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Patients with acute myocardial infarction (AMI) often experience anxiety, an emotion that predicts adverse physiologic outcomes. The purpose of this study was to deter-mine whether a single-item anxiety assessment instrument, the Anxiety Level Index (ALI), is a valid alternative to the State Anxiety Index (SAI) or the anxiety subscale of the Brief Symptom Inventory (BSI) for assessing state anxiety for patients with AMI. In this prospective multicenter study, 243 inpatients with AMI rated their anxiety using the SAI, the anxiety subscale of the BSI, and the ALI. Anxiety Level Index scores were compared to SAI and BSI anxiety subscale scores. There were moderate, positive correlations between the SAl and the ALI (r[s] = 0.52, P < .001), and between the ALI and the anxiety subscale of the BSI (r[s] = 0.45, P < .001). Although ALI scores were moderately and significantly correlated with scores on the SAI and the BSI anxiety subscales, the results of the Bland-Altman method indicate a lack of construct validity of the single-item measure. The quest continues to construct a simple self report measure of anxiety that is appropriate for critically ill patients with AMI. [ABSTRACT FROM AUTHOR]

Background: This study investigates the potential influence of genotype and parent-of-origin effects (POE) on the clinical manifestations of Lynch syndrome (LS) within families carrying (likely) disease-causing MSH6 germline variants., Patients and Methods: A cohort of 1615 MSH6 variant carriers (310 LS families) was analyzed. Participants were categorized based on RNA expression and parental inheritance of the variant. Hazard ratios (HRs) were calculated using weighted Cox regression, considering external information to address ascertainment bias. The findings were cross-validated using the Prospective Lynch Syndrome Database (PLSD) for endometrial cancer (EC)., Results: No significant association was observed between genotype and colorectal cancer (CRC) risk (HR = 1.06, 95% confidence interval [CI]: 0.77-1.46). Patients lacking expected RNA expression exhibited a reduced risk of EC (Reference Cohort 1: HR = 0.68, 95% CI: 0.43-1.03; Reference Cohort 2: HR = 0.63, 95% CI: 0.46-0.87). However, these results could not be confirmed in the PLSD. Moreover, no association was found between POE and CRC risk (HR = 0.78, 95% CI: 0.52-1.17) or EC risk (Reference Cohort 1: HR = 0.93, 95% CI: 0.65-1.33; Reference Cohort 2: HR = 0.8, 95% CI: 0.64-1.19)., Discussion and Conclusion: No evidence of POE was detected in MSH6 families. While RNA expression may be linked to varying risks of EC, further investigation is required to explore this observation., (© 2024 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Purpose: Females with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies., Methods: Exome sequencing of individuals who developed multiple primary malignancies identified 3 individuals with the CHEK2 (NM&#95;007194.4) c.1100del p.(Thr367MetfsTer15) loss-of-function gPV in a biallelic state. We collected the phenotypes of an additional cohort of individuals with CHEK2 biallelic gPVs (n = 291)., Results: In total, 157 individuals (53.4%; 157/294 individuals) developed ≥1 (pre)malignancy. The most common (pre)malignancies next to breast cancer were colorectal- (n = 19), thyroid- (n = 19), and prostate (pre)malignancies (n = 12). Females with biallelic CHEK2 loss-of-function gPVs more frequently developed ≥2 (pre)malignancies and at an earlier age compared with females biallelic for the CHEK2 c.470T>C p.(Ile157Thr) missense variant. Furthermore, 26 males (31%; 26/84 males) with CHEK2 biallelic gPVs developed ≥1 (pre)malignancies of 15 origins., Conclusion: Our study suggests that CHEK2 biallelic gPVs likely increase the susceptibility to develop multiple malignancies in various tissues, both in females and males. However, it is possible that a substantial proportion of individuals with CHEK2 biallelic gPVs is missed as diagnostic testing for CHEK2 often is limited to individuals who developed breast cancer., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Females with PTEN Hamartoma Tumor Syndrome (PHTS) have breast cancer risks up to 76%. This study assessed associations between breast cancer and lifestyle in European female adult PHTS patients. Data were collected via patient questionnaires (July 2020-March 2023) and genetic diagnoses from medical files. Associations between lifestyle and breast cancer were calculated using logistic regression corrected for age. Index patients with breast cancer before PHTS diagnosis (breast cancer index) were excluded for ascertainment bias correction. In total, 125 patients were included who completed the questionnaire at a mean age of 44 years (SD = 13). This included 21 breast cancer indexes (17%) and 39 females who developed breast cancer at 43 years (SD = 9). Breast cancer patients performed about 1.1 times less often 0-1 times/week physical activity than ≥2 times (OR total-adj = 0.9 (95%CI 0.3-2.6); consumed daily about 1.2-1.8 times more often ≥1 than 0-1 glasses of alcohol (OR total-adj = 1.2 (95%CI 0.4-4.0); OR non-breastcancer-index-adj = 1.8 (95%CI 0.4-6.9); were about 1.04-1.3 times more often smokers than non-smokers (OR total-adj = 1.04 (95%CI 0.4-2.8); OR non-breastcancer-index-adj = 1.3 (95%CI 0.4-4.2)); and overweight or obesity (72%) was about 1.02-1.3 times less common (OR total-adj = 0.98 (95%CI 0.4-2.6); OR non-breastcancer-index-adj = 0.8 (95%CI 0.3-2.7)). Similar associations between lifestyle and breast cancer are suggested for PHTS and the general population. Despite not being statistically significant, results are clinically relevant and suggest that awareness of the effects of lifestyle on patients' breast cancer risk is important.

Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This study aimed to identify the various causes of the discordant phenotypes of colorectal cancer (CRC) and endometrial cancer (EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6 variant diagnosed with CRC or EC were categorized based on an microsatellite instability (MSI)/IHC test outcome that might fail to result in a diagnosis of LS (eg, retained staining of all 4 mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6 variant carriers with CRC or EC (n = 590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, 2 out of 3 MSI/IHC cases were found to be concordant with the MSH6 variant, and NGS showed that 4 discordant IHC results were sporadic rather than LS-associated tumors. In 1 case, somatic events explained the discordant phenotype. The use of reflex IHC mismatch repair testing, the current standard in most Western countries, may lead to the misdiagnosis of germline MSH6 variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should be considered in case of a strong positive family history. Germline DNA analysis of the mismatch repair genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: This study aimed to test a computer-driven cardiovascular model for the evaluation of the visceral flow during intra-aortic balloon pump (IABP) assistance., Methods: The model includes a systemic and pulmonary circulation as well as a heart contraction model. The straight polyurethane tube aorta had a single visceral while four windkessel components mimicked resistance compliance of the brachiocephalic, renal and sub-mesenteric, pulmonary, and systemic circulation. Twelve flow probes were placed in the circuit to measure pressures and flows with the IABP on and off., Results: With the balloon off, the meantime to reach the steady state was 48 ± 16 s; with the balloon on, this figure was 178 ± 20 s. The stability of pressure and flow signals was obtained after 72 ± 11 min. The number of cycles of stability of the system was 93 [86-103]. Measurements were reliable either with samples of 10 or 20 beats. Bland Altman method demonstrated the reliability of measurements. Finally, all measurements were comparable to published in vivo data., Conclusion: The presented mock circulation was reliable and gave values with high accuracy both at baseline and during mechanical assistance. This system allows evaluation of the mesenteric flow during IABP, under different clinical/hemodynamic conditions. Nonetheless, its translational potential needs to be further evaluated.

Early-onset breast cancer may be due to Li-Fraumeni Syndrome (LFS). Current national and international guidelines recommend that TP53 genetic testing should be considered for women with breast cancer diagnosed before the age of 31 years. However, large studies investigating TP53 mutation prevalence in this population are scarce. We collected nationwide laboratory records for all young breast cancer patients tested for TP53 mutations in the Netherlands. Between 2005 and 2016, 370 women diagnosed with breast cancer younger than 30 years of age were tested for TP53 germline mutations, and eight (2.2%) were found to carry a (likely) pathogenic TP53 sequence variant. Among BRCA1/BRCA2 mutation negative women without a family history suggestive of LFS or a personal history of multiple LFS-related tumours, the TP53 mutation frequency was < 1% (2/233). Taking into consideration that TP53 mutation prevalence was comparable or even higher in some studies selecting patients with breast cancer onset at older ages or HER2-positive breast cancers, raises the question of whether a very early age of onset is an appropriate single TP53 genetic testing criterion.

Introduction: Mismatch repair deficiency (dMMR) can be found in Lynch syndrome (LS)-associated colorectal carcinoma and in 15% of sporadic colorectal cancer (CRC). Outcome of MMR-deficiency testing is important for surgical decisions as extended colectomy is recommended in young LS-patients with CRC. Moreover, the finding of a dMMR tumour has consequences for the choices of adjuvant chemotherapy as MMR-deficient CRC is resistant to 5-fluorouracil (5-FU) monotherapy. Aims of our study are to evaluate whether MMR-deficiency testing leads to (1) identification of LS, (2) change in surgical treatment and (3) adjustment of systemic therapy in patients with dMMR CRC., Methods: We performed a multicentre, retrospective study, in a community hospital and a University Medical Centre. We included all CRC-patients between 2012 and 2016 who were tested for microsatellite instability. We collected clinical data such as gender, age, referral to clinical geneticist, surgical procedure and choice of chemotherapy., Results: We analysed 225 CRCs. Twenty-four (10.7%) of 225 CRC were MMR-deficient. Of the 24 patients with dMMR CRC, 18 (75%) were referred to the clinical geneticist and in nine (37%) patients a MMR mutation was identified. In one (4%) of the 24 patients, a subtotal colectomy was performed. In seven (35%) out of 20 MMR deficient patients, the chemotherapy regimen was adjusted., Conclusions: The finding of a dMMR CRC had consequences for decisions on chemotherapy in a relative high proportion of patients. We recommend testing in all patients with CRC independent of age at diagnosis, as proper treatment decisions and genetic counselling are very important.

Background: The use of the intra-aortic balloon pump (IABP) as a support device remains controversial due to the fact that a number of studies have shown no benefit in end mortality whilst using this device. One of the reasons for this could be the increase in vascular complications when using the pump. Therefore, the aim of the present review was to assess the current literature available with regards to IABP vascular complications during the clinical situation., Methods: A literature search was performed, searching for IABP complications in adult human studies between 1990 and 2016., Results: A total of 20 reports were identified as fitting the criteria of this study. The majority of vascular complications were limb ischemia, bleeding or mesenteric ischemia. The overall incidence of vascular complications ranged from 0.94% to 31.1%. Diabetes, peripheral vascular disease and hypertension, as well as smoking were all identified as risk factors for complications following IABP. Furthermore, studies supported the use of sheathless balloon insertion to reduce the risk of complications., Conclusion: Major vascular complications, including limb and mesenteric ischemia as well as bleeding and hemorrhage, have been associated with IABP. However, the incidence of these complications was generally low. Further studies are still required to truly understand the risk/benefit associated with the use of IABP.

Context: Paraganglioma (PGL) has the highest degree of heritability among human neoplasms. Current clinical understanding of germline SDHA mutation carriers is limited., Objective: To estimate the contribution of SDHA mutations in PGL and to assess clinical manifestations and age-related penetrance., Design: Nationwide retrospective cohort study., Setting: Tertiary referral centers in the Netherlands (multicenter)., Patients: Germline SDHA analysis was performed in 393 patients with genetically unexplained PGL. Subsequently, 30 index SDHA mutation carriers and 56 nonindex carriers were studied., Main Outcome Measures: SDHA mutation detection yield, clinical manifestations, and SDHA-related disease penetrance., Results: Pathogenic germline SDHA variants were identified in 30 of the 393 referred patients with PGL (7.6%), who had head and neck PGL (21 of 174 [12%]), pheochromocytoma (4 of 191 [2%]), or sympathetic PGL (5 of 28 [18%]). The median age at diagnosis was 43 years (range, 17 to 81 years) in index SDHA mutation carriers compared with 52 years (range, 7 to 90 years) in nonmutation carriers (P = 0.002). The estimated penetrance of any SDHA-related manifestation was 10% at age 70 years (95% confidence interval, 0% to 21%) in nonindex mutation carriers., Conclusion: Germline SDHA mutations are relatively common (7.6%) in patients with genetically unexplained PGL. Most index patients presented with apparently sporadic PGL. In this SDHA series, the largest assembled so far, we found the lowest penetrance of all major PGL predisposition genes. This suggests that recommendations for genetic counseling of at-risk relatives and stringency of surveillance for SDHA mutation carriers might need to be reassessed., (Copyright © 2017 Endocrine Society)

Germline mutations of the gene encoding succinate dehydrogenase subunit B (SDHB) predispose to head-and-neck-paraganglioma (HNPGL), sympathetic PGL, pheochromocytoma and renal cell carcinoma for which regular surveillance is required. SDHB-associated tumors harbor germline and somatic mutations, consistent with Knudson's two-hit hypothesis. To assess the penetrance and optimal surveillance for different manifestations of SDHB mutation carriers. This study included all SDHB mutation carriers who were followed at the Department of Endocrinology at the University Medical Center of Groningen. Kaplan-Meier curves were used to assess the penetrance. Poisson process was used to assess the optimal age to start surveillance and intervals. Ninety-one SDHB-mutation carriers (38 men and 53 women) were included. Twenty-seven mutation carriers (30 %) had manifestations, with an overall penetrance 35 % at the age of 60 years. We calculated that optimal surveillance for HNPGL could start from an age of 27 years with an interval of 3.2 years. This study underscores the relatively low penetrance of disease in SDHB mutation carriers. Use of the Poisson approach provides a more accurate estimation of the age to initiate surveillance and length of intervals for HNPGL. These results may give rise to reconsider the current guidelines regarding the screening of these mutation carriers., Competing Interests: The authors have no conflicts of interest to declare.

Objectives: We compare a short and a standard-size balloon with same filling volumes to verify the differences in terms of visceral flow, coronary circulation and haemodynamic performance during aortic counterpulsation in an animal model of myocardial ischaemia-reperfusion injury., Methods: Eighteen healthy pigs underwent 120-min ligation of the left anterior descending coronary artery followed by 6 h of reperfusion, and they were randomly assigned to have intra-aortic balloon counterpulsation (IABP) with a 40-ml short-balloon (n = 6) or a 40-ml standard-length balloon (n = 6), or to undergo no IABP implantation (controls, n = 6). Haemodynamics and visceral and coronary flows were measured at baseline (t0), at 2 h of ischaemia (t1) and every hour thereafter until 6 h of reperfusion (from tR1 to tR6), respectively., Results: Mesenteric flows increased significantly at tR1 only in the short-balloon group (P < 0.001) and it was constantly higher than in the standard-balloon group regardless of mean arterial pressure, systemic vascular resistance and cardiac output (CO; all, P < 0.001). Renal blood flows were significantly increased during IABP treatment with values constantly and significantly higher in short balloons at any following experimental step (all, P < 0.05). IABP improved CO and coronary blood flow, and reduced afterload, myocardial resistances and myocardial oxygen consumption without differences between the short and the standard-length balloon (all, P > 0.05)., Conclusions: The short balloon prevents visceral ischaemia and, compared with the standard-size balloon, it does not lose IABP beneficial cardiac and coronary-related effects. Further studies are warranted to confirm our findings., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objective: We present the first testing study on the ABLA-BOX, a new in vitro module of hybrid atrial fibrillation ablation., Methods: ABLA-BOX consists of two chambers that mimic the epicardial and endocardial sides of the heart. The septum between chambers provides catheter access on both sites of the cardiac tissue. A circuit, filled with freshly obtained porcine blood, including a pump, an oxygenator, and a heating device, circulate the blood inside the system. Left atrial fresh tissue is mounted on a tissue holder and magnetically fixed. Epicardial and endocardial catheters are fixed on the catheter holders and blocked with the locker knob. The system allows control of ablation force, flow rate, temperature, and flow pattern., Results: Epicardial contact force of 100 g and endocardial force of 30 g resulted in larger lesion volumes (P < 0.001), areas (P < 0.001), and lesion diameters (P = 0.03 and P = 0.008), than the combination of 100/20 g. In addition, with a flow rate of 5 L/min, lesion volumes (P = 0.02), areas (P < 0.001), and diameters (both, P < 0.001) were significantly larger in comparison with those of 3 L/min. Furthermore, dimensions (both, P < 0.001), volume (P < 0.001), and area (P < 0.001) of the lesions at a circulating blood temperature of 38.0°C were larger than with a lower blood temperature (36.0°C). Finally, ablations made under stable flow pattern resulted in greater lesion diameters (P = 0.04 and P = 0.03) as well as larger volumes (P = 0.02) and areas (P = 0.03) than under turbulent-like flow reproduced with the system rotor set to 400 rpm., Conclusions: The ABLA-BOX allowed easy hybrid ablation with different setups, which can provide cardiologists and cardiac surgeons with reliable and more valuable insights.

Purpose: Data on epicardial contact force efficacy in dual epicardial-endocardial atrial fibrillation ablation procedures are lacking. We present an in vitro study on the importance of epicardial and endocardial contact forces during this procedure., Methods: The in vitro setup consists of two separate chambers, mimicking the endocardial and epicardial sides of the heart. A circuit, including a pump and a heat exchanger, circulates porcine blood through the endocardial chamber. A septum, with a cut out, allows the placement of a magnetically fixed tissue holder, securing porcine atrial tissue, in the middle of both chambers. Two trocars provide access to the epicardium and endocardium. Force transducers mounted on both catheter holders allow real-time contact force monitoring, while a railing system allows controlled contact force adjustment. We histologically assessed different combinations of epi-endocardial radiofrequency ablation contact forces using porcine atria, evaluating the ablation's diameters, area, and volume., Results: An epicardial ablation with forces of 100 or 300 g, followed by an endocardial ablation with a force of 20 g did not achieve transmurality. Increasing endocardial forces to 30 and 40 g combined with an epicardial force ranging from 100 to 300 and 500 g led to transmurality with significant increases in lesion's diameters, area, and volumes., Conclusions: Increased endocardial contact forces led to larger ablation lesions regardless of standard epicardial pressure forces. In order to gain transmurality in a model of a combined epicardial-endocardial procedure, a minimal endocardial force of 30 g combined with an epicardial force of 100 g is necessary.

Objectives: This proof-of-concept study examined the haemodynamic performance as well as the coronary and visceral organ perfusion using a new short balloon for intra-aortic counterpulsation (IABP) in a swine model of myocardial ischaemia., Methods: Eighteen healthy pigs underwent 120-min ligation of the left anterior descending coronary artery followed by 6 h of reperfusion, and they were randomly assigned into 3 groups undergoing IABP implantation with a 35-ml short balloon (n = 6), a 40-ml short balloon (n = 6) or no IABP implantation (controls, n = 6). Haemodynamics, and visceral and coronary flows were measured at baseline (t0), at 2 h of ischaemia (t1) and every hour thereafter until 6 h of reperfusion (from tR1 to tR6), respectively., Results: Mesenteric and renal flows increased significantly at tR1 only in the IABP groups (all, P < 0.001) and were significantly higher than controls throughout the reperfusion periods (P < 0.001). Coronary systolic and diastolic blood flows increased only at tR1 in the IABP groups (all, P < 0.001) but were higher than controls at tR1-tR6. The IABP was associated with enhanced haemodynamics compared with controls. No difference was detected using different balloon volumes (all, P > 0.05)., Conclusions: The new short balloon significantly increased visceral flow, enhanced haemodynamics and improved coronary circulation during reperfusion following myocardial ischaemia in our experimental model., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objective: Visceral ischemia can be a potentially life-threatening complication of intra-aortic balloon pump (IABP) support. A shorter IABP catheter might lead to a reduction of visceral complications. In this animal study, we evaluate the effects of a 35-mL short catheter in comparison with a 40-mL standard-sized catheter., Methods: Eighteen healthy swine underwent 120-minute ligation of the left anterior descending coronary artery followed by 6 hours of reperfusion being supported by either a short IABP catheter (short group) (n = 6) or a long IABP catheter (long group) (n = 6) or with no assistance (controls) (n = 6). Hemodynamics, visceral and coronary flows, as well as biochemical markers were evaluated throughout the different phases of the protocol., Results: Mesenteric flows increased significantly at reperfusion (P < 0.001 both) remaining constant afterward (all, P > 0.05) in the short group, while remaining significantly lower in the long group at the start of reperfusion, remaining constantly lower than the short group and controls (P < 0.001 vs short, P < 0.003 vs controls). In both long and short groups, catheters improved renal flows at reperfusion (P < 0.001 both) without any further variation (P > 0.05). In the short group, the flows were higher during the whole of reperfusion (all, P < 0.05). Intra-aortic balloon pump support improved hemodynamic indices and coronary blood flows during reperfusion to a similar extent in both the small and the long group (P > 0.05)., Conclusions: The short IABP catheter proved to be as effective as the standard-sized catheter in supporting hemodynamics and coronary circulation. Furthermore, it even improves visceral flows in comparison with conventional IABP catheters.

Objective: Our aim was to evaluate a new inflatable lung retractor, the "Spacemaker", and its efficacy in facilitating minimally invasive cardiothoracic surgery without the need of one lung ventilation or carbon dioxide overpressure insufflation., Methods: The device was tested in 12 anesthetized pigs (90-100 kg) placed on standard endotracheal ventilation. The device was introduced into the right or left side of the chest, depending on the intended procedure to be performed, via a 3-cm incision in the fifth intercostal space. A total of seven animals were used to evaluate hemodynamic and respiratory response to the device, whereas another five animals were used to assess the feasibility of a variety of minimally invasive cardiothoracic surgical procedures., Results: Introduction was easy and unhindered. The device was inflated up to 0.6 bar, thereby pushing the lung tissue gently away cranially, posteriorly, and caudally without interfering with pulmonary function or resulting in respiratory compromise. In addition, hemodynamics remained stable throughout the experiments. Different closed-chest surgical procedures such as left atrial appendage exclusion, pulmonary vein exposure, pacemaker lead placement, and endoscopic stabilization for coronary surgery, were successfully performed. Removal was quick and complete in all cases, and lung tissue showed no remnant atelectasis., Conclusions: The "Spacemaker" may represent a reliable alternative to current conventional techniques to facilitate minimally invasive cardiothoracic surgery. Further research is warranted to confirm the effectiveness and the safety of this device and to optimize the model before its use in humans and its introduction into clinical practice.

High circulating insulin-like growth factor 1 (IGF-1) levels are firmly established as a risk factor for developing breast cancer, especially estrogen positive tumors. The effect of circulating IGF-1 on prognosis once a tumor is established is unknown. The authors explored the effect of IGF-1 blood levels and of it's main binding protein, IGFBP-3, on overall survival and occurrence of second primary breast tumors in breast cancer patients, as well as reproductive and lifestyle factors that could modify this risk. Patients were accrued from six hospitals in the Netherlands between 1998 and 2003. Total IGF-1 and IGFBP-3 were measured in 582 plasma samples. No significant association between IGF-1 and IGFBP-3 plasma levels and overall survival was found. However, in a multivariate Cox regression model including standard prognostic variables high IGF-1 levels were related to worse overall survival in patients receiving endocrine therapy (HR = 1.37, 95% CI: 1.11, 1.69, P 0.004). These data at least indicate that higher IGF-1 levels, and as a consequence most likely IGF-1-induced signaling, are related to a less favorable overall survival in breast cancer patients treated with endocrine therapy. Interventions aimed at reducing circulating levels of IGF-1 in hormone receptor positive breast cancer may improve survival., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.

Background: AZD1305 is an investigational antiarrhythmic agent for management of atrial fibrillation. It blocks various cardiac ion currents at different potencies and has atrial-predominant electrophysiological effects. We investigated the electrophysiological and proarrhythmic effects of AZD1305 versus dofetilide in dogs with chronic complete atrioventricular block and myocardial hypertrophic remodeling., Methods and Results: AZD1305 was administered to anesthetized mongrel dogs before and >2 weeks after the induction of atrioventricular block and ventricular and atrial electrophysiological parameters were assessed. In all dogs, the selective I(Kr) blocker dofetilide was used to examine susceptibility to acquired torsades de pointes in chronic atrioventricular block and for comparison. At normal sinus rhythm, AZD1305 increased QT and RR intervals from 290±7 to 397±15 ms (+37%, P<0.0001) and from 603±22 to 778±32 ms (+29%, P=0.002), respectively. In the same animals at chronic atrioventricular block, AZD1305 increased the QT interval from 535±28 to 747±36 ms (+40%, P<0.0001), similar to the QT prolongation by dofetilide (511±22 to 703±45 ms [+38%, P<0.0001]). AZD1305 slightly slowed the idioventricular rhythm. Whereas all (n=14) chronic atrioventricular block animals exhibited torsades de pointes on dofetilide, the arrhythmia was induced in only 4 of 11 dogs after AZD1305. Beat-to-beat variability of left-ventricular monophasic-action-potential duration increased after dofetilide (2.3±0.2 to 6.3±0.7 ms; P<0.0001) but not after AZD1305 (2.8±0.3 to 3.7±0.3 ms; P=0.20) despite similar left-ventricular monophasic-action-potential duration prolongations., Conclusions: Despite causing similar degrees of repolarization delay as the selective I(Kr) blocker dofetilide, the combined ion-channel blocker AZD1305 induces less repolarization instability and has a lower ventricular proarrhythmic potential in the remodeled dog heart.

Background: Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition caused by germline FLCN mutations, and characterised by fibrofolliculomas, pneumothorax and renal cancer. The renal cancer risk, cancer phenotype and pneumothorax risk of BHD have not yet been fully clarified. The main focus of this study was to assess the risk of renal cancer, the histological subtypes of renal tumours and the pneumothorax risk in BHD., Methods: In this study we present the clinical data of 115 FLCN mutation carriers from 35 BHD families., Results: Among 14 FLCN mutation carriers who developed renal cancer 7 were <50 years at onset and/or had multifocal/bilateral tumours. Five symptomatic patients developed metastatic disease. Two early-stage cases were diagnosed by surveillance. The majority of tumours showed characteristics of both eosinophilic variants of clear cell and chromophobe carcinoma. The estimated penetrance for renal cancer and pneumothorax was 16% (95% minimal confidence interval: 6-26%) and 29% (95% minimal confidence interval: 9-49%) at 70 years of age, respectively. The most frequent diagnosis in families without identified FLCN mutations was familial multiple discoid fibromas., Conclusion: We confirmed a high yield of FLCN mutations in clinically defined BHD families, we found a substantially increased lifetime risk of renal cancer of 16% for FLCN mutation carriers. The tumours were metastatic in 5 out of 14 patients and tumour histology was not specific for BHD. We found a pneumothorax risk of 29%. We discuss the implications of our findings for diagnosis and management of BHD.

Background: Amiodarone is currently the most effective antiarrhythmic drug for sinus rhythm maintenance. However, due to serious extracardiac adverse effects, prophylactic amiodarone therapy is only appropriate for patients at high risk for postoperative atrial fibrillation (AF). We hypothesized that epicardial application of an amiodarone-releasing hydrogel would produce therapeutic myocardial drug concentrations, while systemic levels would remain low., Methods: Goats were fitted with right atrial epicardial patch electrodes. A poly(ethylene glycol)-based hydrogel with amiodarone (1mg/kg bw) (n=10) or without drug (n=6) was applied to the right atrial epicardium. Atrial effective refractory period (AERP), conduction time and atrial response to burst pacing (rapid atrial response, RAR) were assessed up to 28days in awake goats. Myocardial, plasma and extracardiac tissue amiodarone concentrations were analysed by high-performance liquid chromatography., Results: The amiodarone-loaded hydrogel produced therapeutic drug concentrations in the right atrium up to 21days after application. In this period, AERP and conduction time were prolonged, while RAR inducibility was reduced (P<0.05) compared to animals treated with drug-free hydrogel. Mean amiodarone concentrations in the right atrium were 1 order of magnitude higher than in other heart chambers and 2 orders of magnitude higher than in extracardiac tissues. Plasma amiodarone levels remained below the detection limit (<10ng/mL) during the 28-day follow-up., Conclusions: Epicardial application of an amiodarone-releasing hydrogel reduces atrial vulnerability to tachyarrhythmias up to 3weeks, while extracardiac drug levels remain low. Therefore, amiodarone-releasing hydrogel could be applied during cardiac surgery to prevent postoperative AF at minimal risk for extracardiac adverse side effects., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.

Objectives: Atrial dilatation predisposes to atrial fibrillation. Although several animal models focus on the initiating mechanisms of atrial fibrillation in dilated atria, a model of left atrial overload resulting in persistent atrial fibrillation in nonanesthetized animals has not been presented thus far., Methods: In 24 goats a vascular shunt was implanted between the aorta and the left atrium through a left thoracotomy. In 6 animals the shunt was ligated immediately (control group). Ultrasonic crystals were implanted to monitor atrial dilatation. Bipolar electrodes were positioned epicardially on the left atrium for measurement of the atrial effective refractory period, conduction times, and atrial fibrillation duration., Results: Four weeks of overload resulted in an increase of left atrial pressure (23.1 +/- 6.8 mm Hg in the open-shunt group vs 7.0 +/- 1.9 mm Hg in the control group, P = .002) and a progressive dilatation of the left atrium (135% +/- 20% in the open-shunt group vs 98% +/- 8.0% in the control group, P = .002). Among the open-shunt group's long-term survivors (n = 12), 9 animals showed prolonged atrial fibrillation (>1 hour), and of these, 6 were in persistent atrial fibrillation (>1 week). The atrial effective refractory period increased during the first week and remained prolonged until death (182 +/- 11 ms in the open-shunt group vs 161 +/- 15 ms, P = .03). The conduction time did not change. An increase in collagen formation was noticed in both groups, without a significant difference between them., Conclusions: A chronic aortic to left atrial shunt is a feasible model in the goat. It induces progressive left atrial dilatation with an increased atrial fibrillation duration up to hours in the majority of animals. Prolonged atrial fibrillation duration could not be explained by a shortening of atrial effective refractory period or increase in fibrosis.

Multiple myeloma (MM) is a relatively rare haematological malignancy seen in older persons. It has an unknown aetiology and usually occurs incidentally within a family. However, several families have been reported with multiple cases of MM, so that the existence of hereditary MM has been postulated although no causative germline mutations have been detected so far. First-degree relatives of MM patients have been reported to have a relative risk between two and four times higher than normal of developing MM and we presume the risks are higher for relatives in the case of familial MM. Here we report on two families with MM who requested presymptomatic screening of healthy relatives. Although risk estimates for asymptomatic relatives in these types of families are not available, a clinically significant risk of developing MM cannot be excluded. We suggest that, in a research setting, screening for MM could be offered to individuals with more than one first-degree affected relative, or to those with one first-degree and at least one second-degree relative with MM. We propose a screening programme of annual protein electrophoresis of blood and urine, starting at age 40 (or earlier if a family member presented with MM at a younger age).

The objective of this study was to investigate venous collapse (VC) related to venous drainage during the use of an extracorporeal life support circuit. A mock circulation was built containing a centrifugal pump and a collapsible vena cava model to simulate VC under controlled conditions. Animal experiments were performed for in vivo verification. Changing pump speed had a different impact on flow during a collapsed and a distended caval vein in both models. Flow measurement in combination with pump speed interventions allows for the detection and quantitative assessment of the degree of VC. Additionally, it was verified that a quick reversal of a VC situation could be achieved by a two-step pump speed intervention, which also proved to be more effective than a straightforward decrease in pump speed.

Clinicians commonly sedate critically ill patients. Sedatives should be administered to achieve predetermined end points. Most currently available scales used to assess sedation are inadequate because they focus on a single domain, such as consciousness. The development of the American Association of Critical-Care Nurses' Sedation Assessment Scale is described. This new scale consists of 5 domains: consciousness, agitation, anxiety, sleep, and patient-ventilator synchrony. A major advantage of the scale is that its domains parallel common goals of sedation therapy for critically ill patients. The proposed measurements for each domain are based on a comprehensive evaluation of the science and expert recommendations. Before the scale is widely used, clinical testing is required to determine its validity and reliability in a variety of critically ill patients and care situations.

The CHEK2 1100delC mutation was recently identified as a low-penetrance breast cancer susceptibility allele. The mutation occurred more frequently in families with clustering of breast and colorectal cancers (CRCs) than in families with clustering of breast cancer only. Hence, the 1100delC mutation could also be a low-penetrance CRC susceptibility allele. To test this hypothesis, we examined the mutation in 629 unselected CRC cases, 230 controls, and 105 selected CRCs diagnosed in patients before age 50. The mutation was observed in 1.6% of unselected patients and in 0.3% of controls (Not significant (NS)). After stratifying unselected patients according to defined genetic risk (on the basis of age at diagnosis and family history of colorectal and endometrial cancer), the highest frequency was observed in high-risk patients (12.5%), followed by moderate-risk patients (3.3%), and was lowest in low-risk patients (1.0%, P(trend) 0.014). In selected patients, 1.6% carried the mutation (NS). Subgroup analyses for tumor localization, gender, and age at diagnosis did not reveal an association with the 1100delC genotype. In addition, a pooled analysis, combining data of one published study in unselected CRC cases and our study, also did not reveal an association. In conclusion, the frequency of the 1100delC genotype was neither significantly increased in unselected CRC patients nor in selected CRC patients diagnosed before age 50. However, after stratifying unselected CRC patients according to defined genetic risk, a significant trend of increasing frequency was observed. Together, the results are consistent with a low-penetrance effect (OR 1.5-2.0) of the CHEK2 1100delC on CRC risk. Large case-control studies are required to clarify the exact role of the CHEK2 1100delC mutation in CRC., (Copyright 2005 Wiley-Liss, Inc.)

CHEK2 is low-penetrance breast cancer susceptibility gene. The 1100delC mutation may interact with variants/mutations in other breast cancer susceptibility loci. We identified a risk haplotype in the HLA class III region in breast cancer patients [de Jong MM, Nolte IM, de Vries EGE, et al. The HLA class III subregion is responsible for an increased breast cancer risk. Hum Mol Genet 2003, 12, 2311-2319] and tested whether it interacted with 1100delC mutation. The CHEK2 1100delC mutation was analysed in the same series of patients and controls as in the HLA breast cancer study. In 962 unselected breast cancer patients, the 1100delC mutation was observed in 2.9% and in 367 controls in 1.4% (NS). The highest 1100delC frequency occurred in high-risk (4.4%), followed by moderate-risk (3.8%), and lowest in low genetic risk patients (2.4%, P(trend) 0.029). In HLA risk haplotype carriers no increased breast cancer risk was observed in the presence of 1100delC mutation. Patients more often had one than both genetic risk factors. The 1100delC mutation and the HLA risk haplotype confer increased breast cancer risks, but an interactive effect on breast cancer between both factors is unlikely. In contrast, the effect of 1100delC mutation on breast cancer risk was limited to individuals without HLA risk haplotype, suggesting a mutual excluding effect between these risk factors.

Purpose: Recently, we found a certain haplotype in the human leukocyte antigen Class III subregion to be associated with breast cancer. Epidemiologic studies have shown that breast cancer and colorectal cancer have several risk factors in common. In view of these studies and because polymorphisms located in the human leukocyte antigen III region have been found to be associated with colorectal cancer, we wondered whether the same region also is involved in colorectal cancer susceptibility., Methods: The human leukocyte antigen region was genotyped with 14 microsatellite markers in germline DNA from 643 colorectal cancer patients and 841 family-based controls. Association analyses and the Haplotype Sharing Statistic were used to search for differences between patients and controls. Subgroup analyses were performed for gender, age at diagnosis, and localization of the tumor., Results: The Haplotype Sharing Statistic analysis revealed neither a difference in mean haplotype sharing between all patients and controls, nor in any of the subgroups. The single allele, genotype, and two-locus association analyses for all patients and for the different subgroups did not show an association with colorectal cancer for the 14 microsatellite markers. Also, no association was observed between the tumor necrosis factor-beta polymorphism and colorectal cancer., Conclusions: No association was observed between commonly occurring haplotypes and alleles in the human leukocyte antigen region and colorectal cancer risk.

Background and Aims: In one small study, the DCC Arg201Gly polymorphism has been observed more frequently in colorectal cancer cases compared with controls. We wondered whether these results could be replicated in a much larger study., Methodology: The DCC Arg201 Gly polymorphism was genotyped in 625 unselected Caucasian colorectal cancer patients and 220 controls. Association analysis was used to search for a difference between patients and controls. Subgroup analyses were performed for site of tumour, gender, age at diagnosis, family history of colorectal cancer and modified Dukes classification., Results: The association analyses revealed no difference in Arg201Gly genotype frequency between patients and controls, neither overall nor for different subgroups according to site of tumour, gender, age at diagnosis, family history of colorectal cancer and modified Dukes classification., Conclusion: No association was observed between the Arg201Gly polymorphism of DCC and colorectal cancer risk.

Recently we identified a new variant, S845G, in the MLH3 gene in 7 out of 327 patients suspected of hereditary nonpolyposis colorectal cancer but not fulfilling the Amsterdam criteria and in 1 out of 188 control subjects. As this variant might play a role in causing sporadic colorectal cancer, we analyzed its prevalence in sporadic colorectal cancer patients. We analyzed a small part of exon 1 of the MLH3 gene, including the S845G variant, in germline DNA of 467 white sporadic colorectal cancer patients and 497 white controls. The S845G variant was detected in five patients and eight controls; the results thus indicate that this variant does not confer an increased colorectal cancer risk. Another variant (P844L) was clearly a polymorphism. Three other missense variants were rare and the sample size of the study was too small to conclude whether they are pathogenic. In conclusion, no association was observed between two MLH3 variants (P844L and S845G) and colorectal cancer risk.

BRCA1 and BRCA2 germline mutations account for <5% of breast cancer cases. Less penetrant breast cancer susceptibility genes are likely to exist. Earlier studies have suggested involvement of the HLA region. The HLA region was genotyped with 24 microsatellite markers and markers for two single nucleotide polymorphisms (SNPs) in TNFalpha and TNFbeta, in germline DNA from 956 breast cancer patients and 1271 family-based controls. Association analyses and the haplotype sharing statistic (HSS) were used to search for differences in haplotype sharing between patients and controls. Based on criteria known to influence genetic breast cancer risk, patients were divided into groups of high, moderate and low risk. The HSS revealed a significant difference in mean haplotype sharing between patients and controls for four consecutive markers (D6S2671, TNFa, D6S2672 and MICA), the highest being at D6S2671 (P=0.017). Subgroup analyses showed that moderate-risk patients were responsible for this difference, with the strongest association for D6S2672 (P=0.0009). A single haplotype was more frequent and longer in moderate-risk patients than in controls. The results were confirmed with association analyses. Individuals homozygous for haplotype 110-184 (D6S2672-MICA) were observed in 9.0% of moderate-risk patients and 1.5% of controls [odds ratio (OR)=7.14], while heterozygotes were at a lower risk (OR=1.41), suggesting a recessive effect. No association was observed between the two SNPs in TNFalpha (-308) and TNFbeta (intron 1) and breast cancer risk. The results reveal a potential role of the HLA class III subregion in susceptibility to breast cancer in patients at moderate familial risk.

This report focuses on low-penetrance genes that are associated with colorectal adenoma and/or cancer or that are in strong linkage disequilibrium with colorectal adenoma and/or cancer causing variants. A pooled analysis was performed for 30 polymorphisms in 20 different genes that have been reported in more than one colorectal adenoma or cancer study. An association with colorectal cancer was found for seven polymorphisms in seven genes reported in more than one study; no associations were found with colorectal adenoma. Four of the polymorphisms exhibited an increased colorectal cancer risk [GSTT1, NAT2 (phenotype), HRAS1, and ALDH2]. Two others [MTHFR, Tp53 (intron 3)] exhibited a decreased risk. For the tumor necrosis factor (TNF)a polymorphism of the TNF-alpha gene, one allele was associated with an increased risk (a2 allele) and two other TNFa alleles with decreased risks (a5 and a13 allele). No association with colorectal adenoma and/or cancer was detected for 23 other polymorphisms in 15 genes. However, of all 30 polymorphisms, only three pooled analyses had sufficiently large samples to confirm (MTHFR) or to exclude (GSTM1 and NAT2 genotype) the association with a P < 0.0026 and a power of 90%. Eighteen polymorphisms in 15 genes were each described in only one study, all with very small sample sizes. For 11 polymorphisms in 10 of these genes, an association with colorectal adenoma and/or cancer was found. Only simultaneous genotyping and combined analysis of different polymorphisms in large numbers of patients and controls, stratified by ethnicity, gender, and tumor localization and taking relevant dietary and lifestyle habits into account, will make it possible to describe the exact relations between polymorphisms and colorectal cancer susceptibility with an adequate power.

This review focuses on genes other than the high penetrance genes BRCA1 and BRCA2 that are involved in breast cancer susceptibility. The goal of this review is the discovery of polymorphisms that are either associated with breast cancer or that are in strong linkage disequilibrium with breast cancer causing variants. An association with breast cancer at a 5% significance level was found for 13 polymorphisms in 10 genes described in more than one breast cancer study. Our data will help focus on the further analysis of genetic polymorphisms in populations of appropriate size, and especially on the combinations of such polymorphisms. This will facilitate determination of population attributable risks, understanding of gene-gene interactions, and improving estimates of genetic cancer risks.

Laparoscopic cholecystectomy (LCE) has become the procedure of choice for symptomatic gallstones in children. However, there is concern about the disadvantages of cholecystectomy. Numerous postoperative symptoms and a possible correlation of the procedure with a higher incidence of right-sided colon carcinoma have been described. Therefore, it has been suggested to remove the gallstones via a cholecystotomy, leaving the gallbladder in place. This is the first report on the functional and symptomatic outcome of laparoscopic cholecystotomy (LCO) versus LCE in a consecutive series of children. A follow-up study of all children who underwent surgery for symptomatic gallstone disease from 1993 to 1999 was performed. Nine underwent LCO and 8 standard LCE. The procedure was chosen according to the preference of the surgeon. Patients and parents underwent a standardized follow-up interview. The intensitiy of six gastrointestinal symptoms was graded from 0 to 3. The patients and parents scored the symptomatic outcome using a 100-point visual analogue scale. There were no intraoperative complications. Bleeding of a port site required suturing in 1 patient after LCO, and fever with a further uneventful course occurred in another after LCE. The mean duration of hospital stay was 3.0 days after LCO and 2.4 days after LCE. In 1 patient a missed gallstone was identified 4 weeks after LCO. The patient underwent LCE with a further uneventful course. At follow-up (mean 20.7 months after LCO, 28.3 months after LCE, P = n.s.) there was a tendency toward a lower incidence of symptoms after LCO. Symptoms were reported by 3 of 8 patients after LCO and 5 of 8 after LCE. The mean score of the symptomatic outcome was not statistically different. All patients with LCO were free of stones on ultrasound examination with normal contraction of the gallbladder. LCO thus represents an alternative approach. We consider LCO for children with symptomatic cholecystolithiasis before the onset of puberty. However, data on the long-term outcome from larger series are mandatory before a general recommendation can be given.

A migration test under agar for leukocytes was developed. Leukocytes moved quite a distance under anaerobic Blood Agar Base (blood agar), a Gibco product. Migration on stained and coloured plates was visualized by projection with a profile projector, making the use of a light microscope superfluous. A migration index was defined. Reproducibility was good enough to allow paired comparisons of leukocyte populations subjected to different treatments. Migration was the result of spontaneous and chemotactically directed migration. Cell-labelling complexes as 111In-oxinate and 111In-tropolonate--ligand concentration 3.5 micrograms/mL in the ultimate cell preparation--did not affect leukocyte migration. 111In-pyrithionate (mercapto pyridine-N-oxide) significantly impaired cell motility. The motility test described could be used as retrospective analysis in abscess localization studies using 111In labelled leukocytes.

The effect of oxine sulfate, oxine sulfonate, tropolone, and Merc (2 mercaptopyridine-1-oxide) were compared with oxine, with respect to their capability of labeling blood cells when complexed to indium-111 (111In). Indium-111 oxine sulfate performed similarly to [111In]oxine with regard to cell labeling capability. Indium-111 oxine sulfonate had no labeling ability. Indium-111 tropolone and Merc were not superior to [111In]oxine as cell labeling agents. Carbon dioxide (CO2) and a CO2 generating compound, diethyl pyrocarbonate, dramatically improved the cell labeling ability in plasma of [111In]tropolone and Merc. In the case of oxine, this improvement was less distinct. Theoretical aspects of the CO2 cell labeling stimulating effect are discussed in terms of intra- and extracellular transferrin and lactoferrin iron (indium) binding capacity. Indium-111 tropolone behaved favorably with respect to inhibition of leukocyte migration, compared with oxine and Merc. Combined with the property of easy cell labeling and good solubility in water, also in the complexed state, tropolone must be regarded as the most suitable cell labeling ligand.