Iodine uptake of adrenal glands: A novel and reliable spectral dual-layer computed tomographic-derived biomarker for acute septic shock.

OBJECTIVES: Septic shock is a potentially fatal condition. This study aims to assess whether iodine uptake and iodine density of abdominal organs on dual-layer spectral detector computed tomography (SDCT) could serve as a new imaging biomarker for patients in septic shock. METHODS: Here, 95 patients who received contrast-enhanced abdominal CT examinations were included and separated into two groups: group A - septic shock; group B - no shock condition. Preselected abdominal (right and left adrenal gland, right and left kidney, infrarenal inferior vena cava (IVC), pancreas, spleen, and liver) localizations were independently evaluated by two radiologists, who measured iodine concentrations (mg/ml) and Hounsfield units (HU). RESULTS: In all, 1520 measurements of iodine concentrations in mg/ml and HU were performed, with 27 patients in group A and 68 in group B. Iodine concentrations in mg/ml and HU correlated significantly in all organs measured. The corresponding correlation coefficient (r) ranged from 0.809 (pancreas) to 0.963 (right kidney). Inter-rater reliability (IRR) was very good for mg/ml (κ = 0.8; p < 0.01) and good for HU (κ = 0.773; p < 0.01) measurements. The mean iodine concentration and HU of the adrenal glands in septic and nonseptic patients was 4.88 ± 1.16 mg/ml/153 ± 36 HU and 2.67 ± 1.07 mg/ml/112 ± 41 HU, respectively. Iodine concentrations in the adrenal glands were significantly higher in group A than in group B patients (p < 0.01). The other organs remained unaffected and no significant difference was observed between patients in group A and B. Patients in group A presented significantly more often with an iodine uptake of >3.5 mg/ml of one adrenal gland (sensitivity = 0.926, specificity = 0.849, AUC = 0.951) or/and a combined concentration of >7 mg/ml of both adrenal glands (sensitivity = 0.889, specificity = 0.836, AUC = 0.928). CONCLUSION: SDCT-derived iodine concentration of the adrenal glands could serve as a novel imaging biomarker for patients in acute septic shock. Our data suggest that an iodine uptake of >3.5 mg/ml of at least one adrenal gland or a combined iodine uptake of >7 mg/ml in both adrenal glands identifies patients in this condition.

Two separate, large cohorts reveal potential modifiers of age-associated variation in visual reaction time performance.

To identify potential factors influencing age-related cognitive decline and disease, we created MindCrowd. MindCrowd is a cross-sectional web-based assessment of simple visual (sv) reaction time (RT) and paired-associate learning (PAL). svRT and PAL results were combined with 22 survey questions. Analysis of svRT revealed education and stroke as potential modifiers of changes in processing speed and memory from younger to older ages (ntotal = 75,666, nwomen = 47,700, nmen = 27,966; ages 18-85 years old, mean (M)Age = 46.54, standard deviation (SD)Age = 18.40). To complement this work, we evaluated complex visual recognition reaction time (cvrRT) in the UK Biobank (ntotal = 158,249 nwomen = 89,333 nmen = 68,916; ages 40-70 years old, MAge = 55.81, SDAge = 7.72). Similarities between the UK Biobank and MindCrowd were assessed using a subset of MindCrowd (UKBb MindCrowd) selected to mirror the UK Biobank demographics (ntotal = 39,795, nwomen = 29,640, nmen = 10,155; ages 40-70 years old, MAge = 56.59, SDAge = 8.16). An identical linear model (LM) was used to assess both cohorts. Analyses revealed similarities between MindCrowd and the UK Biobank across most results. Divergent findings from the UK Biobank included (1) a first-degree family history of Alzheimer's disease (FHAD) was associated with longer cvrRT. (2) Men with the least education were associated with longer cvrRTs comparable to women across all educational attainment levels. Divergent findings from UKBb MindCrowd included more education being associated with shorter svRTs and a history of smoking with longer svRTs from younger to older ages.

Smoking is associated with impaired verbal learning and memory performance in women more than men.

Vascular contributions to cognitive impairment and dementia (VCID) include structural and functional blood vessel injuries linked to poor neurocognitive outcomes. Smoking might indirectly increase the likelihood of cognitive impairment by exacerbating vascular disease risks. Sex disparities in VCID have been reported, however, few studies have assessed the sex-specific relationships between smoking and memory performance and with contradictory results. We investigated the associations between sex, smoking, and cardiovascular disease with verbal learning and memory function. Using MindCrowd, an observational web-based cohort of ~ 70,000 people aged 18-85, we investigated whether sex modifies the relationship between smoking and cardiovascular disease with verbal memory performance. We found significant interactions in that smoking is associated with verbal learning performance more in women and cardiovascular disease more in men across a wide age range. These results suggest that smoking and cardiovascular disease may impact verbal learning and memory throughout adulthood differently for men and women.

[Long-term complications, monitoring and interventional treatment of large vessel vasculitis]. / Langzeitkomplikationen, Monitoring und interventionelle Therapien bei Großgefäßvaskulitiden.

Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) both belong to the group of large vessel vasculitides and require long-term drug treatment. Glucocorticoids (GC) are the first choice for the treatment of both diseases. For GCA immunosuppressants, such as tocilizumab or methotrexate should be considered in cases of treatment refractory and relapses or if there is a high risk for GC-related adverse events. In TAK patients the use of immunosuppressive agents should be considered for all patients. In the course of the disease, severe disease-associated and treatment-associated complications can occur. The most frequent disease-associated complications include visual impairment up to blindness in GCA, as well as vascular stenoses with ischemia and aortic aneurysms with possible dissection in GCA and TAK. Percutaneous transluminal angioplasty (PTA) and stenting are minimally invasive, low-risk interventional procedures for GCA and TAK patients with clinically significant vascular stenoses, despite a tendency to restenosis. Interventional procedures should be weighed up against vascular surgical approaches depending on the localization and the total clinical situation. All interventions should be conducted in a phase of stable remission when possible. For monitoring of disease activity in patients with GCA and TAK, assessment of clinical manifestations as well as C­reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) are useful; however, both are unreliable under interleukin­6 block with tocilizumab. The value of new biomarkers independent from interleukin­6 and the importance of imaging (sonography, magnetic resonance angiography, computed tomography and positron emission tomography-CT) for monitoring GCA and TAK still have to be investigated in future studies.

Non-Contrast-Enhanced Carotid MRA: Clinical Evaluation of a Novel Ungated Radial Quiescent-Interval Slice-Selective MRA at 1.5T.

BACKGROUND AND PURPOSE: Non-contrast-enhanced MRA techniques have experienced a renaissance due to the known correlation between the use of gadolinium-based contrast agents and the development of nephrogenic systemic fibrosis and the deposition of gadolinium in some brain regions. The purpose of this study was to assess the diagnostic performance of ungated non-contrast-enhanced radial quiescent-interval slice-selective MRA of the extracranial supra-aortic arteries in comparison with conventional contrast-enhanced MRA in patients with clinical suspicion of carotid stenosis. MATERIALS AND METHODS: In this prospective study, both MRA pulse sequences were performed in 31 consecutive patients (median age, 68.8 years; 19 men). For the evaluation, the cervical arterial system was divided into 35 segments (right and left side). Three blinded reviewers separately evaluated these segments. An ordinal scoring system was used to assess the image quality of arterial segments and the stenosis grading of carotid arteries. RESULTS: Overall venous contamination in quiescent-interval slice-selective MRA was rated as "none" by all readers in 84.9% of cases and in 8.1% of cases in contrast-enhanced MRA (P < .0001). The visualization quality of arterial segments was considered good to excellent in 40.2% for the quiescent-interval slice-selective MRA and in 52.2% for the contrast-enhanced MRA (P < .0001). The diagnostic accuracy of ungated quiescent-interval slice-selective MRA concerning the stenosis grading showed a total sensitivity and specificity of 85.7% and 90.0%, respectively. CONCLUSIONS: Ungated quiescent-interval slice-selective MRA can be used clinically as an alternative to contrast-enhanced MRA without a significantly different image quality or diagnostic accuracy for the detection of carotid stenosis at 1.5T.

Calcium isotope ratios in blood and urine: A new biomarker for the diagnosis of osteoporosis.

We assessed the potential of Calcium (Ca) isotope fractionation measurements in blood (δ44/42CaBlood) and urine (δ44/42CaUrine) as a new biomarker for the diagnosis of osteoporosis. One hundred post-menopausal women aged 50 to 75 years underwent dual-energy X-ray absorptiometry (DXA), the gold standard for determination of bone mineral density. After exclusion of women with kidney failure and vitamin D deficiency (<25 nmol/l) 80 women remained in the study. Of these women 14 fulfilled the standard diagnostic criteria for osteoporosis based on DXA. Both the δ44/42CaBlood (p < 0.001) and δ44/42CaUrine (p = 0.004) values were significantly different in women with osteoporosis (δ44/42CaBlood: -0.99 ±â€¯0.10‰, δ 44/42CaUrine: +0.10 ±â€¯0.21‰, (Mean ±â€¯one standard deviation (SD), n = 14)) from those without osteoporosis (δ44/42CaBlood: -0.84 ±â€¯0.14‰, δ44/42CaUrine: +0.35 ±â€¯0.33‰, (SD), n = 66). This corresponded to the average Ca concentrations in morning spot urine samples ([Ca]Urine) which were higher (p = 0.041) in those women suffering from osteoporosis ([Ca]Urine-Osteoporosis: 2.58 ±â€¯1.26 mmol/l, (SD), n = 14) than in the control group ([Ca]Urine-Control: 1.96 ±â€¯1.39 mmol/l, (SD), n = 66). However, blood Ca concentrations ([Ca]Blood) were statistically indistinguishable between groups ([Ca]Blood, control: 2.39 ±â€¯0.10 mmol/l (SD), n = 66); osteoporosis group: 2.43 ±â€¯0.10 mmol/l (SD, n = 14) and were also not correlated to their corresponding Ca isotope compositions. The δ44/42CaBlood and δ44/42CaUrine values correlated significantly (p = 0.004 to p = 0.031) with their corresponding DXA data indicating that both Ca isotope ratios are biomarkers for osteoporosis. Furthermore, Ca isotope ratios were significantly correlated to other clinical parameters ([Ca]Urine, ([Ca]Urine/Creatinine)) and biomarkers (CRP, CTX/P1NP) associated with bone mineralization and demineralization. From regression analysis it can be shown that the δ44/42CaBlood values are the best biomarker for osteoporosis and that no other clinical parameters need to be taken into account in order to improve diagnosis. Cut-off values for discrimination of subjects suffering from osteoporosis were - 0.85‰ and 0.16‰ for δ44/42CaBlood and δ44/42CaUrine, respectively. Corresponding sensitivities were 100% for δ44/42CaBlood and ~79% for δ44/42CaUrine. Apparent specificities were ~55% for δ44/42CaBlood and ~71%. The apparent discrepancy in the number of diagnosed cases is reconciled by the different methodological approaches to diagnose osteoporosis. DXA reflects the bone mass density (BMD) of selected bones only (femur and spine) whereas the Ca isotope biomarker reflects bone Ca loss of the whole skeleton. In addition, the close correlation between Ca isotopes and biomarkers of bone demineralization suggest that early changes in bone demineralization are detected by Ca isotope values, long before radiological changes in BMD can manifest on DXA. Further studies are required to independently confirm that Ca isotope measurement provide a sensitive, non-invasive and radiation-free method for the diagnosis of osteoporosis.

A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus.

Mutations in CASK cause X-linked intellectual disability, microcephaly with pontine and cerebellar hypoplasia, optic atrophy, nystagmus, feeding difficulties, GI hypomotility, and seizures. Here we present a patient with a de novo carboxyl-terminus splice site mutation in CASK (c.2521-2A>G) and clinical features of the rare FG syndrome-4 (FGS4). We provide further characterization of genotype-phenotype correlations in CASK mutations and the presentation of nystagmus and the FGS4 phenotype. There is considerable variability in clinical phenotype among patients with a CASK mutation, even among variants predicted to have similar functionality. Our patient presented with developmental delay, nystagmus, and severe gastrointestinal and gastroesophageal complications. From a cognitive and neuropsychological perspective, language skills and IQ are within normal range, although visual-motor, motor development, behavior, and working memory were impaired. The c.2521-2A>G splice mutation leads to skipping of exon 26 and a 9 base-pair deletion associated with a cryptic splice site, leading to a 28-AA and a 3-AA in-frame deletion, respectively (p.Ala841_Lys843del and p.Ala841_Glu868del). The predominant mutant transcripts contain an aberrant guanylate kinase domain and thus are predicted to degrade CASK's ability to interact with important neuronal and ocular development proteins, including FRMD7. Upregulation of CASK as well as dysregulation among a number of interactors is also evident by RNA-seq. This is the second CASK mutation known to us as cause of FGS4. © 2017 Wiley Periodicals, Inc.

Engineering of Tomato Glandular Trichomes for the Production of Specialized Metabolites.

Glandular trichomes are specialized tissues on the epidermis of many plant species. On tomato they synthesize, store, and emit a variety of metabolites such as terpenoids, which play a role in the interaction with insects. Glandular trichomes are excellent tissues for studying the biosynthesis of specialized plant metabolites and are especially suitable targets for metabolic engineering. Here we describe the strategy for engineering tomato glandular trichomes, first with a transient expression system to provide proof of trichome specificity of selected promoters. Using microparticle bombardment, the trichome specificity of a terpene-synthase promoter could be validated in a relatively fast way. Second, we describe a method for stable expression of genes of interest in trichomes. Trichome-specific expression of another terpene-synthase promoter driving the yellow-fluorescence protein-gene is presented. Finally, we describe a case of the overexpression of farnesyl diphosphate synthase (FPS), specifically in tomato glandular trichomes, providing an important precursor in the biosynthetic pathway of sesquiterpenoids. FPS was targeted to the plastid aiming to engineer sesquiterpenoid production, but interestingly leading to a loss of monoterpenoid production in the transgenic tomato trichomes. With this example we show that trichomes are amenable to engineering though, even with knowledge of a biochemical pathway, the result of such engineering can be unexpected.

Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease.

We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0 ± 5.2 years compared with 41.1 ± 7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy.

Early pregnancy maternal and fetal angiogenic factors and fetal and childhood growth: the Generation R Study.

STUDY QUESTION: What are the effects of maternal and fetal soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) concentrations on fetal and childhood growth patterns? SUMMARY ANSWER: An angiogenic profile that is characterized by both low early pregnancy maternal sFlt-1 and PlGF concentrations and higher sFlt-1 concentrations, lower PlGF concentrations or a higher sFlt-1:PlGF ratio in umbilical cord blood is associated with a reduced fetal and childhood growth. WHAT IS KNOWN ALREADY: An imbalance in maternal and fetal sFlt-1 and PlGF concentrations has been suggested to affect pregnancy outcomes. However, their effects on longitudinal fetal and childhood growth remain largely unknown. STUDY DESIGN, SIZE, DURATION: This study was performed in 5980 mothers and 4108 of their children, participating in the Generation R Study; a population-based prospective cohort study from fetal life onwards in Rotterdam, the Netherlands (2001-2005). PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood samples were obtained from mothers in early and mid-pregnancy and from the umbilical vein at delivery. Fetal and childhood growth characteristics (weight and length) were measured repeatedly by ultrasound and physical examinations until the age of 6 years. We assessed the associations of maternal and fetal angiogenic factors with fetal and childhood growth using repeated measurement regression models. Logistic regression models were used to determine associations between angiogenic factors and small for gestational age at birth (SGA). MAIN RESULTS AND THE ROLE OF CHANCE: Compared with early pregnancy maternal sFlt-1 concentrations in the lowest quintile, early pregnancy maternal sFlt-1 concentrations in the highest quintile were associated with a higher fetal weight growth resulting in a higher birthweight (difference in birthweight 0.33 standard deviation score (SDS); 95% Confidence Interval (CI) 0.25-0.41), a lower risk of SGA (Odds Ratio (OR) 0.36; 95% CI 0.27-0.48) and a subsequent higher weight growth until the age of 6 years. Early pregnancy maternal PlGF concentrations in the lowest quintile were associated with a reduced weight growth pattern resulting in a smaller birthweight (difference in birthweight -0.34 SDS; 95% CI -0.44, -0.25), an increased risk of SGA (OR 3.48; 95% CI 2.39-5.08) and a lower weight growth throughout childhood. An early pregnancy maternal sFlt-1:PlGF ratio in the highest quintile was associated with a higher fetal weight growth pattern from 30 weeks onwards, resulting in a higher weight at birth (difference in birthweight 0.09 SDS; P-value <0.05), which remained present until the age of 2 years. Newborns with higher umbilical cord sFlt-1 concentrations, lower PlGF concentrations or a higher sFlt-1:PlGF ratio showed a lower fetal and childhood weight growth from 30 weeks gestation onwards until the age of 6 years (P-value <0.05). Similar patterns were observed in relation to fetal and childhood length growth. LIMITATIONS, REASONS FOR CAUTION: The study is an observational study. Therefore, no causal relationships can be established. WIDER IMPLICATIONS OF THE FINDINGS: Both a maternal and fetal angiogenic imbalance may affect fetal and childhood growth. Changes in angiogenic profiles may be involved in the pathways linking fetal growth restriction with the long-term risk of vascular disease in adulthood. STUDY FUNDING/COMPETING INTERESTS: The first phase of the Generation R Study is made possible by financial support from The Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam, and the Netherlands Organization for Health Research and Development (ZonMw 21000074). V.W.V.J. received additional grants from the Netherlands Organization for Health Research and Development (ZonMw VIDI). M.I.B.-B. is financially supported by the Bo Hjelt foundation (grant 2009). The authors have no competing interests.

Late enhanced computed tomography in Hypertrophic Cardiomyopathy enables accurate left-ventricular volumetry.

OBJECTIVES: Late enhancement (LE) multi-slice computed tomography (leMDCT) was introduced for the visualization of (intra-) myocardial fibrosis in Hypertrophic Cardiomyopathy (HCM). LE is associated with adverse cardiac events. This analysis focuses on leMDCT derived LV muscle mass (LV-MM) which may be related to LE resulting in LE proportion for potential risk stratification in HCM. METHODS: N=26 HCM-patients underwent leMDCT (64-slice-CT) and cardiovascular magnetic resonance (CMR). In leMDCT iodine contrast (Iopromid, 350 mg/mL; 150mL) was injected 7 minutes before imaging. Reconstructed short cardiac axis views served for planimetry. The study group was divided into three groups of varying LV-contrast. LeMDCT was correlated with CMR. RESULTS: The mean age was 64.2 ± 14 years. The groups of varying contrast differed in weight and body mass index (p < 0.05). In the group with good LV-contrast assessment of LV-MM resulted in 147.4 ± 64.8 g in leMDCT vs. 147.1 ± 65.9 in CMR (p > 0.05). In the group with sufficient contrast LV-MM appeared with 172 ± 30.8 g in leMDCT vs. 165.9 ± 37.8 in CMR (p > 0.05). Overall intra-/inter-observer variability of semiautomatic assessment of LV-MM showed an accuracy of 0.9 ± 8.6 g and 0.8 ± 9.2 g in leMDCT. All leMDCT-measures correlated well with CMR (r > 0.9). CONCLUSIONS: LeMDCT primarily performed for LE-visualization in HCM allows for accurate LV-volumetry including LV-MM in > 90% of the cases. KEY POINTS: • LeMDCT of relatively low contrast allows for LV planimetry in HCM. • The correlation of leMDCT-based LV volumetry with gold-standard CMR was excellent (r > 0.9). • LeMDCT requires approximately 2.0mL/kgBW of dye to achieve acceptable contrast.

Hypertrophic cardiomyopathy in cardiac CT: a validation study on the detection of intramyocardial fibrosis in consecutive patients.

Hypertrophic Cardiomyopathy (HCM) confers a 4-5 %/year-risk for sudden cardiac death. Intramyocardial fibrosis (IF) is associated with this risk. The gold standard of IF visualization is cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE-CMR). In view of a number of CMR-limitations the hypothesis of this study was that late enhanced multi-slice computed tomography (leMDCT) enables demonstration of late enhancement (LE) indicating IF. In a prospective single-center validation study leMDCT research-scans were exclusively performed for IF-imaging in HCM-patients not including non-invasive coronary angiography during first-pass (64-slice; 80 kV; Iopromide, 150 mL, injected 7 min before scanning). Applying a 17-segment-polar-map short cardiac axis views (multiplanar reformations; 5 mm slice thickness) were analysed in order to exclude/detect, localize and measure LE practicing the manual quantification method if present. Finally, leMDCT and LGE-CMR data were unblinded for intermodal correlation. We included n = 24 patients consecutively (64.0 ± 14.5 years of age). LE was demonstrated by LGE-CMR in n = 14/24 patients (prevalence 58 %). Patient- and segment-based sensitivity in leMDCT was 100 and 68 %, respectively. In leMDCT tissue density of LE was 142 ± 51 versus 89.9 ± 19.3 HU in remote myocardium (p < 0.001). Signal-to-noise-ratio (SNR) and contrast-to-noise-ratio (CNR) appeared to be 7.3 ± 3.3 and 2.3 ± 1, respectively. Sizing of LE-area gave 2.2 ± 1.4 cm(2) in leMDCT versus 2.9 ± 2.4 cm(2) in LGE-CMR (r = 0.93). Intra-/interobserver variability was assessed with an accuracy of 0.36 cm(2) (r = 0.91) and 0.47 cm(2) (r = 0.82), respectively. In consecutive HCM patients leMDCT can reliably detect intramyocardial fibrosis marked by LE. In view of a comparatively low SNR and CNR leMDCT may alternatively be applied in case of CMR contraindications.

[Chronic periaortitis]. / Chronische Periaortitis.

Chronic periaortitis is an inflammatory and fibrosing disease presenting as periaortal fibrosis and formation of aortic aneurysms which are mostly localized in the retroperitoneum and occasionally in the mediastinum. Inflammatory vasculitic involvement of large vessels is also possible. In addition to symptoms of systemic inflammation, mechanical complications also occur whereby obstruction of the ureter is the most frequent. The diagnosis is made by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) and if the findings are atypical the diagnosis should be confirmed by biopsy. After exclusion of a secondary genesis, in which case therapy of the underlying illness would be necessary, idiopathic chronic periaortitis can be treated with steroids. In cases of refractory and relapsing courses the administration of further immunosuppressive medication can be necessary. Duration of therapy, dosage and indications for immunosuppressive medication are currently unclear and have to be defined in further randomized controlled trials with larger cohorts. If complications occur, interventional or operative treatment can be necessary; in cases of hydronephrosis the placement of double-J-stents is usually sufficient.

Different functions of hyperpolarization-activated cation channels for hippocampal sharp waves and ripples in vitro.

Hyperpolarization-activated currents (I(h)) affect multiple neuronal functions including membrane potential, intrinsic firing properties, synaptic integration and frequency-dependent resonance behavior. Consistently, I(h) plays a key role for oscillations at the cellular and network level, including theta and gamma oscillations in rodent hippocampal circuits. Little is known, however, about the contribution of I(h) to a prominent memory-related pattern of network activity called sharp-wave-ripple complexes (SPW-R). Here we report that pharmacological suppression of I(h) induces specific changes in SPW-R in mouse hippocampal slices depending on the specific drug used and the region analyzed. Spontaneous generation of the events was reduced by blocking I(h) whereas the amplitude was unaffected or increased. Interestingly, the superimposed ripple oscillations at ∼200 Hz persisted with unchanged frequency, indicating that I(h) is not critical for generating this rhythmic pattern. Likewise, coupling between field oscillations and units was unchanged, showing unaltered recruitment of neurons into oscillating assemblies. Control experiments exclude a contribution of T-type calcium channels to the observed effects. Together, we report a specific contribution of hyperpolarization-activated cation currents to the generation of sharp waves in the hippocampus.

A periconceptional energy-rich dietary pattern is associated with early fetal growth: the Generation R study.

OBJECTIVE: To identify periconceptional maternal dietary patterns associated with crown-rump length (CRL), estimated fetal weight (EFW) and birthweight. DESIGN: Population-based prospective birth cohort study. SETTING: Rotterdam, the Netherlands. PARTICIPANTS: For this study, 847 pregnant Dutch women were eligible. Women were included between 2001 and 2005. METHODS: Information on nutritional intake was collected by a semiquantitative food frequency questionnaire. For extracting dietary patterns, principal component factor analysis was used. Fetal growth was assessed using ultrasound measurements. Information on birth outcomes was retrieved from medical records. Multivariate regression analyses were used. MAIN OUTCOME MEASURES: Crown-to-rump length, estimated fetal weight in second and third trimester and birthweight. RESULTS: An 'energy-rich dietary pattern' was identified, characterised by high intakes of bread, margarine and nuts. A significant association was shown between a high adherence to this dietary pattern (difference, mm: 2.15, 95% confidence interval 0.79-3.50) and CRL (linear trend analyses P = 0.015). No association was revealed between increasing adherence to this dietary pattern and EFW in second or third trimester, or birthweight. CONCLUSION: This study suggests that increasing adherence to an energy-rich dietary pattern is associated with increased CRL in the first trimester.

[Pulmonary emergencies in connective tissues disorders and vasculitides]. / Pneumologische Notfälle bei Kollagenosen und Vaskulitiden.

Pulmonary emergencies in rheumatic diseases are rare, potentially life-threatening conditions that occur either as a manifestation of the disease itself or as an adverse event of immunosuppressive treatment. Diffuse alveolar hemorrhage, tracheal stenosis, acute pneumonitis and drug-induced lung injury belong to this category. The management of these emergencies requires intensive cooperation between rheumatology and pulmonology. The latter contributes its experience in the care of related conditions, specific endoscopic techniques and local interventions as well as the indispensable and life-supporting forms of assisted ventilation. The present article summarizes the current knowledge on diagnostic and therapeutic procedures including the newly available B-cell directed treatments.

MRI of the lung (3/3)-current applications and future perspectives.

BACKGROUND: MRI of the lung is recommended in a number of clinical indications. Having a non-radiation alternative is particularly attractive in children and young subjects, or pregnant women. METHODS: Provided there is sufficient expertise, magnetic resonance imaging (MRI) may be considered as the preferential modality in specific clinical conditions such as cystic fibrosis and acute pulmonary embolism, since additional functional information on respiratory mechanics and regional lung perfusion is provided. In other cases, such as tumours and pneumonia in children, lung MRI may be considered an alternative or adjunct to other modalities with at least similar diagnostic value. RESULTS: In interstitial lung disease, the clinical utility of MRI remains to be proven, but it could provide additional information that will be beneficial in research, or at some stage in clinical practice. Customised protocols for chest imaging combine fast breath-hold acquisitions from a "buffet" of sequences. Having introduced details of imaging protocols in previous articles, the aim of this manuscript is to discuss the advantages and limitations of lung MRI in current clinical practice. CONCLUSION: New developments and future perspectives such as motion-compensated imaging with self-navigated sequences or fast Fourier decomposition MRI for non-contrast enhanced ventilation- and perfusion-weighted imaging of the lung are discussed. Main Messages • MRI evolves as a third lung imaging modality, combining morphological and functional information. • It may be considered first choice in cystic fibrosis and pulmonary embolism of young and pregnant patients. • In other cases (tumours, pneumonia in children), it is an alternative or adjunct to X-ray and CT. • In interstitial lung disease, it serves for research, but the clinical value remains to be proven. • New users are advised to make themselves familiar with the particular advantages and limitations.

Correlation of serum level of high mobility group box 1 with the burden of granulomatous inflammation in granulomatosis with polyangiitis (Wegener's).

OBJECTIVES: To investigate the correlation of serum levels of high mobility group box 1 (HMGB1) with the extent of granulomatous inflammation in granulomatosis with polyangiitis (GPA). METHODS: From 169 patients with GPA, 17 patients with granulomatous inflammation, without evidence of vasculitis were identified and 36 patients without measurable 'granuloma' formation. HMGB1 serum levels were determined and compared between the two groups, using a Mann-Whitney U test. Serum levels of 26 healthy individuals served as controls. In a further 21 patients with GPA with a pulmonary granulomatous manifestation from the study population, CT volumetry of 'granuloma' was performed. Volumes were compared with serum levels of HMGB1 (Spearman rank order test). RESULTS: Serum levels of HMGB1 were significantly higher in patients with predominant granulomatous disease than in patients without measurable 'granuloma' manifestations (6.44 ± 4.53 ng/ml vs 3.85 ± 2.88 ng/ml; p=0.0107). In both groups, levels of HMGB1 were significantly higher than in controls (2.34 ± 2.01 ng/ml; p<0.01). A positive correlation of HMGB1 serum levels with volumes of pulmonary 'granuloma' (r=0.761, p<0.0017) was seen. CONCLUSIONS: HMGB1 serum levels are significantly higher in GPA with predominant granulomatous manifestations and correlate with volumes of pulmonary 'granuloma'. HMGB1 may be used as a marker of the burden of granulomatous inflammation in GPA.