Oral Everolimus for Treatment of a Giant Left Ventricular Rhabdomyoma in a Neonate—Rapid Tumor Regression Documented by Real Time 3D Echocardiography

The presented case reports on successful treatment with everolimus in a neonate with left ventricular giant rhabdomyoma. The authors used a different dosage regime compared to literature and documented rapid tumor regression by 3D echocardiography.     

Isolation of DNA from the centromere of human chromosome 7 by microdissection

Centromeres remain the least characterized regions of human chromosomes because they have a very high content of repetitive DNA. Here, we describe a micro-dissection library from the centromeric region of human chromosome 7 and its use for generating sequence tagged sites (STSs). The library contains about 1500 clones with an average insert size of 150 bp and only about 15% of the clones harbour repetitive human DNA. Seven clones hybridizing to alphoid DNA were found to correspond to a fragment of the D7Z2 alphoid array on chromosome 7, thus confirming the origin of the library. A number of clones not containing known repetitive DNA were used to generate STSs that identified yeast artificial chromosomes (YACs) and in turn allowed the STSs to be placed on the physical map. One STS is located between the two Genethon genetic markers closest to the centromere on the q side. Another STS was located 3–4 cM away in 7q11.2, while a third identified YACs containing both low-copy and alphoid sequences that are not yet mapped but are clearly centromeric. The library therefore comprises a collection of sequences from the centromeric region of chromosome 7 that can be used to generate STSs and to map the entire centromeric region.This revised version was published online in November 2005 with corrections to the Cover Date.     

Active detachment involves inhibition of cell-matrix contacts of malignant melanoma cells by secretion of melanoma inhibitory activity

Melanoma inhibitory activity (MIA) has been identified as a small protein secreted from malignant melanoma cells. Recent results revealed a direct interaction of MIA and epitopes within extracellular matrix proteins including fibronectin. The aim of this study was to analyze functional consequences mediated by this interaction. Here we show that MIA interferes specifically with attachment of melanoma cells to fibronectin, a phenomenon we refer to as active detachment. Antibodies inhibiting binding of alpha4beta1 and alpha5beta1 integrins to fibronectin cross-react specifically with MIA, suggesting that MIA shares significant structural homology with the binding pockets of these integrins and thereby masks the respective epitopes on extracellular matrix molecules. Several peptides derived from fibronectin and from a phage display screening were tested with respect to a potential MIA-inhibitory effect. In vitro tests identified two peptides affecting MIA function; both inhibited growth of melanoma metastases in vivo. In summary, we conclude that MIA may play a role in tumor progression and spread of malignant melanomas via mediating active detachment of cells from extracellular matrix molecules within their local milieu. Further, our results suggest that inhibiting MIA functions in vivo may provide a novel therapeutic strategy for metastatic melanoma disease.     

Early detection of metastasis by alterations in the cellular immune system in the murine liver and blood

We investigated the reaction of the cellular immune system of liver and blood in the C57BL/6 mouse to a metastasizing Lewis lung carcinoma. The cellular immune system of the liver consists of mature and immature macrophages, B-cells, T-cells including their subpopulations, and natural killer cells, and their percentage frequencies differ significantly from those in the corresponding mononuclear blood cell (MBC) compartment. This suggests that the hepatic immune cells represent a system with autonomous function showing a typical homing of its members. Imminent metastasis to the liver is signalled by impressive alterations in the percentage frequencies of nonparenchymal liver cells (NPLC). There are a dramatic loss of mature macrophages, an increase in immature macrophages, a reduction of T-helper cells leading to a low CD4/CD8 ratio, and an increase in natural killer cells. In the blood, the corresponding precursor cells show comparable changes with a delay of at least 2 days. Early metastasis is accompanied by a significant increase in mononuclear NPLC producing tumour necrosis factor . The alterations in percentage frequencies of the NPLC during tumour metastasis differ markedly from the changes in these cells in the liver during endotoxinaemia.     

Orbital surgery – perioperative problems and results

Fragestellung: Orbitotomien nehmen innerhalb der Ophthalmochirurgie auf Grund der involvierten anatomischen Strukturen und des daraus resultierenden Spektrums m?glicher perioperativer Probleme eine Sonderstellung ein. Um einen überblick über die Art und H?ufigkeit intra- und postoperativer Probleme bei Orbitotomien zu erhalten, führten wir eine retrospektive Auswertung an unserer Klinik durchgeführter Orbitotomien durch. Patienten und Methode: Es wurden 48 Orbitotomien bei 46 Patienten berücksichtigt, die zwischen 08/1995 und 02/1998 operiert wurden. Ergebnisse: Schwerwiegende intraoperative Komplikationen waren mit zwei transfusionspflichtigen Blutungen und einer Liquorfistel selten. Sie wurden interdisziplin?r behandelt. Postoperativ traten vorübergehende funktionelle St?rungen mit guter Rückbildungstendenz wie Visusminderungen (35 %), Motilit?tsst?rungen mit oder ohne Doppelbildwahrnehmung (20 %) und Lidfehlstellungen auf. Ihnen liegt v. a. die postoperative ?dem- und H?matombildung zugrunde. Persistierende Funktionseinschr?nkungen waren dagegen selten (10 %). Schlu?folgerung: Unsere Untersuchung zeigt, da? perioperativ bei Orbitotomien v. a. vorübergehende funktionelle Einschr?nkungen auftreten, die sich rasch zurückbilden. Schwere Komplikationen sind dagegen selten, treten v. a. intraoperativ auf und k?nnen eine interdisziplin?re Therapie erfordern.      

Differential gene expression in peripheral blood lymphocytes of cancer patients treated with whole body hyperthermia and chemotherapy: a pilot study.

PURPOSE: The effect of whole body hyperthermia (WBH) at 41.8-42 degrees C on the cellular immune system is still poorly investigated. The aim of this study was to identify genes that become upregulated in peripheral blood lymphocytes (PBLs) of cancer patients during a combined treatment with WBH and chemotherapy by generating complex arrays of cDNA. METHODS: PBLs were obtained from four patients with different malignancies treated with WBH and varying cytostatic schedules before treatment and immediately thereafter. After constructing subtracted cDNA libraries, clones were screened for cDNA induction by dot-blot and semi-quantitative RT-PCR (sq-RT-PCR). RESULTS: Among 192 clones, 39 cDNAs were significantly upregulated. Sequencing revealed three groups of genes for which upregulation of mRNA was confirmed by sq-RT-PCR. The first group consisted of genes encoding for various heat shock proteins (HSP 60, 90a, 90b, 105). Further sq-RT-PCR demonstrated differential expression of HSP27 and HSP70 as well. The second group (calcyclin-binding-protein, haemoglobin-beta-chain) comprised genes without pre-specified association to hyperthermia. The cDNA encoding macrophage-inflammatory-protein-1-beta was also observed and may be associated with the pre-described activation of lymphocyte sub-populations during WBH. CONCLUSION: Treatment with WBH and chemotherapy elicits significant short-term effects on the expression of a variety of genes responsible for cellular integrity, stimulation and migration of immune effector cells. Further investigation is warranted to more clearly define the role of those genes for the clinical effect of WBH.     

The impact of visual dysfunctions in recent-onset psychosis and clinical high-risk state for psychosis

Subtle subjective visual dysfunctions (VisDys) are reported by about 50% of patients with schizophrenia and are suggested to predict psychosis states. Deeper insight into VisDys, particularly in early psychosis states, could foster the understanding of basic disease mechanisms mediating susceptibility to psychosis, and thereby inform preventive interventions. We systematically investigated the relationship between VisDys and core clinical measures across three early phase psychiatric conditions. Second, we used a novel multivariate pattern analysis approach to predict VisDys by resting-state functional connectivity within relevant brain systems. VisDys assessed with the Schizophrenia Proneness Instrument (SPI-A), clinical measures, and resting-state fMRI data were examined in recent-onset psychosis (ROP, n = 147), clinical high-risk states of psychosis (CHR, n = 143), recent-onset depression (ROD, n = 151), and healthy controls (HC, n = 280). Our multivariate pattern analysis approach used pairwise functional connectivity within occipital (ON) and frontoparietal (FPN) networks implicated in visual information processing to predict VisDys. VisDys were reported more often in ROP (50.34%), and CHR (55.94%) than in ROD (16.56%), and HC (4.28%). Higher severity of VisDys was associated with less functional remission in both CHR and ROP, and, in CHR specifically, lower quality of life (Qol), higher depressiveness, and more severe impairment of visuospatial constructability. ON functional connectivity predicted presence of VisDys in ROP (balanced accuracy 60.17%, p = 0.0001) and CHR (67.38%, p = 0.029), while in the combined ROP + CHR sample VisDys were predicted by FPN (61.11%, p = 0.006). These large-sample study findings suggest that VisDys are clinically highly relevant not only in ROP but especially in CHR, being closely related to aspects of functional outcome, depressiveness, and Qol. Findings from multivariate pattern analysis support a model of functional integrity within ON and FPN driving the VisDys phenomenon and being implicated in core disease mechanisms of early psychosis states.Subject terms: Predictive markers, Psychosis     

Getting the most out of your IP--patent management along its life cycle

Effectively managing and optimizing the value of the patent portfolio is a major challenge for many firms, especially those in knowledge intensive industries, such as the pharmaceutical, biotechnological and chemical industry. However, insights on effective patent portfolio strategies are rare. Therefore, in this article we investigate in detail how firms successfully manage and optimize their patent portfolios to increase their overall competitiveness. We discover that successful patent portfolio management is rooted in managing the patents along their life cycles. Based on the findings of ten case studies, we develop a holistic patent life cycle management model reflecting five distinctive phases of patent management: explore, generate, protect, optimize and decline. We conclude with how our findings can be used in practice.     

Prognostic value of tissue Doppler imaging in patients with chronic congestive heart failure

BACKGROUND: The prognostic value of tissue Doppler imaging (TDI) in patients with chronic congestive heart failure (CHF) has not been compared against conventional measures of systolic, diastolic and overall left ventricular LV performance. The aim of this study was to assess the prognostic value of TDI-derived parameters in patients with CHF. METHODS: One hundred thirty-two subjects with chronic CHF [due to ischemic (n=82) or dilated (n=50) cardiomyopathy, 101 males, mean age 57+/-11 years] underwent conventional two-dimensional/Doppler echocardiography and assessment of the Tei-index (isovolumic contraction time and isovolumic relaxation time divided by ejection time). Systolic, early and late diastolic mitral annular velocities (S', E' and A') were derived from pulsed TDI. A cardiac event (cardiac death, urgent cardiac transplantation or hospitalization due to decompensated CHF) was defined as the combined study endpoint. RESULTS: The patients were followed for a mean of 224+/-123 days. Thirty-one patients suffered an event (cardiac death, n=5; urgent cardiac transplantation, n=2; hospitalization due to CHF, n=24). In patients with event, ejection fraction was lower (25+/-10 vs. 32+/-9%), mitral deceleration time was shorter (138+/-58 vs. 193+/-72 ms), and the peak mitral E/E'-ratio (16.1+/-6.6 vs. 10.6+/-5.0) was significantly elevated as compared to patients free of events (p<0.001 for all comparisons). In those patients, the Tei-index was elevated (1.09+/-0.39 vs. 0.86+/-0.26, p<0.01), and a restrictive mitral filling pattern was more frequent (51.6 vs. 17.5%, p<0.001). Stepwise multivariate analysis identified the mitral E/E'-ratio (p<0.001) and the Tei-index (p=0.019) as the only independent predictors of a combined event. E/E'-ratio was the best predictor of hospitalization due to CHF also. In patients with mitral E/E'-ratio>12.5 or Tei-index>0.90, outcome was poor. CONCLUSIONS: In subjects with chronic CHF, the mitral E/E'-ratio is a stronger predictor of future cardiac events than conventional parameters of systolic, diastolic or overall LV performance. The E/E'-ratio may be a useful addition in the routine follow-up of such patients.