Vascularization of carotid plaque in recently symptomatic patients is associated with the occurrence of transcranial microembolic signals.

BACKGROUND AND PURPOSE: Microembolic signals (MES) are detectable in the middle cerebral artery by transcranial ultrasound downstream to atherosclerotic lesions of the internal carotid artery (ICA) in patients with stroke or transient ischaemic attack. The occurrence of MES predicts future risk of stroke in patients with symptomatic and asymptomatic carotid stenosis. The detection of intra-plaque neo-vascularization by contrast-enhanced ultrasound (CEUS) in atherosclerotic plaques of the ICA is associated with future cardiovascular/cerebrovascular events. We investigated whether there is an association between both surrogate markers of future vascular events. METHODS: Forty-one patients with symptomatic atherosclerotic plaques underwent ipsilateral transcranial ultrasound MES detection for 30 min followed by a CEUS investigation of the plaque. The occurrence and number of MES was documented, and the degree of intra-plaque neo-vascularization was measured semi-quantitatively. RESULTS: During the 30 min investigation, 17 patients had MES and nine of them showed neo-vascularization of the atherosclerotic plaque. The remaining 24 patients did not have MES, and only in four patients of this group could plaque neo-vascularization be demonstrated (P = 0.020). CONCLUSIONS: We found an association between the occurrence of MES and the presence of neo-vascularization in patients with symptomatic atherosclerotic carotid plaque. Therefore, plaque neo-vascularization might also be a surrogate marker of future stroke risk.

[Silent brain infarcts]. / Klinisch stumme Hirninfarkte.

Silent brain infarctions are frequently found by modern cerebral imaging. Up to 30% of persons without a clinical history of stroke were found to have silent brain infarction in epidemiological studies. "Silent" refers to ischemic brain lesions for which no matching clinical syndrome can be found based on history or clinical investigation. Age, education, and ethnic background have a strong impact on noticing and reporting stroke symptoms. The current clinical definition of stroke is insensitive for cognitive deficits which can also be caused by brain infarctions. The majority of silent brain infarctions are localized in the subcortical white matter of the brain; however, about 10% of silent brain infarctions are cortical. Silent brain infarctions are strongly associated with stroke risk factors and comorbidities that are known to cause clinically overt stroke. Silent brain infarctions are 5 to 10 times more frequent than clinically overt strokes. Silent brain infarctions as defined by DWI lesions on MRI imaging are a frequent finding during operative or interventional procedures and their monitoring may help improve the respective techniques in order to decrease the risk of periprocedural stroke.

Tissue interaction in the development of thymus lymphocytes.

Thymic rudiments from chick and mouse embryos have been cultured in diffusion chambers on the chick chorioallantois. In this situation their supply of blood-borne stem cells is cut off. Although rudiments from older embryos become fully lymphoid under these circumstances, primordia from early embryos fail to develop any lymphoid cells. Early chick rudiments will however develop completely if they are grafted directly to the chorioallantois where they receive a vascular supply. It is concluded that stem cells first enter the chick thymic anlage at between 6 and 7 days' incubation and the mouse thymic rudiment between 10 and 11 days' gestation. During the following few days of development there is a rapid inflow of stem cells to the rudiments. Since it is likely that stem cells, once they have entered the thymic primordium, are capable of only limited proliferation, it must be concluded that an inflow of stem cells continues once full lymphopoiesis has begun, although perhaps at a reduced rate. Finally, the importance of the interaction between stem cell and organ rudiment to normal thymic development is discussed in relation to the pathogenesis of thymic anomalies.

Fluorescent light induces malignant transformation in mouse embryo cell cultures.

Fluorescent light induced a dose-dependent malignant transformation in mouse C3H10T1/2 cells. A plateau in the dose-response curve for transformation was correlated with that observed with ultraviolet light exposure. The similarity in the two dose-response patterns suggests that similar molecular processes may be involved in the induction of malignant transformation by the two types of radiation.

Accuracy of perfusion-CT in predicting malignant middle cerebral artery brain infarction.

BACKGROUND: We performed a prospective study on patients with middle cerebral artery(MCA) ischemic stroke to evaluate the accuracy of perfusion-CT imaging(PCT) to predict the development of malignant brain infarction (MBI). METHODS: 106 patients(women 37 %, mean age 65 years)underwent native cranial computed tomography (CCT), CT angiography(CTA) and PCT after a median of 2 h after stroke onset. We assessed the patency of the MCA and the area of tissue ischemia (AIT)according to cerebral blood flow(CBF), cerebral blood volume (CBV) and time-to-peak (TTP)maps. Optimum sensitivity, specificity,positive (PPV) and negative predictive values (NPV) were calculated for the end-point MBI (= midline shift > 5 mm or decompressive surgery) by means of receiver operating characteristics(ROC). RESULTS: 20 patients (19 %)developed a MBI. In these patients,a larger AIT was found in all perfusion maps as compared to the remaining patients (p < 0.001). All perfusion maps had a very high NPV (95.4-98.4 %), a high sensitivity (85-95 %) and specificity (71.6-77.9 %) and only a moderate PPV (44-47.4 %). Best prediction was found for CBF maps with AIT of > 27.9 % of the hemisphere. CONCLUSION: PCT allows the discrimination of patients without a relevant risk for MBI from those having a 50 % risk of MBI development. Due to the high sensitivity and specificity, PCT is a reliable tool in detecting MBI. Because of PCT's better availability, it is the method of choice at present for an early risk stratification of acute stroke patients.

Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice.

Thymic atrophy is a prominent feature of malnutrition. Forty-eight hours' starvation of normal mice reduced the total thymocyte count to 13% of that observed in freely fed controls, predominantly because of a diminution in the cortical CD4(+)CD8(+) thymocyte subpopulation. Prevention of the fasting-induced fall in the level of the adipocyte-derived hormone leptin by administering exogenous recombinant leptin protected mice from these starvation-induced thymic changes. The ob/ob mouse, which is unable to produce functional leptin because of a mutation in the obese gene, has impaired cellular immunity together with a marked reduction in the size and cellularity of the thymus. We found that ob/ob mice had a high level of thymocyte apoptosis resulting in a ratio of CD4(+)CD8(+) (cortical) to CD4(-)CD8(-) (precursor) thymocytes that was 4-fold lower than that observed in wild-type mice. Peripheral administration of recombinant leptin to ob/ob mice reduced thymocyte apoptosis and substantially increased both thymic cellularity and the CD4(+)CD8(+)/CD4(-)CD8(-) ratio. In contrast, a comparable weight loss in pair-fed PBS-treated ob/ob mice had no impact on thymocyte number. In vitro, leptin protected thymocytes from dexamethasone-induced apoptosis. These data indicate that reduced circulating leptin concentrations are pivotal in the pathogenesis of starvation-induced lymphoid atrophy.

Low rate of contrast-induced Nephropathy after CT perfusion and CT angiography in acute stroke patients.

BACKGROUND: The aim of the study was to assess (i) the rate of contrast-induced nephropathy (CIN), (ii) the amount and time course of renal dysfunction, (iii) the identification of risk factors and calculation of a risk score for CIN in acute stroke patients after CT perfusion (CTP) and CT angiography (CTA). METHODS: 162 patients were investigated,who had received 140 ml of non-ionic low osmolar contrast agent (300 mg iodine per ml, Ultravist 300, Schering AG) for CTA and CTP. We assessed electrolytes, creatinine, and creatinine clearance before and up to 7 days after administration of contrast agent. In addition, the risk factors for CIN were recorded and a previously validated risk score for CIN was calculated. We also assessed the amount of crystalloid fluid substitution and newly prescribed drugs. CIN was defined as an increase of the serum creatinine-level of > 0.5 mg/dl or > 25% above baseline within 48 hours after contrast agent administration. RESULTS: 154 patients (94 %) received crystalloid fluid substitution (mean 6.1 l) within 48 h after contrast agent administration. During follow-up the creatinine values and the creatinine clearance remained stable while sodium and potassium increased significantly (p < 0.0001) after contrast agent administration. In patients with a pathological creatinine value on admission (n = 40), the creatinine clearance did not decrease significantly (p = 0.18). The risk score for developing a CIN was low in the majority of stroke patients. A manifest CIN occurred in 3 patients (2 %). No patient had to be hemodialysed. CONCLUSION: CIN is a rare complication in acute stroke patients examined by multimodal contrast-based CT due to the low prevalence of risk factors associated with CIN. In conjunction with appropriate fluid substitution, low osmolar nonionic contrast agents seem to be safe in clinical routine.

Negative ultrasound findings in patients with cervical artery dissection. Negative ultrasound in CAD.

BACKGROUND: Cervical artery dissection (CAD) is a common cause of ischemic stroke in the younger age group. Modern imaging techniques allow the depiction of the mural hematoma, even in CADs with only subtle vessel alterations. The aim of this retrospective study was (1) to characterize the angiological features in CAD and (2) to determine the frequency of initially normal ultrasonography (US) findings. METHODS: 86 patients aged 44 +/- 11 years with CAD of the internal carotid (ICA), (n = 55) or the vertebral artery (VA), (n = 31), admitted to our hospital within 8 days (mean 1.6 days) of symptom onset, were included. CAD was confirmed either by CT-angiography, MRI of the neck, MR-angiography or digital substraction angiography (DSA) and was compared with the results of the initial as well as repeated US examinations of the arteries supplying the brain. RESULTS: In 75 patients (81.2 %) signs of vessel stenosis or occlusion were found while 11 patients (12.8%) with CAD of the ICA (n = 9) and the VA (n = 2) had normal US findings. The site of dissection in the US negative patients was highly variable without a predilection site. In 2 of 7 patients with repeated US examinations, complete vessel occlusion was found on follow-up, while in 5 patients again normal results were found. In four patients, there were changing findings in two alternative confirming imaging methods (MRI/DSA, CT/MRI) and in one patient conflicting findings (CT/MRI). Brain infarctions had occurred in 7 of the initially sonographically normal patients while the other 4 had suffered from transient (n = 2) or local (n = 2) symptoms only. CONCLUSION: Approximately 1 out of 8 patients with subsequently proven CAD has negative initial neurovascular US findings despite comprehensive examination. In patients with suspected CAD and negative US examination, repeated US examinations and further diagnostic imaging, especially MRI is necessary.

Thy-1 antigen on normal and neoplastic rat mammary tissues: changes in location and amount of antigen during differentiation of cultured stem cells.

With the use of immunofluorescent and immunocytochemical techniques on histologic sections of mammary glands from inbred WF rats, the thymocyte differentiation antigen (Thy-1) was identified partially on and immediately adjacent to the myoepithelial cells of ducts and alveoli. This antigen was absent from epithelial cells lining such structures. Some fibroblastic cells external to these structures also bore Thy-1. During glandular development the intensity of fluorescence due to the binding of Thy-1 antibodies increased as the myoepithelial cells matured. Similarly, mammary adenocarcinomas induced by 7,12-dimethylbenz[a]anthracene (DMBA) and N-methyl-N-nitrosourea contained elongated, presumptive myoepithelial cells that demonstrated varying degrees of Thy-1 immunofluorescence. This phenomenon was qualitatively mimicked by cultured cell lines from normal and DMBA-induced tumors. Elongated myoepithelial-like and fibroblast-like cells possessed Thy-1, whereas the cuboidal epithelial cell lines failed to express this antigen on the cell surface. Measurement of the relative number of Thy-1 molecules per cell by antiserum absorption techniques suggested that a neoplastic stem cell line, rat mammary (Rama) 25, contained about 3 X 10(5) Thy-1 molecules per cell in a form not directly accessible at the cell surface to anti-Thy-1 antibodies; the number of cryptic Thy-1 molecules was reduced when this cell line differentiated to alveolar-like cells in culture. However, when this cell line differentiated to myoepithelial-like cells, approximately 5 X 10(6) molecules per cell were exposed to anti-Thy-1 antibodies with a concomitant reduction of the cryptic pool. Morphologic maturation of elongated, myoepithelial-like cell line variants was also accompanied by increased surface Thy-1 fluorescence. Thus some of the myoepithelial cells in normal glands and tumors may arise by differentiation of epithelial stem cells and a spectrum of maturation states of the myoepithelial cell may exist as monitored by cellular morphology and surface Thy-1 expression.

Toll-like receptor mRNA expression patterns in human dendritic cells and monocytes.

The innate immune system recognises a wide spectrum of pathogens without a need for prior exposure. The main cells responsible are monocytes, macrophages, dendritic cells (DC) and neutrophils phagocytose microbial pathogens triggering a cytokine network resulting in the development of inflammatory and specific immune responses. Findings in the Toll-like receptor (TLR) family, initially discovered in Drosophila, further elucidated these processes. Toll-like receptors induce activation of an innate immune response and at present ten TLRs have been identified, named TLRs 1-10. In addition to the ignition of the innate immune response, evidence implicates the TLR family in a spectrum of systemic disorders following bacterial infections including sepsis and multiple organ failure, and can be detrimental, leading to tissue injury. In this project, our main goal was to investigate the effects of a TLR4 ligand, lipolysaccharide (LPS) in human DC and monocytes. Our hypothesis is that different professional APCs, express different mRNA TLR transcripts. Our findings indicate that TLR expression patterns change in relation to the pathogen involved and in the case of DC, and the maturation stage the latter are upon challenging. Our results and interpretation showed significant alteration of transcript expression patterns upon LPS challenge in all cell subsets, with DC subsets expressing different TLR mRNA patterns as they go through different maturation stages.

Preexisting human anti-murine immunoglobulin reactivity due to polyclonal rheumatoid factors.

We report that sera from healthy controls, patients with ovarian or lung cancer, and patients with rheumatoid arthritis all contain IgM polyclonal rheumatoid factors which recognize antigenic determinants on murine and to a greater extent human immunoglobulin IgG. The major part of this reactivity is directed against conserved, shared antigenic determinants present on both human and murine IgG. Such antigenicity resides in the protein and not the carbohydrate moiety of IgG, since deglycosylation of the target murine monoclonal antibody did not result in any loss of antibody binding. Studies comparing the binding of polyclonal and monoclonal rheumatoid factors (from patients with rheumatoid arthritis and mixed essential cryoglobulinaemia, respectively) to murine and human IgG show that the antigenic determinants recognized by polyclonal rheumatoid factors are present on both whereas the antigenic determinant recognized by the monoclonal rheumatoid factors is present only on human IgG. Furthermore, patients with rheumatoid arthritis display an elevated human IgM anti-murine immunoglobulin response similar to that seen in cancer patients who have received murine monoclonal antibody therapy. We therefore conclude that, where possible, F(ab')2 fragments of murine monoclonal antibodies should be used for in vivo tumor localization studies to avoid possible immune complex formation, and that patients with rheumatoid arthritis should be considered to be possibly at higher risk of developing immune complex disease, were these rheumatoid factors to bind to the administered murine antibodies in vivo.

Source of oncofetal ED-B-containing fibronectin: implications of production by both tumor and endothelial cells.

ED-B fibronectin (FN) is a FN isoform derived from alternative splicing of the primary transcript of a single gene. Its expression on tumor stroma and neoformed tumor vasculature and its absence, with few exceptions, in normal adult tissues imply a prognostic and diagnostic value for ED-B FN. We investigated the location and source of ED-B FN because this will be of importance both in understanding its role in tumor development and in designing strategies to target this molecule. We have confirmed that ED-B FN is expressed in the majority of breast and colorectal carcinoma tissue samples, with strong immunohistochemical staining around the tumor cells and in the tumor stroma. No staining of tumor neovasculature was seen. ED-B FN is produced by a range of tumor and endothelial (both primary and transformed) cell lines, as detected by reverse transcription-PCR, but is not expressed at the plasma membrane. Strong expression of human ED-B FN is seen in tumor xenografts. These data indicate that neoplastic cells can act as the source of ED-B FN in tumors. The lack of cell surface expression on tumor cell lines has clear implications for the design of therapeutic strategies which target this molecule.

Interleukin 4 receptor expression on human lung tumors and normal lung.

Interleukin 4 (IL-4) receptors were detected by a monoclonal antibody on tumor cells of 10 of 29 squamous cell carcinomas and 6 of 17 adenocarcinomas of the lung. None of the small cell carcinomas or carcinoid tumors stained. Parallel sections stained for epidermal growth factor receptors showed that all but 2 of the IL-4 receptor-positive tumors also expressed epidermal growth factor receptors. Positive labeling for IL-4 receptors was also obtained on nonneoplastic bronchial epithelium and on lymphocytes and macrophages infiltrating the tumor stroma. The role of IL-4 and its receptor in normal human lung is unknown, but the expression of IL-4 receptors on particular subtypes of lung tumors suggests that they may have a role in differentiation or proliferation of squamous and adenocarcinomas.

Development of primary and secondary immune responses to mouse monoclonal antibodies used in the diagnosis and therapy of malignant neoplasms.

Human anti-mouse immunoglobulin immune responses were studied in ten patients, eight with ovarian cancer and two with grade IV gliomas, diagnosed and treated with radiolabeled (123I, 131I) murine monoclonal antibodies. It was found that serum from these patients before treatment and from 18 control healthy individuals contained detectable antibodies to antigenic determinants on the Fc but not the F(ab')2 portion of mouse immunoglobulin. No change in this reactivity occurred after the initial (imaging) dose of monoclonal antibodies. However, repeated administration of mouse immunoglobulins for therapy resulted in an elevated immune response directed against determinants on both Fc and F(ab')2 regions of mouse immunoglobulin. This response contained increased levels of immunoglobulin M as well as immunoglobulin G and showed a marked prozone effect in our enzyme linked immunosorbent assay system. None of the immunized patients developed a detectable antiidiotypic response.

Clearance of 131I-labeled murine monoclonal antibody from patients' blood by intravenous human anti-murine immunoglobulin antibody.

Five patients treated with intraperitoneal 131I-labeled mouse monoclonal antibody for ovarian cancer also received i.v. exogenous polyclonal human anti-murine immunoglobulin antibody. The pharmacokinetics of 131I-labeled monoclonal antibody in these patients were compared with those of 28 other patients receiving i.p.-radiolabeled monoclonal antibody for the first time without exogenous human anti-murine immunoglobulin, and who had no preexisting endogenous human anti-murine immunoglobulin antibody. Patients receiving i.v. human anti-murine immunoglobulin antibody demonstrated a rapid clearance of 131I-labeled monoclonal antibody from their circulation. The (mean) maximum 131I blood content was 11.4% of the injected activity in patients receiving human anti-murine immunoglobulin antibody compared to 23.3% in patients not given human anti-murine immunoglobulin antibody. Intravenous human anti-murine immunoglobulin antibody decreased the radiation dose to bone marrow (from 131I-labeled monoclonal antibody in the vascular compartment) 4-fold. Following the injection of human anti-murine immunoglobulin antibody, 131I-monoclonal/human anti-murine immunoglobulin antibody immune complexes were rapidly transported to the liver. Antibody dehalogenation in the liver was rapid, with 87% of the injected 131I excreted in 5 days. Despite the efficient hepatic uptake of immune complexes, dehalogenation of monoclonal antibody was so rapid that the radiation dose to liver parenchyma from circulating 131I was decreased 4-fold rather than increased. All patients developed endogenous human anti-murine immunoglobulin antibody 2 to 3 weeks after treatment.

Micromotion at the tibial plateau in primary and revision total knee arthroplasty: fixed versus rotating platform designs.

OBJECTIVES: Initial stability of tibial trays is crucial for long-term success of total knee arthroplasty (TKA) in both primary and revision settings. Rotating platform (RP) designs reduce torque transfer at the tibiofemoral interface. We asked if this reduced torque transfer in RP designs resulted in subsequently reduced micromotion at the cemented fixation interface between the prosthesis component and the adjacent bone. METHODS: Composite tibias were implanted with fixed and RP primary and revision tibial trays and biomechanically tested under up to 2.5 kN of axial compression and 10° of external femoral component rotation. Relative micromotion between the implanted tibial tray and the neighbouring bone was quantified using high-precision digital image correlation techniques. RESULTS: Rotational malalignment between femoral and tibial components generated 40% less overall tibial tray micromotion in RP designs than in standard fixed bearing tibial trays. RP trays reduced micromotion by up to 172 µm in axial compression and 84 µm in rotational malalignment models. CONCLUSIONS: Reduced torque transfer at the tibiofemoral interface in RP tibial trays reduces relative component micromotion and may aid long-term stability in cases of revision TKA or poor bone quality.Cite this article: Mr S. R. Small. Micromotion at the tibial plateau in primary and revision total knee arthroplasty: fixed versus rotating platform designs. Bone Joint Res 2016;5:122-129. DOI: 10.1302/2046-3758.54.2000481.

The radiotoxicity of iodine-125 in ataxia telangiectasia fibroblasts.

Normal and ataxia telangiectasia fibroblast strains were labeled with 3H- or 125I-labelled iododeoxyuridine, were stored at -75 degrees C to accumulate damage, and were thawed for survival assays. X-ray survival of frozen, unlabeled cells was also determined. The ataxia telangiectasia strains were about twice as sensitive as normal (based upon survival curve slopes) when irradiated with X-rays or 3H decays under frozen conditions. Accumulated 125I decays, while about 13 times more toxic than 3H decays, also killed ataxia telangiectasia cells about twice as efficiently as normal cells. These results indicate that a large proportion of 125I-induced damage--at least 50%--is subject to repair in normal cells. In addition, they suggest that ataxia telangiectasia cells less capably repair a lesion that is induced in common by X-rays and 125I, but in larger porportion by the latter--probably a DNA double-strand break.

Fluorescent-light-induced lethality and DNA repair in normal and xeroderma pigmentosum fibroblasts.

Cell survival and induction of endonuclease-sensitive sites in DNA were measured in human fibroblast cells exposed to fluorescent light or germicidal ultraviolet light. Cells from a xeroderma pigmentosum patient were hypersensitive to cell killing by fluorescent light, although less so than for germicidal ultraviolet light. Xeroderma pigmentosum cells were deficient in the removal of fluorescent light-induced endonuclease sites that are probably pyrimidine dimers, and both the xeroderma pigmentosum and normal cells removed these sites with kinetics indistinguishable from those for ultraviolet light-induced sites. A comparison of fluorescent with ultraviolet light data demonstrates that there are markedly fewer pyrimidine dimers per lethal event for fluorescent than for ultraviolet light, suggesting a major role for non-dimer damage in fluorescent light lethality.

Adjuvant radiation versus observation: a cost analysis of alternate management schemes in early-stage testicular seminoma.

PURPOSE: This study was designed to compare costs of adjuvant radiation versus observation in the management of early-stage testicular seminoma after inguinal orchiectomy. MATERIALS AND METHODS: A line-by-line inspection of the charges generated during a course of adjuvant pelvic and paraaortic radiotherapy and of three cycles of bleomycin, etoposide, and platinum salvage chemotherapy was performed for five patients who received irradiation and five patients who received salvage chemotherapy. The average charge for either treatment was then calculated. Only those charges directly associated with the diagnosis of seminoma were included in the analysis. Follow-up charges were also generated from the patients' billing records. The optimum follow-up regimen for either management option was derived from a synthesis of the international literature. A 5% rate of failure was assumed if adjuvant irradiation was administered, and a 15% rate of failure was assumed if observation was the option chosen. Charges were truncated at 5 years. RESULTS: The total charge generated over 5 years based on following a policy of observation is $27,223 per patient versus $19,557 if the option of adjuvant irradiation in chosen. Using University of Wisconsin institutional reimbursement rates, the estimated costs were $20,487 and $14,722 for the option of observation and adjuvant radiation, respectively. The cost equivalence point between the two options occurs at 2.5 years, when the initial cost of adjuvant radiotherapy is matched by the cost generated during the period of observation. The maximum cost difference is achieved by 5 years. CONCLUSION: Following a policy of observation postorchiectomy for early-stage testicular seminoma generates 39% more medical costs per patient over a 5-year follow-up period than does following the standard policy of adjuvant irradiation to the pelvic and paraaortic regions, with no reported difference in outcome.