The propeptide mediates formation of stromal stores of PROMIC-1: role in determining prostate cancer outcome

The extracellular matrix (ECM) is a reservoir of cellular binding proteins and growth factors that are critical for normal cell behavior, and aberrations in the ECM invariably accompany malignancies such as prostate cancer. Carcinomas commonly overexpress macrophage inhibitory cytokine 1 (MIC-1), a proapoptotic and antitumorigenic transforming growth factor-beta superfamily cytokine. Here we show that MIC-1 is often secreted in an unprocessed propeptide containing form. It is variably processed intracellularly, with unprocessed forms being secreted from several tumor lines, including prostate carcinoma lines, PC-3 and LNCaP. Once secreted, only unprocessed proMIC-1 binds ECM, demonstrating for the first time the occurrence of extracellular stores of MIC-1. The propeptide mediates this association via its COOH-terminal 89 amino acids. Xenograft models bearing tumors secreting various engineered forms of MIC-1 show that the propeptide regulates the balance between ECM stores and circulating serum levels of mature MIC-1 in vivo. The absence of propeptide results in approximately 20-fold increase in serum MIC-1 levels. The significance of stromal MIC-1 stores was evaluated in prostate cancer tissue cores, which show major variation in stromal levels of MIC-1. Stromal MIC-1 levels are linked to prostate cancer outcome following radical prostatectomy, with decreasing stromal levels providing an important independent predictor of disease relapse. In low-grade localized prostate cancer (Gleason sum score < or = 6), the level of MIC-1 stromal stores was the best predictor of future relapse when compared with all other clinicopathologic variables. The secretion and ECM association of unprocessed proMIC-1 is likely to play a central role in modulating local bioavailability of MIC-1 which can affect patient outcome in prostate cancer and other epithelial tumors.     

Staging of brain pathology related to sporadic Parkinson's disease

Sporadic Parkinson's disease involves multiple neuronal systems and results from changes developing in a few susceptible types of nerve cells. Essential for neuropathological diagnosis are alpha-synuclein-immunopositive Lewy neurites and Lewy bodies. The pathological process targets specific induction sites: lesions initially occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus. Thereafter, less vulnerable nuclear grays and cortical areas gradually become affected. The disease process in the brain stem pursues an ascending course with little interindividual variation. The pathology in the anterior olfactory nucleus makes fewer incursions into related areas than that developing in the brain stem. Cortical involvement ensues, beginning with the anteromedial temporal mesocortex. From there, the neocortex succumbs, commencing with high order sensory association and prefrontal areas. First order sensory association/premotor areas and primary sensory/motor fields then follow suit. This study traces the course of the pathology in incidental and symptomatic Parkinson cases proposing a staging procedure based upon the readily recognizable topographical extent of the lesions.     

Glutamic acid decarboxylase immunoreactivity in sector CA 1 of the human Ammon's horn

Summary The distribution of glutamic acid decarboxylase (GAD) immunoreactive neurons, fibres and punctae in sector CA 1 of the adult human Ammon's horn was studied in Vibratome sections (40 m thick) of tissue obtained at surgery and autopsy. On light microscopical examination, the materal did not show pathological changes. The antibody was visualized by the unlabelled antibody enzyme method. GAD-immunoreactive neurons, fibres and punctae were present in all layers. Most immunoreactive neurons were located in the stratum pyramidale and stratum lacunosum. Their size ranged from 8 m in the stratum lacunosum to about 50 m in the stratum oriens. The somata offered a wide range of shapes, multiform to fusiform with the long axis aligned parallel or vertically to the alveus. All somata belonged to the heterogeneous group of non-pyramidal neurons. The dendrites either radiated in all directions or tended to run in two opposite directions. After bleaching the chromogen and staining for lipofuscin pigment granules and basophilic material, it turned out that within the stratum pyramidale all formerly GAD-immunoreactive neurons belonged to the group of lipofuscin-laden non-pyramidal neurons. Within the other layers, a few formerly GAD-immunoreactive neurons were devoid of lipofuscin pigment. The highest density of GAD-immunoreactive punctae was found in the stratum lacunosum. In addition to numerous GAD-immunoreactive punctae in the pyramidal layer and in the stratum radiatum there were thin GAD-immunoreactive fibres of varying length extending into various directions.Abbreviations CA cornu ammonis - CCK cholecystokinin - CN 4-chloro-1-naphthol - GABA -aminobutyric acid - GAD glutamic acid decarboxylase - lac stratum lacunosum - mol stratum moleculare - or stratum oriens - pyr stratum pyramidale - rad stratum radiatum - VIP vasoactive intestinal polypeptide     

Developmental and food-access-dependent changes in effector systems activated by leptin

In small mammals leptin reduces fat stores not only by inhibiting food intake but also by disinhibiting metabolic cold defense. Presuming that postnatal age and feeding regime set the conditions for either mode of leptin action, we compared the caloric equivalents of changes in fat mass, metabolic rate (MR) and food intake (FI) induced by 10-day treatments with leptin, in rats treated from postnatal days 7, 15, 25 onward and in adult mice that were free-feeding or food restricted. Whereas MR changes are known to dominate from postnatal days 7-16, changes in MR explained only about 50% and 30% of the leptin-induced changes in fat mass between days 15-24 and days 25-34, respectively. In adult mice of similar body weights, leptin-induced reductions in fat mass under free-feeding conditions were due only to FI decreases but due only to MR increases under food-restricted conditions. Thus, the same leptin treatment induces the same percentage decrease in body fat content by driving the two effectors differently, depending on age and feeding conditions. Consequently, in assessing the effects of leptin under various physiological conditions, short-term measurements of FI or MR alone are not sufficient. Instead, determination of the resultant decreases in total body fat is required.     

The interplay between host haemostatic systems and Leptospira spp. infections

Abstract

Hemostasis is a defence mechanism that protects the integrity of the vascular system and is comprised of the coagulation cascade, fibrinolysis, platelet aggregation, and vascular endothelium. Besides the primary function in preserving the vascular integrity, the haemostatic system cooperates with immune and inflammatory processes to eliminate invading pathogens during microbial infections. Under pathological manifestations, hemostasis must therefore interact in a coordinated manner with inflammatory responses and immune reactions. Several pathogens can modulate these host-derived countermeasures by specifically targeting certain haemostatic components for their own benefit. Thus, the ability to modulate host defence systems has to be considered as an essential bacterial virulence mechanism. Complications that bacterial pathogens can induce are therefore often the consequence of evoked host responses. A comprehensive understanding of the molecular mechanisms triggered in infectious processes may help to develop prophylactic methods and novel therapies for the patients suffering from a particular infectious disease. This review aims to provide a critical updated compiling of recent studies on how the pathogenic Leptospira can interact with and manipulate the host haemostatic systems and the consequences for leptospirosis pathogenesis.     

The pigment architecture of the human frontal lobe

Summary The precentral, subcentral, and frontal region of the human frontal lobe were examined by means of stereomicroscopical analysis using 800 m thick pigment preparations.The precentral region can be divided into markedly externoteniate ganglionic core fields and weakly externoteniate paraganglionic belt areas. The core fields are in addition characterized by a conspicuous population of pigment-laden Betz-pyramids in layer ^pVb. A typical pattern of pigmentation permits their clear distinction from other pyramidal cells of the fifth layer. When passing to the paraganglionic belt areas devoid of Betz-pyramids, the uniform multiform layer splits into a strongly pigmented ^pVIa and a more pallid ^pVIb.The subcentral region at the lowermost extremity of the central sulcus displays features of both frontal and parietal areas.The frontal region is mainly formed of equoteniate areas but comprises also a tongue-shaped internoteniate territory medially and an elongated externoteniate area laterally. Extended parts of the frontal region which abut upon the paraganglionic belt are endowed with unusually large and pigmentladen IIIc-pyramids. Pyramids of this type can be rarely encountered within the human isocortex but occur in great number in circumscribed specialized regions such as the temporal magnopyramidal region which represents probably the speech centre of Wernicke. Within the frontal lobe, two magnopyramidal regions can be distinguished. The superofrontal magnopyramidal region stretches out over large parts of the superior frontal convolution whereas the inferofrontal one is small and covers mainly posterior parts of the inferior frontal gyrus. As to its location, the superofrontal magnopyramidal region includes the supplementary motor region which is known to be involved in the performance of speech. On account of its unique structure and its location, the inferofrontal magnopyramidal region is considered to represent the morphological counterpart of the speech centre of Broca.     

Tranexamsäure und Endoprothetik: zwischen „off label use“ und „evidence-based medicine“

Die Anaesthesiologie -     

Transvenous Endomyocardial Biopsy: A Comparison of 2 Approaches

BackgroundEndomyocardial biopsy (EMB) is a well-established procedure for the diagnosis of specific myocardial diseases and represents the gold standard in monitoring allografts after heart transplantation. In our study, we compared 2 different approaches for harvesting EMB in order to optimize patient safety and efficacy of the procedure.MethodsAs a standard approach for harvesting EMB, a venous introducer sheath was inserted percutaneously via the internal jugular vein using the Seldinger technique. Thereafter, a bioptome was repeatedly introduced throughout this sheath into the right ventricle (RV), each time passing the tricuspid valve (TV). Alternatively, a coronary sinus catheter was inserted via an introducer sheath placed in the subclavian vein and only once was introduced into RV cavity. Hence, just a unique passage of TV was required. Thereafter, a bioptome was introduced via this catheter and precisely guided to the targeted biopsy site.ResultsA standard approach was used with 34 patients, and a modified technique was used with 37 patients. Patient characteristics were comparable in both cohorts, and analyses of peri-procedural parameters identified only marginal differences between the groups. Interestingly, the number of harvested tissue samples per procedure was higher in the modified approach compared to the standard approach. No complications occurred.ConclusionThe modified approach for EMB is a safe procedure. The facilitated bioptome-guidance and enhanced protection of TV may prevent periprocedural complications.