X-2), with similar peak luminosities and decay times. Optical and infrared imaging did not detect a clear counterpart, with best limits of V>21, B>22 in quiescence from archival Hubble Space Telescope imaging, g'>22 during the August outburst from Gemini-South GMOS imaging, and J {approx_gt} 18.5 and K {approx_gt} 17 during the July outburst from CTIO 4 m ISPI imaging. Archival Chandra X-ray images of the core do not detect the quiescent counterpart (L{sub X} < (1-2) x 10{sup 31} erg s{sup -1}) and place a bolometric luminosity limit of L{sub NS} < 6 x 10{sup 31} erg s{sup -1} (one of the lowest measured) for a hydrogen atmosphere neutron star. A short Chandra observation 10 days into quiescence found two photons at NGC 6440 X-2's position, suggesting enhanced quiescent emission at L{sub X} {approx} 6 x 10{sup 31} erg s{sup -1}. NGC 6440 X-2 currently shows the shortest recurrence time ({approx}31 days) of any known X-ray transient, although regular outbursts were not visible in the bulge scans before early 2009. Fast, low-luminosity transients like NGC 6440 X-2 may be easily missed by current X-ray monitoring.
Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound ...abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short‐rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis–van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes. The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.
Ciliopathies are inherited disorders due to defects in the biosynthesis and/or function of primary cilia. The skeletal ciliopathies are a subset of recessive ciliary phenotypes that have abnormalities primarily affecting the skeleton. Mutations in 25 different genes have been characterized in this group of disorders, identifying proteins that are required for normal skeletal development.
Abstract
We present 22 new (+3 confirmed) cataclysmic variables (CVs) in the non-core-collapsed globular cluster 47 Tucanae (47 Tuc). The total number of CVs in the cluster is now 43, the largest ...sample in any globular cluster so far. For the identifications we used near-ultraviolet (NUV) and optical images from the Hubble Space Telescope, in combination with X-ray results from the Chandra X-ray Observatory. This allowed us to build the deepest NUV CV luminosity function of the cluster to date. We found that the CVs in 47 Tuc are more concentrated towards the cluster centre than the main-sequence turn-off stars. We compared our results to the CV populations of the core-collapsed globular clusters NGC 6397 and NGC 6752. We found that 47 Tuc has fewer bright CVs per unit mass than those two other clusters. That suggests that dynamical interactions in core-collapsed clusters play a major role creating new CVs. In 47 Tuc, the CV population is probably dominated by primordial and old dynamically formed systems. We estimated that the CVs in 47 Tuc have total masses of ∼1.4 M⊙. We also found that the X-ray luminosity function of the CVs in the three clusters is bimodal. Additionally, we discuss a possible double degenerate system and an intriguing/unclassified object. Finally, we present four systems that could be millisecond pulsar companions given their X-ray and NUV/optical colours. For one of them we present very strong evidence for being an ablated companion. The other three could be CO or He white dwarfs.
Objective The present study assessed the clinical and echocardiographic outcomes for 1000 patients undergoing minimally invasive mitral valve surgery. Methods The Brigham Cardiac Valve database was ...reviewed. From August 1996 to November 2011, 1000 patients had undergone minimally invasive mitral valve surgery (median follow-up, 7 years). Data on the surgical approach, complications, reoperations, and late survival were tabulated. Late echocardiographic data on the recurrence of mitral regurgitation after mitral repair in myxomatous disease were also collected. Survival, freedom from reoperation and recurrent mitral regurgitation (grade ≥ 3+) were evaluated with life tables and Kaplan-Meier analyses. Results The mean patient age was 57 years. Of the 1000 patients, 41% were women. Myxomatous degenerative disease was the predominant pathologic entity (86%). A lower hemisternotomy was the predominant surgical approach (75%). Mitral repair was performed in 923 patients and replacement in 77. Eight operative deaths (0.8%) occurred. A total of 44 patients with failed mitral repairs underwent reoperation, with 1 mitral valve replaced again on the same operative day for atrioventricular groove disruption. Nine failed repairs were repaired again (9/44 20%). A total of 106 late deaths occurred. The overall survival at 15 years was 79% ± 3%. Freedom from reoperation at 15 years was 90% ± 3% for repairs and 100% for replacements. Late echocardiograms were acquired for 615 of 815 eligible mitral repair patients with myxomatous disease (75%). Freedom from recurrent mitral regurgitation (grade ≥ 3+) at 1, 5, and 10 years was 99% ± 1%, 87% ± 2%, and 69% ± 4%, respectively. Conclusions Minimally invasive mitral valve surgery is effective, with excellent late results. The durability of minimally invasive mitral valve repair compared favorably with conventional full sternotomy methods at late follow-up.
PDF
