Clinical and genetic studies on the causes and prognosis of intracranial haemorrhage

Introduction: Intracranial haemorrhage occurs within the compartments of the intracranial vault (skull). Spontaneous (non-traumatic) intracerebral haemorrhage (ICH) and aneurysmal subarachnoid haemorrhage (aSAH) have a high mortality and morbidity rate, while convexity subarachnoid haemorrhage (cSAH) in older people is associated with a high risk of future intracranial bleeding. In this thesis I present several studies investigating factors associated with the development and prognosis of ICH, aSAH cSAH. Methods: I evaluated patients recruited to the Genetics and Observational Subarachnoid Haemorrhage (GOSH) study with aSAH or unruptured intracranial aneurysm as well as patients with ICH recruited to the Clinical Relevance Of Cerebral Microbleeds In Stroke (CROMIS-2) study, both multicentre observational studies recruiting patients from the UK. Individual patient data was also collected for meta-analysis of published studies. Main findings: 1) We found a different risk factor profile in patients with aSAH compared to patients with unruptured intracranial aneurysms and continued our research by validating a prediction model for the prediction of long-term functional outcome after aSAH; 2) in our cohort of patients with convexity SAH we found that it is associated with a higher rate of symptomatic ICH in patients with probable cerebral amyloid angiopathy (CAA); 3) our genetic association analysis showed that Haptoglobin might be associated with mortality after ICH. Additionally, Apolipoprotein E is associated with novel neuroimaging markers of CAA. In our genome-wide association analysis we found new loci (rs4675692) associated with ICH status in a genome-wide association study (but did not find a repeat expansion for C9orf72) and finally found previously reported and novel genetic variants in familial aSAH. Conclusion: These findings, in diverse cohorts, confirm the importance of clinical, radiological and genetic factors for disease expression and prognosis in different forms of intracranial haemorrhage

The d(10) route to dye-sensitized solar cells: step-wise assembly of zinc(II) photosensitizers on TiO2 surfaces

Dye-sensitized solar cells have been assembled using a sequential approach: a TiO2 surface was functionalized with an anchoring ligand, followed by metallation with Zn(OAc)(2) or ZnCl2, and subsequent capping with a chromophore functionalized 2,2`:6`,2 ``-terpyridine; the DSCs exhibit surprisingly good efficiencies confirming the effectiveness of the new strategy for zinc-based DSC fabrication

Analysis of a jet stream induced gravity wave associated with an observed ice cloud over Greenland

International audienceA polar stratospheric ice cloud (PSC type II) was observed by airborne lidar above Greenland on 14 January 2000. It was the unique observation of an ice cloud over Greenland during the SOLVE/THESEO 2000 campaign. Mesoscale simulations with the hydrostatic HRM model are presented which, in contrast to global analyses, are capable to produce a vertically propagating gravity wave that induces the low temperatures at the level of the PSC afforded for the ice formation. The simulated minimum temperature is ~8 K below the driving analyses and ~4.5 K below the frost point, exactly coinciding with the location of the observed ice cloud. Despite the high elevations of the Greenland orography the simulated gravity wave is not a mountain wave. Analyses of the horizontal wind divergence, of the background wind profiles, of backward gravity wave ray-tracing trajectories, of HRM experiments with reduced Greenland topography and of several diagnostics near the tropopause level provide evidence that the wave is emitted from an intense, rapidly evolving, anticyclonically curved jet stream. The precise physical process responsible for the wave emission could not be identified definitely, but geostrophic adjustment and shear instability are likely candidates. In order to evaluate the potential frequency of such non-orographic polar stratospheric cloud events, the non-linear balance equation diagnostic is performed for the winter 1999/2000. It indicates that ice-PSCs are only occasionally generated by gravity waves emanating from spontaneous adjustment

Analysis of a jet stream induced gravity wave associated with an observed ice cloud over Greenland

International audienceA polar stratospheric ice cloud (PSC type II) was observed by airborne lidar above Greenland on 14 January 2000. Is was the unique observation of an ice cloud over Greenland during the SOLVE/THESEO 2000 campaign. Mesoscale simulations with the hydrostatic HRM model are presented which, in contrast to global analyses, are capable to produce a vertically propagating gravity wave that induces the low temperatures at the level of the PSC afforded for the ice formation. The simulated minimum temperature is ~8 K below the driving analyses and ~3 K below the frost point, exactly coinciding with the location of the observed ice cloud. Despite the high elevations of the Greenland orography the simulated gravity wave is not a mountain wave. Analyses of the horizontal wind divergence, of the background wind profiles, of backward gravity wave ray-tracing trajectories, of HRM experiments with reduced Greenland topography and of several instability diagnostics near the tropopause level provide consistent evidence that the wave is emitted by the geostrophic adjustment of a jet instability associated with an intense, rapidly evolving, anticyclonically curved jet stream. In order to evaluate the potential frequency of such non-orographic polar stratospheric cloud events, an approximate jet instability diagnostic is performed for the winter 1999/2000. It indicates that ice-PSCs are only occasionally generated by gravity waves emanating from an unstable jet

Validation and Optimization of Barrow Neurological Institute Score in Prediction of Adverse Events and Functional Outcome After Subarachnoid Hemorrhage-Creation of the HATCH (Hemorrhage, Age, Treatment, Clinical State, Hydrocephalus) Score.

BACKGROUND: The Barrow Neurological Institute (BNI) score, measuring maximal thickness of aneurysmal subarachnoid hemorrhage (aSAH), has previously shown to predict symptomatic cerebral vasospasms (CVSs), delayed cerebral ischemia (DCI), and functional outcome. OBJECTIVE: To validate the BNI score for prediction of above-mentioned variables and cerebral infarct and evaluate its improvement by integrating further variables which are available within the first 24 h after hemorrhage. METHODS: We included patients from a single center. The BNI score for prediction of CVS, DCI, infarct, and functional outcome was validated in our cohort using measurements of calibration and discrimination (area under the curve [AUC]). We improved it by adding additional variables, creating a novel risk score (measure by the dichotomized Glasgow Outcome Scale) and validated it in a small independent cohort. RESULTS: Of 646 patients, 41.5% developed symptomatic CVS, 22.9% DCI, 23.5% cerebral infarct, and 29% had an unfavorable outcome. The BNI score was associated with all outcome measurements. We improved functional outcome prediction accuracy by including age, BNI score, World Federation of Neurologic Surgeons, rebleeding, clipping, and hydrocephalus (AUC 0.84, 95% CI 0.8-0.87). Based on this model we created a risk score (HATCH-Hemorrhage, Age, Treatment, Clinical State, Hydrocephalus), ranging 0 to 13 points. We validated it in a small independent cohort. The validated score demonstrated very good discriminative ability (AUC 0.84 [95% CI 0.72-0.96]). CONCLUSION: We developed the HATCH score, which is a moderate predictor of DCI, but excellent predictor of functional outcome at 1 yr after aSAH

Diurnal and dietary-induced changes in cholesterol synthesis correlate with levels of mRNA for HMG-CoA reductase

We determined the extent to which diurnal variation in cholesterol synthesis in liver is controlled by steady-state mRNA levels for the rate-limiting enzyme in the pathway, hydroxymethylglutaryl (HMG)-CoA reductase. Rats 30 days of age and maintained on a low-cholesterol diet since weaning were injected intraperitoneally wit

Sarcoidosis - a multisystem disease.

Sarcoidosis is a systemic inflammatory disease, characterised by granuloma formation upon an unknown trigger in genetically predisposed individuals. The inflammation is characterised by an activation of both the innate immune system, with macrophages differentiating into epitheloid cells and dendritic cells, and the adaptive immune system, particularly T helper (Th) 1 and Th17 cells. Since all organs can be affected to varying extents, clinical presentation is often diverse. Most commonly, the lungs, lymph nodes, skin and eyes are involved, whereas cardiac, renal and neurological manifestations are less common but associated with higher morbidity. Depending on the clinical symptoms, a detailed evaluation including thorough clinical examination, imaging and laboratory tests should explore all possible organ involvements. In some patients, fatigue manifests as a para-sarcoidosis symptom impacting quality of life, even if sarcoidosis is in remission. Some acute syndromic presentations, such as Löfgren's syndrome, have a good prognosis and are commonly self-limiting. If possible, a topical treatment, for example for cutaneous sarcoidosis or bronchial involvement, should be applied. Treatment of severe cases with persisting disease activity necessitates long-term immunosuppressive drugs, with glucocorticoids as the first-line option. Steroid-sparing and second-line drugs include methotrexate, azathioprine, mycophenolate mofetil and immunomodulators such hydroxychloroquine, with the latter being first-line therapy in cutaneous sarcoidosis. Tumour necrosis factor-alpha inhibitors (particularly adalimumab and infliximab) are used as third-line agents but are administered earlier in cases of persistent disease activity, severe organ-involvement or intolerance to conventional drugs. Treatment decisions should be based on a multidisciplinary approach, depending on organ involvement and treatment tolerability. Para-sarcoidosis manifestations, particularly fatigue, should also be carefully addressed, where the patient could also be enrolled in multidimensional rehabilitation programmes. With various organ involvement and different phenotypes, larger studies including real-world data from registries are necessary to evaluate different sarcoidosis endotypes and preferential treatment pathways

Identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia.

Gestational disorders such as intrauterine growth restriction (IUGR) and pre-eclampsia (PE) are main causes of poor perinatal outcomes worldwide. Both diseases are related with impaired materno-fetal nutrient transfer, but the crucial transport mechanisms underlying IUGR and PE are not fully elucidated. In this study, we aimed to identify membrane transporters highly associated with transplacental nutrient deficiencies in IUGR/PE. In silico analyses on the identification of differentially expressed nutrient transporters were conducted using seven eligible microarray datasets (from Gene Expression Omnibus), encompassing control and IUGR/PE placental samples. Thereby 46 out of 434 genes were identified as potentially interesting targets. They are involved in the fetal provision with amino acids, carbohydrates, lipids, vitamins and microelements. Targets of interest were clustered into a substrate-specific interaction network by using Search Tool for the Retrieval of Interacting Genes. The subsequent wet-lab validation was performed using quantitative RT-PCR on placentas from clinically well-characterized IUGR/PE patients (IUGR, n = 8; PE, n = 5; PE+IUGR, n = 10) and controls (term, n = 13; preterm, n = 7), followed by 2D-hierarchical heatmap generation. Statistical evaluation using Kruskal-Wallis tests was then applied to detect significantly different expression patterns, while scatter plot analysis indicated which transporters were predominantly influenced by IUGR or PE, or equally affected by both diseases. Identified by both methods, three overlapping targets, SLC7A7, SLC38A5 (amino acid transporters), and ABCA1 (cholesterol transporter), were further investigated at the protein level by western blotting. Protein analyses in total placental tissue lysates and membrane fractions isolated from disease and control placentas indicated an altered functional activity of those three nutrient transporters in IUGR/PE. Combining bioinformatic analysis, molecular biological experiments and mathematical diagramming, this study has demonstrated systematic alterations of nutrient transporter expressions in IUGR/PE. Among 46 initially targeted transporters, three significantly regulated genes were further investigated based on the severity and the disease specificity for IUGR and PE. Confirmed by mRNA and protein expression, the amino acid transporters SLC7A7 and SLC38A5 showed marked differences between controls and IUGR/PE and were regulated by both diseases. In contrast, ABCA1 may play an exclusive role in the development of PE