The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism.

Reprogramming of cellular metabolism is a key event during tumorigenesis. Despite being known for decades (Warburg effect), the molecular mechanisms regulating this switch remained unexplored. Here, we identify SIRT6 as a tumor suppressor that regulates aerobic glycolysis in cancer cells. Importantly, loss of SIRT6 leads to tumor formation without activation of known oncogenes, whereas transformed SIRT6-deficient cells display increased glycolysis and tumor growth, suggesting that SIRT6 plays a role in both establishment and maintenance of cancer. By using a conditional SIRT6 allele, we show that SIRT6 deletion in vivo increases the number, size, and aggressiveness of tumors. SIRT6 also functions as a regulator of ribosome metabolism by corepressing MYC transcriptional activity. Lastly, Sirt6 is selectively downregulated in several human cancers, and expression levels of SIRT6 predict prognosis and tumor-free survival rates, highlighting SIRT6 as a critical modulator of cancer metabolism. Our studies reveal SIRT6 to be a potent tumor suppressor acting to suppress cancer metabolism.

Colorectal cancer in the elderly and the influence of lead time bias: better survival does not equate with improved life expectancy.

AIMS: Poorer outcomes in those aged ≥80 years who undergo colorectal cancer surgery have been previously reported. Little is known about the natural history of those managed non-operatively. We explored outcomes in all patients with colorectal cancer aged ≥80 years at time of diagnosis based on treatment received. METHODS: Patients ≥80 years diagnosed with colorectal cancer in one hospital trust between 1998 and 2011 were identified from a prospectively maintained database. Primary endpoints were age at diagnosis, age at death/censor and mortality at 30, 90 and 365 days. RESULTS: Six hundred sixty-eight patients were identified. Four hundred twelve (61.7%) underwent surgery, 44 (6.6%) received endoscopic therapy and 212 (31.7%) had no active treatment. Of those who underwent surgery, 359 (87.1%) had resectional surgery, 34 (8.3%) defunctioning only, 13 (3.2%) received bypass surgery and 6 (1.5%) had an open and close laparotomy. The mean age at diagnosis was younger in those who underwent surgical resection (83.7 years) compared to those having defunctioning surgery (84.9 years, P = 0.043), endoscopic therapy (85.1 years, P = 0.008) or no surgical intervention (85.6 years, P < 0.001). There was no significant difference in the mean age of death or censor between groups. CONCLUSIONS: There was no significant difference in age at death or censor between treatment groups among patients aged ≥80 years presenting with colorectal cancer, suggesting that differences in the observed survival time are heavily influenced by lead time bias. Age at death or censor should be reported in addition to survival times in this age group to enable fair comparison of outcomes.

Fascicular tachycardia in infancy and the use of verapamil: a case series and literature review.

OBJECTIVE: Guidelines state that verapamil is contraindicated in infants. This is based on reports of cardiovascular collapse and even death after rapid intravenous administration of verapamil in infants with supraventricular tachycardia (SVT). We wish to challenge this contraindication for the specific indication of verapamil sensitive ventricular tachycardia (VSVT) in infants. DESIGN: Retrospective case series and critical literature review. SETTING: Hospitals within New Zealand. PATIENTS: We present a series of three infants/young children with VSVT or 'fascicular VT'. RESULTS: Three children aged between 8 days and 2 years presented with tachycardia 200-220 beats per minute with right bundle brunch block and superior axis. Adenosine failed to cardiovert and specialist review diagnosed VSVT. There were no features of cardiovascular shock. Verapamil was given as a slow infusion over 10-30 min (rather than as a push) and each successfully cardioverted without incident. Critical review of the literature reveals that cardiovascular collapses were associated with a rapid intravenous push in cardiovascularly compromised infants and/or infants given other long-acting antiarrhythmics prior to verapamil. CONCLUSIONS: Verapamil is specifically indicated for the treatment of fascicular VT, and for this indication should be used in infancy, as well as in older children, as first-line treatment or after failure of adenosine raises suspicion of the diagnosis. We outline how to distinguish this tachycardia from SVT and propose a strategy for the safe intravenous slow infusion of verapamil in children, noting that extreme caution is necessary with pre-existing ventricular dysfunction.

Stercoral perforation of the colon in a heroin addict.

A 27-year-old female heroin addict presented with a peritonitic and distended abdomen. Her medical history included depression and a 3-year history of heroin abuse with attendant constipation. CT scan showed free intraperitoneal gas, massive faecal distension of the rectum and sigmoid colon and likely bowel necrosis. She underwent an emergency Hartmann's procedure for perforation of the sigmoid colon. Pathology identified two areas of stercoral ulceration, one of them being the area of perforation. Postoperatively, the patient developed a deep vein thrombosis and is now on anticoagulant therapy. She was discharged 4 weeks after admission. The patient has been reviewed at follow-up clinic by the surgical team and specialist stoma nurses. She is coping well with good stoma function. We will perform a colonoscopy to identify any further areas of stercoral ulceration but there are no plans for further surgery at present.

Retrospective epidemiology of acute rheumatic fever: a 10-year review in the Waikato District Health Board area of New Zealand.

BACKGROUND: Acute rheumatic fever (ARF) is a preventable disease which remains a prominent burden of health in New Zealand, with an annual incidence comparable to that of developing countries. AIM: The aim of this study was to describe the epidemiology of ARF and recurrent ARF cases in the Waikato District Health Board (DHB) area of New Zealand from 1 January 2002 to 31 December 2011. METHODS: A total of 106 cases of ARF and four cases of recurrent ARF were identified through the Public Health Database - EpiSurv and the Hospital coding system, ICD-10. RESULTS: The overall Waikato DHB annual incidence of ARF was 3.1 per 100,000 population with Maori children aged 5-14 years experiencing higher rates of 46.1 per 100,000 population. Eighty-five percent of the cases were of Maori ethnicity, and 10% Pacific. Almost three-quarters of all cases lived in areas of the three most deprived deciles as described by the New Zealand Deprivation Index 2006. DISCUSSION: The rates of ARF seen in the Waikato DHB are comparable to that seen previously locally and nationally. High risk groups have been identified as children aged 5-14 years, Maori and Pacific ethnicity, and those living in lower socioeconomic areas which could be targeted by the Rheumatic Fever Prevention Programme (RFPP) with the intention to reduce the incidence of ARF nationally to 0.4 cases per 100,000 population by 2017.

Community detection of long QT syndrome with a clinical registry: an alternative to ECG screening programs?

BACKGROUND: Long QT syndrome (LQTS) prevalence is estimated at 4 of 10,000 based on community electrocardiogram (ECG) screening, about which there is disagreement regarding efficacy, accuracy, cost-effectiveness, and practicality. Family studies of autosomal dominant conditions such as LQTS have revealed 8-9 gene-positive family members per proband. OBJECTIVE: To evaluate a cardiac/genetic registry and family screening program as a tool to identify LQTS in the community. METHODS: Possible LQTS probands were referred to the New Zealand Cardiac Inherited Disease service. The registry was first established in the northern region (population 2.03 million), including central Auckland (population 0.46 million). After clinical evaluation, genetic testing and family cascade screening were initiated. Genotype-positive individuals were classified as definite LQTS, and others were classified as definite or probable LQTS by clinical and ECG criteria. RESULTS: One hundred twelve probands were identified (presentation: 7 sudden death, 82 cardiac event, 16 ECG abnormality, and 7 sudden death of a family member). Following cascade screening, 309 patients with LQTS were identified (248 definite and 61 probable). Two hundred twenty patients had LQTS-causing mutations identified (120 [55%] LQT1, 78 [35%] LQT2, 19 [9%] LQT3, 1 [0.5%] LQT 5, and 2 [1%] LQT7). Thus far, an average of 2.1 definitely or probably affected family members have been identified per proband. The community detection rate is 1.5 of 10,000 for the whole region and 2.2 of 10,000 in Auckland. CONCLUSIONS: A high level of community detection of LQTS is possible using a clinical registry. With adequate resourcing, this has the potential to be an effective alternative to community ECG screening.

Telomere attrition and decreased fetuin-A levels indicate accelerated biological aging and are implicated in the pathogenesis of colorectal cancer.

PURPOSE: Increasing chronological age is a risk factor for many types of cancer including colorectal. An understanding of the biology of aging and factors which regulate it may provide insight into cancer pathogenesis. The role of telomere biology in both the cancer and aging process could prove useful in this regard. EXPERIMENTAL DESIGN: Using quantitative PCR, we determined telomere length in the peripheral blood leukocytes of 64 colorectal cancer (CRC) patients and 1,348 controls. We also measured telomere length in 32 colorectal tumor samples and matched normal tissue. We aimed to assess whether telomere lengths were reflected in circulating mediators of inflammation and redox control factors, including fetuin-A, a circulating modulator of calcium homeostasis. RESULTS: CRC patients had shorter telomeres [adjusted mean ratio of relative telomere repeat copy number to single-copy gene number (RelT/S) = 0.61] compared with chronologically older controls (mean age = 75, adjusted mean RelT/S = 0.70; ANCOVA, P = 0.004). Telomere length in tumor tissue [median = 0.43, interquartile range (IQR) = 0.40] was significantly shorter than adjacent normal tissue (median = 0.65, IQR = 0.28; P = 0.004). Patients with low fetuin-A levels were shown to have significantly shorter telomeres (P = 0.041). Patients with rectal tumors had significantly higher levels of fetuin-A than those with colonic tumors (P = 0.045). CONCLUSIONS: We have observed that patients with CRC display clear evidence of telomere attrition compared with controls. This is congruent with accelerated biological aging in the pathogenesis of CRC. An imbalance in redox control mechanisms and calcium homeostasis may be a contributing factor to telomere dynamics in our patients. Furthermore, fetuin-A levels can be used to distinguish between colon and rectal cancers.

Prospective, population-based long QT molecular autopsy study of postmortem negative sudden death in 1 to 40 year olds.

BACKGROUND: Retrospective investigation of sudden unexplained death in the young (SUDY) reveals that a high proportion is due to inherited heart disease. OBJECTIVE: The purpose of this study was to ascertain the diagnostic value of postmortem long QT (LQT) genetic analysis in a prospective study of SUDY victims 1-40 years old. METHODS: Denaturing high-performance liquid chromatography or direct sequencing of LQT genes 1, 2, 3, 5, and 6 was performed, in a National New Zealand protocol, in SUDY victims aged 1-40 years. RESULTS: Over 26 months (2006-2008), DNA was stored at autopsy from 52 victims of sudden unexpected death. Further testing revealed a diagnosis in 19 cases (poisoning 4, dilated cardiomyopathy 3, myocarditis 3, other 9). The remaining 33 cases underwent genetic testing (age at death 18 months-40 years, median 25 years). Eighteen (55%) died during sleep or at rest, and 7 (21%) died during light activity. Rare missense variants in LQT genes were found in 5 (15%) cases (confidence interval 3%-27%): T96R in KCNQ1 (11-year-old male), P968L in KCNH2 (32-year-old female), P2006A in SCN5A (34-year-old female), and R67H and R98W in KCNE1 (17- and 38-year-old females, respectively). Evidence of pathogenicity was provided by in vitro evidence (T96R), family phenotype-genotype co-segregation (R98W, P2006A), and/or previous reports (R67H, P968L, P2006A, R98W). Family cardiac investigation was possible in 23 (70%) families and revealed probable cause of death for 5 (15%) other victims (confidence interval 3%-27%). CONCLUSION: Most community SUDY occurs at rest or during light activity. A diagnostic rate of 15% supports the transition of LQT genetic autopsy, combined with family investigation, into routine medical practice.