MOZ (MYST3, KAT6A) inhibits senescence via the INK4A-ARF pathway.

Cellular senescence is an important mechanism that restricts tumour growth. The Ink4a-Arf locus (also known as Cdkn2a), which encodes p16(INK4A) and p19(ARF), has a central role in inducing and maintaining senescence. Given the importance of cellular senescence in restraining tumour growth, great emphasis is being placed on the identification of novel factors that can modulate senescence. The MYST-family histone acetyltransferase MOZ (MYST3, KAT6A), first identified in recurrent translocations in acute myeloid leukaemia, has been implicated in both the promotion and inhibition of senescence. In this study, we investigate the role of MOZ in cellular senescence and show that MOZ is a potent inhibitor of senescence via the INK4A-ARF pathway. Primary mouse embryonic fibroblasts (MEFs) isolated from Moz-deficient embryos exhibit premature senescence, which was rescued on the Ink4a-Arf(-/-) background. Importantly, senescence resulting from the absence of MOZ was not accompanied by DNA damage, suggesting that MOZ acts independently of the DNA damage response. Consistent with the importance of senescence in cancer, expression profiling revealed that genes overexpressed in aggressive and highly proliferative cancers are expressed at low levels in Moz-deficient MEFs. We show that MOZ is required to maintain normal levels of histone 3 lysine 9 (H3K9) and H3K27 acetylation at the transcriptional start sites of at least four genes, Cdc6, Ezh2, E2f2 and Melk, and normal mRNA levels of these genes. CDC6, EZH2 and E2F2 are known inhibitors of the INK4A-ARF pathway. Using chromatin immunoprecipitation, we show that MOZ occupies the Cdc6, Ezh2 and Melk loci, thereby providing a direct link between MOZ, H3K9 and H3K27 acetylation, and normal transcriptional levels at these loci. This work establishes that MOZ is an upstream inhibitor of the INK4A-ARF pathway, and suggests that inhibiting MOZ may be one way to induce senescence in proliferative tumour cells.

A radiological diary of gallstone migration in a patient with acute pancreatitis.

This case report is interesting in radiologically showing migration of stones from the gallbladder via the biliary tree and into the gastrointestinal tract.

Change in access blood flow over time predicts vascular access thrombosis.

BACKGROUND: Vascular access thrombosis accounts for at least $1 billion dollars in annual expenses and 25% of hospitalizations for chronic hemodialysis patients. Low vascular access blood flow (less than 800 ml/min) has been shown to modestly increase the relative risk for thrombosis in the subsequent three months. In this study, it is hypothesized that a time-dependent decrease in vascular access blood flow may be more predictive of subsequent thrombosis especially in vascular accesses with flows more than 800 ml/min, since it would indicate the development of a critical outlet stenosis in the graft. METHODS: Ninety-five accesses in 91 CHD patients were prospectively followed over 18 months. Vascular access blood flow was measured every six months by the ultrasound dilution technique. Thrombotic events were recorded during the three study periods. RESULTS: A total of 34 thrombotic events in 95 accesses were documented through the total study duration. Accesses that thrombosed had a 22% decrease in vascular access blood flow during the first observation period and a further 41% decrease during the second observation period as compared to 4% drop and 15% increase during the first and second observation periods, respectively, for accesses that did not thrombose. There was an estimated 13.6-fold (95%, confidence interval 2.68 to 69.16) increase in the relative risk of thrombosis for accesses with more than 35% decrease in vascular access blood flow compared to those accesses with no change in blood flow. There was no statistical difference in the average vascular access blood flow of all patients over the study period. CONCLUSIONS: Accesses that show a large (>15%) decrement in vascular access blood flow are associated with a high risk of thrombosis. Serial measurements of vascular access blood flow predict access thrombosis.

Predictive measures of vascular access thrombosis: a prospective study.

Malfunction of permanent vascular accesses remains a cause of frequent and costly morbidity in patients receiving chronic hemodialysis (CHD). Several recommendations for routine monitoring of these permanent vascular accesses for incipient failure have been proposed. In this study, multiple indicators of incipient vascular access dysfunction, including "venous" and "arterial" pressures at serial blood flows (200 ml/min, 300 ml/min, and 400 ml/min), percent urea recirculation, Doppler ultrasound, and access blood flow by ultrasound dilution technique were simultaneously evaluated in a total of 220 vascular accesses in 170 chronic hemodialysis patients in two separate study periods (6 months apart). The rate of thrombosis was determined within the subsequent 12 weeks of each study period to assess the short-term predictive power of access thrombosis. During the period of follow-up, there were 34 thrombotic events in 172 polytetrafluoroethylene (PTFE) grafts and only one thrombotic event in 48 arterio-venous fistulas (AVF). Therefore, the statistical analysis was limited to the PTFE grafts. When grafts with thromboses were compared to those without thrombosis by univariate analysis, access blood flow measured either by ultrasound dilution technique (875 +/- 426 ml/min with thrombosis vs. 1193 +/- 677 ml/min without thrombosis, P = 0.001) or by Doppler ultrasound (762 +/- 420 ml/min with thrombosis vs. 1171 +/- 657 ml/min without thrombosis, P = 0.001) were significantly different in the two groups. There was good correlation (r = 0.79, P = 0.0001) between the blood flows determined by both techniques. The grade of stenosis determined by ultrasound was also a statistically significant predictor (P = 0.02). "Venous" and "arterial" pressures were numerically similar and were not statistically different between the accesses that did and those that did not thrombose. When multivariate analysis was used, there was a significantly increased risk of thrombosis only with decreasing access blood flow determined by ultrasound dilution techniques after adjusting for other confounding variables. When the average blood flow of all grafts (1134 ml/min) is considered as the reference access blood flow (relative risk of 1.0), the relative risk of a PTFE thrombotic event within the subsequent 12 weeks was 1.23 at a blood flow 950 ml/min, 1.67 at a blood flow of 650 ml/min and to 2.39 at a blood flow of 300 ml/min. In summary, access blood flow measured by either Dilution or Doppler is a reliable indicator of subsequent short-term thrombosis risk. Other proposed methods of evaluating access dysfunction were not useful in our patients. If simple to use, cost-effective devices to measure dialysis access blood flow become readily available, the measurement of access blood flow will likely become the method of choice for screening of PTFE vascular access dysfunction in hemodialysis patients.

An unusual cause for respiratory difficulty after thyroidectomy.

Problems with breathing immediately after extubation following thyroidectomy are rare, but can usually be attributed to a surgical error such as damage to one or both recurrent laryngeal nerves. Tracheomalacia may also cause respiratory distress following extubation. We present an unusual cause of failure to resume spontaneous respiration after thyroidectomy.

Comparison of peptide and nonpeptide receptor-mediated responses in rat tail artery.

Chronic uremia and metabolic acidosis impair vascular responses to norepinephrine (NE) and also cause multiple metabolic defects in skeletal muscle. These studies were conducted to determine whether decreased vascular responsiveness resulted from putative second messenger metabolism. Tail arteries were used from rats with metabolic acidosis or nonacidotic uremia and from normal controls. In normal arteries, the maximal responses were the same for arginine vasopressin (AVP), NE, and mixtures of the two agonists, suggesting that the two receptor types use the same transduction mechanism. Nonetheless, qualitative differences exist between AVP- and NE-induced responses: (a) Concentration-response curves are steeper for AVP than for NE, (b) EC50 values are similar for AVP between inositol phosphates (IP assays) and contraction, but not for NE, and (c) arteries from rats with metabolic acidosis or uremia show selective blunting of biochemical and contractile responses to NE but not to AVP. We conclude that these metabolic derangements selectively affect alpha-adrenergic receptors, but not AVP receptors or the transduction mechanism leading to contraction.

Conservative surgery for early breast cancer results from a district hospital.

Wide local excision followed by radiotherapy was offered as an alternative to mastectomy to 93 women on 96 occasions. Complications attributable to the surgery occurred in 4 per cent whilst 37.5 per cent developed complications secondary to the radiotherapy. The complications were generally of a mild nature. Nine patients (9.3%) have developed regional recurrence and seventeen (17.7%) distant metastases with a mean follow up of 53.4 months.

Polydioxanone suture in the gastrointestinal tract.

A randomized prospective trial was undertaken of polydioxanone suture (PDS) versus conventional suture material in 98 patients undergoing anastomoses in the gastrointestinal tract. Nine patients died within 6 months of surgery, one of these being related to an anastomotic leak. All other patients were followed up for between one and three and a half years. In 57 colonic anastomoses, 30 were randomized to a single layer of 2/0 (BPC) interrupted PDS and 27 to a single of 2/0 (BPC) interrupted silk. Follow up sigmoidoscopy and barium enemas were used to confirm the clinical suspicion of 6 benign anastomotic strictures, 5 of which occurred in the PDS group. At this stage, the colonic arm of the trial was discontinued because the 19% stricture rate with PDS was deemed unacceptable. In a second limb of the study, patients were randomized to two layers of 2/0 (BPC) continuous PDS or 2/0 (BPC) continuous chromic catgut. There were no significant differences in 32 gastric or small bowel anastomoses and in particular, no anastomotic strictures were apparent. The reasons for the high rate of stricture formation when using PDS for large bowel anastomoses are unclear. However, it would seem to be a suitable alternative to chromic catgut when confined to the stomach and small intestine.

Sportsmedicine forum.

A Forum For Our Readers Sportsmedicine Forum is intended to provide a sounding board for our readers. Perhaps you have a special way to treat a common medical problem, or you may want to air your views on a controversial topic. You may object to an article that we have published, or you may want to support one. You may have a new trend to report, identified through an interesting case or a series of patients. Whatever your ideas, we invite you to send them to us. Illustrative figures are welcomed. Address correspondance to Sports medicine Forum, THE PHYSIC/AN AND SPORTSMEDICINE, 4530 W 77th St, Minneapolis, MN 55435.

Complications of T-tube drainage of the common bile duct.

The complications associated with T-tube drainage of the common bile duct following biliary surgery were studied prospectively. A high rate of complications especially associated with T-tube removal was found. Biliary leakage and bacteraemia were the two main problems though in most cases caused minimal clinical upset. Alternatives to T-tube drainage are discussed. It is suggested that if T-tubes are to be used broad spectrum antibiotic cover should be employed at the time of removal.

Abdominal wound closure: a controlled trial of polyamide (nylon) and polydioxanone suture (PDS).

Two hundred and thirty three patients with major laparotomy wounds, either midline or transverse, were randomly allocated to mass closure using No 1 (BPC) polyamide (Nylon) or polydioxanone suture (PDS). Wounds were assessed during the hospital stay and postoperatively in outpatients, at six weeks and six months, for evidence of wound failure or wound infection. Two wound failures occurred in the PDS group (one burst abdomen and one incisional hernia) although neither was directly attributable to suture failure. The overall wound infection rate was 13.3%; 2.9% being major infections and the majority (two thirds) occurring in the PDS group. There were no reported wound sinuses or wound pain in either group at six months. Polydioxanone suture may be an alternative to polyamide for laparotomy closure but is associated with a higher, though not statistically significant, incidence of wound failure and infection.

An assessment of operative choledochoscopy--a worthwhile procedure or not?

The results of a nine year survey of biliary surgery are reported. The incidence of retained common bile duct stones prior to choledochoscopy was 4%. When choledochoscopy became available, the incidence of retained stones rose to 9%. This disappointing rise is probably due to inexperience with the technique and post-exploratory cholangiography is still considered mandatory.

Absent vas deferens in association with renal abnormalities.

Absence of the vas deferens, especially if unilateral, should alert the clinician to an underlying renal anomaly, and further urological investigation is mandatory. If the vas is shown to be bilaterally absent in an infant, cystic fibrosis should be excluded. In the context of vasectomy, exploration of the palpably absent side should be unnecessary if intravenous urography detects a combined anomaly, although post-operative seminal analysis will still need to be performed.

Hepatic artery aneurysm following cholecystectomy.

A rare case is reported of an hepatic artery aneurysm developing 5 months after cholecystectomy. This presented as massive haemobilia as a result of the aneurysm communicating with the cystic duct stump. The diagnosis was delayed owing to the complicating features of Waldenström's macroglobulinaemia and jejunal diverticulosis.

Intussusception in the adult.

Intussusception in the adult is an uncommon cause of intestinal obstruction. Seventeen cases were seen at two teaching hospitals over a twenty-year period. A local causative lesion was present in all cases; a malignant tumour was present in two out of seven intussusceptions arising in the small intestine and in seven out of ten arising in the large intestine. More than half the cases had a protracted clinical course prior to diagnosis.