Nutrient-responsive mTOR signalling grows on Sterile ground

The control of cell growth, that is cell size, is largely controlled by mTOR (the mammalian target of rapamycin), a large serine/threonine protein kinase that regulates ribosome biogenesis and protein translation. mTOR activity is regulated both by the availability of growth factors, such as insulin/IGF-1 (insulin-like growth factor 1), and by nutrients, notably the supply of certain key amino acids. The last few years have seen a remarkable increase in our understanding of the canonical, growth factor-regulated pathway for mTOR activation, which is mediated by the class I PI3Ks (phosphoinositide 3-kinases), PKB (protein kinase B), TSC1/2 (the tuberous sclerosis complex) and the small GTPase, Rheb. However, the nutrient-responsive input into mTOR is important in its own right and is also required for maximal activation of mTOR signalling by growth factors. Despite this, the details of the nutrient-responsive signalling pathway(s) controlling mTOR have remained elusive, although recent studies have suggested a role for the class III PI3K hVps34. In this issue of the Biochemical Journal, Findlay et al. demonstrate that the protein kinase MAP4K3 [mitogen-activated protein kinase kinase kinase kinase-3, a Ste20 family protein kinase also known as GLK (germinal centre-like kinase)] is a new component of the nutrient-responsive pathway. MAP4K3 activity is stimulated by administration of amino acids, but not growth factors, and this is insensitive to rapamycin, most likely placing MAP4K3 upstream of mTOR. Indeed, MAP4K3 is required for phosphorylation of known mTOR targets such as S6K1 (S6 kinase 1), and overexpression of MAP4K3 promotes the rapamycin-sensitive phosphorylation of these same targets. Finally, knockdown of MAP4K3 levels causes a decrease in cell size. The results suggest that MAP4K3 is a new component in the nutrient-responsive pathway for mTOR activation and reveal a completely new function for MAP4K3 in promoting cell growth. Given that mTOR activity is frequently deregulated in cancer, there is much interest in new strategies for inhibition of this pathway. In this context, MAP4K3 looks like an attractive drug target since inhibitors of this enzyme should switch off mTOR, thereby inhibiting cell growth and proliferation, and promoting apoptosis.

TAP deficiency syndrome: chronic rhinosinusitis and conductive hearing loss

Nose-ear-throat manifestations of immunodeficiency disorders represent a diagnostic challenge for clinicians as these diseases often constitute the initial sign for connective disorders or autoimmune disease. The history of chronic rhinosinusitis and conductive hearing loss is often non specific. Therefore attention to an HLA class I deficiency must be considered if the disease has not been diagnosed on routine examination. One of the syndromes is due to a defective TAP complex, the peptide transporter complex associated with antigen presentation. Herein, we report two sisters with TAP-deficiency. The treatment of choice for TAP-deficient patients is conservative.

Preliminary results following reinforcement of the pulmonary autograft to prevent dilatation after the Ross procedure

OBJECTIVE: The Ross operation remains a controversially discussed procedure, because concern exists regarding late dilatation of the neoaortic root and progressive regurgitation of the autograft valve. We present our early experience with an external reinforcement of the autograft, which is inserted into a prosthetic Dacron graft with an artificial aortic root configuration. This detail should help to prevent neoaortic root dilatation. PATIENTS AND METHODS: Between 2006 and 2007, 12 patients (mean age 16 +/- 38 years; range 15-38 years) underwent a Ross procedure by this technique. Indications were aortic regurgitation (n = 2), aortic stenosis (n = 5), and combined aortic stenosis and insufficiency (n = 5). A bicuspid aortic valve was present in 9 patients. Balloon valvuloplasty had been performed in 7 patients. Follow-up was performed by clinical and echocardiographic examinations. RESULTS: No early or late deaths occurred in this small series, and freedom from reoperation is 100%. Echocardiographic follow-up confirmed absence of aortic insufficiency in 11 patients after a mean of 11 months (range 2-30 months). In 1 patient, a small asymmetric regurgitation jet was already observed at discharge echocardiography. As expected, no neoaortic root dilatation was observed during follow-up. All patients are in New York Heart Association class I. CONCLUSIONS: The present technique is a simple and reproducible technical step that does not require significant additional time. Inclusion of the autograft within a root prosthesis may be especially indicated in situations known for late autograft dilatation, namely, bicuspid aortic valve, predominant aortic insufficiency, and ascending aortic enlargement.

Impact of changing definitions for myocardial infarction: a report from the AMIS registry

BACKGROUND: To assess the impact of the new definitions of myocardial infarction, we retrospectively analyzed 9190 patients from 63 hospitals with reported peak troponin values included between 2001 and 2007 in the Swiss AMIS (Acute Myocardial Infarction in Switzerland) Plus registry. METHODS: Patients were classified as belonging to the "classic" myocardial infarction group (peak total CK or CK-MB above the upper limit of normal, or troponin T [TnT] >0.1 microg/L or troponin I [TnI] >0.1-0.8 microg/L [depending on the assay]) or "new" myocardial infarction group (TnT >0.01 microg/L or TnI >0.01-0.07 microg/L). RESULTS: There were 489 patients in the "new" group who were similar to the 8701 "classic" patients in terms of age, sex, and prevalence of both diabetes and renal failure, but more frequently had a history of prior coronary artery disease, hypertension, and hyperlipidemia. At admission, they less frequently had ST elevation on their electrocardiogram, were more frequently in Killip class I, and received less primary percutaneous coronary intervention. Hospital mortality was 3.5% in the "new" and 6.7% in the "classic" myocardial infarction group (P=.004). In a subset of patients with a longer follow-up, mortality at 3 and 12 months was 1% and 5.6%, respectively, for "new" and 1.6% and 4%, respectively, for "classic" myocardial infarction (NS). CONCLUSIONS: Patients with minimal elevation of serum troponin have smaller infarctions, less aggressive treatment, fewer early complications, and a better early prognosis than patients with higher serum biomarker levels. After discharge, however, their prognosis currently appears no different from that of patients with a "classic" myocardial infarction event.

The Ross procedure in infants and young children

BACKGROUND: This study reviews our experience with the Ross procedure in infants and young children. METHODS: From September 1993 to September 2004, 52 children less than 15 years of age underwent a Ross procedure. The patients ranged in age from 4 days to 15 years old (median, 5 years). Fifteen patients (29%) were less than 2 years of age. The predominant indication for the Ross procedure was aortic stenosis. Sixteen patients underwent a Ross-Konno procedure for severe left ventricular outflow tract obstruction. Thirty-four patients had 48 previous interventions. Preoperatively, 6 patients showed severe left ventricular dysfunction, and 2 of the patients required ventilation and inotropic support. Concomitant procedures were performed in 8 patients. Three patients had a mitral valve replacement, 2 patients had a ventricular septal defect closure and an aortic arch reconstruction, 2 patients had aortic arch reconstructions, and 1 patient had resection of a coarctation and a ventricular septal defect closure. RESULTS: Patients were followed up for a median of 43 months (range, 1 to 130). Overall survival was 85% +/- 5% at 1 and 82% +/- 5% at 2, 5, and 10 years. Hospital mortality was 5 of 52 patients (9.6%). All deaths occurred in neonates or infants less than 2 months of age, who needed urgent surgery. Three patients died late of noncardiac causes. At last follow-up, all patients were classified in New York Heart Association functional class I or II. No patient had endocarditis of the autograft or the right ventricular outflow tract replacement. During the follow-up, no event of thrombembolism was observed. No patient required the insertion of a permanent pacemaker. Overall freedom from reoperation is 57% +/- 15% at 10 years. One patient required the replacement of the autograft at 6 months postoperatively. The development of mild aortic insufficiency was observed in 24 patients, and moderate aortic insufficiency in 1 patient during follow-up. Freedom from reoperation for the right ventricular outflow tract replacement is 60% +/- 15% at 10 years. CONCLUSIONS: The Ross procedure represents an attractive approach to aortic valve disease in young children. However, a high early mortality rate has to be considered when performing this procedure in neonates or infants who present in critical preoperative condition.

Quality of life of grown-up congenital heart disease patients after congenital cardiac surgery

BACKGROUND: Due to better early and long-term outcome, the increasing population of grown-ups with congenital heart disease (GUCH) brings up unexpected quality of life (QoL) issues. The cardiac lesion by itself is not always the major problem for these patients, since issues pertaining to QoL and psychosocial aspects often predominate. This study analyses the QoL of GUCH patients after cardiac surgery and the possible impact of medical and psychosocial complications. PATIENTS AND METHODS: A questionnaire package containing the SF-36 health survey (health related QoL), the HADS test (anxiety/depression aspects) and an additional disease specific questionnaire was sent to 345 patients (mean 26+/-11 years) operated for isolated transposition of the great arteries (TGA), tetralogy of Fallot (TOF), and ventricular septal defect (VSD). The scores were compared with age- and gender-matched standard population data and in relation to the underlying congenital heart disease (CHD). RESULTS: In all SF-36 and HADS health dimensions the GUCH patients showed excellent scores (116+/-20), which are comparable to the standard population (100+/-15), regardless of the initial CHD (p=0.12). Eighty-two percent of the patients were found to be in NYHA class I and 83% patients declared that they do not consider their QoL to be limited by their malformation. Complications like reoperations (p=0.21) and arrhythmias (p=0.10) do not show significant impact on the QoL. The additional questionnaire revealed that 76% of adult patients have a fulltime job, 18% receive a full or partial disability pension, 21% reported problems with insurances, most of them regarding health insurances (67%), and 4.4% of adult patients declared to have renounced the idea of having children due to their cardiac malformation. CONCLUSION: QoL in GUCH patients following surgical repair of isolated TOF, TGA and VSD is excellent and comparable to standard population, this without significant difference between the diagnosis groups. However, these patients are exposed to a high rate of complications and special psychosocial problems, which are not assessed by standardized questionnaires, such as the SF-36 and HADS. These findings highlight the great importance for a multidisciplinary and specialized follow-up for an adequate management of these complex patients.

Cathepsin G is differentially expressed in primary human antigen-presenting cells

Cathepsins are required for the processing of antigens in order to make them suitable for loading on major histocompatibility complex (MHC) class II molecules, for subsequent presentation to CD4(+) T cells. It was shown that antigen processing in monocyte-derived dendritic cells (DC), a commonly used DC model, is different from that of primary human DC. Here, we report that the two subsets of human myeloid DC (mDC) and plasmacytoid DC (pDC) differ in their cathepsin distribution. The serine protease cathepsin G (CatG) was detected in mDC1, mDC2, pDC, cortical thymic epithelial cells (cTEC) and high levels of CatG were determined in pDC. To address the role of CatG in the processing and presentation of a Multiple Sclerosis-associated autoantigen myelin basic protein (MBP), we used a non-CatG expressing fibroblast cell line and fibroblasts, which were preloaded with purified CatG. We find that preloading fibroblasts with CatG results in a decrease of MBP84-98-specific T cell proliferation, when compared to control cells. Our data suggest a different processing signature in primary human antigen-presenting cells and CatG may be of functional importance.

Early loading of nonsubmerged titanium implants with a chemically modified sand-blasted and acid-etched surface: 6-month results of a prospective case series study in the posterior mandible focusing on peri-implant crestal bone changes and implant stability quotient (ISQ) values

PURPOSE: The aim of this prospective case series study was to evaluate the short-term success rates of titanium screw-type implants with a chemically modified sand-blasted and acid-etched (mod SLA) surface after 3 weeks of healing. MATERIAL AND METHODS: A total of 56 implants were inserted in the posterior mandible of 40 partially edentulous patients exhibiting bone densities of class I to III. After a healing period of 3 weeks, all implants were functionally loaded with a screw-retained crown or fixed dental prosthesis. The patients were recalled at weeks 4, 7, 12, and 26 for monitoring and assessment of clinical and radiological parameters, including implant stability quotient (ISQ) measurements. RESULTS: None of the implants failed to integrate. However, two implants were considered "spinners" at day 21 and left unloaded for an extended period. Therefore, 96.4% of the inserted implants were loaded according to the protocol tested. All 56 implants including the "spinners" showed favorable clinical and radiographic findings at the 6-month follow-up examination. The ISQ values increased steadily throughout the follow-up period. At the time of implant placement, the range of ISQ values exhibited a mean of 74.33, and by week 26, a mean value of 83.82 was recorded. Based on strict criteria, all 56 implants were considered successfully integrated, resulting in a 6-month survival and success rate of 100.0%. CONCLUSION: This prospective study using an early-loading protocol after 3 weeks of healing demonstrated that titanium implants with the modified SLA surface can achieve and maintain successful tissue integration over a period of at least 6 months. The ISQ method seems feasible to monitor implant stability during the initial wound-healing period.