Object-Oriented Legacy System Trace-based Logic Testing

When reengineering legacy systems, it is crucial to assess if the legacy behavior has been preserved or how it changed due to the reengineering effort. Ideally if a legacy system is covered by tests, running the tests on the new version can identify potential differences or discrepancies. However, writing tests for an unknown and large system is difficult due to the lack of internal knowledge. It is especially difficult to bring the system to an appropriate state. Our solution is based on the acknowledgment that one of the few trustable piece of information available when approaching a legacy system is the running system itself. Our approach reifies the execution traces and uses logic programming to express tests on them. Thereby it eliminates the need to programatically bring the system in a particular state, and handles the test-writer a high-level abstraction mechanism to query the trace. The resulting system, called TESTLOG, was used on several real-world case studies to validate our claims.

Validity of an automatic measure protocol in distal femur for allograft selection from a three-dimensional virtual bone bank system

Osteoarticular allograft is one possible treatment in wide surgical resections with large defects. Performing best osteoarticular allograft selection is of great relevance for optimal exploitation of the bone databank, good surgery outcome and patient’s recovery. Current approaches are, however, very time consuming hindering these points in practice. We present a validation study of a software able to perform automatic bone measurements used to automatically assess the distal femur sizes across a databank. 170 distal femur surfaces were reconstructed from CT data and measured manually using a size measure protocol taking into account the transepicondyler distance (A), anterior-posterior distance in medial condyle (B) and anterior-posterior distance in lateral condyle (C). Intra- and inter-observer studies were conducted and regarded as ground truth measurements. Manual and automatic measures were compared. For the automatic measurements, the correlation coefficients between observer one and automatic method, were of 0.99 for A measure and 0.96 for B and C measures. The average time needed to perform the measurements was of 16 h for both manual measurements, and of 3 min for the automatic method. Results demonstrate the high reliability and, most importantly, high repeatability of the proposed approach, and considerable speed-up on the planning.

Phenology for tropoclimatological surveys and large-scale mapping

Biotic and abiotic phenological observations can be collected from continental to local spatial scale. Plant phenological observations may only be recorded wherever there is vegetation. Fog, snow and ice are available as phenological para-meters wherever they appear. The singularity of phenological observations is the possibility of spatial intensification to a microclimatic scale where the equipment of meteorological measurements is too expensive for intensive campaigning. The omnipresence of region-specific phenological parameters allows monitoring for a spatially much more detailed assessment of climate change than with weather data. We demonstrate this concept with phenological observations with the use of a special network in the Canton of Berne, Switzerland, with up to 600 observations sites (more than 1 to 10 km² of the inhabited area). Classic cartography, gridding, the integration into a Geographic Information System GIS and large-scale analysis are the steps to a detailed knowledge of topoclimatic conditions of a mountainous area. Examples of urban phenology provide other types of spatially detailed applications. Large potential in phenological mapping in future analyses lies in combining traditionally observed species-specific phenology with remotely sensed and modelled phenology that provide strong spatial information. This is a long history from cartographic intuition to algorithm-based representations of phenology.

N-H center dot center dot center dot pi hydrogen-bonding and large-amplitude tipping vibrations in jet-cooled pyrrole-benzene

The N-H center dot center dot center dot pi hydrogen bond is an important intermolecular interaction in many biological systems. We have investigated the infrared (IR) and ultraviolet (UV) spectra of the supersonic-jet cooled complex of pyrrole with benzene and benzene-d(6) (Pyr center dot Bz, Pyr center dot Bz-d(6)). DFT-D density functional, SCS-MP2 and SCS-CC2 calculations predict a T-shaped and (almost) C(s) symmetric structure with an N-H center dot center dot center dot pi hydrogen bond to the benzene ring. The pyrrole is tipped by omega(S(0)) = +/- 13 degrees relative to the surface normal of Bz. The N center dot center dot center dot ring distance is 3.13 angstrom. In the S(1) excited state, SCS-CC2 calculations predict an increased tipping angle omega(S(1)) = +/- 21 degrees. The IR depletion spectra support the T-shaped geometry: The NH stretch is redshifted by -59 cm(-1), relative to the "free" NH stretch of pyrrole at 3531 cm(-1), indicating a moderately strong N-H center dot center dot center dot pi interaction. The interaction is weaker than in the (Pyr)(2) dimer, where the NH donor shift is -87 cm(-1) [Dauster et al., Phys. Chem. Chem. Phys., 2008, 10, 2827]. The IR C-H stretch frequencies and intensities of the Bz subunit are very similar to those of the acceptor in the (Bz)(2) dimer, confirming that Bz acts as the acceptor. While the S(1) <- S(0) electronic origin of Bz is forbidden and is not observable in the gas-phase, the UV spectrum of Pyr center dot Bz in the same region exhibits a weak 0(0)(0) band that is red-shifted by 58 cm(-1) relative to that of Bz (38 086 cm(-1)). The origin appears due to symmetry-breaking of the p-electron system of Bz by the asymmetric pyrrole NH center dot center dot center dot pi hydrogen bond. This contrasts with (Bz)(2), which does not exhibit a 0(0)(0) band. The Bz moiety in Pyr center dot Bz exhibits a 6a(0)(1) band at 0(0)(0) + 518 cm(-1) that is about 20x more intense than the origin band. The symmetry breaking by the NH center dot center dot center dot pi hydrogen bond splits the degeneracy of the v(6)(e(2g)) vibration, giving rise to 6a' and 6b' sub-bands that are spaced by similar to 6 cm(-1). Both the 0(0)(0) and 6(0)(1) bands of Pyr center dot Bz carry a progression in the low-frequency (10 cm(-1)) excited-state tipping vibration omega', in agreement with the change of the omega tipping angle predicted by SCS-MP2 and SCS-CC2 calculations.

TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study

Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms.

Interactions between the microbiota and the immune system

The large numbers of microorganisms that inhabit mammalian body surfaces have a highly coevolved relationship with the immune system. Although many of these microbes carry out functions that are critical for host physiology, they nevertheless pose the threat of breach with ensuing pathologies. The mammalian immune system plays an essential role in maintaining homeostasis with resident microbial communities, thus ensuring that the mutualistic nature of the host-microbial relationship is maintained. At the same time, resident bacteria profoundly shape mammalian immunity. Here, we review advances in our understanding of the interactions between resident microbes and the immune system and the implications of these findings for human health.

Regulation of immune cell entry into the central nervous system

The central nervous system (CNS) has long been regarded as an immune privileged organ implying that the immune system avoids the CNS to not disturb its homeostasis, which is critical for proper function of neurons. Meanwhile, it is accepted that immune cells do in fact gain access to the CNS and that immune responses can be mounted within this tissue. However, the unique CNS microenvironment strictly controls these immune reactions starting with tightly controlling immune cell entry into the tissue. The endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid (CSF) barrier, which protect the CNS from the constantly changing milieu within the bloodstream, also strictly control immune cell entry into the CNS. Under physiological conditions, immune cell migration into the CNS is kept at a very low level. In contrast, during a variety of pathological conditions of the CNS such as viral or bacterial infections, or during inflammatory diseases such as multiple sclerosis, immunocompetent cells readily traverse the BBB and likely also the choroid plexus and subsequently enter the CNS parenchyma or CSF spaces. This chapter summarizes our current knowledge of immune cell entry across the blood CNS barriers. A large body of the currently available information on immune cell entry into the CNS has been derived from studying experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Therefore, most of this chapter discussing immune cell entry during CNS pathogenesis refers to observations in the EAE model, allowing for the possibility that other mechanisms of immune cell entry into the CNS might apply under different pathological conditions such as bacterial meningitis or stroke.

Examining the gateway to the limbic system with diffusion tensor imaging: the perforant pathway in dementia

Current treatments for Alzheimer's disease (AD) are only able to slow the progression of mental deterioration, making early and reliable diagnosis an essential part of any promising therapeutic strategy. In the initial stages of AD, the first neuropathological alterations occur in the perforant pathway (PP), a large neuronal fiber tract located at the entrance to the limbic system. However, to date, there is no sensitive diagnostic tool for performing in vivo assessments of this structure. In the present bimodal magnetic resonance imaging (MRI) study, we examined 10 elderly controls, 10 subjects suffering from mild cognitive impairment (MCI), and 10 AD patients in order to evaluate the sensitivity of diffusion tensor imaging (DTI), a new MRI technique, for detecting changes in the PP. Furthermore, the diagnostic explanatory power of DTI data of the PP should be compared to high-resolution MRI volumetry and intervoxel coherences (COH) of the hippocampus and the entorhinal cortex, two limbic regions also involved in the pathophysiology of early AD. DTI revealed a marked decrease in COH values in the PP region of MCI (right side: 26%, left side: 29%, as compared to controls) and AD patients (right side: 37%, left side: 43%, as compared to controls). Reductions in COH values of the PP region were significantly correlated with cognitive impairment. DTI data of the PP zone were the only parameter differing significantly between control subjects and MCI patients, while the volumetric measures and the COH values of the hippocampus and the entorhinal cortex did not. DTI of medial temporal brain regions is a promising non-invasive tool for the in vivo diagnosis of the early/preclinical stages of AD.

Identifying breast cancer patients at risk for Central Nervous System (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG)

BACKGROUND: We sought to determine whether a high-risk group could be defined among patients with operable breast cancer in whom a search of occult central nervous system (CNS) metastases was justified. PATIENTS AND METHODS: We evaluated data from 9524 women with early breast cancer (42% node-negative) who were randomized in International Breast Cancer Study Group clinical trials between 1978 and 1999, and treated without anthracyclines, taxanes, or trastuzumab. We identified patients whose site of first event was CNS and those who had a CNS event at any time. RESULTS: Median follow-up was 13 years. The 10-year incidence (10-yr) of CNS relapse was 5.2% (1.3% as first recurrence). Factors predictive of CNS as first recurrence included: node-positive disease (10-yr = 2.2% for > 3 N+), estrogen receptor-negative (2.3%), tumor size > 2 cm (1.7%), tumor grade 3 (2.0%), < 35 years old (2.2%), HER2-positive (2.7%), and estrogen receptor-negative and node-positive (2.6%). The risk of subsequent CNS recurrence was elevated in patients experiencing lung metastases (10-yr = 16.4%). CONCLUSION: Based on this large cohort we were able to define risk factors for CNS metastases, but could not define a group at sufficient risk to justify routine screening for occult CNS metastases.

Complex genital system of a haplogyne spider (Arachnida, Araneae, Tetrablemmidae) indicates internal fertilization and full female control over transferred sperm

The female genital organs of the tetrablemmid Indicoblemma lannaianum are astonishingly complex. The copulatory orifice lies anterior to the opening of the uterus externus and leads into a narrow insertion duct that ends in a genital cavity. The genital cavity continues laterally in paired tube-like copulatory ducts, which lead into paired, large, sac-like receptacula. Each receptaculum has a sclerotized pore plate with associated gland cells. Paired small fertilization ducts originate in the receptacula and take their curved course inside the copulatory ducts. The fertilization ducts end in slit-like openings in the sclerotized posterior walls of the copulatory ducts. Huge masses of secretions forming large balls are detectable in the female receptacula. An important function of these secretory balls seems to be the encapsulation of spermatozoa in discrete packages in order to avoid the mixing of sperm from different males. In this way, sperm competition may be completely prevented or at least severely limited. Females seem to have full control over transferred sperm and be able to express preference for spermatozoa of certain males. The lumen of the sperm containing secretory balls is connected with the fertilization duct. Activated spermatozoa are only found in the uterus internus of females, which is an indication of internal fertilization. The sperm cells in the uterus internus are characterized by an extensive cytoplasm and an elongated, cone-shaped nucleus. The male genital system of I. lannaianum consists of thick testes and thin convoluted vasa deferentia that open into the wide ductus ejaculatorius. The voluminous globular palpal bulb is filled with seminal fluid consisting of a globular secretion in which only a few spermatozoa are embedded. The spermatozoa are encapsulated by a sheath produced in the genital system. The secretions in females may at least partly consist of male secretions that could be involved in the building of the secretory balls or play a role in sperm activation. The male secretions could also afford nutriments to the spermatozoa.

Mast fruiting of large ectomycorrhizal African rain forest trees: importance of dry season intensity, and the resource limitation hypothesis

Mast fruiting is a distinctive reproductive trait in trees. This rain forest study, at a nutrient-poor site with a seasonal climate in tropical Africa, provides new insights into the causes of this mode of phenological patterning. •  At Korup, Cameroon, 150 trees of the large, ectomycorrhizal caesalp, Microberlinia bisulcata, were recorded almost monthly for leafing, flowering and fruiting during 1995–2000. The series was extended to 1988–2004 with less detailed data. Individual transitions in phenology were analysed. •  Masting occurred when the dry season before fruiting was drier, and the one before that was wetter, than average. Intervals between events were usually 2 or 3 yr. Masting was associated with early leaf exchange, followed by mass flowering, and was highly synchronous in the population. Trees at higher elevation showed more fruiting. Output declined between 1995 and 2000. •  Mast fruiting in M. bisulcata appears to be driven by climate variation and is regulated by internal tree processes. The resource-limitation hypothesis was supported. An ‘alternative bearing’ system seems to underlie masting. That ectomycorrhizal habit facilitates masting in trees is strongly implied.

Antitumor activity of an epithelial cell adhesion molecule targeted nanovesicular drug delivery system

Site-specific delivery of anticancer agents to tumors represents a promising therapeutic strategy because it increases efficacy and reduces toxicity to normal tissues compared with untargeted drugs. Sterically stabilized immunoliposomes (SIL), guided by antibodies that specifically bind to well internalizing antigens on the tumor cell surface, are effective nanoscale delivery systems capable of accumulating large quantities of anticancer agents at the tumor site. The epithelial cell adhesion molecule (EpCAM) holds major promise as a target for antibody-based cancer therapy due to its abundant expression in many solid tumors and its limited distribution in normal tissues. We generated EpCAM-directed immunoliposomes by covalently coupling the humanized single-chain Fv antibody fragment 4D5MOCB to the surface of sterically stabilized liposomes loaded with the anticancer agent doxorubicin. In vitro, the doxorubicin-loaded immunoliposomes (SIL-Dox) showed efficient cell binding and internalization and were significantly more cytotoxic against EpCAM-positive tumor cells than nontargeted liposomes (SL-Dox). In athymic mice bearing established human tumor xenografts, pharmacokinetic and biodistribution analysis of SIL-Dox revealed long circulation times in the blood with a half-life of 11 h and effective time-dependent tumor localization, resulting in up to 15% injected dose per gram tissue. These favorable pharmacokinetic properties translated into potent antitumor activity, which resulted in significant growth inhibition (compared with control mice), and was more pronounced than that of doxorubicin alone and nontargeted SL-Dox at low, nontoxic doses. Our data show the promise of EpCAM-directed nanovesicular drug delivery for targeted therapy of solid tumors.

Transgenic system for conditional induction and rescue of chronic myocardial hibernation provides insights into genomic programs of hibernation

A key energy-saving adaptation to chronic hypoxia that enables cardiomyocytes to withstand severe ischemic insults is hibernation, i.e., a reversible arrest of contractile function. Whereas hibernating cardiomyocytes represent the critical reserve of dysfunctional cells that can be potentially rescued, a lack of a suitable animal model has hampered insights on this medically important condition. We developed a transgenic mouse system for conditional induction of long-term hibernation and a system to rescue hibernating cardiomyocytes at will. Via myocardium-specific induction (and, in turn, deinduction) of a VEGF-sequestering soluble receptor, we show that VEGF is indispensable for adjusting the coronary vasculature to match increased oxygen consumption and exploit this finding to generate a hypoperfused heart. Importantly, ensuing ischemia is tunable to a level at which large cohorts of cardiomyocytes are driven to enter a hibernation mode, without cardiac cell death. Relieving the VEGF blockade even months later resulted in rapid revascularization and full recovery of contractile function. Furthermore, we show that left ventricular remodeling associated with hibernation is also fully reversible. The unique opportunity to uncouple hibernation from other ischemic heart phenotypes (e.g., infarction) was used to determine the genetic program of hibernation; uncovering hypoxia-inducible factor target genes associated with metabolic adjustments and induced expression of several cardioprotective genes. Autophagy, specifically self-digestion of mitochondria, was identified as a key prosurvival mechanism in hibernating cardiomyocytes. This system may lend itself for examining the potential utility of treatments to rescue dysfunctional cardiomyocytes and reverse maladaptive remodeling.