Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10-8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

[Availability of mechanical thrombectomy for acute stroke : Analysis of the health care reality in Germany]. / Verfügbarkeit der mechanischen Thrombektomie bei akutem Hirninfarkt : Analyse der Versorgungsrealität in Deutschland.

BACKGROUND: Mechanical thrombectomy (MT) has become an evidence-based therapy for stroke patients with proximal vessel occlusion of the anterior cerebral circulation. Nationwide availability of MT for all eligible patients within the shortest possible time window is a major challenge. AIM OF THE STUDY: Nationwide analysis of the rates of systemic thrombolysis (STL) and MT in Germany according to region and hospital-based evaluation. METHODS: The evaluation involved data analysis of the diagnosis-related groups (DRG) statistics and structured quality reports of hospitals for 2010 and 2014. The rates and changes of STL and MT were evaluated in the 413 German districts with reference to the corresponding case number of patients with acute ischemic stroke. RESULTS: Nationwide recanalization treatment rates increased from 2010 to 2014 both for STL (from 8.0% to 11.6%) and MT (from 0.7% to 2.3%). High variations were observed depending on the patient's place of residence (STL = 3.4-36.7%, MT = 0-7.4%). In 2014 a total of 5526 MT were coded in a total of 244,757 ischemic strokes. A total of 134 hospitals with more than 2 MT per year were identified; however, 21% of the nationwide MTs were performed in only 7 hospitals with more than 100 MT/year. In 308 (75%) of the 413 districts, not a single MT was performed. CONCLUSION: Due to a narrow net of certified stroke units with nationwide availability of STL, excellent structural conditions for treatment of acute stroke patients are already established in Germany. With regard to the nationwide availability of MT, there is still a need for optimization. Despite the increasing number of hospitals providing MT as an emergency procedure, a trend toward large intervention centers with supraregional catchment areas can be observed.

Metal exposure in the physically and mentally challenged children of Punjab, India.

UNLABELLED: We collected 149 hair samples at the Baba Farid Centre at Faridkot in Punjab, India to evaluate the trace and toxic metal concentration via ICP-MS. A total of 53 elements were tested. The hair of the children tested showed high values for Ba, Cd, Mn, Pb and U, signifying long-term exposure. Urine baseline testing supported hair analysis findings for all the elements listed above; a DMSA (Dimercapto Succinic Acid) challenge test raised urinary values for lead. Testing of six randomly selected water samples showed concentrations above the European maximum contaminant level for uranium (U) in three samples and lead (Pb) in one.Research aim:To evaluate if hair analysis and/or urine provocation confirm or refute long term metal intoxication. To support or refute that hair mineral analysis confirms urine challenge test results. To support or refute that a DMSA urine challenge test provides a valuable treatment option for metal exposure in children. CONCLUSION: Our results documented that hair and urine mineral analysis results are supportive of each other, and are both useful diagnostic tools in chelation therapy. We also documented that a DMSA challenge test confirms long term exposure as detected through hair mineral analysis. This indicates that the chelating agent DMSA (Dimercapto succinic acid) provides a safe and valuable treatment option for lead overexposure.

Towards clinical trials of lie detection with fMRI.

Recent reports of successful fMRI-based discrimination between lie and truth in single subjects raised the interest of prospective users and a public concern about the potential scope of this technology. The increased scrutiny highlighted the lack of controlled "real life", i.e. prospective clinical trials of this technology that conform to the common standards of medical device development. The ethics of conducting such trials given the paucity of data on fMRI-based lie detection has also been questioned. To probe the potential issues of translating the laboratory research into practice, we conducted a case study in which we adapted the standard Guilty Knowledge Test (GKT), a well-established model of producing deception, to the common scenario of lying on a resume. The task consisted of questions about pertinent items on the subject's resume, three of which could be independently verified as truth (KNOWN) and three that could not be verified and were thus termed UNKNOWN. The subject had an incentive to lie on all UNKNOWN items, and on debriefing confirmed that he had done so. Data was preprocessed, masked with a priori regions of interest, thresholded, and qualitatively evaluated for consistency with the previously reported prefronto-parietal Lie > Truth pattern. Deceptive responses to two out of the three UNKNOWN items were associated with the predicted prefronto-parietal fMRI pattern. In the third UNKNOWN this pattern was absent, and instead, increased limbic (amygdala and hippocampus) response was observed. Based on published prefronto-parietal Lie response pattern, only the first two items could be categorized as Lie. If confirmed, this demonstration of amygdala and hippocampus activation in a Lie > Truth contrast illustrates the need to integrate the limbic system and its emotional and cognitive correlates into the existing model of deception. Our experiment suggests an approach to a naturalistic scenario and the research questions that need to be answered in order to set the stage for prospective clinical trials of fMRI-based lie detection.

fMRI investigation of the cognitive structure of the Concealed Information Test.

We studied the cognitive basis of the functional magnetic resonance imaging (fMRI) pattern of deception in three participants performing the Concealed Information Test (CIT). In all participants, the prefrontoparietal lie activation was similar to the pattern derived from the meta-analysis (N = 40) of our previously reported fMRI CIT studies and was unchanged when the lie response was replaced with passive viewing of the target items. When lies were replaced with irrelevant responses, only the left inferior gyrus activation was common to all subjects. This study presents a systematic strategy for testing the cognitive basis of deception models, and a qualitative approach to single-subject truth-verification fMRI tests.

[Thrombophilias in patients with ischemic stroke. Indication and calculated costs for evidence-based diagnostics and treatment]. / Thrombophilien bei Patienten mit ischämischem Schlaganfall. Indikation und Kostenermittlung einer evidenzbasierten Diagnostik und Therapie.

Patients with ischemic stroke are sometimes found to have an underlying inherited (deficiency of protein C, protein S, antithrombin III, activated protein C resistance, prothrombin gene mutation, hyperhomocysteinemia) or acquired thrombophilia (lupus anticoagulant and anticardiolipin antibodies, hyperhomocysteinemia). Patient selection for thrombophilia screening is, therefore, a frequent question in managing patients with ischemic stroke. In this review we discuss patient selection and timing for laboratory tests for thrombophilia screening in stroke patients based on a literature review and we calculated overall costs per year in Germany for testing patients older than 18 years with an ischemic stroke of undetermined cause. As there is a lack of studies comparing anticoagulation with antiplatelet therapy in patients with diagnosed thrombophilia, laboratory screening for thrombophilia even in a selected group of patients with cryptogenic ischemic stroke remains of questionable value at present. An exception appears to be testing for lupus anticoagulant and anticardiolipin antibodies in younger patients with suspected antiphospholipid syndrome (two positive test results necessary), because anticoagulation seems to be superior to aspirin in patients with antiphospholipid syndrome.

Ultrasound-guided internal jugular venous cannulation: an introduction for non-radiologists to a technique that is here to stay.

The availability of relatively low-cost, portable ultrasound units has increased interest among non-radiologists in performing image-guided central venous cannulation, especially in high-risk patients. The essential elements of this relatively simple method of increasing the success and safety of internal jugular cannulation are presented.

Changes in apparent diffusion coefficients of metabolites in rat brain after middle cerebral artery occlusion measured by proton magnetic resonance spectroscopy.

Diffusion-weighted proton MR spectroscopy and imaging have been applied to a rat brain model of unilateral middle cerebral artery occlusion between 1 and 4 hr post occlusion. Similar apparent diffusion coefficients (ADC) of most metabolites were observed within each hemisphere. In the ischemic ipsilateral hemisphere, the ADCs were (0.083--0.116). 10(-3) mm(2)/sec for lactate (Lac), alanine (Ala), gamma-amino butyric acid (GABA), N-acetyl aspartate (NAA), glutamine (Gln), glutamate (Glu), total creatine (tCr), choline-containing compounds (Cho), and myo-inositol (Ins), in the contralateral hemisphere (0.138--0.158). 10(-3) mm(2)/sec for NAA, Glu, tCr, Cho, and Ins. Higher ADCs was determined for taurine (Tau) in the ipsilateral (0.144. 10(-3) mm(2)/sec) and contralateral (0.198. 10(-3) mm(2)/sec) hemisphere. In the ischemic hemisphere, a relative ADC decrease to 65--75% was observed for NAA, Glu, tCr, Cho, Ins and Tau, which was similar to the decrease of the water ADC (to 67%). The results suggest a common cause of the observed ADC changes and provide a broader experimental basis to evaluate theories of water and metabolite diffusion. Magn Reson Med 45:383-389, 2001.

Breast cancer risk in relation to adipose concentrations of organochlorine pesticides and polychlorinated biphenyls in Long Island, New York.

To assess a possible etiological role of organochlorine compounds in breast cancer development on Long Island, a high-risk region of New York State, concentrations of organochlorine pesticides and polychlorinated biphenyls (PCBs) were measured in the adipose tissue of 232 women with breast cancer and 323 hospital controls admitted to surgery for benign breast disease or non-breast-related conditions. Seven pesticide residues and 14 PCB congeners were assayed via a supercritical fluid extraction method followed by gas chromatography with electron capture detection. After adjustment for age and body mass index, which were strongly correlated with organochlorine levels, adipose concentrations of 1,1-dichloro-2,2-di(4-chlorophenyl)ethylene, total pesticides, and total polychlorinated biphenyls (PCBs) did not differ significantly between cases and controls. The relative abundance of individual pesticide species and PCB congeners was similar in cases and controls. Odds ratios adjusted for age, BMI, hospital, and race gave no evidence of a dose-response for 1,1-dichloro-2,2-di(4-chlorophenyl)ethylene, total pesticides, or total PCBs, whether stratified by estrogen receptor status or not. Breast cancer risk among Long Island residents was not elevated compared with residents of the adjacent New York City borough of Queens. We did not confirm a previously reported association between breast cancer risk and levels of PCB congener 118 (2,3',4,4',5-pentachlorobiphenyl), nor did we observe an association with the most abundant congener 153 (2,2',4,4',5,5'-hexachlorobiphenyl), a strong inducer of phase I enzymes that was reported recently to have estrogenic properties. Only PCB congener 183 (2,2',3,4,4',5',6-heptachlorobiphenyl), which is also an inducer, was significantly associated with risk, with an adjusted odds ratio of 2.0 (95% confidence interval, 1.2-3.4) in women with adipose levels >5.67 ng/g; the biological importance of this observation is unclear without confirmation in additional studies. Although neither the present nor other studies have provided convincing evidence of an association between body burden of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane and PCBs with cancer of the breast, these compounds are rated as "possible" and "probable" human carcinogens, respectively, by the International Agency for Research on Cancer. Investigations of associations with cancer at other sites should be carried out.

Spreading waves of transient and prolonged decreases in water diffusion after subarachnoid hemorrhage in rats.

Diffusion-weighted MRI (DWI), which can detect cortical spreading depressions (SDs) as propagating waves of reduced apparent diffusion coefficient (ADC) of water, was used to investigate whether spreading depression occurs after subarachnoid hemorrhage (SAH) induced by endovascular perforation in the rat. Eleven rats underwent SAH while positioned in the magnet. The ADC measurements had a temporal resolution of 12 sec. Transient decreases in ADC to 74 +/- 5% of pre-SAH values were observed in three rats after SAH, which propagated over the cortex with an average speed of 4.2 +/- 0. 6 mm/min, consistent with an SD wave. Furthermore, in all 11 rats, a wavefront of reduced ADC, which did not resolve within the 12 min observation period, spread at a speed of 3.2 +/- 1.7 mm/min in the ipsilateral cortex, and again is consistent with the speed of SD propagation. Therefore, spreading depression-like cellular depolarization is a consequence of acute subarachnoid hemorrhage in rats. Magn Reson Med 44:110-116, 2000.

Calcium affinity, cooperativity, and domain interactions of extracellular EF-hands present in BM-40.

The structure and function of cytosolic Ca(2+)-binding proteins containing EF-hands are well understood. Recently, the presence of EF-hands in an extracellular protein was for the first time proven by the structure determination of the EC domain of BM-40 (SPARC (for secreted protein acidic and rich in cysteine)/osteonectin) (Hohenester, E., Maurer, P., Hohenadl, C., Timpl, R., Jansonius, J. N., and Engel, J. (1996) Nat. Struct. Biol. 3, 67-73). The structure revealed a pair of EF-hands with two bound Ca(2+) ions. Two unusual features were noted that distinguish the extracellular EF-hands of BM-40 from their cytosolic counterparts. An insertion of one amino acid into the loop of the first EF-hand causes a variant Ca(2+) coordination, and a disulfide bond connects the helices of the second EF-hand. Here we show that the extracellular EF-hands in the BM-40 EC domain bind Ca(2+) cooperatively and with high affinity. The EC domain is thus in the Ca(2+)-saturated form in the extracellular matrix, and the EF-hands play a structural rather than a regulatory role. Deletion mutants demonstrate a strong interaction between the EC domain and the neighboring FS domain, which contributes about 10 kJ/mol to the free energy of binding and influences cooperativity. This interaction is mainly between the FS domain and the variant EF-hand 1. Certain mutations of Ca(2+)-coordinating residues changed affinity and cooperativity, but others inhibited folding and secretion of the EC domain in a mammalian cell line. This points to a function of EF-hands in extracellular proteins during biosynthesis and processing in the endoplasmic reticulum or Golgi apparatus.

Penumbral tissue alkalosis in focal cerebral ischemia: relationship to energy metabolism, blood flow, and steady potential.

The effect of focal ischemia on tissue pH was studied at various times up to 6 hours after permanent middle cerebral artery occlusion in rats. Tissue pH was imaged by using umbelliferone fluorescence and correlated with cerebral blood flow, ATP content, and recordings of the steady potential. Circumscribed foci of allalosis (pH 7.32+/-0.11) were detected with increasing frequency in penumbral regions having near-to-normal ATP concentrations and cerebral blood flow values between 20% and 40% of control. Both the infarct core, defined by ATP loss and cerebral blood flow values of less than 20% of control, and the inner peri-infarct rim were consistently acidic (pH 6.03+/-0.36 and 6.53+/-0.24, respectively). Treatment with the glutamate antagonist dizocilpine (MK-801) suppressed negative shifts of the steady potential and reduced significantly the occurrence of alkalosis observed in 90% of untreated but only in 44% of treated animals. Penumbral alkalosis appeared to be a time-dependent event occurring 30 to 60 minutes after the passage of peri-infarct depolarizations. The diversity of penumbral pH changes reflects the local disturbance of pH regulation and, possibly, the differential fate of penumbral subareas.

The effects of two stereoisomers of N-acetylcysteine on photochemical damage by UVA and blue light in rat retina.

High doses of light can cause damage to the retina, e.g. during intraocular surgery. Previously, thiols have been demonstrated to protect against retinal damage in various damage models. Such protection is very promising for clinical practice. Retinal light damage can be caused by a relatively short exposure to high irradiance levels. These conditions occur during intraocular surgery. In the current study we therefore investigated whether the thiol N-acetylcysteine protects against retinal light damage under high irradiance conditions in the rat retina. Two stereoisomers of this thiol were tested for protection against two spectrally defined types of retinal light damage. Shortly after administration N-acetyl-L-cysteine in doses of 270-1000 mg/kg intraperitoneally protected against 380 nm (UVA) light but not against 470 nm (blue) light. Two hours after injection the protection had diminished. We observed no protection by the stereoisomer N-acetyl-D-cysteine. From this study we conclude that N-acetyl-L-cysteine protects stereospecifically against retinal damage in the UV but not in the visible part of the spectrum. This limits the possible applications.

Temporal sequence of changes in rat retina after UV-A and blue light exposure.

Two spectral types of retinal light damage were induced in pigmented rats by irradiating small retinal patches at either 380 or 470 nm. The temporal sequence of changes in the retina was followed for up to 2 months by funduscopy and histology. For both damage types, fundus changes were best visible after 3 days. Histology showed that 380 nm specifically damaged photoreceptor cells, particularly the rods. All cell compartments of the rods, including the nucleus were affected already after 3 h. In the next days, damaged rods degenerated. At high doses (2.5 x the funduscopic threshold dose) all rods in the irradiated area were lost, resulting in a local photoreceptor lesion, which was still present at 2 months after the irradiation. At 470 nm, damage occurred both in the photoreceptor layer and in the pigment epithelium. Acute changes, at 1 h after irradiation, consisted mainly of damaged mitochondria in these layers. Next, the pigment epithelium showed swelling, an altered melanin distribution and, at high doses (2.5 x threshold), interruptions of the monolayer. Degeneration of photoreceptor cells was initially limited to a few scattered cells, but 3 days after high doses focal areas of massive degeneration were seen. At late stages, the cells of the pigment epithelium recovered and the photoreceptor layer showed a loss of cells. The results show that the spectral damage types are distinct in the early phases, indicating that different mechanisms are involved. Yet, the end effect of both damage types after exposure at doses up to 2.5 x the funduscopic threshold is remarkably similar and consists of local photoreceptor lesions.

Simultaneous recording of evoked potentials and T2*-weighted MR images during somatosensory stimulation of rat.

Somatosensory evoked potentials (SEP) and T2*-weighted nuclear magnetic resonance (NMR) images were recorded simultaneously during somatosensory stimulation of rat to investigate the relationship between electrical activation of the brain tissue and the signal intensity change in functional NMR imaging. Electrical forepaw stimulation was performed in Wistar rats anesthetized with alpha-chloralose. SEPs were recorded with calomel electrodes at stimulation frequencies of 1.5, 3, 4.5, and 6 Hz. At the same time, T2*-weighted imaging was performed, and the signal intensity increase during stimulation was correlated with the mean amplitude of the SEP. Both the stimulation-evoked signal intensity increase in T2*-weighted images and the amplitude of SEPs were dependent on the stimulation frequency, with the largest signals at a stimulation frequency of 1.5 Hz and decreasing activations with increasing frequencies. The feasibility of simultaneous, artifact-free recordings of T2*-weighted NMR images and of evoked potentials is proved. Furthermore, the study demonstrates-in the intact brain-the validity of functional magnetic resonance imaging for estimating the intensity of electrocortical activation.