Multiparametric MRI and T2/FLAIR mismatch complements the World Health Organization 2021 classification for the diagnosis of IDH-mutant 1p/19q non-co-deleted/ATRX-mutant astrocytoma.

AIM: To investigate whether T2-weighted imaging-fluid-attenuated inversion recovery (T2/FLAIR) mismatch, T2∗ dynamic susceptibility contrast (DSC) perfusion, and magnetic resonance spectroscopy (MRS) correlated with the histological diagnosis and grading of IDH (isocitrate dehydrogenase)-mutant, 1p/19q non-co-deleted/ATRX (alpha-thalassemia mental retardation X-linked)-mutant astrocytoma. MATERIALS: Imaging of 101 IDH-mutant diffuse glioma cases of histological grades 2-3 (2019-2021) were analysed retrospectively by two neuroradiologists blinded to the molecular diagnosis. T2/FLAIR mismatch sign is used for radio-phenotyping, and pre-biopsy multiparametric MRI images were assessed for grading purposes. Cut-off values pre-determined for radiologically high-grade lesions were relative cerebral blood volume (rCBV) ≥2, choline/creatine ratio (Cho/Cr) ≥1.5 (30 ms echo time [TE]), Cho/Cr ≥1.8 (135 ms TE). RESULTS: Sixteen of the 101 cases showed T2/FLAIR mismatch, all of which were histogenetically confirmed IDH-mutant 1p/19q non-co-deleted/ATRX mutant astrocytomas; 50% were grade 3 (8/16) and 50% grade 2 (8/16). None showed contrast enhancement. Nine of the 16 had adequate multiparametric MRI for analysis. Any positive value by combining rCBV ≥2 with Cho/Cr ≥1.5 (30 ms TE) or Cho/Cr ≥1.8 (135 ms TE) predicted grade 3 histology with sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 100%. CONCLUSION: The T2/FLAIR mismatch sign detected diffuse astrocytomas with 100% specificity. When combined with high Cho/Cr and raised rCBV, this predicted histological grading with high accuracy. The future direction for imaging should explore a similar integrated layered approach of 2021 classification of central nervous system (CNS) tumours combining radio-phenotyping and grading from structural and multiparametric imaging.

Connexins in the control of vasomotor function.

Vascular endothelial cells, as well as smooth muscle cells, show heterogeneity with regard to their receptor expression and reactivity. For the vascular wall to act as a functional unit, the various cells' responses require integration. Such an integration is not only required for a homogeneous response of the vascular wall, but also for the vasomotor behaviour of consecutive segments of the microvascular arteriolar tree. As flow resistances of individual sections are connected in series, sections require synchronization and coordination to allow effective changes of conductivity and blood flow. A prerequisite for the local coordination of individual vascular cells and different sections of an arteriolar tree is intercellular communication. Connexins are involved in a dual manner in this coordination. (i) By forming gap junctions between cells, they allow an intercellular exchange of signalling molecules and electrical currents. In particular, the spread of electrical currents allows for coordination of cell responses over longer distances. (ii) Connexins are able to interact with other proteins to form signalling complexes. In this way, they can modulate and integrate individual cells' responses also in a channel-independent manner. This review outlines mechanisms allowing the vascular connexins to exert their coordinating function and to regulate the vasomotor reactions of blood vessels both locally, and in vascular networks. Wherever possible, we focus on the vasomotor behaviour of small vessels and arterioles which are the main vessels determining vascular resistance, blood pressure and local blood flow.

Numerical modeling of compensation mechanisms for peripheral arterial stenoses.

The goal of this paper is to develop a numerical model for physiological mechanisms that help to compensate reduced blood flow caused by a peripheral arterial stenosis. Thereby we restrict ourselves to the following compensation mechanisms: Metabolic regulation and arteriogenesis, i.e., growth of pre-existing collateral arteries. Our model is based on dimensionally reduced differential equations to simulate large time periods with low computational cost. As a test scenario, we consider a stenosis located in the right posterior tibial artery of a human. We study its impact on blood supply for different narrowing degrees by the help of numerical simulations. Moreover, the efficiency of the above compensation mechanisms is examined. Our results reveal that even a complete occlusion of this artery exhibiting a cross-section area of 0.442cm(2) can be compensated at rest, if metabolic regulation is combined with collateral arteries whose total cross-section area accounts for 8.14% of the occluded artery.

The influence of an unilateral carotid artery stenosis on brain oxygenation.

We study the impact of varying degrees of unilateral stenoses of an carotid artery on pulsatile blood flow and oxygen transport from the heart to the brain. For the numerical simulation a model reduction approach is used involving non-linear 1-D transport equation systems, linear 1-D transport equations and 0-D models. The haemodynamic effects of vessels beyond the outflow boundaries of the 1-D models are accounted for using a 0-D lumped three element windkessel model. At the cerebral outflow boundaries the 0-D windkessel model is extended by metabolic autoregulation, based on the cerebral oxygen supply. Additionally lumped parameter models are applied to incorporate the impact of the carotid stenosis. Our model suggests that for a severe unilateral stenosis in the right carotid artery the partial pressure of oxygen in the brain area at risk can only be restored, if the corresponding cerebral resistance is significantly decreased and if the circle of Willis (CoW) is complete.

Gap junctional communication promotes apoptosis in a connexin-type-dependent manner.

Gap junctions (GJs) have been described to modulate cell death and survival. It still remains unclear whether this effect requires functional GJ channels or depends on channel-independent effects of connexins (Cx), the constituents of GJs. Therefore, we analysed the apoptotic response to streptonigrin (SN, intrinsic apoptotic pathway) or to α-Fas (extrinsic apoptotic pathway) in HeLa cells expressing Cx43 as compared with empty vector-transfected (CTL) cells. Apoptosis assessed by annexin V-fluorescein isothiocyanate/propidium iodide staining was significantly higher in HeLa-Cx43 compared with HeLa-CTL cells. Moreover, the cleavage of caspase-7 or Parp occurred earlier in HeLa-Cx43 than in HeLa-CTL cells. Comparative analysis of the effect of two further (endothelial) Cx (Cx37 and Cx40) on apoptosis revealed that apoptosis was highest in HeLa-Cx43 and lowest in HeLa-Cx37 cells, and correlated with the GJ permeability (assessed by spreading of a GJ-permeable dye and locally induced Ca(2+) signals). Pharmacologic inhibition of GJ formation in HeLa-Cx43 cells reduced apoptosis significantly. The role of GJ communication was further analysed by the expression of truncated Cx43 proteins with and without channel-forming capacity. Activation of caspases was higher in cells expressing the channel-building part (HeLa-Cx43NT-GFP) than in cells expressing the channel-incompetent C-terminal part of Cx43 (HeLa-Cx43CT-GFP) only. A hemichannel-dependent release and, hence, paracrine effect of proapoptotic signals could be excluded since the addition of a peptide (Pep)-blocking Cx43-dependent hemichannels (but not GJs) did not reduce apoptosis in HeLa-Cx43 cells. Treatment with SN resulted in a significant higher increase of the intracellular free Ca(2+) concentration in HeLa-Cx43 and HeLa-Cx43NT-GFP cells compared with HeLa-CTL or HeLa-Cx43CT-GFP cells, suggesting that Ca(2+) or a Ca(2+)-releasing agent could play a signalling role. Blocking of inositol triphosphate receptors reduced the SN-induced Ca(2+) increase as well as the increase in apoptosis. Our observations suggest that Cx43 and Cx40 but not Cx37 promote apoptosis via gap junctional transfer of pro-apoptotic signals between cells.

Magnetic stents retain nanoparticle-bound antirestenotic drugs transported by lipid microbubbles.

PURPOSE: Coating coronary stents with antirestenotic drugs revolutionized interventional cardiology. We developed a system for post-hoc drug delivery to uncoated stents. METHODS: We coupled rapamycin or a chemically similar fluorescent dye to superparamagnetic nanoparticles. The antiproliferative activity of rapamycin coupled to nanoparticles was confirmed in vitro in primary porcine vascular cells. The particles were then incorporated into lipid based microbubbles. Commercially available stents were made magnetizable by nickel plating and used to induce strong field gradients in order to capture magnetic microbubbles from flowing liquids when placed in an external magnetic field. RESULTS: Nanoparticle bound Rapamycin dose dependently inhibited cell proliferation in vitro. Magnetic microcbubbles carrying coated nanoparticles were caught by magnets placed external to a flow-through tube. Plating commercial stents with nickel resulted in increased deposition at stent struts and allowed for widely increased distance of external magnets. Deposition depended on circulation time and velocity and distance of magnets. Deposited microbubbles were destroyed by ultrasound and delivered their cargo to targeted sites. CONCLUSIONS: Drugs can be incorporated into nanoparticle loaded microbubbles and thus be delivered to magnetizable stents from circulating fluids by applying external magnetic fields. This technology could allow for post-hoc drug coating of already implanted vascular stents.

Isolation and functional characterization of pericytes derived from hamster skeletal muscle.

AIM: At the interface of tissue and capillaries, pericytes (PC) may generate electrical signals to be conducted along the skeletal muscle vascular network, but they are functionally not well characterized. We aimed to isolate and cultivate muscle PC allowing to analyse functional properties considered important for signal generation and conduction. METHODS: Pericytes were enzymatically isolated from hamster thigh muscles and further selected during a 16-30 days' cultivation period. PC markers were studied by fluorescence activated cell scanning (FACS) and immunocytochemistry. Electrical properties of the cultured PC were investigated by patch clamp technique as well as the membrane potential sensitive dye DiBAC(4) (3). RESULTS: The cultured cells showed typical PC morphology and were positive for NG2, alpha smooth muscle actin, PDGFR-ß and the gap junction protein Cx43. Expressions of at least one single or combinations of several markers were found in 80-90% of subpopulations. A subset of the patched cells expressed channel activities consistent with a Kv1.5 channel. In vivo presence of the channels was confirmed in sections of hamster thigh muscles. Interleukin-8, a myokine known to be released from exercising muscle, increased the expression but not the activity of this channel. Pharmacologic stimulation of the channel activity by flufenamic acid induced hyperpolarization of PC alone but not of endothelial cells [human umbilical vein endothelial cells (HUVEC)] alone. However, hyperpolarization was observed in HUVEC adjacent to PC when kept in co-culture. CONCLUSION: We established a culture method for PC from skeletal muscle. A first functional characterization revealed properties which potentially enable these cells to generate hyperpolarizing signals and to communicate them to endothelial cells.

Control of muscle blood flow during exercise: local factors and integrative mechanisms.

Understanding the control mechanisms of blood flow within the vasculature of skeletal muscle is clearly fascinating from a theoretical point of view due to the extremely tight coupling of tissue oxygen demands and blood flow. It also has practical implications as impairment of muscle blood flow and its prevention/reversal by exercise training has a major impact on widespread diseases such as hypertension and diabetes. Here we analyse the role of mediators generated by skeletal muscle activity on smooth muscle relaxation in resistance vessels in vitro and in vivo. We summarize their cellular mechanisms of action and their relative roles in exercise hyperaemia with regard to early and late responses. We also discuss the consequences of interactions among mediators with regard to identifying their functional significance. We focus on (potential) mechanisms integrating the action of the mediators and their effects among the cells of the intact arteriolar wall. This integration occurs both locally, partly due to myoendothelial communication, and axially along the vascular tree, thus enabling the local responses to be manifest along an entire functional vessel path. Though the concept of signal integration is intriguing, its specific role on the control of exercise hyperaemia and the consequences of its modulation under physiological and pathophysiological conditions still await additional analysis.

Prothrombotic effects of diclofenac on arteriolar platelet activation and thrombosis in vivo.

BACKGROUND: Diclofenac, like selective cyclooxygenase-2 inhibitors, which alter vascular levels of platelet active prostaglandins, has been reported to increase rates of acute myocardial infarction. OBJECTIVE: The study was performed to investigate, in an animal model of arterial thrombosis in vivo, whether diclofenac differentially influences platelet activation and thrombosis in vessels under non-stimulated conditions or during acute systemic inflammation, such as induced by tumor necrosis factor-alpha (TNF-alpha). METHODS: Platelet-vessel wall interaction (PVWI), firm platelet adhesion and arterial thrombosis following vessel injury were analyzed by intravital microscopy in arterioles of hamsters in the dorsal skinfold chamber model. Prostacyclin [prostaglandin I(2) (PGI(2))] and thromboxane A(2) (TxA(2)) metabolites were measured. In vitro, endothelial adhesion molecule expression in cultured human microvascular endothelial cells was analyzed. RESULTS: Under non-stimulated conditions, diclofenac (1 mg kg(-1)) enhanced PVWI, which was not mediated by increased adhesion molecule expression, but by decreased systemic PGI(2) levels. Following ferric chloride-induced endothelial injury, diclofenac accelerated thrombotic vessel occlusion time, an effect that was reversed by the stable PGI(2) analog iloprost. TNF-alpha, through induction of endothelial adhesion molecule expression, also enhanced PVWI, firm adhesion, and arterial thrombosis, but simultaneous treatment with TNF-alpha and diclofenac did not have an additive effect. CONCLUSIONS: By decreasing levels of PGI(2) without, at the same time, altering prothrombotic TxA(2) levels, diclofenac can exert prothrombotic effects. However, this is not the case when an inflammatory situation is created by TNF-alpha treatment. These data may explain the enhanced risk of acute myocardial infarction observed in patients taking diclofenac.

Epithelioid hemangioendothelioma of the spine: report of two cases and review of the literature.

We report two patients with spinal epithelioid hemangioendothelioma (EH), an uncommon vascular, potentially malignant tumour. Neurological signs, diagnostic images, surgical techniques and complications, histology and the role of adjuvant therapy are discussed. Primary manifestation of EH of the vertebral column is rare. Thorough preoperative clinical and radiological workup, radical surgical excision, and close postoperative follow-up are recommended.

Size-dependent fine-structure splitting in self-organized InAs/GaAs quantum dots.

A systematic variation of the exciton fine-structure splitting with quantum dot size in single quantum dots grown by metal-organic chemical vapor deposition is observed. The splitting increases from to as much as with quantum dot size. A change of sign is reported for small quantum dots. Model calculations within the framework of eight-band theory and the configuration interaction method were performed. Different sources for the fine-structure splitting are discussed, and piezoelectricity is pinpointed as the only effect reproducing the observed trend.

Rapidly reversible dementia in cerebral amyloid inflammatory vasculopathy.

This report discusses a biopsy proven case of cerebral amyloid angiopathy, with additional prominent vascular inflammatory features, characterized by a rapidly progressive dementia and leukoencephalopathy, where the clinical and radiological abnormalities resolved rapidly with minimal therapeutic intervention. We propose the term cerebral amyloid inflammatory vasculopathy (CAIV) to describe this condition.

Opposing effects of nitric oxide on different connexins expressed in the vascular system.

Gap junctions--clusters of intercellular channels built by connexins (Cx)--are thought to be important for vascular cell functions such as differentiation, control of tone, or growth. In the vascular system, gap junctions can be formed by four different connexins (Cx37, Cx40, Cx43 and Cx45). The permeability of these connexin-formed gap junctions determines the amount of intercellular coupling and can be modulated by several vasoactive substances such as prostacyclin or nitric oxide (NO). We demonstrate here that NO has specific effects on certain connexins. Using two different techniques--injection of a fluorescent dye in single cells as well as detection of the de novo formation of gap junctions by a flow cytometry based technique--we found that NO decreases the functional coupling in Cx37 containing gap junctions whereas it increases the de novo formation of gap junctions containing Cx40. We conclude that NO, in addition to its known vasomotor effects, has a novel role in controlling intercellular coupling resulting in opposing effects depending on the specific connexin expressed in the cells.

Systems analysis in health care: framework and example.

OBJECTIVES: Due to the high complexity of structures and processes in health care, thorough systems analyses in health care run the risk of becoming very complex and difficult to handle. Therefore, we aimed to support systematic systems analysis in health care by developing a comprehensive framework that presents and describes potential areas of analysis. METHODS: A framework for systems analysis in health care was developed and applied in a health care setting. To provide a clear structure, the framework describes the potential views and levels of systems analyses in a health care environment. RESULTS: The framework comprises five views (roles and responsibilities, information processing and tools, communication, business processes, teams structure and cooperation) and five levels of analysis (overall organization, organizational unit, staff member, role, task). The framework was successfully applied in an analysis of the structures and processes of the Department of Child and Adolescent Psychiatry of the University Medical Center Heidelberg. CONCLUSIONS: The proposed comprehensive framework aims to structure the views and levels of systems analysis in the complex health care environment. Our first experiences support the usefulness of such a framework.

Analysis and modelling of the multi-professional treatment process: preliminary results.

This paper presents first results of a research project aimed at improving co-operative work initiatives in hospitals. A holistic analysis of the treatment process is presented as a precondition for process reengineering, quality measurements and improvement of multi-professional co-operation. Treatment process modelling attempts within the last years have concentrated on specialised points of views, such as business process modelling or communication modelling. In contrast, we have developed a framework consisting of several views of the treatment process. We tested our framework in a broad system analysis within the Department of Child and Adolescent Psychiatry of the Heidelberg University Hospitals. Our preliminary results support the framework. Weaknesses were described precisely in both the field of organisational procedures and information management.

[Examination of body concept of female patients with borderline personality disorder]. / Untersuchungen zum Körperkonzept bei Patientinnen mit Borderline-Persönlichkeitsstörung.

The operationalized diagnosis of borderline personality disorder (BPD) by DSM-IV and ICD-10 (research criteria) is meanwhile considered as valid and reliable. A disturbed or inappropriate body image within the group of borderline patients is not assessed by these instruments. Using the "Frankfurter Körperkonzeptskalen" [6], we compared the body concept of 47 female patients with BPD with a group of patients with the diagnosis of Bulimia nervosa and with a representative sample of healthy subjects. We found highly significant differences between patients with BPD and the clinical controls as well as to the norm group. Neither dissociative symptoms nor sexual child abuse correlate with the extent of the negative body concept. Correlations between self-concept (Giessen-Test) and body concept as well as clinical implications of these findings are discussed.

A randomized evaluation of a computer-based nursing documentation system.

A two-month randomized, controlled trial based on 60 patients has been performed on a ward of the Department of Psychiatry at Heidelberg University Medical Center, Germany, to investigate the influence of computer-based nursing documentation on time investment for documentation, quality of documentation and user acceptance. Time measurements, questionnaires, documentation analysis and interviews were used to compare patients documented with the computer-based system (PIK group) with the control group (patients documented with the paper-based system). The results showed the advantages and disadvantages of computer-based nursing documentation. Time needed for nursing care planning was lower in the PIK group. Some formal aspects of quality were considerably better in the PIK group. On the other hand, time required for documentation of tasks and for report writing was greater in the PIK group. User acceptance increased significantly during the study. The interviews indicated a positive influence of PIK on the cooperation between nurses and physicians.

Hypoxia-induced upregulation of eNOS gene expression is redox-sensitive: a comparison between hypoxia and inhibitors of cell metabolism.

Several papers report a hypoxia-induced upregulation of the endothelial nitric oxide synthase (eNOS) mRNA expression. Since there is no known hypoxia-sensitive element binding site in the eNOS promoter, we reasoned that the effect of hypoxia could be simulated by a metabolically elicited alteration of the redox state. Therefore, cultured porcine aortic endothelial cells (PAEC) were exposed to hypoxia (1-10% O(2)) or inhibitors of cellular energy metabolism including rotenone, 2, 4 dinitrophenol (DNP) and 2-deoxyglucose for 6 to 24 h. Additionally, cells were treated with lactate and nicotinic acid to alter the cellular NAD(P)H/NAD(P) ratio without changes of energy supply. The cellular NAD(P)H/NAD(P) ratio was used as an index of the cellular redox state and determined using the MTT-assay. Hypoxia increased eNOS mRNA transcription and MTT-reduction in a manner inversely proportional to pO(2). Exposure to rotenone, DNP, and lactate increased the NAD(P)H/NAD(P) ratio, MTT-reduction, and eNOS mRNA also in parallel. In contrast, 2-deoxyglucose and nicotinic acid attenuated both MTT-reduction and eNOS mRNA expression. In order to study a potential role of the redox regulated transcription factor complex AP-1 in hypoxia-induced eNOS mRNA transcription, c-jun expression was determined and decoy experiments were performed. c-jun expression paralleled changes of eNOS mRNA expression and MTT-reduction. Furthermore, in the presence of oligodeoxynucleotides corresponding to the AP-1 binding sites of the eNOS promoter, the hypoxia and chemically induced eNOS mRNA expression was completely abolished. We propose that hypoxia, by altering cellular metabolism, leads to an increase in the cellular NAD(P)H/NAD(P) ratio which favors enhanced eNOS expression by redox-sensitive AP-1 mediated transcriptional control.

Endothelium-specific replacement of the connexin43 coding region by a lacZ reporter gene.

The murine gap junction protein connexin43 (Cx43) is expressed in blood vessels, with vastly different contribution by endothelial and smooth muscle cells. We have used the Cre recombinase under control of TIE2 transcriptional elements to inactivate a floxed Cx43 gene specifically in endothelial cells. Cre-mediated deletion led to replacement of the Cx43 coding region by a lacZ reporter gene. This allowed us to monitor the extent of deletion and to visualize the endothelial expression pattern of Cx43. We found widespread endothelial expression of the Cx43 gene during embryonic development, which became restricted largely to capillaries and small vessels in all adult organs examined. Mice lacking Cx43 in endothelium did not exhibit altered blood pressure, in contrast to mice deficient in Cx40. Our results show that lacZ activation after deletion of the target gene allows us to determine the extent of cell type-specific deletion after phenotypical investigation of the same animal.