The visual impact of fractionated stereotactic conformal radiotherapy on seven eyes with optic nerve sheath meningiomas.

BACKGROUND: Treatment of primary optic nerve sheath meningiomas (ONSMs) remains controversial. Although recent studies have suggested a favorable outcome of radiotherapy, controlled data on the efficacy of fractionated stereotactic conformal radiotherapy (SCRT) in primary ONSMs are still lacking. METHODS: Seven eyes treated with SCRT (total dose: 54 Gy) were compared with six eyes that were not treated because of patient or physician preference. The indication for intervention was deterioration of visual function with or without imaging evidence of tumor progression. Patients with secondary ONSMs and those with neurofibromatosis type 2 were excluded. The mean follow-up period was 57 months for the treated eyes and 61 months for the untreated eyes. RESULTS: Among the seven treated eyes, visual acuity improved in six, five of which sustained improvement of three or more Snellen lines. One eye deteriorated by two lines. Visual field improved in four eyes, remained stable in two, and deteriorated in one. Four untreated eyes showed worsening of visual acuity and two remained stable. Visual field deteriorated in three eyes and was stable in three. None of the untreated eyes experienced improvement in visual acuity or visual field. No complications of treatment were documented. CONCLUSIONS: In agreement with previous reports, these results indicate that SCRT is superior to observation in its impact on visual function in eyes with primary ONSMs.     

Beiträge zur Kenntnis der Knochenmark -Funktion

Ohne Zusammenfassung     

Effects of the Ca2+ sensitizers EMD 57033 and CGP 48506 on myocardial contractility and Ca2+ transients in human ventricular and atrial myocardium

Zusammenfassung Ca²⁺-Sensitizer, wie z.B. EMD 57033 (EMD) und CGP 48506 (CGP) erhöhen die Kontraktionskraft ohne dabei den intrazellulären Ca²⁺-Transienten zu erhöhen und sind somit möglicherweise für die Behandlung der menschlichen Herzinsuffizienz von Bedeutung. Es ist jedoch unklar, ob sich Ca²⁺-Sensitizer in ihrem pharmakokinetischen Wirkprinzip am menschlichen Myokard unterscheiden. Daher wurde der Einfluss von EMD und CGP auf die Kontraktionskraft und den intrazellulären Ca²⁺-Transienten (Fura 2) an linksventrikulären Papillarmuskelstreifen (PAP) von menschlichem insuffizientem Myokard sowie in rechtsatrialen Trabekeln (RA) von Patienten untersucht, die sich einer aortokoronaren Bypass-Operation unterziehen mussten. In PAP wurde die Kraft effizienter und stärker nach Applikation von EMD (EC₅₀ EMD: 4,7ǃ,0 7mol/l, max. PIE EMD: +12,0DŽ,0 mN/mm²) erhöht als nach CGP (EC₅₀: 16,9lj,6 7mol/l, max. PIE: +6,4DŽ,8 mN/mm²). Ähnliche Ergebnisse wurden an RA erhalten. Carbachol (100 7mol/l) hatte keinen Einfluss auf die positiv inotrope Wirkung von EMD und CGP. Beide Ca²⁺-Sensitizer erhöhten signifikant die Relaxationszeit und die diastolischen Spannung. EMD und CGP veränderten den intrazellulären Ca²⁺-Transienten nicht. Schlussfolgerung Die Ca²⁺-Sensitizer EMD und CGP erhöhen cAMP- und Ca²⁺-unabhängig die Kontraktionskraft am menschlichen Myokard. Da sie die Relaxation beeinträchtigen, ist ihr therapeutischer Nutzen für die Herzinsuffizienz begrenzt. Summary Ca²⁺ sensitizers like EMD 57033 (EMD) and CGP 48506 (CGP) may be advantageous for the treatment of human heart failure, as they increase force of contraction without increasing the intracellular Ca²⁺ transients or energy consumption. However, whether or not Ca²⁺ sensitizers differ in their mode of action in human myocardium is not fully understood. The present study investigates the influence of EMD and CGP on force of contraction (FOC) and the intracellular Ca²⁺ transient (fura-2 ratio method) in left ventricular papillary muscle strips from left ventricular failing human myocardium (DCM, n=28) as well as in right atrial trabeculae (RA, n=21) obtained from patients undergoing cardiac bypass surgery. In isolated trabeculae of DCM, FOC was more efficacious and potently increased after application of EMD (EC₅₀ EMD: 4.7ǃ.0 7mol/l, max. PIE EMD: +12.0DŽ.0 mN/mm²) than CGP (EC₅₀: 16.9lj.6 7mol/l, max. PIE: +6.4DŽ.8 mN/mm²). Similar results were obtained in RA. Application of carbachol (100 7mol/l) had no effect on the positive inotropic effect of EMD or CGP. Both Ca²⁺ sensitizers significantly increased time to half peak relaxation as well as diastolic tension in DCM. EMD (10 7mol/l) and CGP (30 7mol/l) did not affect the Ca²⁺ transients in RA. The Ca²⁺ sensitizers EMD and CGP increase cAMP and Ca²⁺ independently from the force of contraction in the human myocardium. However, their therapeutic use in human heart failure may be limited as they impair relaxation.     

Does continuous flow apheresis influence viability in allogeneic hematopoietic stem cell harvest?

One of the important clinical variables determining the success of hematopoietic stem cell transplantation is the number of viable CD34+ stem cells transfused to the patient. G-CSF mobilized peripheral blood stem cells from 17 healthy donors were collected by continuous flow apheresis. The median (range) proportions of early apoptotic (Annexin V-FITC(pos)/7-AAD(neg)) and viable (Annexin V-FITC(neg)/7-AAD(neg)) CD45(dim)CD34+ stem cells were 1.5 (0.9-3.7)% and 97.7 (82.8-100)% in the peripheral blood before apheresis and 2.6 (0.8-7.9)% and 97.3 (91.9-99)% in the apheresis products, respectively. Despite an increase in the number of apoptotic cells among all cell compartments, this was statistically significant only in CD34+ cells and granulocytes. The majority of the cells still retained their viability.     

Brain activity and connectivity in response to negative affective stimuli: Impact of dysphoric mood and sex across diagnoses

Negative affective stimuli elicit behavioral and neural responses which vary on a continuum from adaptive to maladaptive, yet are typically investigated in a dichotomous manner (healthy controls vs. psychiatric diagnoses). This practice may limit our ability to fully capture variance from acute responses to negative affective stimuli to psychopathology at the extreme end. To address this, we conducted a functional magnetic resonance imaging study to examine the neural responses to negative valence/high arousal and neutral valence/low arousal images as a function of dysphoric mood and sex across individuals (n = 99) who represented traditional categories of healthy controls, major depressive disorder, bipolar psychosis, and schizophrenia. Observation of negative (vs. neutral) stimuli elicited blood oxygen‐level dependent responses in the following circuitry: periaqueductal gray, hypothalamus (HYPO), amygdala (AMYG), hippocampus (HIPP), orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and greater connectivity between AMYG and mPFC. Across all subjects, severity of dysphoric mood was associated with hyperactivity of HYPO, and, among females, right (R) AMYG. Females also demonstrated inverse relationships between severity of dysphoric mood and connectivity between HYPO ‐ R OFC, R AMYG ‐ R OFC, and R AMYG ‐ R HIPP. Overall, our findings demonstrated sex‐dependent deficits in response to negative affective stimuli increasing as a function of dysphoric mood state. Females demonstrated greater inability to regulate arousal as mood became more dysphoric. These findings contribute to elucidating biosignatures associated with response to negative stimuli across disorders and suggest the importance of a sex‐dependent lens in determining these biosignatures. Hum Brain Mapp 37:3733–3744, 2016. © 2016 Wiley Periodicals, Inc .     

Prenatal exposure to a pro-inflammatory stimulus causes delays in the development of the innate immune response to LPS in the offspring

Growing evidence suggests that maternal health during the prenatal period is a critical determinant of adult immuno-competence. This study aimed to characterise the innate immune response to bacterial exposure in rat offspring following maternal exposure to a pro-inflammatory stimulus. The offspring's innate immune responses were investigated at four developmental timepoints in the rat by determination of immune cell subtypes and TNF-alpha and IL-1beta response to in-vivo LPS exposure. The pre-weaned offspring of exposed dams demonstrated no immune response to the LPS challenge, whereas control offspring responded with a typical elevation in cytokine levels. In pubescence no differences were observed between the responses of the control and exposed offspring. In adulthood and senescence, offspring of endotoxin treated dams had significantly less monocytes in circulation than control offspring and differential sex effects were only evident in these older animals. The developmental profile of immune functioning following prenatal immune activation has not previously been demonstrated. This study highlights the prenatal period as one of importance in determining later immune function.     

Can oats be taken in a gluten-free diet? A systematic review

OBJECTIVE: There has long been doubt about the need to exclude oats from a gluten-free diet (GFD). The objective of this study was to review the literature in order to arrive at a firm recommendation. MATERIAL AND METHODS: Electronic databases were searched up to February 2006 using the terms "oats" and "coeliac disease". RESULTS: Twenty relevant studies were found and presented. Early studies were small and uncontrolled and mostly indirect. In 10 studies involving 165 patients, only 1 patient was shown to have histological damage as a result of consuming oats. CONCLUSIONS: Coeliac patients can, to some advantage, include oats in a GFD although there may be the occasional patient who is also oats sensitive. Previous conflicting results may have been partly due to contamination of oats by wheat. Lest contamination is present and exceeds the safe threshold, we recommend that coeliac patients should only add oats to their GFD when they are established on a conventional GFD, and stop eating oats if they develop any symptoms.     

Photodynamic molecular beacon as an activatable photosensitizer based on protease-controlled singlet oxygen quenching and activation

Molecular beacons are FRET-based target-activatable probes. They offer control of fluorescence emission in response to specific cancer targets, thus are useful tools for in vivo cancer imaging. Photodynamic therapy (PDT) is a cell-killing process by light activation of a photosensitizer (PS) in the presence of oxygen. The key cytotoxic agent is singlet oxygen ((1)O(2)). By combining these two principles (FRET and PDT), we have introduced a concept of photodynamic molecular beacons (PMB) for controlling the PS's ability to generate (1)O(2) and, ultimately, for controlling its PDT activity. The PMB comprises a disease-specific linker, a PS, and a (1)O(2) quencher, so that the PS's photoactivity is silenced until the linker interacts with a target molecule, such as a tumor-associated protease. Here, we report the full implementation of this concept by synthesizing a matrix metalloproteinase-7 (MMP7)-triggered PMB and achieving not only MMP7-triggered production of (1)O(2) in solution but also MMP7-mediated photodynamic cytotoxicity in cancer cells. Preliminary in vivo studies also reveal the MMP7-activated PDT efficacy of this PMB. This study validates the core principle of the PMB concept that selective PDT-induced cell death can be achieved by exerting precise control of the PS's ability to produce (1)O(2) by responding to specific cancer-associated biomarkers. Thus, PDT selectivity will no longer depend solely on how selectively the PS can be delivered to cancer cells. Rather, it will depend on how selective a biomarker is to cancer cells, and how selective the interaction of PMB is to this biomarker.     

Interleukin-18 as a mediator of systemic juvenile idiopathic arthritis

The objective of this report is to explore the balance between serum and synovial fluid levels of interleukin (IL)-18 in children with juvenile idiopathic arthritis (JIA). Blood samples were obtained from 81 children with JIA and 18 control children. Synovial fluid samples were collected from 16 children with oligoarticular JIA. Concentrations of IL-18 were determined using commercial kit. Patients with systemic JIA had higher serum levels of IL-18 than patients with other forms of JIA or control children, both during the active (median, range: 6,240, 1,600–78,750 pg/ml) and inactive (1,615, 513–3,270 pg/ml) phase of disease [analysis of variance (ANOVA), P < 0.05). Levels of IL-18 in sera of children with oligoarticular JIA (255, 89–4,342 pg/ml) were similar to the respective synovial fluid levels (217, 89–1,245 pg/ml). Serum levels of IL-18 were proportional to the erythrocyte sedimentation rate and levels of C-reactive protein, but inversely proportional to the haemoglobin levels. IL-18 appears to be an important mediator of systemic JIA, while it seems of a lesser relevance in pathogenesis of other JIA forms. Therefore, inhibition of IL-18 might be a base for a successful biological therapy for systemic JIA.