The impact of lymphadenectomy and lymph node metastasis on the outcomes of radical cystectomy for bladder cancer

CONTEXT: The presence of lymph node metastases and the extent of lymphadenectomy have both been shown to influence the outcome of patients with muscle-invasive bladder cancer. OBJECTIVE: Current standards for detection of lymph node metastases, lymph-node mapping studies, histopathologic techniques, and risk factors in relation to lymph node involvement are discussed. The impact of lymph node metastases and the extent of lymphadenectomy on the outcome of patients treated with radical cystectomy are analyzed. EVIDENCE ACQUISITION: A systematic literature review of bladder cancer and lymph nodes was performed searching the electronic databases Pubmed/Medline, Cochrane, and Embase. Articles were selected based on title, abstract, study format, and content by a consensus of all participating authors. EVIDENCE SYNTHESIS: Lymph node status is highly consequential in bladder cancer patients because the presence of lymph node metastases is predictive of poor outcome. Knowledge of primary landing sites of lymph node metastases is important for optimum therapeutic management. Accurate pathologic work-ups of resected lymph node tissue are mandatory. Molecular markers could potentially guide therapeutic decisions in the future because they may enable the detection of micrometastatic disease. In current series, radical cystectomy with an extended lymphadenectomy seems to provide a clinically meaningful therapeutic benefit compared with a limited approach. However, the anatomic boundaries of lymph node dissection are still under debate. Therefore, large prospective multicenter trials are needed to validate the influence of extended lymph node dissection on disease-specific survival. CONCLUSIONS: An extended pelvic lymph node dissection (encompassing the external iliac vessels, the obturator fossa, the lateral and medial aspects of the internal iliac vessels, and at least the distal half of the common iliac vessels together with its bifurcation) can be curative in patients with metastasis or micrometastasis to a few nodes. Therefore, the procedure may be offered to all patients undergoing radical cystectomy for invasive bladder cancer.

An integrated nano-scale approach to profile miRNAs in limited clinical samples

Profiling miRNA expression in cells that directly contribute to human disease pathogenesis is likely to aid the discovery of novel drug targets and biomarkers. However, tissue heterogeneity and the limited amount of human diseased tissue available for research purposes present fundamental difficulties that often constrain the scope and potential of such studies. We established a flow cytometry-based method for isolating pure populations of pathogenic T cells from bronchial biopsy samples of asthma patients, and optimized a high-throughput nano-scale qRT-PCR method capable of accurately measuring 96 miRNAs in as little as 100 cells. Comparison of circulating and airway T cells from healthy and asthmatic subjects revealed asthma-associated and tissue-specific miRNA expression patterns. These results establish the feasibility and utility of investigating miRNA expression in small populations of cells involved in asthma pathogenesis, and set a precedent for application of our nano-scale approach in other human diseases. The microarray data from this study (Figure 7) has been submitted to the NCBI Gene Expression Omnibus (GEO; http://ncbi.nlm.nih.gov/geo) under accession no. GSE31030.

Trochanteric flip osteotomy for cranial extension and muscle protection in acetabular fracture fixation using a Kocher-Langenbeck approach

OBJECTIVE: To describe the advantages and surgical technique of a trochanteric flip osteotomy in combination with a Kocher-Langenbeck approach for the treatment of selected acetabular fractures. DESIGN: Consecutive series, teaching hospital. METHODS: Through mobilization of the vastus lateralis muscle, a slice of the greater trochanter with the attached gluteus medius muscle can be flipped anteriorly. The gluteus minimus muscle can then be easily mobilized, giving free access to the posterosuperior and superior acetabular wall area. Damage to the abductor muscles by vigorous retraction can be avoided, potentially resulting in less ectopic ossification. Ten consecutive cases of acetabular fractures treated with this approach are reported. In eight cases, an anatomic reduction was achieved; in the remaining two cases with severe comminution, the reduction was within one to three millimeters. The trochanteric fragment was fixed with two 3.5-millimeter cortical screws. RESULTS: All osteotomies healed in anatomic position within six to eight weeks postoperatively. Abductor strength was symmetric in eight patients and mildly reduced in two patients. Heterotopic ossification was limited to Brooker classes 1 and 2 without functional impairment at an average follow-up of twenty months. No femoral head necrosis was observed. CONCLUSION: This technique allows better visualization, more accurate reduction, and easier fixation of cranial acetabular fragments. Cranial migration of the greater trochanter after fixation with two screws is unlikely to occur because of the distal pull of the vastus lateralis muscle, balancing the cranial pull of the gluteus medius muscle.

An integrated approach for reconstructing surface models of the proximal femur from sparse input data for surgical navigation

A patient-specific surface model of the proximal femur plays an important role in planning and supporting various computer-assisted surgical procedures including total hip replacement, hip resurfacing, and osteotomy of the proximal femur. The common approach to derive 3D models of the proximal femur is to use imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI). However, the high logistic effort, the extra radiation (CT-imaging), and the large quantity of data to be acquired and processed make them less functional. In this paper, we present an integrated approach using a multi-level point distribution model (ML-PDM) to reconstruct a patient-specific model of the proximal femur from intra-operatively available sparse data. Results of experiments performed on dry cadaveric bones using dozens of 3D points are presented, as well as experiments using a limited number of 2D X-ray images, which demonstrate promising accuracy of the present approach.

Extended resection for thyroid disease has less operative morbidity than limited resection

BACKGROUND: Theodor Kocher, surgeon and Nobel laureate, has influenced thyroid surgery all over the world: his treatment for multinodular goiter-subtotal thyroidectomy-has been the "Gold Standard" for more than a century. However, based on a new understanding of molecular growth mechanisms in goitrogenesis, we set out to evaluate if a more extended resection yields better results. METHODS: Four thousand three hundred and ninety-four thyroid gland operations with 5,785 "nerves at risk" were prospectively analyzed between 1972 and 2002. From 1972 to 1990, the limited Kocher resections were performed, and from 1991 to 2002 a more radical resection involving at least a hemithyroidectomy was performed. RESULTS: The incidence of postoperative nerve palsy was 3.6%; in the first study period and 0.9%; in the second (P < 0.001, Fisher's exact). Postoperative hypoparathyroidism decreased from 3.2%; in the first period to 0.64%; in the second (P < 0.01). The rate of reoperation for recurrent disease was 11.1%; from 1972 to 1990 and 8.5%; from 1991 to 2002 (P < 0.01). CONCLUSIONS: Extended resection for multinodular goiter not only significantly reduced morbidity, but also decreased the incidence of operations for recurrent disease. Our findings in a large cohort corroborate the suggestions that Kocher's approach should be replaced by a more radical resection, which actually was his original intention more than 130 years ago.

Rotational atherectomy followed by drug-eluting stent implantation (Rota-DES): a rational approach for complex calcified coronary lesions

Rotational atherectomy has been regaining interest over the last couple of years after it almost has disappeared from most interventional catheterization laboratories for several years due to failure to prove its original concept of improving long term results of percutaneous coronary interventions (PCI) as was repeatedly shown in studies in the 1990s. Its revival coupled the introduction of drug-eluting stents (DES); these devices have led to treating much more complex lesions and high-risk patients by PCI. However, real-world experience suggested that off-label use of DES is associated with a higher rate of early and late stent thrombosis. Therefore, more attention is now being paid to the initial implantation technique of DES including aggressive lesion preparation to facilitate stent delivery and expansion. The limited studies with rot-ablation and DES showed promising results with no long term safety concerns. In these studies, a subtle observation was made suggesting that rot-ablation prior to DES implantation in such lesions may have an add-on effect on long term outcome compared to DES alone. An ongoing multicenter study is investigating such effect among complex calcified coronary lesions. Even if this additive benefit does not prove true, rot-ablation remains an efficient tool for preparing certain lesions to facilitate effective and safe DES implantation. Therefore, interventional training programs should focus on this difficult technique to bridge the gap of experience which resulted from neglecting it for several years. In this regard, dedicated courses at experienced sites as well as medical simulation may be appropriate.

Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach

There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting beta(2)-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided; allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze; benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.

Limited open reduction and internal fixation of displaced intra-articular fractures of the calcaneum

The extended lateral L-shaped approach for the treatment of displaced intra-articular fractures of the calcaneum may be complicated by wound infection, haematoma, dehiscence and injury to the sural nerve. In an effort to reduce the risk of problems with wound healing a technique was developed that combined open reduction and fixation of the joint fragments and of the anterior process with percutaneous reduction and screw fixation of the tuberosity. A group of 24 patients with unilateral isolated closed Sanders type II and III fractures was treated using this technique and compared to a similar group of 26 patients managed by the extended approach and lateral plating. The operation was significantly shorter (p < 0.001) in the first group, but more minor secondary procedures and removal of heel screws were necessary. There were no wound complications in this group, whereas four minor complications occurred in the second group. The accuracy and maintenance of reduction, and ultimate function were equivalent.

Antiretroviral therapy in resource-limited settings 1996 to 2006: patient characteristics, treatment regimens and monitoring in sub-Saharan Africa, Asia and Latin America

OBJECTIVES: To describe temporal trends in baseline clinical characteristics, initial treatment regimens and monitoring of patients starting antiretroviral therapy (ART) in resource-limited settings. METHODS: We analysed data from 17 ART programmes in 12 countries in sub-Saharan Africa, South America and Asia. Patients aged 16 years or older with documented date of start of highly active ART (HAART) were included. Data were analysed by calculating medians, interquartile ranges (IQR) and percentages by regions and time periods. Not all centres provided data for 2006 and 2005 and 2006 were therefore combined. RESULTS: A total of 36,715 patients who started ART 1996-2006 were included in the analysis. Patient numbers increased substantially in sub-Saharan Africa and Asia, and the number of initial regimens declined, to four and five, respectively, in 2005-2006. In South America 20 regimes were used in 2005-2006. A combination of 3TC/D4T/NVP was used for 56% of African patients and 42% of Asian patients; AZT/3TC/EFV was used in 33% of patients in South America. The median baseline CD4 count increased in recent years, to 122 cells/microl (IQR 53-194) in 2005-2006 in Africa, 134 cells/microl (IQR 72-191) in Asia, and 197 cells/microl (IQR 61-277) in South America, but 77%, 78% and 51%, respectively, started with <200 cells/microl in 2005-2006. In all regions baseline CD4 cell counts were higher in women than men: differences were 22cells/microl in Africa, 65 cells/microl in Asia and 10 cells/microl in South America. In 2005-2006 a viral load at 6 months was available in 21% of patients Africa, 8% of Asian patients and 73% of patients in South America. Corresponding figures for 6-month CD4 cell counts were 74%, 77% and 81%. CONCLUSIONS: The public health approach to providing ART proposed by the World Health Organization has been implemented in sub-Saharan Africa and Asia. Although CD4 cell counts at the start of ART have increased in recent years, most patients continue to start with counts well below the recommended threshold. Particular attention should be paid to more timely initiation of ART in HIV-infected men.

Novel functional profiling approach combining reverse phase protein microarrays and human 3-D ex vivo tissue cultures: expression of apoptosis-related proteins in human colon cancer

Cancer is caused by a complex pattern of molecular perturbations. To understand the biology of cancer, it is thus important to look at the activation state of key proteins and signaling networks. The limited amount of available sample material from patients and the complexity of protein expression patterns make the use of traditional protein analysis methods particularly difficult. In addition, the only approach that is currently available for performing functional studies is the use of serial biopsies, which is limited by ethical constraints and patient acceptance. The goal of this work was to establish a 3-D ex vivo culture technique in combination with reverse-phase protein microarrays (RPPM) as a novel experimental tool for use in cancer research. The RPPM platform allows the parallel profiling of large numbers of protein analytes to determine their relative abundance and activation level. Cancer tissue and the respective corresponding normal tissue controls from patients with colorectal cancer were cultured ex vivo. At various time points, the cultured samples were processed into lysates and analyzed on RPPM to assess the expression of carcinoembryonic antigen (CEA) and 24 proteins involved in the regulation of apoptosis. The methodology displayed good robustness and low system noise. As a proof of concept, CEA expression was significantly higher in tumor compared with normal tissue (p<0.0001). The caspase 9 expression signal was lower in tumor tissue than in normal tissue (p<0.001). Cleaved Caspase 8 (p=0.014), Bad (p=0.007), Bim (p=0.007), p73 (p=0.005), PARP (p<0.001), and cleaved PARP (p=0.007) were differentially expressed in normal liver and normal colon tissue. We demonstrate here the feasibility of using RPPM technology with 3-D ex vivo cultured samples. This approach is useful for investigating complex patterns of protein expression and modification over time. It should allow functional proteomics in patient samples with various applications such as pharmacodynamic analyses in drug development.

Multilocus sequence typing (MLST) of Mycoplasma hyopneumoniae: a diverse pathogen with limited clonality

A multilocus sequence typing (MLST) scheme was established and evaluated for Mycoplasma hyopneumoniae, the etiologic agent of enzootic pneumonia in swine with the aim of defining strains. Putative target genes were selected by genome sequence comparisons. Out of 12 housekeeping genes chosen and experimentally validated, the 7 genes efp, metG, pgiB, recA, adk, rpoB, and tpiA were finally used to establish the MLST scheme. Their usefulness was assessed individually and in combination using a set of well-defined field samples and strains of M. hyopneumoniae. A reduction to the three targets showing highest variation (adk, rpoB, and tpiA) was possible resulting in the same number of sequence types as using the seven targets. The established MLST approach was compared with the recently described typing method using the serine-rich repeat motif-encoding region of the p146 gene. There was coherence between the two methods, but MLST resulted in a slightly higher resolution. Farms recognized to be affected by enzootic pneumonia were always associated with a single M. hyopneumoniae clone, which in most cases differed from farm to farm. However, farms in close geographic or operational contact showed identical clones as defined by MLST typing. Population analysis showed that recombination in M. hyopneumoniae occurs and that strains are very diverse with only limited clonality observed. Elaborate classical MLST schemes using multiple targets for M. hyopneumoniae might therefore be of limited value. In contrast, MLST typing of M. hyopneumoniae using the three genes adk, rpoB, and tpiA seems to be sufficient for epidemiological investigations by direct amplification of target genes from lysate of clinical material without prior cultivation.

The Pricing Discount for Limited Liquidity: Evidence from SWX Swiss Exchange and the Nasdaq

We investigate the pricing discount for limited liquidity. Unlike previous studies that have examined the relation between histroical returns and liquidity, ours looks directly at current stock prices. This approach requires less data and yields up-to-date information about limited liquidity discounts. We analyze data from the Swiss exchange and the Nasdaq during 1995-2001, and find a statistically and economically significant price-liquidity relation in both markets. We test the robustness of that relation with a procedure that does not rely on specific distributional assumptions. Our findings are unaffected. Accordingly, the discount suffered by the least liquid securities is about 30%.

Adapting agricultural land management to climate change: a regional multi-objective optimization approach

In several regions of the world, climate change is expected to have severe impacts on agricultural systems. Changes in land management are one way to adapt to future climatic conditions, including land-use changes and local adjustments of agricultural practices. In previous studies, options for adaptation have mostly been explored by testing alternative scenarios. Systematic explorations of land management possibilities using optimization approaches were so far mainly restricted to studies of land and resource management under constant climatic conditions. In this study, we bridge this gap and exploit the benefits of multi-objective regional optimization for identifying optimum land management adaptations to climate change. We design a multi-objective optimization routine that integrates a generic crop model and considers two climate scenarios for 2050 in a meso-scale catchment on the Swiss Central Plateau with already limited water resources. The results indicate that adaptation will be necessary in the study area to cope with a decrease in productivity by 0–10 %, an increase in soil loss by 25–35 %, and an increase in N-leaching by 30–45 %. Adaptation options identified here exhibit conflicts between productivity and environmental goals, but compromises are possible. Necessary management changes include (i) adjustments of crop shares, i.e. increasing the proportion of early harvested winter cereals at the expense of irrigated spring crops, (ii) widespread use of reduced tillage, (iii) allocation of irrigated areas to soils with low water-retention capacity at lower elevations, and (iv) conversion of some pre-alpine grasslands to croplands.

A reverse crystal Engineering approach

The enormous impact of crystal engineering in modern solid state chemistry takes advantage from the connection between a typical basic science field and the word engineering. Regrettably, the engineering aspect of organic or metal organic crystalline materials are limited, so far, to descriptive structural features, sometime entangled with topological aspects, but only rarely with true material design. This should include not only the fabrication and structural description at micro- and nano-scopic level of the solids, but also a proper reverse engineering, a fundamental discipline for engineers. Translated into scientific language, the reverse crystal engineering refers to a dedicated and accurate analysis of how the building blocks contribute to generate a given material property. This would enable a more appropriate design of new crystalline material. We propose here the application of reverse crystal engineering to optical properties of organic and metal organic framework structures, applying the distributed atomic polarizability approach that we have extensively investigated in the past few years[1,2].

A physical approach on flood risk vulnerability of buildings

The design of efficient hydrological risk mitigation strategies and their subsequent implementation relies on a careful vulnerability analysis of the elements exposed. Recently, extensive research efforts were undertaken to develop and refine empirical relationships linking the structural vulnerability of buildings to the impact forces of the hazard processes. These empirical vulnerability functions allow estimating the expected direct losses as a result of the hazard scenario based on spatially explicit representation of the process patterns and the elements at risk classified into defined typological categories. However, due to the underlying empiricism of such vulnerability functions, the physics of the damage-generating mechanisms for a well-defined element at risk with its peculiar geometry and structural characteristics remain unveiled, and, as such, the applicability of the empirical approach for planning hazard-proof residential buildings is limited. Therefore, we propose a conceptual assessment scheme to close this gap. This assessment scheme encompasses distinct analytical steps: modelling (a) the process intensity, (b) the impact on the element at risk exposed and (c) the physical response of the building envelope. Furthermore, these results provide the input data for the subsequent damage evaluation and economic damage valuation. This dynamic assessment supports all relevant planning activities with respect to a minimisation of losses, and can be implemented in the operational risk assessment procedure.