Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity

Background: Without neonatal initiation of treatment, 80–90% of patients with glutaric aciduria type 1 (GA1) develop striatal injury during the first six years of life resulting in a complex, predominantly dystonic movement disorder. Onset of motor symptoms may be acute following encephalopathic crisis or insidious without apparent crisis. Additionally, so-called late-onset GA1 has been described in single patients diagnosed after the age of 6 years. With the aim of better characterizing and understanding late-onset GA1 we analyzed clinical findings, biochemical phenotype, and MRI changes of eight late-onset patients and compared these to eight control patients over the age of 6 years with early diagnosis and start of treatment. Results: No late-onset or control patient had either dystonia or striatal lesions on MRI. All late-onset (8/8) patients were high excretors, but only four of eight control patients. Two of eight late-onset patients were diagnosed after the age of 60 years, presenting with dementia, tremor, and epilepsy, while six were diagnosed before the age of 30 years: Three were asymptomatic mothers identified by following a positive screening result in their newborns and three had non-specific general symptoms, one with additional mild neurological deficits. Frontotemporal hypoplasia and white matter changes were present in all eight and subependymal lesions in six late-onset patients. At comparable age a greater proportion of late-onset patients had (non-specific) clinical symptoms and possibly subependymal nodules compared to control patients, in particular in comparison to the four clinically and MR-wise asymptomatic low-excreting control patients. Conclusions: While clinical findings are non-specific, frontotemporal hypoplasia and subependymal nodules are characteristic MRI findings of late-onset GA1 and should trigger diagnostic investigation for this rare disease. Apart from their apparent non-susceptibility for striatal injury despite lack of treatment, patients with late-onset GA1 are not categorically different from early treated control patients. Differences between late-onset patients and early treated control patients most likely reflect greater cumulative neurotoxicity in individuals remaining undiagnosed and untreated for years, even decades as well as the higher long-term risk of high excretors for intracerebral accumulation of neurotoxic metabolites compared to low excretors

Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia

Background: Until today, adult and pediatric clinical trials investigating single-agent or combinatorial HDAC inhibitors including vorinostat in solid tumors have largely failed to demonstrate efficacy. These results may in part be explained by data from preclinical models showing significant activity only at higher concentrations compared to those achieved with current dosing regimens. In the current pediatric trial, we applied an intra-patient dose escalation design. The purpose of this trial was to determine a safe dose recommendation (SDR) of single-agent vorinostat for intra-patient dose escalation, pharmacokinetic analyses (PK), and activity evaluation in children (3-18 years) with relapsed or therapy-refractory malignancies. Results: A phase I intra-patient dose (de)escalation was performed until individual maximum tolerated dose (MTD). The starting dose was 180 mg/m(2)/day with weekly dose escalations of 50 mg/m(2) until DLT/maximum dose. After MTD determination, patients seamlessly continued in phase II with disease assessments every 3 months. PK and plasma cytokine profiles were determined. Fifty of 52 patients received treatment. n = 27/50 (54%) completed the intra-patient (de)escalation and entered phase II. An SDR of 130 mg/m(2)/day was determined (maximum, 580 mg/m(2)/day). n = 46/50 (92%) patients experienced treatment-related AEs which were mostly reversible and included thrombocytopenia, fatigue, nausea, diarrhea, anemia, and vomiting. n = 6/50 (12%) had treatment-related SAEs. No treatment-related deaths occurred. Higher dose levels resulted in higher C-max. Five patients achieved prolonged disease control (> 12 months) and showed a higher C-max (> 270 ng/mL) and MTDs. Best overall response (combining PR and SD, no CR observed) rate in phase II was 6/27 (22%) with a median PFS and OS of 5.3 and 22.4 months. Low levels of baseline cytokine expression were significantly correlated with favorable outcome. Conclusion: An SDR of 130 mg/m(2)/day for individual dose escalation was determined. Higher drug exposure was associated with responses and long-term disease stabilization with manageable toxicity. Patients with low expression of plasma cytokine levels at baseline were able to tolerate higher doses of vorinostat and benefited from treatment. Baseline cytokine profile is a promising potential predictive biomarker

Beiträge zur Geschichte des Landkreises Regensburg 37

Heimat gestern und heute III - 56 Arbeitsproben von 12 Autoren; darin: Detterbeck, Pius: Mei Häuserl, mei Goat´n (S. 3); Fendl, Josef, Herbst im Jura (bei Schönhofen), Die Jahreszeit der fünf Sinne, Terra incognita, Schlecht verteilt, Diplomatisch (S. 4-5); Heigl, Margot: Hoamat, Grod a Hausfrau, Liebeserklärung, "Bayernbild", "Blaue" Volksmusik, Glück, Zeit, Kloana Unterschied (S. 6-8); Hemrich, Hans: Dö staade Zeit, Abschied, olt (S. 9-10); Kraus, Josef: A Pferdl, Nie Altwerden, Die alt Mauer, Scho wieder (S. 11-16); Mühldorfer, Albert: Koa Arbat, Mia samma aa wea, Wöiltbürger, Sanierung, Landschaftsplanung, Versaamt is versaamt, Rest-WAA-heit (S. 17-18); Rosenmeier, Maria: Fortschritt, Oasn, Schauspieler, Menschn, Moral, Generationsproblem, Glockenklang, Walhalla - Ruhmestempel (S. 19-20); Seitz, Angelika: Regensburg, August 85, wintergedeck, spätaugust, i bin unschuldig, im Normalfall (S. 21-23); Stadler, Ali: Gestern war´s, Woaßt as no? (S. 24-25); Staudigl, Franz Xaver: Beratzhausener Skizzen, Friedhof, Ansichtskarte "Partie am Marktplatz", Allegorie? (S. 26-27); Weigert, Hans: Macha, Da Duillnbock (S. 28-30); Zenger, Georg: Blick ins Allerseelenland (S. 31

Beiträge zur Geschichte des Landkreises Regensburg 25

Heimat gestern und heute II - 41 Arbeitsproben von 12 Autore

Brain Magnetic Resonance Imaging Reveals Different Courses of Disease in Pediatric and Adult Cerebral Malaria.

BACKGROUND: Cerebral malaria is a common presentation of severe Plasmodium falciparum infection and remains an important cause of death in the tropics. Key aspects of its pathogenesis are still incompletely understood, but severe brain swelling identified by magnetic resonance imaging (MRI) was associated with a fatal outcome in African children. In contrast, neuroimaging investigations failed to identify cerebral features associated with fatality in Asian adults. METHODS: Quantitative MRI with brain volume assessment and apparent diffusion coefficient (ADC) histogram analyses were performed for the first time in 65 patients with cerebral malaria to compare disease signatures between children and adults from the same cohort, as well as between fatal and nonfatal cases. RESULTS: We found an age-dependent decrease in brain swelling during acute cerebral malaria, and brain volumes did not differ between fatal and nonfatal cases across both age groups. In nonfatal disease, reversible, hypoxia-induced cytotoxic edema occurred predominantly in the white matter in children, and in the basal ganglia in adults. In fatal cases, quantitative ADC histogram analyses also demonstrated different end-stage patterns between adults and children: Severe hypoxia, evidenced by global ADC decrease and elevated plasma levels of lipocalin-2 and microRNA-150, was associated with a fatal outcome in adults. In fatal pediatric disease, our results corroborate an increase in brain volume, leading to augmented cerebral pressure, brainstem herniation, and death. CONCLUSIONS: Our findings suggest distinct pathogenic patterns in pediatric and adult cerebral malaria with a stronger cytotoxic component in adults, supporting the development of age-specific adjunct therapies

(Table 1) Li, B and Sr isotopic composition and concentration in ODP Leg 209 samples

Spinel harzburgites from ODP Leg 209 (Sites 1272A, 1274A) drilled at the Mid-Atlantic ridge between 14°N and 16°N are highly serpentinized (50-100%), but still preserve relics of primary phases (olivine >= orthopyroxene >> clinopyroxene). We determined whole-rock B and Li isotope compositions in order to constrain the effect of serpentinization on d11B and d7Li. Our data indicate that during serpentinization Li is leached from the rock, while B is added. The samples from ODP Leg 209 show the heaviest d11B (+29.6 to +40.52 per mil) and lightest d7Li (-28.46 to +7.17 per mil) found so far in oceanic mantle. High 87Sr/86Sr ratios (0.708536 to 0.709130) indicate moderate water/rock ratios (3 to 273, on the average 39), in line with the high degree of serpentinization observed. Applying the known fractionation factors for 11B/10B and 7Li/6Li between seawater and silicates, serpentinized peridotite in equilibrium with seawater at conditions corresponding to those of the studied drill holes (pH: 8.2; temperature: 200 °C) should have d11B of +21.52 per mil and d7Li of +9.7 per mil. As the data from ODP Leg 209 are clearly not in line with this, we modelled a process of seawater-rock interaction where d11B and d7Li of seawater evolve during penetration into the oceanic plate. Assuming chemical equilibrium between fluid and a rock with d11B and d7Li of ODP Leg 209 samples, we obtain d11B and d7Li values of +50 to +60 per mil, -2 to +12 per mil, respectively, for the coexisting fluid. In the oceanic domain, no hydrothermal fluids with such high d11B have yet been found, but are predicted by theoretical calculations. Combining the calculated water/rock ratios with the d7Li and d11B evolution in the fluid, shows that modification of d7Li during serpentinization requires higher water/rock ratios than modification of d11B. Extremely heavy d11B in serpentinized oceanic mantle can potentially be transported into subduction zones, as the B budget of the oceanic plate is dominated by serpentinites. Extremely light d7Li is unlikely to survive as the Li budget is dominated by the oceanic crust, even at small fractions

Boron, lithium and strontium isotopes as tracers of seawater–serpentinite interaction at Mid-Atlantic ridge, ODP Leg 209

Spinel harzburgites from ODP Leg 209 (Sites 1272A, 1274A) drilled at the Mid-Atlantic ridge between 14°N and 16°N are highly serpentinized (50–100%), but still preserve relics of primary phases (olivine ≥ orthopyroxene >> clinopyroxene). We determined whole-rock B and Li isotope compositions in order to constrain the effect of serpentinization on δ11B and δ7Li. Our data indicate that during serpentinization Li is leached from the rock, while B is added. The samples from ODP Leg 209 show the heaviest δ11B (+ 29.6 to + 40.52‰) and lightest δ7Li (− 28.46 to + 7.17‰) found so far in oceanic mantle. High 87Sr/86Sr ratios (0.708536 to 0.709130) indicate moderate water/rock ratios (3 to 273, on the average 39), in line with the high degree of serpentinization observed. Applying the known fractionation factors for 11B/10B and 7Li/6Li between seawater and silicates, serpentinized peridotite in equilibrium with seawater at conditions corresponding to those of the studied drill holes (pH: 8.2; temperature: 200 °C) should have δ11B of + 21.52‰ and δ7Li of + 9.7‰. As the data from ODP Leg 209 are clearly not in line with this, we modelled a process of seawater–rock interaction where δ11B and δ7Li of seawater evolve during penetration into the oceanic plate. Assuming chemical equilibrium between fluid and a rock with δ11B and δ7Li of ODP Leg 209 samples, we obtain δ11B and δ7Li values of + 50 to + 60‰, − 2 to + 12‰, respectively, for the coexisting fluid. In the oceanic domain, no hydrothermal fluids with such high δ11B have yet been found, but are predicted by theoretical calculations. Combining the calculated water/rock ratios with the δ7Li and δ11B evolution in the fluid, shows that modification of δ7Li during serpentinization requires higher water/rock ratios than modification of δ11B. Extremely heavy δ11B in serpentinized oceanic mantle can potentially be transported into subduction zones, as the B budget of the oceanic plate is dominated by serpentinites. Extremely light δ7Li is unlikely to survive as the Li budget is dominated by the oceanic crust, even at small fractions

Does medical students personality have an impact on their intention to show empathic behavior?

Several studies have demonstrated a correlation between specific personal traits and empathy. However, it is not clear if persons with certain personality traits lack the intent to show empathic behavior or if other factors independent of their intent are affecting their empathic behavior. To answer this question, we asked 132 medical students to fill out questionnaires evaluating the General Intention to Show Empathic Behavior (GISEB) and the five personality traits measured by NEO Five-Factor Inventory (NEO-FFI). Additionally, we evaluated the influence of other factors, such as age, gender, curricular progress (second versus fourth year), and preferred specialization after graduation. We performed a Pearsons correlation and a regression analysis. Results indicate that the five personality traits and gender have little influence on the General Intention (GISEB), only extraversion (r=.221, 95% CI [.013.394], p=.027), and agreeableness (r=.229, 95% CI [.021.428], p=.022) correlated with the intention. The only predictor for General Intention (GISEB) was curricular progress (=.27, p<.05), showing a decrease of General Intention to Show Empathic Behavior from second to fourth year of university (U=1203.5, p=.002). A further finding indicates that gender and personality influence the students wish of specialization after graduation: Agreeableness (F(12, 53)=2.376, p=.016) impacted the preferred specialization. Our study demonstrated that medical students personality might not notably impact the intention to show empathic behavior. Further research is needed to investigate moderating effects.(VLID)360172

Wiener klinische Wochenschrift / Competency in medical history taking : the training physicians view

Background Because effective communication skills are crucial for every physician, this study evaluated students competence to take a sufficient medical history. This ability was measured via reports from the students supervising and training physicians. Methods A total of 24 physicians from several different departments were interviewed‚ and a stratification of medical specialties was performed due to the current supply-relevant number of medical doctors in the country. A qualitative content analysis was then performed. Results The analysis revealed the students lack of expertise and ability to take a structured and complete medical history. Additionally, the lack of students engagement was criticized by the training physicians. An insufficiency of student supervision was also shown as only half of the departments have a fixed supervisor for the students during the internship. Conclusion The data showed the need for a refinement of the training of communicative skills at university and the practical training at hospitals.(VLID)362079