Showing papers by "Johann S. Braun published in 2002"

Pneumococcal pneumolysin and H2O2 mediate brain cell apoptosis during meningitis

Abstract: Pneumococcus is the most common and aggressive cause of bacterial meningitis and induces a novel apoptosis-inducing factor–dependent (AIF–dependent) form of brain cell apoptosis. Loss of production of two pneumococcal toxins, pneumolysin and H2O2, eliminated mitochondrial damage and apoptosis. Purified pneumolysin or H2O2 induced microglial and neuronal apoptosis in vitro. Both toxins induced increases of intracellular Ca2+ and triggered the release of AIF from mitochondria. Chelating Ca2+ effectively blocked AIF release and cell death. In experimental pneumococcal meningitis, pneumolysin colocalized with apoptotic neurons of the hippocampus, and infection with pneumococci unable to produce pneumolysin and H2O2 significantly reduced damage. Two bacterial toxins, pneumolysin and, to a lesser extent, H2O2, induce apoptosis by translocation of AIF, suggesting new neuroprotective strategies for pneumococcal meningitis.

Group B streptococcal β-hemolysin induces mortality and liver injury in experimental sepsis

Abstract: New Zealand White rabbits were challenged with the wild-type (wt) group B streptococci (GBS) serotype III strain (COH1) and its isogenic nonhemolytic (NH) and hyperhemolytic (HH) mutants. Mortality differed significantly between rabbits infected with the HH mutant IN40 (67%), compared with rabbits infected with the wt COH1 strain (27%) and the NH strains COH1-20 and COH1:cyl EDcat (13% and 0%, respectively; P , :05). Histopathologically, disseminated septic microabscesses surrounded by necrotic foci were found exclusively in the livers of HH mutant IN40–i nfected animals. Serum transaminase levels were 20-fold higher in the HH-infected group, compared with rabbits infected with the other strains. Positive TUNEL (in situ terminal deoxynucleotide transferase– mediated dUTP nick end labeling) staining and activation of caspase-3 in hepatocytes were more frequent in HH-infected than in wt-infected animals and absent in the NH mutant COH1-20– infected group, indicating that GBS b-hemolysin triggers apoptotic pathways in hepatocytes. This work provides the first evidence that GBSb-hemolysin plays a crucial role in the pathophysiology of GBS sepsis by inducing liver failure and high mortality. On an annual basis, sepsis syndrome is diagnosed in � 1,000,000 patients in Europe and the United States. The incidence of grampositive sepsis has risen since the 1980s, and, today, gram-positive organisms cause � 50% of all cases of sepsis [1]. Group B streptococci (GBS; Streptococcus agalactiae ) are a major etiologic agent of pneumonia, meningitis, and septic shock in human newborn infants. The most thoroughly studied virulence factor of GBS is its antiphagocytic capsule [2], but the purified capsular polysaccharide is relatively innocuous, with regard to host injury. Like other gram-positive bacteria, GBS possess the cell-wall components peptidoglycan and lipoteichoic acid, with potentially toxic properties [3]. High concentrations of peptidoglycan and lipoteichoic acid of Staphylococcus aureus and Streptococcus pneumoniae, which seldom occur clinically, have been shown to induce characteristic signs of septic shock, such as hypotension,

Diagnostic Pitfall: Atypical Cerebral Venous Drainage via the Vertebral Venous System

Abstract: We report a case of atypical cerebral venous drainage in a 38-year-old woman with symptoms of benign paroxysmal positional vertigo. Thrombosis of the left internal jugular vein and sigmoid sinus was suspected on the basis of spin-echo and time-of-flight MR findings, but multisection CT angiograms showed a patent sigmoid sinus and predominant drainage via the emissary veins toward the vertebral plexus, with only a minor contribution of the jugular veins. This case illustrates the variability of the venous anatomy in the craniocervical region.

Differential post-transcriptional regulation of p21WAF1/Cip1 levels in the developing nervous system following γ-irradiation

Abstract: Radiation-induced death in the developing brain is p53-dependent. However, genetic studies indicate that the signalling pathways that couple irradiation to p53 expression can vary between different developing neural populations [Herzog et al. (1998) Science, 280, 1089-1091]. Here we establish that signalling downstream of p53 also exhibits brain region-specific differences that are associated with the relative vulnerability of some cell populations to radiation-induced killing in the mouse. Following γ-irradiation, p53 and p21 W A F 1 / c i p 1 , but not Bax, protein levels increased in the developing cerebellum. In contrast, neither p21 W A F 1 / c i p 1 nor Bax protein levels were elevated in the retina following irradiation, despite increased p53 expression. In the retina, p53 expression was associated with cells destined to die, whereas in the cerebellum, p53 was expressed in both radiation-sensitive and radiation-resistant neuroblasts of the external granule cell layer. Although p21 W A F 1 / c i p 1 mRNA was expressed in all p53-positive neuroblasts after irradiation, p21 W A F 1 / c i p 1 protein was only detected in radiation-resistant neuroblasts of the cerebellum. Thus, p 2 1 WAF1/cip1 was subject to post-transcriptional regulation with p21 W A F 1 / c i p 1 protein only accumulating in cells destined to survive irradiation. Nevertheless, p21 W A F 1 / c i p 1 function was not essential for radiation resistance, as postmitotic neuroblasts in the external granule cell layer were spared in p21 W A F 1 / c i p 1 knockout mice.

Intracerebral hemorrhages, fibrinolysis, and prostate carcinoma.

Abstract: Sirs: The causes of intracerebral hemorrhages (ICHs) are diverse. The majority of ICHs are caused by hypertension. After the exclusion of the common causes of ICH rare underlying conditions are often underdiagnosed. One is blood coagulation disturbances, which are responsible for about 5–6 % of ICHs according to 4 epidemiologic studies [1]. Blood coagulation disturbances can be induced by a broad range of diseases. An 80-year-old man had suffered from his first ICH three years previously, affecting the left parietooccipital region, resulting in a moderate hemiparesis, predominantly facio-brachial, with motor aphasia. This ICH was preceded by a minor ischemic stroke, the cause of which and that of the ICH remained unknown. A careful evaluation of possible primary disorders led to no relevant findings in his medical history. Two months before admission to our hospital, ICH occurred again at the same location. On the day of admission to our hospital the patient was still confused with regard to person, time and location. He suffered from global aphasia, ideomotor and ideatory apraxia, and central hemiparesis of the right side. Electrocardiogram and radiography of the chest were normal. Doppler ultrasonography revealed hypoplasia of the left vertebral artery; no abnormality of the intracranial vessels was found. Magnetic resonance angiography of the intracranial vessels showed no indications of angiomas, aneurysms or local stenoses. In the electroencephalogram, a previously undetected focus of slow wave abnormalities was found in the right hemisphere. Subsequent cranial MRI verified a new hemorrhagic focus in the right temporooccipital region (Fig. 1). Cerebrospinal fluid (CSF) showed a slightly elevated lymphomonocytic cell count (21/3/μl), increased total protein (1.07 g/l), and normal IgG-index (0.54). These results could be explained by a moderate disruption of the blood-brain barrier by ICH. The CSF culture was sterile. The most striking result of the first blood examination was a decrease of fibrinogen < 50 mg/dl (normal 150–350 mg/dl). Thrombocytes CE3 were also decreased (105,000/μl). Partial thromboplastin time was normal, international normalized ratio (INR) was 1.5. Clotting factor XIII was decreased to 29 % (normal 73–155 %). Further investigation of the blood coagulation system proved that there was fibrinolysis: D-dimer 12 mg/l (normal < 0.5 mg/l) and fibrin degradation products 80–100 μg/ml (normal < 10 μg/ml) were elevated due to the cleavage of fibrinogen and fibrin. Looking for the reason of the blood coagulation disturbance, an enlarged and indurated prostate, as well as a prostate specific antigen (PSA) of 22 ng/ml (normal < 4 ng/ml), highly suggestive of a prostate tumor, were found. Before performing prostate biopsy, the patient died from respiratory arrest and cardiac insufficiency. At autopsy massive thrombosis of leg and pelvic veins as well as emboli in both pulmonary main artery branches were evident. There was no tumor detectable at any other site, e. g., in the gut, lung, liver or brain. Neuropathological examination showed no signs of chronic hypertension or amyloid angiopathy. Brain vessels exhibited only slight signs of arteriosclerosis. Metastatic brain tumors were excluded. Histology verified a multilocular, little differentiated prostate LETTER TO THE EDITORS