Operative strategy for fistula-in-ano without division of the anal sphincter

We would like to thank Mr ER MacDonald for his contribution in data collection during the early years of the study. The material in this paper was presented as a poster at the annual meeting of the American Society of Colon and Rectal Surgeons held in Vancouver, Canada, May 2011.Peer reviewedPublisher PD

Human exercise-induced circulating progenitor cell mobilization is nitric oxide-dependent and is blunted in South Asian men

This article is available open access through the publisher’s website. Copyright @ 2010 American Heart Foundation.Objective— Circulating progenitor cells (CPC) have emerged as potential mediators of vascular repair. In experimental models, CPC mobilization is critically dependent on nitric oxide (NO). South Asian ethnicity is associated with reduced CPC. We assessed CPC mobilization in response to exercise in Asian men and examined the role of NO in CPC mobilization per se. Methods and Results— In 15 healthy, white European men and 15 matched South Asian men, CPC mobilization was assessed during moderate-intensity exercise. Brachial artery flow-mediated vasodilatation was used to assess NO bioavailability. To determine the role of NO in CPC mobilization, identical exercise studies were performed during intravenous separate infusions of saline, the NO synthase inhibitor l-NMMA, and norepinephrine.  Flow-mediated vasodilatation (5.8%±0.4% vs 7.9%±0.5%; P=0.002) and CPC mobilization (CD34+/KDR+ 53.2% vs 85.4%; P=0.001; CD133+/CD34+/KDR+ 48.4% vs 73.9%; P=0.05; and CD34+/CD45− 49.3% vs 78.4; P=0.006) was blunted in the South Asian group. CPC mobilization correlated with flow-mediated vasodilatation and l-NMMA significantly reduced exercise-induced CPC mobilization (CD34+/KDR+ −3.3% vs 68.4%; CD133+/CD34+/KDR+ 0.7% vs 71.4%; and CD34+/CD45− −30.5% vs 77.8%; all P<0.001). Conclusion— In humans, NO is critical for CPC mobilization in response to exercise. Reduced NO bioavailability may contribute to imbalance between vascular damage and repair mechanisms in South Asian men.British Heart Foundatio

Hepatic artery aneurysm repair: a case report

<p>Abstract</p> <p>Introduction</p> <p>Hepatic artery aneurysms remain a clinically significant entity. Their incidence continues to rise slowly and mortality from spontaneous rupture is high. Repair is recommended in those aneurysms greater than 2 cm in diameter. It is not surprising that vascular comorbidities, such as ischaemic heart disease, are common in surgical patients, particularly those with arterial aneurysms such as these. The decision of when to operate on patients who require urgent surgery despite having recently suffered an acute coronary syndrome remains somewhat of a grey and controversial area. We discuss the role of delayed surgery and postoperative followup of this vascular problem.</p> <p>Case presentation</p> <p>A 58-year-old man was admitted with a 5.5 cm hepatic artery aneurysm. The aneurysm was asymptomatic and was an incidental finding as a result of an abdominal computed tomography scan to investigate an episode of haemoptysis (Figure <figr fid="F1">1</figr>). Three weeks prior to admission, the patient had suffered a large inferior myocardial infarction and was treated by thrombolysis and primary coronary angioplasty. Angiographic assessment revealed a large aneurysm of the common hepatic artery involving the origins of the hepatic, gastroduodenal, left and right gastric arteries and the splenic artery (Figures <figr fid="F2">2</figr> and <figr fid="F3">3</figr>). Endovascular treatment was not considered feasible and immediate surgery was too high-risk in the early post-infarction period. Therefore, surgery was delayed for 3 months when aneurysm repair with reconstruction of the hepatic artery was successfully performed. Graft patency was confirmed with the aid of an abdominal arterial duplex. Plasma levels of conventional liver function enzymes and of alpha-glutathione-<it>S</it>-transferase were within normal limits. This was used to assess the extent of any hepatocellular damage perioperatively. The patient made a good recovery and was well at his routine outpatient check-ups.</p> <p>Conclusion</p> <p>There is no significant difference in cardiac risk in patients who have undergone vascular surgery within 6 months of a myocardial infarction compared with those who have had the operation in the 6 to12 month time frame. Use of alpha-glutathione-<it>S</it>-transferase gives an indication of the immediate state of hepatic function and should be used in addition to traditional liver function tests to monitor hepatic function postoperatively.</p

CTLA-4 Activation of Phosphatidylinositol 3-Kinase (PI 3-K) and Protein Kinase B (PKB/AKT) Sustains T-Cell Anergy without Cell Death

The balance of T-cell proliferation, anergy and apoptosis is central to immune function. In this regard, co-receptor CTLA-4 is needed for the induction of anergy and tolerance. One central question concerns the mechanism by which CTLA-4 can induce T-cell non-responsiveness without a concurrent induction of antigen induced cell death (AICD). In this study, we show that CTLA-4 activation of the phosphatidylinositol 3-kinase (PI 3-K) and protein kinase B (PKB/AKT) sustains T-cell anergy without cell death. CTLA-4 ligation induced PI 3K activation as evidenced by the phosphorylation of PKB/AKT that in turn inactivated GSK-3. The level of activation was similar to that observed with CD28. CTLA-4 induced PI 3K and AKT activation also led to phosphorylation of the pro-apoptotic factor BAD as well as the up-regulation of BcL-XL. In keeping with this, CD3/CTLA-4 co-ligation prevented apoptosis under the same conditions where T-cell non-responsiveness was induced. This effect was PI 3K and PKB/AKT dependent since inhibition of these enzymes under conditions of anti-CD3/CTLA-4 co-ligation resulted in cell death. Our findings therefore define a mechanism by which CTLA-4 can induce anergy (and possibly peripheral tolerance) by preventing the induction of cell death

Rectal Transmission of Transmitted/Founder HIV-1 Is Efficiently Prevented by Topical 1% Tenofovir in BLT Humanized Mice

Rectal microbicides are being developed to prevent new HIV infections in both men and women. We focused our in vivo preclinical efficacy study on rectally-applied tenofovir. BLT humanized mice (n = 43) were rectally inoculated with either the primary isolate HIV-1(JRCSF) or the MSM-derived transmitted/founder (T/F) virus HIV-1(THRO) within 30 minutes following treatment with topical 1% tenofovir or vehicle. Under our experimental conditions, in the absence of drug treatment we observed 50% and 60% rectal transmission by HIV-1(JRCSF) and HIV-1(THRO), respectively. Topical tenofovir reduced rectal transmission to 8% (1/12; log rank p = 0.03) for HIV-1(JRCSF) and 0% (0/6; log rank p = 0.02) for HIV-1(THRO). This is the first demonstration that any human T/F HIV-1 rectally infects humanized mice and that transmission of the T/F virus can be efficiently blocked by rectally applied 1% tenofovir. These results obtained in BLT mice, along with recent ex vivo, Phase 1 trial and non-human primate reports, provide a critically important step forward in the development of tenofovir-based rectal microbicides

Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control

DNA replication stress is a source of genomic instability. Here we identify ​changed mutation rate 1 (​Cmr1) as a factor involved in the response to DNA replication stress in Saccharomyces cerevisiae and show that ​Cmr1—together with ​Mrc1/​Claspin, ​Pph3, the chaperonin containing ​TCP1 (CCT) and 25 other proteins—define a novel intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins in response to genotoxic stress. The diversity of proteins that localize to INQ indicates that other biological processes such as cell cycle progression, chromatin and mitotic spindle organization may also be regulated through INQ. Similar to ​Cmr1, its human orthologue ​WDR76 responds to proteasome inhibition and DNA damage by relocalizing to nuclear foci and physically associating with CCT, suggesting an evolutionarily conserved biological function. We propose that ​Cmr1/​WDR76 plays a role in the recovery from genotoxic stress through regulation of the turnover of sumoylated and phosphorylated proteins

A portable prototype magnetometer to differentiate ischemic and non-ischemic heart disease in patients with chest pain

Background: Magnetocardiography (MCG) is a non-invasive technique used to measure and map cardiac magnetic fields. We describe the predictive performance of a portable prototype magnetometer designed for use in acute and routine clinical settings. We assessed the predictive ability of the measurements derived from the magnetometer for the ruling-out of healthy subjects and patients whose chest pain has a non-ischemic origin from those with ischemic heart disease (IHD). Methods: MCG data were analyzed from a technical performance study, a pilot clinical study, and a young healthy reference group. Participants were grouped to enable differentiation of those with IHD versus non-IHD versus controls: Group A (70 IHD patients); Group B (69 controls); Group C (37 young healthy volunteers). Scans were recorded in an unshielded room. Between-group differences were explored using analysis of variance. The ability of 10 candidate MCG predictors to predict normal/abnormal cases was analyzed using logistic regression. Predictive performance was internally validated using repeated five-fold cross-validation. Results: Three MCG predictors showed a significant difference between patients and age-matched controls (P<0.001); eight predictors showed a significant difference between patients and young healthy volunteers (P<0.001). Logistic regression comparing patients with controls yielded a specificity of 35.0%, sensitivity of 95.4%, and negative predictive value for the ruling-out of IHD of 97.8% (area under the curve 0.78). Conclusion: This analysis represents a preliminary indication that the portable magnetometer can help rule-out healthy subjects and patients whose chest pain has a non-ischemic origin from those with IHD

Cardiovascular magnetic resonance in patients with pectus excavatum compared with normal controls

<p>Abstract</p> <p>Purpose</p> <p>To assess cardiothoracic structure and function in patients with pectus excavatum compared with control subjects using cardiovascular magnetic resonance imaging (CMR).</p> <p>Method</p> <p>Thirty patients with pectus excavatum deformity (23 men, 7 women, age range: 14-67 years) underwent CMR using 1.5-Tesla scanner (Siemens) and were compared to 25 healthy controls (18 men, 7 women, age range 18-50 years). The CMR protocol included cardiac cine images, pulmonary artery flow quantification, time resolved 3D contrast enhanced MR angiography (CEMRA) and high spatial resolution CEMRA. Chest wall indices including maximum transverse diameter, pectus index (PI), and chest-flatness were measured in all subjects. Left and right ventricular ejection fractions (LVEF, RVEF), ventricular long and short dimensions (LD, SD), mid-ventricle myocardial shortening, pulmonary-systemic circulation time, and pulmonary artery flow were quantified.</p> <p>Results</p> <p>In patients with pectus excavatum, the pectus index was 9.3 ± 5.0 versus 2.8 ± 0.4 in controls (P < 0.001). No significant differences between pectus excavatum patients and controls were found in LV ejection fraction, LV myocardial shortening, pulmonary-systemic circulation time or pulmonary flow indices. In pectus excavatum, resting RV ejection fraction was reduced (53.9 ± 9.6 versus 60.5 ± 9.5; P = 0.013), RVSD was reduced (P < 0.05) both at end diastole and systole, RVLD was increased at end diastole (P < 0.05) reflecting geometric distortion of the RV due to sternal compression.</p> <p>Conclusion</p> <p>Depression of the sternum in pectus excavatum patients distorts RV geometry. Resting RVEF was reduced by 6% of the control value, suggesting that these geometrical changes may influence myocardial performance. Resting LV function, pulmonary circulation times and pulmonary vascular anatomy and perfusion indices were no different to controls.</p

A comparison of echocardiography to invasive measurement in the evaluation of pulmonary arterial hypertension in a rat model

Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by progressive elevation in pulmonary artery pressure (PAP) and total pulmonary vascular resistance (TPVR). Recent advances in imaging techniques have allowed the development of new echocardiographic parameters to evaluate disease progression. However, there are no reports comparing the diagnostic performance of these non-invasive parameters to each other and to invasive measurements. Therefore, we investigated the diagnostic yield of echocardiographically derived TPVR and Doppler parameters of PAP in screening and measuring the severity of PAH in a rat model. Serial echocardiographic and invasive measurements were performed at baseline, 21 and 35 days after monocrotaline-induction of PAH. The most challenging echocardiographic derived TPVR measurement had good correlation with the invasive measurement (r = 0.92, P < 0.001) but also more simple and novel parameters of TPVR were found to be useful although the non-invasive TPVR measurement was feasible in only 29% of the studies due to lack of sufficient tricuspid valve regurgitation. However, echocardiographic measures of PAP, pulmonary artery flow acceleration time (PAAT) and deceleration (PAD), were measurable in all animals, and correlated with invasive PAP (r = −0.74 and r = 0.75, P < 0.001 for both). Right ventricular thickness and area correlated with invasive PAP (r = 0.59 and r = 0.64, P < 0.001 for both). Observer variability of the invasive and non-invasive parameters was low except in tissue-Doppler derived isovolumetric relaxation time. These non-invasive parameters may be used to replace invasive measurements in detecting successful disease induction and to complement invasive data in the evaluation of PAH severity in a rat model