Loss of Drosophila Ataxin-7, a SAGA subunit,reduces H2B ubiquitination and leads to neural and retinal degeneration

The Spt–Ada–Gcn5–acetyltransferase (SAGA) chromatin-modifying complex possesses acetyltransferase and deubiquitinase activities. Within this modular complex, Ataxin-7 anchors the deubiquitinase activity to the larger complex. Here we identified and characterized Drosophila Ataxin-7 and found that reduction of Ataxin-7 protein results in loss of components from the SAGA complex. In contrast to yeast, where loss of Ataxin-7 inactivates the deubiquitinase and results in increased H2B ubiquitination, loss of Ataxin-7 results in decreased H2B ubiquitination and H3K9 acetylation without affecting other histone marks. Interestingly, the effect on ubiquitination was conserved in human cells, suggesting a novel mechanism regulating histone deubiquitination in higher organisms. Consistent with this mechanism in vivo, we found that a recombinant deubiquitinase module is active in the absence of Ataxin-7 in vitro. When we examined the consequences of reduced Ataxin-7 in vivo, we found that flies exhibited pronounced neural and retinal degeneration, impaired movement, and early lethality.     

The risks of radiation therapy and lymphedema in shoulder surgery

BackgroundRadiation therapy has proven efficacy for cancer treatment but is not without short- and long-term side effects, including radiation-induced lymphedema. There has been limited evidence on the secondary effects of prior radiation therapy on shoulder surgery. The purpose of this study is to evaluate the short-term outcomes of shoulder arthroplasty and rotator cuff repair (RCR) in patients who have undergone ipsilateral radiation therapy and/or have preoperative upper extremity lymphedema.MethodsDuke Enterprise Data Unified Content Explorer was used to query for patients who underwent RCR at our institution. Patients with radiation therapy for breast or lung cancer prior to ipsilateral RCR or shoulder arthroplasty were included. Patients with less than 2 years of follow-up were excluded. Data variables included primary tumor type, dates of cancer diagnoses, radiation treatment, axillary lymph node dissection (aLND), presence of lymphedema, index shoulder operations, most recent follow-up, and surgical and medical complications within the 90-day postoperative period. Additional oncologic variables included total Gray (Gy) delivered.ResultsTwenty-one patients underwent radiation therapy and subsequent shoulder arthroplasty or RCR (13 RCR, 3 total shoulder arthroplasty, 5 reverse shoulder arthroplasty). There were 20 females and 1 male with an average age of 65.6 years (47-82) and average clinical follow-up of 4.4 years (2.0-7.4). Oncologic diagnoses included lung (4.8%) and breast (95.2%) cancer. Average radiation dose delivered was 53.3 Gy (38.5-64) in the cohort. The average time from last external beam radiation therapy to shoulder surgery was 4.3 years (0.3-18.0). One of 13 (7.7%) 90-day postoperative complications was reported in the RCR cohort: a superficial vein thrombosis. One of 8 (12.5%) 90-day complications was reported in the arthroplasty cohort: a clinically suspected but radiographically absent acromial stress fracture in a reverse shoulder arthroplasty that did not require operative intervention. Overall, there were no revisions, reoperations, or shoulder-related unplanned inpatient 90-day readmissions. Among 10 patients with prior aLND, 3 (30%) (2 RCR, 1 arthroplasty) experienced new or worsening upper extremity lymphedema within the immediate postoperative period.ConclusionA minority of patients having undergone prior radiation therapy and aLND who subsequently underwent ipsilateral shoulder surgery experienced worsening subjective upper extremity lymphedema. Although 10% of these radiation therapy patients experienced minor complications within 90 days of their shoulder surgery, none were severe enough to merit inpatient admission or revision surgery.     

A GCH1 haplotype confers sex‐specific susceptibility to pain crises and altered endothelial function in adults with sickle cell anemia

GTP cyclohydrolase (GCH1) is rate limiting for tetrahydrobiopterin (BH4) synthesis, where BH4 is a cofactor for nitric oxide (NO) synthases and aromatic hydroxylases. GCH1 polymorphisms are implicated in the pathophysiology of pain, but have not been investigated in African populations. We examined GCH1 and pain in sickle cell anemia where GCH1 rs8007267 was a risk factor for pain crises in discovery (n = 228; odds ratio [OR] 2.26; P = 0.009) and replication (n = 513; OR 2.23; P = 0.004) cohorts. In vitro, cells from sickle cell anemia subjects homozygous for the risk allele produced higher BH4. In vivo physiological studies of traits likely to be modulated by GCH1 showed rs8007267 is associated with altered endothelial dependent blood flow in females with SCA (8.42% of variation; P = 0.002). The GCH1 pain association is attributable to an African haplotype with where its sickle cell anemia pain association is limited to females (OR 2.69; 95% CI 1.21–5.94; P = 0.01) and has the opposite directional association described in Europeans independent of global admixture. The presence of a GCH1 haplotype with high BH4 in populations of African ancestry could explain the association of rs8007267 with sickle cell anemia pain crises. The vascular effects of GCH1 and BH4 may also have broader implications for cardiovascular disease in populations of African ancestry. Am. J. Hematol. 89:187–193, 2014. © 2013 Wiley Periodicals, Inc.     

Reaching Children Never Previously Vaccinated for Influenza Through a School-Located Vaccination Program

Objectives. We determined the success of the school-located vaccination (SLV) program, implemented in 2009 in New York City to deliver pandemic influenza A (H1N1) monovalent vaccine (pH1N1), versus provider offices in reaching children who had never previously received influenza vaccine.Methods. We compared the immunization history of children vaccinated in school versus provider offices. We included records in the Citywide Immunization Registry with pH1N1 administered between October 2009 and March 2010 to elementary school-aged children.Results. In total, 96 524 children received pH1N1 vaccine in schools, and 102 933 children received pH1N1 vaccine in provider offices. Of children vaccinated in schools, 34% had never received seasonal influenza vaccination in the past, compared with only 10% of children vaccinated at provider offices (P < .001). Children vaccinated in schools were more likely to have received a second dose of pH1N1 in 2009–2010 than those vaccinated in provider offices (80% vs 45%).Conclusions. The SLV program was more successful at reaching children who had never received influenza immunization in the past and should be considered as a strategy for delivering influenza vaccine in routine and emergency situations.Improving vaccination coverage in children may lead to decreased morbidity and mortality in the general population, including decreasing influenza deaths and illness in adults.1–4 In 2006, the Advisory Committee on Immunization Practices recommended influenza vaccine for healthy children aged 6 months to 4 years5 and expanded their recommendation in subsequent years to include children aged 5 to 18 years.6 The goal of vaccinating all children annually raises a significant operational question of how to target children most effectively.Pediatricians provide the majority of immunizations given to children. However, after the 4- to 6-year-old well child visits, children may not visit medical providers regularly. School-located vaccination (SLV) offers a convenient alternative because it reaches the majority of children regardless of their access to medical care,7 and schools have been successfully used for hepatitis B vaccination administration in the past.8,9 SLV also offers parents the convenience of not having to make a trip to the provider’s office or even be present. Jurisdictions such as Hawaii have routinely offered influenza vaccine through schools and have achieved vaccination rates as high as 46% in children aged 5 to 13 years.10Despite the potential advantages of SLV, to our knowledge, whether it successfully reaches children who otherwise would have gone unvaccinated is unknown. We examined this issue in New York City (NYC) in 2009 when the NYC Department of Health and Mental Hygiene offered pandemic influenza A (H1N1) monovalent vaccine (pH1N1) through an elementary school–located campaign. During this influenza season, because of a late-emerging strain of novel H1N1, pH1N1 vaccine was developed and offered separately from routine seasonal influenza vaccination. Using data on pH1N1 vaccination from the Citywide Immunization Registry (CIR), the NYC Department of Health and Mental Hygiene’s Immunization Information System, we compared the demographic characteristics and immunization history of children vaccinated through the SLV campaign with those of children vaccinated in medical provider offices. We examined the proportion of children in each setting for whom the pH1N1 vaccine was the first influenza vaccine ever received to determine the potential for SLV programs to effectively reach children who have not previously received an influenza vaccination and who therefore might be unlikely to get vaccinated in the current season as well. We also predicted the probability of being vaccinated at schools controlling for demographic characteristics and immunization history.