Lagrange-Singularitäten

In dieser Arbeit wird eine Deformationstheorie fürLagrange-Singularitäten entwickelt. Wir definieren einen Komplex von Moduln mit nicht-linearem Differential, densogenannten Lagrange-de Rham-Komplex, dessen ersteKohomologie isomorph zum Raum der infinitesimalenLagrange-Deformationen ist. Wir beschreiben die Beziehung diesesKomplexes zur Theorie der Moduln über dem Ring vonDifferentieloperatoren. Informationen zur Obstruktionstheorie vonLagrange-Deformationen werden aus derzweiten Kohomologie des Lagrange-de Rham-Komplexes gewonnen.Wir zeigen, dass unter einer geometrischen Bedingung an dieSingularität ie Kohomologie von des Lagrange-deRham-Komplexes ausendlich dimensionalen Vektorräumen besteht. Desweiteren wirdeine Methode zur effektiven Berechnung dieser Kohomologie fürquasi-homogene Lagrange-Flächensingularitäten entwickelt. UnterZuhilfenahme von Computeralgebra wird diese Methode für konkreteBeispiele angewendet.

Immunohistochemical and Molecular Prognostic/Predictive Markers in Neoplastic Diseases

Traditional morphological examinations are not anymore sufficient for a complete evaluation of tumoral tissue and the use of neoplastic markers is of utmost importance. Neoplastic markers can be classified in: diagnostic, prognostic and predictive markers. Three markers were analyzed. 1) Insulin-like growth factor binding protein 2 (IGFBP2) was immunohistochemically examined in prostatic tissues: 40 radical prostatectomies from hormonally untreated patients with their preoperative biopsies, 10 radical prostatectomies from patients under complete androgen ablation before surgery and 10 simple prostatectomies from patients with bladder outlet obstruction. Results were compared with α-methylacyl-CoA racemase (AMACR). IGFBP2 was expressed in the cytoplasm of untreated adenocarcinomas and, to a lesser extent, in HG-PIN; the expression was markedly lower in patients after complete androgen ablation. AMACR was similarly expressed in both adenocarcinoma and HG-PIN, the level being similar in both lesions; the expression was slightly lower in patients after complete androgen ablation. IGFBP2 may be used a diagnostic marker of prostatic adenocarcinomas. 2) Heparan surface proteoglycan immunohistochemical expression was examined in 150 oral squamous cell carcinomas. Follow up information was available in 93 patients (range: 6-34 months, mean: 19±7). After surgery, chemotherapy was performed in 8 patients and radiotherapy in 61 patients. Multivariate and univariate overall survival analyses showed that high expression of syndecan-1 (SYN-1) was associated with a poor prognosis. In patients treated with radiotherapy, such association was higher. SYN-1 is a prognostic marker in oral squamous cell carcinomas; it may also represent a predictive factor for responsiveness to radiotherapy. 3) EGFR was studied in 33 pulmonary adenocarcinomas with traditional DNA sequencing methods and with two mutation-specific antibodies. Overall, the two antibodies had 61.1% sensitivity and 100% specificity in detecting EGFR mutations. EGFR mutation-specific antibodies may represent a predictive marker to identify patients candidate to tyrosine kinase inhibitors therapy.

Applicazioni cliniche e sperimentali dell’ecografia toracica in pneumologia: la diagnostica precoce delle patologie pleuropolmonari

Lung ultrasound use is increasing in respiratory medicine thanks to its development in the latest years. Actually it allows to study diseases of the chest wall (traumas, infections, neoplasms), diaphragm (paralysis, ipokinesis), pleura (effusions, pneumothorax, thickenings, neoplasms) and lung parenchyma (consolidations, interstitial syndromes, peripheral lesions). One of the most useful application of chest ultrasound is the evaluation of effusions. However, no standardized approach for ultrasound-guided thoracenthesis is available. Our study showed that our usual ultrasonographic landmark (“V-point”) could be a standard site to perform thoracenthesis: in 45 thoracenthesis no pneumothorax occurred, drainage was always successful at first attempt. Values of maximum thickness at V-point and drained fluid volume showed a significative correlation. Proteins concentration of ultrasound patterns of effusions (anechoic, ipoechoic, moving echoic spots, dense moving spots, hyperechoic) were compared to those of the macroscopic features of fluids showing connection between light-yellow fluid and echoic moving spots pattern and between ipoechoic/dense moving spots and cloudy-yellow/serum-haematic fluids. These observations suggest that ultrasound could predict chemical-physical features of effusions. Lung ultrasound provides useful information about many disease of the lung, but actually there is not useful in obstructive bronchial diseases. Analysing diaphragmatic kinetics using M-mode through transhepatic scan we described a similarity between diaphragm excursion during an expiratory forced maneuver and the volume/time curve of spirometry. This allowed us to identify the M-mode Index of Obstruction (MIO), an ultrasound-analogue of FEV1/VC. We observed MIO values of normal subjects (9) and obstructed patients (9) comparing the two groups. FEV1/VC and MIO showed a significant correlation suggesting that MIO may be affected by airways obstruction; MIO values were significatively different between normal and obstructed so that it could identify an obstructive syndrome. The data show that it is possible to suspect the presence of obstructive syndrome of the airways using ultrasonography of the diaphragm.

Biomarkers in chronic obstructive pulmonary diseases. Clinical and functional correlations.

Asthma and chronic obstructive pulmonary disease (COPD) are two distinct lung diseases with distinctive clinical and inflammatory features. A proportion of asthmatic patients experience a fixed airflow obstruction that persists despite optimal pharmacologic treatment for reasons that are still largely unknown. We found that patients with asthma and COPD sharing a similar fixed airflow obstruction have an increased lung function decline and frequency of exacerbations. Nevertheless, the decline in lung function is associated with specific features of the underlying inflammation. Airway inflammation increases during asthma exacerbation and disease severity. Less is known about the correlations between symptoms and airway inflammation in COPD patients. We found that there is no correlation between symptoms and lung function in COPD patients. Nevertheless symptoms changes are associated with specific inflammatory changes: cough is associated with an increase of sputum neutrophils in COPD, dyspnoea is associated with an increase of eosinophils. The mechanisms of this correlation remain unknown. Neutrophils inflammation is associated with bacterial colonization in stable COPD. Is not known whether inhaled corticosteroids might facilitate bacterial colonization in COPD patients. We found that the use of inhaled corticosteroids in COPD patients is associated with an increase of airway bacterial load and with an increase of airway pathogen detection. Bacterial and viral infections are the main causes of COPD and asthma exacerbations. Impaired innate immune responses to rhinovirus infections have been described in adult patients with atopic asthma. Whether this impaired immune condition is present early in life and whether is modulated by a concomitant atopic condition is currently unknown. We found that deficient innate immune responses to rhinovirus infection are already present early in life in atopic patients without asthma and in asthmatic subjects. These findings generalize the scenario of increased susceptibility to viral infections to other Th2 oriented conditions.

La terapia combinata di cellule mesenchimali stromali e aceinibitori riduce la fibrosi renale in un modello animale di ostruzione ureterale unilaterale

Le cellule mesenchimali stromali (MSC) sono cellule multipotenti e numerosi studi hanno mostrato i loro effetti benefici nel danno renale acuto ma non sono ancora stati dimostrati potenziali effetti nella malattia renale cronica. L'ostruzione ureterale unilaterale (UUO) è un modello di fibrosi interstiziale nel quale l'attivazione di molecole vasoattive, citochine profibrotiche e infiammatorie gioca un ruolo patogenetico nello sviluppo dell'apoptosi e atrofia tubulare. Il sistema renina-angiotensina (RAS) gioca un ruolo chiave nello sviluppo della fibrosi renale e i farmaci che hanno come target l'angiotensina II, principale mediatore del RAS, sono attualmente la terapia più efficace nel ridurre la progressione della malattia renale cronica. E' noto che gli ACE-inibitori (ACEi) inducono un aumento compensatorio della renina plasmatica per la mancaza del feedback negativo sulla sua produzione. Tuttavia, la renina (R) promuove il danno renale non solo stimolando la produzione di ANGII, ma anche up-regolando geni profibrotici attraverso l'attivazione del recettore renina/prorenina. Lo scopo dello studio è stato indagare se l'infusione di MSC riduceva il danno renalein un modello animale di UUO e comparare gli eventuali effetti protettivi di ACEi e MSC in UUO. Abbiamo studiato 5 gruppi di ratti. A: sham operati. B: ratti sottoposti a UUO che ricevevano soluzione salina. C: ratti sottoposti a UUO che ricevavano MSC 3X106 nella vena della coda al giorno 0. D:ratti sottoposti a UUO che ricevevano lisinopril dal g 1 al g 21. E: ratti sottoposti a UUO che ricevevano MSC 3X106 nella vena della coda al giorno 0 e lisinopril dal g 1 al g 21. I ratti sono stati sacrificati al giorno 7 e 21. I risultati dello studio mostrano che MSC in UUO prevengono l'aumento della renina, riducono la generazione di ANGII e che in terapia combinata con ACEi riducono ulteriormente l'ANGII, determinando una sinergia nel miglioramento della fibrosi renale.

Suppression des allergischen Asthmas durch regulatorische T-Zellen: Mechanismen und potenzielle therapeutische Ansätze

Das allergische Asthma ist eine weit verbreitete, immunologische Erkrankung, deren Prävalenz in den vergangenen 20 Jahren vor allem in industrialisierten Regionen drastisch zugenommen hat. Trotz intensiver Forschung und Entwicklung medikamentöser Therapien steigt die Zahl der Patienten stetig an. Charakteristisch für diese Erkrankung sind entzündliche Veränderungen in der Lunge, erhöhte Atemwegsüberempfindlichkeit (AHR), Mukusproduktion und in chronischen Fällen auch Atemwegsobstruktion. Bei der Entstehung des allergischen Asthmas wird ein anfälliges Individuum durch die Inhalation eines normalerweise unschädlichen, in der Umwelt vorkommenden Antigens (Allergen) sensibilisiert, wodurch im Körper eine eigentlich unangebrachte Immunreaktion in Gang gesetzt wird. CD4+ T-Lymphozyten und ganz besonders die Subpopulationen der T-Helfer 1 (Th1) und Th2 Zellen spielen in dem Prozess eine zentrale Rolle. Obwohl ein Großteil der Asthmatiker mit einer Atemwegseosinophilie und erhöhter Expression der Th2-typischen Zytokine IL-4 und IL-13 ein Th2-typisches Krankheitsbild aufweisen, wurden weitere Asthmaphänotypen identifiziert. Vornehmlich in Patienten, die an schwerem Asthma leiden, sind dominierende Neutrophilie und erhöhte Mengen IFN-γ in den Atemwegen nachweisbar, was auf eine Th1-gesteuerte Immunreaktion hindeutet. Eine effektive, heilende Therapie des Asthmas wurde bislang nicht entwickelt. Die Inhibition der T-Zellantwort etwa durch Applikation allergenspezifischer, regulatorischer T-Zellen (Tregs) gilt als ein vielversprechender, aber nicht vollständig erforschter Ansatz zur Kontrolle der Krankheitssymptome. In diesem Zusammenhang wurden in der vorliegenden Arbeit die Mechanismen und Effekte natürlich vorkommender CD4+CD25+Foxp3+ regulatorischer T-Zellen (nTregs) auf eine Th1 bzw. Th2-induzierte allergische Atemwegserkrankung untersucht. Anhand eines adoptiven Zelltransfermodells unter Einsatz lymphozytendefizienter Rag2-/- Mäuse konnte gezeigt werden, dass sowohl Th1 als auch Th2 Zellen, kombiniert mit mehrfacher, inhalativer Allergenprovokation, eine erhöhte AHR induzieren. Während der Transfer allergenspezifischer Th2 Zellen eine Eosinophilie in der bronchoalveolären Lavage (BAL) und vermehrte Mukusproduktion in den Atemwegen hervorrief, war in Th1-transferierten Tieren zwar eine massive Infiltration neutrophiler Granulozyten zu beobachten, eine Becherzellmetaplasie mit vermehrten, mukusproduzierenden Atemwegsepithelzellen blieb allerdings aus. In vitro und in vivo waren voraktivierte nTregs (preTregs) nur eingeschränkt in der Lage, die Th2-gesteuerte Atemwegserkrankung zu inhibieren. Im Gegensatz dazu konnten die Th1-Effektorfunktionen in vitro und die Th1-induzierte AHR und Atemwegsentzündung in vivo durch preTregs effektiv gehemmt werden, was auf eine unterschiedliche Empfindlichkeit der Th-Subpopulationen weist. Innerhalb der nTreg-vermittelten Suppression wird der sekundäre Botenstoff cAMP auf die zu supprimierende Zelle übertragen und führt zur Hemmung von Proliferation und Zytokinproduktion. Dass dieser Mechanismus nicht nur in vitro, sondern auch in der Suppression der Th2-gesteuerten allergischen Atemwegserkrankung eine Rolle spielt, konnte durch die Störung des intrazellulären cAMP-Abbaus mittels PDE4-Inhibitoren verdeutlicht werden. Sowohl die prophylaktische, als auch die therapeutische Applikation der PDE4-Inhibitoren verstärkte den regulativen Effekt der nTregs auf AHR und Entzündung, korrelierend mit erhöhten, zytosolischen cAMP-Konzentrationen in den Th2 Zellen der Lunge. Trotz des Fortschritts in der Isolation und In vitro-Expansion humaner nTregs ist die Ausbeute an Zellen äußerst limitiert und die Übertragbarkeit größerer Zellmengen nicht zuletzt aufgrund von hohem Kontaminationsrisiko während mehrtägiger In vitro-Expansion fragwürdig. Die Ergebnisse der vorliegenden Arbeit zeigen, dass eine Behandlung mit dem PDE4-Inhibitor die suppressive Kapazität der allergenspezifischen nTregs deutlich erhöhte. Den nTreg-vermittelten Suppressionsmechanismus durch den Einsatz von Pharmazeutika zu unterstützen bietet einen viel versprechenden und realistischen Ansatz zur Therapie des allergischen Asthmas.

Logarithmically smooth deformations of strict normal crossing logarithmically symplectic varieties

In this thesis we give a definition of the term logarithmically symplectic variety; to be precise, we distinguish even two types of such varieties. The general type is a triple $(f,nabla,omega)$ comprising a log smooth morphism $fcolon Xtomathrm{Spec}kappa$ of log schemes together with a flat log connection $nablacolon LtoOmega^1_fotimes L$ and a ($nabla$-closed) log symplectic form $omegainGamma(X,Omega^2_fotimes L)$. We define the functor of log Artin rings of log smooth deformations of such varieties $(f,nabla,omega)$ and calculate its obstruction theory, which turns out to be given by the vector spaces $H^i(X,B^bullet_{(f,nabla)}(omega))$, $i=0,1,2$. Here $B^bullet_{(f,nabla)}(omega)$ is the class of a certain complex of $mathcal{O}_X$-modules in the derived category $mathrm{D}(X/kappa)$ associated to the log symplectic form $omega$. The main results state that under certain conditions a log symplectic variety can, by a flat deformation, be smoothed to a symplectic variety in the usual sense. This may provide a new approach to the construction of new examples of irreducible symplectic manifolds.

The Benefits of Intravenous Thrombolysis Relate to the Site of Baseline Arterial Occlusion in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET)

In ischemic stroke, the site of arterial obstruction has been shown to influence recanalization and clinical outcomes. However, this has not been studied in randomized controlled trials, nor has the impact of arterial obstruction site on reperfusion and infarct growth been assessed. We studied the influence of site and degree of arterial obstruction patients enrolled in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET).

Postural proteinuria associated with left renal vein entrapment: a follow-up evaluation

Imaging studies show entrapment of the left renal vein in the fork between the aorta and proximal superior mesenteric artery in most cases of isolated postural proteinuria. Therefore, it has been postulated that partial obstruction to the flow in the left renal vein in the upright position is a cause of this form of proteinuria. In a girl with isolated postural proteinuria, kidney ultrasonic imaging and Doppler flow scanning showed left renal vein entrapment. Seven years later, a new evaluation showed resolution of both postural proteinuria and left renal vein entrapment. The longitudinal observation provides substantial additional support for entrapment of the left renal vein by the aorta and superior mesenteric artery as a cause of isolated postural proteinuria.

Considerations for prenatal counselling of patients with cardiac rhabdomyomas based on their cardiac and neurologic outcomes

Cardiac rhabdomyomas are benign cardiac tumours with few cardiac complications, but with a known association to tuberous sclerosis that affects the neurologic outcome of the patients. We have analysed the long-term cardiac and neurological outcomes of patients with cardiac rhabdomyomas in order to allow comprehensive prenatal counselling, basing our findings on the records of all patients seen prenatally and postnatally with an echocardiographic diagnosis of cardiac rhabdomyoma encountered from August, 1982, to September, 2007. We analysed factors such as the number and the location of the tumours to establish their association with a diagnosis of tuberous sclerosis, predicting the cardiac and neurologic outcomes for the patients.Cardiac complications include arrhythmias, obstruction of the ventricular outflow tracts, and secondary cardiogenic shock. Arrhythmias were encountered most often during the neonatal period, with supraventricular tachycardia being the commonest rhythm disturbance identified. No specific dimension or location of the cardiac rhabdomyomas predicted the disturbances of rhythm.The importance of the diagnosis of tuberous sclerosis is exemplified by the neurodevelopmental complications, with four-fifths of the patients showing epilepsy, and two-thirds having delayed development. The presence of multiple cardiac tumours suggested a higher risk of being affected by tuberous sclerosis. The tumours generally regress after birth, and cardiac-related problems are rare after the perinatal period. Tuberous sclerosis and the associated neurodevelopmental complications dominate the clinical picture, and should form an important aspect of the prenatal counselling of parents.

Diffusion-weighted MR imaging of native and transplanted kidneys

Applications of diffusion-weighted (DW) magnetic resonance (MR) imaging outside the brain have gained increasing importance in recent years. Owing to technical improvements in MR imaging units and faster sequences, the need for noninvasive imaging without contrast medium administration, mainly in patients with renal insufficiency, can be met successfully by applying this technique. DW MR imaging is quantified by the apparent diffusion coefficient (ADC), which provides information on diffusion and perfusion simultaneously. By using a biexponential fitting process of the DW MR imaging data, these two entities can be separated, because this type of fitting process can serve as an estimate of both the perfusion fraction and the true diffusion coefficient. DW MR imaging can be applied for functional evaluation of the kidneys in patients with acute or chronic renal failure. Impairment of renal function is accompanied by a decreased ADC. Acute ureteral obstruction leads to perfusion and diffusion changes in the affected kidney, and renal artery stenosis results in a decreased ADC. In patients with pyelonephritis, diffuse or focal changes in signal intensity are seen on the high-b-value images, with increased signal intensity corresponding to low signal intensity on the ADC map. The feasibility and reproducibility of DW MR imaging in patients with transplanted kidneys have already been demonstrated, and initial results seem to be promising for the assessment of allograft deterioration. Overall, performance of renal DW MR imaging, presuming that measurements are of high quality, will further boost this modality, particularly for early detection of diffuse renal conditions, as well as more accurate characterization of focal renal lesions.

Science to practice: Can diffusion-weighted MR imaging findings be used as biomarkers to monitor the progression of renal fibrosis?

In an experimental murine model of unilateral ureteral obstruction, Togao et al demonstrated that diffusion-weighted (DW) magnetic resonance (MR) imaging can depict and enable monitoring of abnormal changes in the progression of renal fibrosis; because these microstructural changes are complex and multifactorial, future studies focused on their specificity should be performed before they are applied in clinical trials.

A Portable Image Overlay Projection Device for Computer-Aided Open Liver Surgery

Image overlay projection is a form of augmented reality that allows surgeons to view underlying anatomical structures directly on the patient surface. It improves intuitiveness of computer-aided surgery by removing the need for sight diversion between the patient and a display screen and has been reported to assist in 3-D understanding of anatomical structures and the identification of target and critical structures. Challenges in the development of image overlay technologies for surgery remain in the projection setup. Calibration, patient registration, view direction, and projection obstruction remain unsolved limitations to image overlay techniques. In this paper, we propose a novel, portable, and handheld-navigated image overlay device based on miniature laser projection technology that allows images of 3-D patient-specific models to be projected directly onto the organ surface intraoperatively without the need for intrusive hardware around the surgical site. The device can be integrated into a navigation system, thereby exploiting existing patient registration and model generation solutions. The position of the device is tracked by the navigation system’s position sensor and used to project geometrically correct images from any position within the workspace of the navigation system. The projector was calibrated using modified camera calibration techniques and images for projection are rendered using a virtual camera defined by the projectors extrinsic parameters. Verification of the device’s projection accuracy concluded a mean projection error of 1.3 mm. Visibility testing of the projection performed on pig liver tissue found the device suitable for the display of anatomical structures on the organ surface. The feasibility of use within the surgical workflow was assessed during open liver surgery. We show that the device could be quickly and unobtrusively deployed within the sterile environment.

Paediatric traffic accident and obstructive sleep apnoea by antrochoanal polyps: case report and literature review

Antrochoanal polyps are hyperplasias of the nasal mucosa, which have their origin in the maxillary sinus and extend through the nasal cavity and the choanae into the naso- and oropharynx. In children antrochoanal polyps represent one of the more frequent manifestations of paediatric nasal polyposis. Most studies on antrochoanal polyps in children report only on nasal obstruction, hyponasal speech and snoring, which are also encountered in the most common cause of obstructive sleep apnoea syndrome; i.e. adenoid or tonsillar hyperplasia. Only very few studies report on additional health hazards by antrochoanal polyps ranging from obstructive sleep apnoea syndrome to swallowing disorders and cachexia. We present the case of an 8 year old girl with a bicycle accident caused by excessive daytime sleepiness and obstructive sleep apnoea syndrome due to an extensive antrochoanal polyp. After a transnasal polypectomy and meatotomy type II the obstructive sleep apnoea and day time sleepiness resolved completely. Awareness of this additional health hazard is important and correct evaluation and timely diagnosis of a potential antrochoanal polyp is mandatory because minimally invasive rhinosurgery is highly curative in preventing further impending problems.

[Surgical options in the treatment of chronic venous ulcers]

Surgery offers several options in prevention of chronic venous insufficiency and its sequelae. Both the operation on veins with valve dysfunction to reduce reflux and the elimination of obstruction in thrombosed veins aim for the reduction of venous hypertension. Elevated venous pressure, impairment of cutaneous capillaries and a chronic inflammatory process result in sclerosis of skin and subcutaneous tissue and might proceed to the fascia resulting in a chronic compartment syndrome. Non- healing chronic venous ulcers under conservative therapy for more than three months may be treated by vein-surgery, local wound care therapy like shaving and negative pressure treatment and if necessary by lowering of elevated intracompartimental pressure by fasciotomy or even fasciectomy.