Ascaris lumbricoides infection and its relation to environmental factors in the Mbeya region of Tanzania, a cross-sectional, population-based study.

BACKGROUND: With one quarter of the world population infected, the intestinal nematode Ascaris lumbricoides is one of the most common infectious agents, especially in the tropics and sub-tropics. Infection is caused by oral intake of eggs and can cause respiratory and gastrointestinal problems. To identify high risk areas for intervention, it is necessary to understand the effects of climatic, environmental and socio-demographic conditions on A. lumbricoides infection. METHODOLOGY: Cross-sectional survey data of 6,366 study participants in the Mbeya region of South-Western Tanzania were used to analyze associations between remotely sensed environmental data and A. lumbricoides infection. Non-linear associations were accounted for by using fractional polynomial regression, and socio-demographic and sanitary data were included as potential confounders. PRINCIPAL FINDINGS: The overall prevalence of A. lumbricoides infection was 6.8%. Our final multivariable model revealed a significant non-linear association between rainfall and A. lumbricoides infection with peak prevalences at 1740 mm of mean annual rainfall. Mean annual land surface temperature during the day was linearly modeled and negatively associated with A. lumbricoides infection (odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.78-0.97). Furthermore, age, which also showed a significant non-linear association (infection maximum at 7.7 years), socio-economic status (OR = 0.82, CI = 0.68-0.97), and latrine coverage around the house (OR = 0.80, CI = 0.67-0.96) remained in the final model. CONCLUSIONS: A. lumbricoides infection was associated with environmental, socio-demographic and sanitary factors both in uni- and multivariable analysis. Non-linear analysis with fractional polynomials can improve model fit, resulting in a better understanding of the relationship between environmental conditions and helminth infection, and more precise predictions of high prevalence areas. However, socio-demographic determinants and sanitary conditions should also be considered, especially when planning public health interventions on a smaller scale, such as the community level.

Joint line reconstruction in medial unicompartmental knee arthroplasty: development and validation of a measurement method.

PURPOSE: Preservation of the joint line in total knee arthroplasty (TKA) has shown to be an important factor for the long-term outcome, especially in revision TKA. For unicompartmental knee arthroplasty (UKA), the role of the joint line has neither been investigated nor is it consciously respected during implantation. Thus, the aim was to establish and validate a standardised measurement method to determine the joint line in UKA. METHODS: As there is no established method to evaluate changes in the joint line radiologically, we introduced two methods and correlated them. The methods were first validated in a cadaver model by a controlled rotational study. Then, the joint line of 29 patients with an UKA (Oxford, Biomet, Bridgend, UK) was determined on pre- and post-operative radiographs. Both methods were tested by intra- and inter-rater reliability. RESULTS: Both methods showed a good intra- and inter-rater reliability. Furthermore, there was only little bias in agreement between both methods and raters. Measurements of the 29 UKA patients revealed that the joint line was more distally by a mean of 4.4 ± 1.2 mm after surgery. CONCLUSIONS: The study provides for the first time a reliable and standardised measurement tool to determine the changes in the joint line after implantation of an UKA. The instrument should be used in further studies to evaluate the impact of the joint line on the long-term outcome, the load in the two non-replaced knee compartments and on the ligaments.

The amount of dysfunctional but viable myocardium predicts long-term survival in patients with ischemic cardiomyopathy and left ventricular dysfunction.

To evaluate the prognostic significance of combined myocardial perfusion SPECT and [18F]FDG PET viability scanning for the prediction of survival in patients with ischemic cardiomyopathy (iCMP) and left ventricular dysfunction. 244 patients (64.0 ± 10.6 years, 86 % men) with iCMP and LVEF ≤ 45 % underwent SPECT/PET. Percent scar tissue and SPECT/PET-mismatch (%-mismatch) were calculated and correlated with event-free survival according to the type of therapy (medical therapy with/out revascularization) provided after imaging. Death from any cause was defined as the primary endpoint. Early revascularization (ER) was performed in 113/244 (46 %) patients within 32 ± 52 days (26 bypass surgeries and 87 percutaneous coronary interventions). 65 patients died during follow-up for a median of 33 months. Kaplan-Meier analysis showed that those patients with ≥ 5 % mismatch not undergoing ER had significantly higher mortality than did the group with similar mismatch who did receive ER. Cox analysis identified both SPECT/PET-mismatch and the interaction of SPECT/PET-mismatch with ER as independent predictors for death due to all causes. A threshold of ≥ 5 % SPECT/PET-mismatch predicted best which patients with iCMP and LV dysfunction would benefit from ER in terms of long-term survival.

A genotype-specific, randomized controlled behavioral intervention to improve the neuroemotional outcome of cardiac surgery: study protocol for a randomized controlled trial.

BACKGROUND: Cardiac surgery is one of the most commonly performed surgical procedures worldwide with >700,000 surgeries in 2006 in the US alone. Cardiac surgery results in a considerable exposure to physical and emotional stress; stress-related disorders such as depression or post-traumatic stress disorder are the most common adverse outcomes of cardiac surgery, seen in up to 20% of patients. Using information from a genome-wide association study to characterize genetic effects on emotional memory, we recently identified a single nucleotide polymorphism of the glucocorticoid receptor gene (the Bcll single nucleotide polymorphism) as a significant genetic risk factor for traumatic memories from cardiac surgery and symptoms of post-traumaticstress disorder. The Bcll high-risk genotype (Bcll GG) has a prevalence of 16.6% in patients undergoing cardiac surgery and is associated with increased glucocorticoid receptor signaling under stress. Concomitant animal experiments have confirmed an essential role of glucocorticoid receptor activation for traumatic memory formation during stressful experiences. Early cognitive behavioral intervention has been shown to prevent stress-related disorders after heart surgery. METHODS/DESIGN: The proposed study protocol is based on the above mentioned earlier findings from animal experiments and preclinical studies in volunteers. Patients (n = 872) will be genotyped for the Bcll single nucleotide polymorphism before surgery, which should result in 120 homozygous high-risk carriers of the Bcll GG allele and 240 randomly selected low-risk heterozygous or non-carriers of the single nucleotide polymorphism. All patients will then undergo randomization to either cognitive behavioral intervention or a control intervention consisting of non-specific general information about the role of stress in heart disease. The primary efficacy endpoint will be post-traumatic stress levels at one year after surgery as determined by a standardized questionnaire that has been specifically validated in patients after critical illness. DISCUSSION: The proposed randomized controlled trial intends to demonstrate that a preoperatively administered minimal cognitive behavioral intervention targeted to homozygous carriers of the Bcll *G high-risk allele reduces traumatic memories and post-traumatic stress disorder symptoms after heart surgery to a level seen in non-carriers of the mutation, and thus improves the neuroemotional outcome of cardiac surgery. TRIAL REGISTRATION NUMBER: The trial will be registered at http://www.clinicaltrials.gov/ before commencing with the study.

Association between left ventricular mechanical dyssynchrony with myocardial perfusion and functional parameters in patients with left bundle branch block.

OBJECTIVE: To identify predictors of left ventricular mechanical dyssynchrony (LVMD) in patients with known left bundle branch block (LBBB) using gated single-photon emission computed tomography (SPECT) phase analysis. METHODS: 81 patients (74% male, 70 ± 10 years) with LBBB and suspected or known coronary artery disease underwent ECG-gated myocardial perfusion SPECT. LV perfusion and functional parameters were measured, and phase analysis was performed to quantify LV-dyssynchrony. RESULTS: 35/81 patients (42%) had prior myocardial infarction (MI), and the mean left ventricular ejection fraction (LVEF) was 49% ± 16%. LVMD was present in 58/81 (72%) patients. The summed thickening score (STS) (P < .001; odds ratio 1.22) emerged as independent predictor for the presence of LVMD in a multivariate regression model. In addition, prior MI, low LVEF, summed stress score, summed rest score, summed motion score, and LAD rest extent were identified as predictors of LVMD in a univariate model. Clinical baseline characteristics, cardiac risk factors, and QRS duration (P = .051) had no influence on the presence of LVMD. CONCLUSION: In patients with LBBB, the occurrence of LVMD as assessed by gated SPECT phase analysis is mainly influenced by reduced myocardial contractility as expressed by the STS. Proper discrimination between LVMD arising from known electrical conduction delay as opposed to areas of MI causing reduced regional contractility seems to be mandatory for therapy planning in patients with LVMD.

Prognostic value of cetuximab-related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: results from a randomized trial of the GERMAN AIO CRC Study Group.

Skin toxicity is a frequent adverse event of epidermal growth factor receptor (EGFR) targeting agents. Occurrence of cetuximab-induced skin toxicity (Cet-ST) correlates with better treatment response and longer survival times. Molecular markers predicting Cet-ST are still missing. This investigation analyzed the value of Cet-ST for treatment efficacy in a randomized trial comparing cetuximab plus capecitabine/irinotecan to cetuximab plus capecitabine/oxaliplatin as first-line treatment of metastatic colorectal cancer. Patient characteristics and molecular parameters (KRAS mutation, EGFR-FISH, EGFR-IHC and EGFR intron-1 polymorphism) of the tumour were correlated with response and Cet-ST. Cet-ST grade 0-1 was observed in 31%, grade 2-3 in 69% of patients. Outcome favoured patients with grade 2-3 Cet-ST with regard to overall response rate (62 vs. 41%), PFS (7.8 vs. 5.2 months) and overall survival (OS) (30.3 vs. 18.0 months). First-cycle rash was observed in 66% of patients and corresponded with longer survival (30.7 vs. 20.2 months, p = 0.007). Patients without Cet-ST had a poor outcome (PFS, 1.9 months; OS, 11 months). The correlation of Cet-ST with survival was specifically evident in patients with KRAS codon-12-mutated tumours assumed to be cetuximab resistant. In multivariate analysis of patient characteristics, male gender and younger age were significantly correlated with Cet-ST. Among molecular parameters, no significant correlation with Cet-ST was found. Cet-ST is an early predictor of treatment efficacy in cetuximab-treated patients. This effect of Cet-ST is independent of the KRAS mutation status, suggesting that Cet-ST rather relates to constitutional factors of the patient than alterations of the EGFR pathway in the tumour.

CD133 induces tumour-initiating properties in HEK293 cells.

The pentaspan protein CD133 (Prominin-1) is part of the signature of tumour-initiating cells for various cancer entities. The aim of the present study was to investigate the impact of ectopic CD133 expression on tumourigenic properties of otherwise CD133-negative, non-tumourigenic cells in vitro and in vivo. CD133 was stably transfected into human embryonic kidney 293 (HEK293) which was then sorted for the expression of CD133. The effects of CD133 on cell proliferation were assessed upon standard cell counting of sorted cells at various time points. Severe combined immunodeficient (SCID) mice (n = 30) were injected with HEK293 CD133(high) and CD133(low) transfectants (5 × 10(3), 1 × 10(5), or 5 × 10(6) cells per injection). The expression of CD133, Ki67, CD44s, CD44v6, and EpCAM was analysed upon immunohistochemical staining of cryosections with specific antibodies. In vitro, ectopic expression of CD133 did influence neither cell proliferation nor cell cycle distribution of otherwise CD133-negative HEK293 cells. However, CD133(high) cells generated tumours in vivo in SCID mice with at least 1,000-fold increased frequency compared to CD133(low) cells. Tumour load was also significantly increased in CD133(high) cells as compared to those tumours formed by high numbers of CD133(low) cells. Immunohistochemistry stainings disclosed no changes in Ki67, CD44s, CD44v6, or EpCAM once tumours were formed by either cell type. CD133 induces tumour-initiating properties in HEK293 cells in vivo and is potentially involved in the regulation of tumourigenicity. Future research will aim at the elucidation of molecular mechanisms of CD133-induced tumourigenicity.

Temporal changes in phosphatidylserine expression and glucose metabolism after myocardial infarction: an in vivo imaging study in mice.

Positron emission tomography (PET) for in vivo monitoring of phosphatidylserine externalization and glucose metabolism can potentially provide early predictors of outcome of cardioprotective therapies after myocardial infarction. We performed serial [68Ga]annexin A5 PET (annexin-PET) and [¹8F]fluorodeoxyglucose PET (FDG-PET) after myocardial infarction to determine the time of peak phosphatidylserine externalization in relation to impaired glucose metabolism in infracted tissue. Annexin- and FDG-PET recordings were obtained in female (C57BL6/N) mice on days 1 to 4 after ligation of the left anterior descending (LAD) artery. [68Ga]annexin A5 uptake (%ID/g) in the LAD artery territory increased from 1.7 ± 1.1 on day 1 to 5.0 ± 3.3 on day 2 and then declined to 2.0 ± 1.4 on day 3 (p  =  .047 vs day 2) and 1.6 ± 1.4 on day 4 (p  =  .014 vs day 2). These results matched apoptosis rates as estimated by autoradiography and fluorescein staining. FDG uptake (%ID/g) declined from 28 ± 14 on day 1 to 14 ± 3.5 on day 4 (p < .0001 vs day 1). Whereas FDG-PET revealed continuous loss of cell viability after permanent LAD artery occlusion, annexin-PET indicated peak phosphatidylserine expression at day 2, which might be the optimal time point for therapy monitoring.

Left ventricular dyssynchrony assessed by gated SPECT phase analysis is an independent predictor of death in patients with advanced coronary artery disease and reduced left ventricular function not undergoing cardiac resynchronization therapy.

PURPOSE: Left ventricular (LV) mechanical dyssynchrony (LVMD) was assessed by gated single-photon emission CT myocardial perfusion imaging (MPI) as an independent predictor of death from any cause in patients with known coronary artery disease (CAD) and reduced LV function. METHODS: Between 2001 and 2010, 135 patients (64 ± 11 years of age, 84 % men) with known CAD, reduced LV ejection fraction (LVEF, 38 ± 15 %) and without an implanted cardiac resynchronization therapy device underwent gated MPI at rest. LV functional evaluation, which included phase analysis, was conducted to identify patients with LVMD. Kaplan-Meier survival curves were calculated for death of any cause during a mean follow-up of 2.0 ± 1.7 years. Uni- and multivariate Cox proportional hazards regression models were calculated to identify independent predictors of death from any cause. RESULTS: Of the 135 patients, 30 (22 %) died during follow-up (18 cardiac deaths and 12 deaths from other causes). Kaplan-Meier curves showed a significantly shorter survival time in the patients with severely reduced LVEF (<30 %, n = 45) or with LVMD (n = 81, log-rank test P <0.005). Cox models identified LVMD, LVEF < 30 % and a total perfusion deficit at rest of ≥ 20 % as independent predictors of death from any cause. While patients with LVEF <30 % in conjunction with LVMD had similar survival times irrespective of whether they had early revascularization or medical therapy, those patients with LVEF ≥ 30% and LVMD who underwent revascularization had significantly longer survival. CONCLUSION: In patients with known CAD and reduced LV function, dyssynchrony of the LV is an independent predictor of death from any cause.

18F-FDG PET/CT predicts survival after radioembolization of hepatic metastases from breast cancer.

UNLABELLED: (90)Y radioembolization (selective internal radiation therapy [SIRT]) has emerged as a valuable therapeutic option in unresectable, chemotherapy-refractory hepatic metastases from breast cancer. The objective of the present study was to evaluate (18)F-FDG PET/CT for predicting survival in these patients. METHODS: Fifty-eight consecutive patients with hepatic metastases from breast cancer were treated with SIRT. Before therapy, all patients underwent MRI of the liver. (18)F-FDG PET/CT was performed at baseline and 3 mo after SIRT to calculate percentage changes in maximum (18)F-FDG standardized uptake value (SUV(max)) relative to baseline. A decrease of more than 30% in the follow-up scan, compared with the baseline examination, indicated therapy response. Treatment response at 3 mo was also assessed in 43 patients using contrast-enhanced MRI and CT on the basis of the Response Evaluation Criteria in Solid Tumors. All patients were followed to complete survival data. RESULTS: Overall median survival after SIRT was 47 wk. Response as assessed with SUV(max) correlated significantly with survival after radioembolization, with responders having significantly longer survival (65 wk) than nonresponders (43 wk; P < 0.05). In multivariate analysis the change in SUV(max) was identified as the only independent predictor of survival (hazard ratio, 0.23; P < 0.005). Furthermore, a high pretherapeutic SUV(max) (>20) was associated with a significantly shorter median survival than was an SUV(max) of 20 or less (21 vs. 52 wk; P < 0.005). The presence of extrahepatic metastases (mean survival in both groups, 47 wk; P = 0.92), hormone receptor status (estrogen, P = 0.53; progesterone, P = 0.79; Her-2/neu, P = 0.49), and MRI/CT response (P = 0.91) did not predict survival. CONCLUSION: The change in SUV(max) as assessed by (18)F-FDG PET/CT before and 3 mo after SIRT was identified as the only independent predictor of survival in patients with hepatic metastases of breast cancer.

CD133 is a predictor of poor survival in head and neck squamous cell carcinomas.

BACKGROUND: The pentaspan protein CD133 (Prominin-1) is a predictive marker and part of the signature of tumour-initiating cells (TICs) for various cancer entities. METHODS: The correlation of CD133 expression with clinical parameters was assessed in primary samples of head and neck squamous cell carcinomas (n=98) and normal mucosas (n=24). RESULTS: A gradual and inversely proportional correlation between CD133 expression in primary tumours and decreased overall survival was observed, along with a positive correlation with the presence of lymph node metastases. CONCLUSIONS: CD133 has the potential of being a novel clinically relevant prognostic marker for head and neck malignancies, which is possibly involved in regulation of tumourigenicity.

Analysis of IL2/IL21 gene variants in cholestatic liver diseases reveals an association with primary sclerosing cholangitis.

BACKGROUND/AIMS: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver diseases. METHODS: Four strongly UC-associated single nucleotide polymorphisms (SNPs) within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block were genotyped in 124 PBC and 41 PSC patients. Control allele frequencies from 1,487 healthy, unrelated Caucasians were available from a previous UC association study. RESULTS: The minor alleles of all four markers were associated with a decreased susceptibility to PSC (rs13151961: p = 0.013, odds ratio (OR) 0.34; rs13119723: p = 0.023, OR 0.40; rs6822844: p = 0.031, OR 0.41; rs6840978: p = 0.043, OR 0.46). Moreover, a haplotype consisting of the four minor alleles also had a protective effect on PSC susceptibility (p = 0.0084, OR 0.28). A haplotype of the four major alleles was independently associated with PSC when excluding the patients with concomitant inflammatory bowel disease (p = 0.033, OR 4.18). CONCLUSION: The IL2/IL21 region may be one of the highly suggestive but so far rarely identified shared susceptibility loci for PSC and UC.