Pathways to diabetic limb amputation. Basis for prevention

We defined the causal pathways responsible for 80 consecutive initial lower-extremity amputations to an extremity in diabetic patients at the Seattle Veterans Affairs Medical Center over a 30-mo interval from 1984 to 1987. Causal pathways, either unitary or composed of various combinations of seven potential causes (i.e., ischemia, infection, neuropathy, faulty wound healing, minor trauma, cutaneous ulceration, gangrene), were determined empirically after a synthesis by the investigators of various objective and subjective data. Estimates of the proportion of amputations that could be ascribed to each component cause were calculated. Twenty-three unique causal pathways to diabetic limb amputation were identified. Eight frequent constellations of component causes resulted in 73% of the amputations. Most pathways were composed of multiple causes, with only critical ischemia from acute arterial occlusions responsible for amputations as a singular cause. The causal sequence of minor trauma, cutaneous ulceration, and wound-healing failure applied to 72% of the amputations, often with the additional association of infection and gangrene. We specified precise criteria in the definition of causal pathway to permit estimation of the cumulative proportion of amputations due to various causes. Forty-six percent of the amputations were attributed to ischemia, 59% to infection, 61% to neuropathy, 81% to faulty wound healing, 84% to ulceration, 55% to gangrene, and 81% to initial minor trauma. An identifiable and potentially preventable pivotal event, in most cases an episode involving minor trauma that caused cutaneous injury, preceded 69 to 80 amputations. Defining causal pathways that predispose to diabetic limb amputation suggests practical interventions that may be effective in preventing diabetic limb loss.     

Dynamics of brain-derived proteins in cerebrospinal fluid

Background: The recent theory of blood–cerebrospinal fluid (CSF) barrier function and dysfunction connects molecular flux and CSF flow rate. A reduced CSF flow rate is sufficient to account for the observed hyperbolic relation between different blood-derived protein concentrations in CSF in cases of a blood–CSF barrier dysfunction. Methods: The dynamics of brain-derived proteins in CSF are investigated with reference to the CSF flow rate measured by CSF/serum albumin concentration quotient. Results: Proteins from neurons or glial cells, tau protein, neuron-specific enolase, S-100 protein, all enter CSF primarily in the ventricular and cisternal space. Their concentration between normal ventricular and lumbar CSF is decreasing (in contrast to blood-derived proteins), and in the case of pathologically decreasing CSF flow rate, the concentration in lumbar CSF remains invariantly constant. Concentrations of the primarily leptomeningeal proteins, β-trace protein and cystatin C, increase between normal ventricular and lumbar CSF, and in the case of pathologically decreased CSF flow rate they increase linearly in lumbar CSF (concentrations of blood-derived proteins increase non-linearly). Conclusions: A satisfactory physiological explanation can now be given for the dynamics of proteins in CSF consisting of both brain- and blood-derived fractions (transthyretin, soluble intercellular adhesion molecule (s-ICAM)), as well as the disputed decrease of leptomeningeal protein concentrations (β-trace protein, cystatin C) in cases of bacterial meningitis is also explained. The biophysical treatment of dynamics in the ventricular and lumbar CSF extends the new theory and shows that CSF flow rate is the most relevant parameter for understanding the pathological changes of both blood- and brain-derived proteins in CSF. The impact on diagnosis of neuro-degenerative diseases is discussed.     

Comprehensive visualization of multimodal cardiac imaging data for assessment of coronary artery disease: first clinical results of the SMARTVis tool

Purpose

In clinical practice, both coronary anatomy and myocardial perfusion information are needed to assess coronary artery disease (CAD). The extent and severity of coronary stenoses can be determined using computed tomography coronary angiography (CTCA); the presence and amount of ischemia can be identified using myocardial perfusion imaging, such as perfusion magnetic resonance imaging (PMR). To determine which specific stenosis is associated with which ischemic region, experts use assumptions on coronary perfusion territories. Due to the high variability between patient??s coronary artery anatomies, as well as the uncertain relation between perfusion territories and supplying coronary arteries, patient-specific systems are needed.

Material and methods

We present a patient-specific visualization system, called Synchronized Multimodal heART Visualization (SMARTVis), for relating coronary stenoses and perfusion deficits derived from CTCA and PMR, respectively. The system consists of the following comprehensive components: (1) two or three-dimensional fusion of anatomical and functional information, (2) automatic detection and ranking of coronary stenoses, (3) estimation of patient-specific coronary perfusion territories.

Results

The potential benefits of the SMARTVis tool in assessing CAD were investigated through a case-study evaluation (conventional vs. SMARTVis tool): two experts analyzed four cases of patients with suspected multivessel coronary artery disease. When using the SMARTVis tool, a more reliable estimation of the relation between perfusion deficits and stenoses led to a more accurate diagnosis, as well as a better interobserver diagnosis agreement.

Conclusion

The SMARTVis comprehensive visualization system can be effectively used to assess disease status in multivessel CAD patients, offering valuable new options for the diagnosis and management of these patients.     

LgR5 expression and cancer stem cell hypothesis: clue to define the true origin of esophageal adenocarcinomas with and without Barrett's Esophagus?

Background

Investigation of the expression of an intestinal stem cell marker in esophageal adenocarcinomas (EAC) with and without Barrett''s Esophagus (BE), with respect to a cancer stem cell (CSC) hypothesis.

Materials and methods

Expression of a putative intestinal stem cell marker LgR5 was analyzed in esophageal cancer specimen (n = 70: 41 EAC with BE, 19 EAC without BE, and n = 10 esophageal squamous-cell carcinomas, ESCC) and in the adenocarcinoma cell line OE-33. Ki-67 and Cdx-2 were co-labelled with LgR5 in double staining experiments. Immunhistochemical expression results were confirmed by RT-PCR and correlated with tumor stage and five-year survival rates.

Results

LgR5was found expressed in 35 of 41 (85%) EAC with BE and in 16 of 19 (81%) EAC without BE. By contrast, LgR5 was not found to be expressed in ESCC. Quantification of immunolabeling showed 15% LgR5+ cells in EAC with BE, 32% LgR5+ cells in adjacent BE and 13% in EAC without BE. Immunofluorescence double staining experiments with LgR5 and Ki-67 revealed a subpopulation (~5%) of proliferating LgR+/Ki-67+ cells. On mRNA-level, expression of LgR5 was higher in BE in comparison to EAC (p = 0.0159). High levels of LgR5 expression in BE associated EAC were associated with poorer survival in univariate analysis.

Conclusion

The stem cell marker LgR5 is expressed in EAC, irrespective of association with BE, and appears to have negative impact on survival. The subset of proliferating LgR5+ cells (<5%) might resemble rapidly cycling CSCs, which needs to be substantiated in further investigations.     

Evaluation of patients with previous coronary stent implantation with 64-section CT

PURPOSE: To prospectively evaluate the diagnostic accuracy of 64-section computed tomography (CT) for the assessment of in-stent or peristent restenosis, with conventional coronary angiography as the reference standard. MATERIALS AND METHODS: The study was approved by the medical ethics committee, and informed consent was obtained in all 50 enrolled patients (40 men, 10 women; mean age, 60 years +/- 11 [standard deviation]). In addition to conventional coronary angiography with quantitative coronary angiography, 64-section CT was performed. For each stent, assessability was determined and was related to stent characteristics and heart rate by using a chi(2) test. On the interpretable images of stents and peristent lumina (5.00 mm proximal and distal to the stent), the presence of significant (> or =50%) restenosis was determined. For this analysis, partially overlapping stents were considered to represent a single stent. RESULTS: Of 76 stents, 65 (86%) were determined to be assessable. Increased heart rate and overlapping positioning were associated with increased uninterpretability of the images of stents (P < .05), whereas location of the stent and thickness of the strut were not. In seven patients, stents were placed in an overlapping manner, resulting in 58 stents available for the evaluation of significant (> or =50%) in-stent restenosis. All six significant (> or =50%) in-stent restenoses were detected, and the absence of significant (> or =50%) restenosis was correctly identified in the 52 remaining stents, resulting in sensitivity and specificity of 100%. Sensitivity and specificity for the detection of significant (> or =50%) peristent stenosis were 100% and 98%, respectively. CONCLUSION: In selected patients with previous stent implantation, 64-section CT can be used to evaluate in-stent restenosis with high accuracy. Accordingly, the technique may be useful for noninvasive exclusion of in-stent or peristent restenosis, thereby avoiding invasive imaging in a considerable number of patients.     

Quantitation of intrathecal antibodies in cerebrospinal fluid of subacute sclerosing panencephalitis, herpes simplex encephalitis and multiple sclerosis: discrimination between microorganism-driven and polyspecific immune response

The detection of intrathecal antibody synthesis by qualitative methods or the Antibody-Index (AI) is a relevant tool for diagnosis of inflammatory neurological diseases. An increased AI can be observed for a causative antigen as well as part of a polyspecific immune response. The quantitation of the intrathecal antibody fraction in cerebrospinal fluid (CSF), F(S), helps to discriminate both cases. In contrast to AI, F(S) needs an absolute antibody concentration detected in the ELISA in mg/L. The intrathecally synthesized, "local" antibody concentration in CSF (AB(Loc)) is expressed as the specific fraction of the intrathecally synthesized total IgG (IgG(Loc)) in CSF with F(S)=AB(Loc)/IgG(Loc) x 100 in %. F(S) for HSV or measles has about 20- to 60-fold higher values in virus-caused antibody synthesis in acute herpes simplex encephalitis (mean HSV-F(S)=8.9%) or subacute sclerosing panencephalitis (mean measles-F(S)=18.8%) compared to the polyspecific immune response against these antigens e.g., in multiple sclerosis (0.14% or 0.52%, correspondingly). F(S) helps also to avoid misinterpretations of an increasing AI in cases of therapy control, and allows direct comparison of relative antibody concentrations (R(S)) in blood and intrathecally synthesized fractions in CSF (F(S)): In multiple sclerosis patients F(S):R(S) has a mean ratio of about 3 for the measles, rubella and VZV antibodies. Together with the large variability we find by ranking that about two third of MS patients have no direct correlation of the relative concentrations in serum and intrathecal synthesis. So this concept gains increasingly relevance for analysis of the polyspecific immune response in brain.