CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective DNA repair

Several human disorders mutated in core components of the major DNA double-strand break (DSB) repair pathway, non-homologous end joining (NHEJ), have been described. Cell lines from these patients are characterized by sensitivity to DSB-inducing agents. DNA ligase IV syndrome (LIG4) patients specifically, for unknown reasons, respond particularly badly following treatment for malignancy or BMT. We report the first systematic evaluation of the response of LIG4 syndrome to compounds routinely employed for BMT conditioning. We found human pre-B lymphocytes, a key target population for BMT conditioning, when deficient for DNA ligase IV, unexpectedly exhibit significant sensitivity to CsA the principal prophylaxis for GVHD. Furthermore, we found that CsA treatment alone or in combination with BU and fludarabine resulted in increased levels of DSBs specifically in LIG4 syndrome cells compared to wild-type or Artemis-deficient cells. Our study shows that CsA can induce DSBs and that LIG4 syndrome patient's fail to adequately repair this damage. These DSBs likely arise as a consequence of DNA replication in the presence of CsA. This work has implications for BMT and GVHD management in general and specifically for LIG4 syndrome

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Letter dated 16 February 1967 from Herman A. Gruhn to Lorenzo A. Richards

Letter dated 16 February 1967 from Herman A. Gruhn, Principal of Sierra Junior High School in Riverside, California, to Lorenzo A. Richards of Riverside, thanking him for agreeing to present speech awards at Gage Junior High School on 7 March 1967RIVERSIDE UNIFIED SCHOOL DISTRICT Bruce Miller, Superintendent Riverside, California SIERRA JUNIOR HIGH SCHOOL HERMAN A. GRUHN, PRINCIPAL 49SO CENTRAL AVENUE. P H O N E 684-8300 February 16, 1967 Dear Ren: Thank you for accepting the responsibility of presenting the speech awards at Gage Junior High School on Tuesday, March 7, 1967. They have two assemblies, the first assembly begins at 1:40 p.m. and the second assembly begins at 2:35 p.m. They will want the awards presented at both assemblies. The certificates, medals and plaque are at the school and in­structions for presenting them will be given to you by the principal, Mr. John Mensinger. I would suggest that you be at the school at least fifteen minutes before the assemblies begin, to make arrangements for your presentation. I think it may be nice also, if you could meet the representatives of Gage Junior High School in the lobby of the Mission Inn at 11:50 a.m. on Thursday, March 9, 1967, when they are guests of the Exchange Club. One representative from each school will present his selection for the club. If you can host the representatives of Gage at this occasion, it would be very nice. At the dinner however, I will introduce the principal and he in turn will introduce his guests. Thank you again for your help. <£ HG/hg Mr. L.A. Richards kkSS Fifth Street R i ve rs i de, Ca1i forni a Sincerely, / • i-• HERMAN A. GRUHN Principa

Letter dated 19 February 1968 from Herman A. Gruhn to Lorenzo A. Richards

Letter dated 19 February 1968 from Herman A. Gruhn, Principal of Sierra Junior High School in Riverside, California, to Lorenzo A. Richards, thanking him for accepting the responsibility of presenting the speech awards at Chemewa Junior High School on 7 March, and providing further detailsRIVERSIDE UNIFIED SCHOOL DISTRICT SIERRA JUNIOR HIGH SCHOOL HERMAN A. GRUHN, PRINCIPAL BRUCE MILLER,SUPERINTENDENT February 19, 1968 4950 CENTRAL AVENUE, PHONE 684-8300 RIVERSIDE, CALIFORNIA 92504 Mr. L.A. Richards M+55 Fifth Street Riverside, California Dear Ren: Thank you for accepting the responsibility of presenting the speech awards at Chemewa Junior High School on Thursday, March 7, 1968. They have two assemblies, the first assembly begins at 9:05 a.m. and the second assembly begins at 9:55 a.m. They will want the awards presented at both assemblies. The certificates, medals and plaque are at the school and instructions for presenting them will be given to you by the principal, Mr, Walter Gardner. I would suggest that you be at the school at least fifteen minutes before the assemblies begin, to make arrangements for your presentation. I think it may be nice also, if you could meet the representatives of Chemewa Junior High School in the lobby of the Mission Inn at 11:50 a.m. on Thursday, March ]k, 1968, when they are guests of the Exchange Club. One representative from each school will present his selection for the club, If you can host the representatives of Chemewa at this occasion, it would be very nice. At the luncheon however, I will introduce the principal and he in turn will introduce his guests. Thank you again for your help. Sincerely, HG/hg HERMAN A. GRUHN' Principa