On-line SPE LC-MS/MS for the quantification of Δ9-tetrahydrocannabinol (THC) and its two major metabolites in human peripheral blood by liquid chromatography tandem mass spectrometry

A universal and robust analytical method for the determination of Δ9-tetrahydrocannabinol (THC) and two of its metabolites Δ9-(11-OH)-tetrahydrocannabinol (11-OH-THC) and 11-nor-Δ9-carboxy-tetrahydrocannabinol (THC-COOH) in human whole blood was developed and validated for use in forensic toxicology. Protein precipitation, integrated solid phase extraction and on-line enrichment followed by high-performance liquid chromatography separation and detection with a triple quadrupole mass spectrometer were combined. The linear ranges used for the three cannabinoids were from 0.5 to 20 ng/mL for THC and 11-OH-THC and from 2.5 to 100 ng/mL for THC-COOH, therefore covering the requirements for forensic use. Correlation coefficients of 0.9980 or better were achieved for all three analytes. No relevant hydrolysis was observed for THC-COOH glucuronide with this procedure--in contrast to our previous GC-MS procedure, which obviously lead to an artificial increase of the THC-COOH concentration due to the hydrolysis of the glucuronide-conjugate occurring at high pH during the phase-transfer catalyzed methylation step.

Alcohol dehydrogenase 1C*1 allele is a genetic marker for alcohol-associated cancer in heavy drinkers

Chronic alcohol consumption is associated with an increased risk for upper aerodigestive tract cancer and hepatocellular carcinoma. Increased acetaldehyde production via alcohol dehydrogenase (ADH) has been implicated in the pathogenesis. The allele ADH1C*1 of ADH1C encodes for an enzyme with a high capacity to generate acetaldehyde. So far, the association between the ADH1C*1 allele and alcohol-related cancers among heavy drinkers is controversial. ADH1C genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism in a total of 818 patients with alcohol-associated esophageal (n=123), head and neck (n=84) and hepatocellular cancer (n=86) as well as in patients with alcoholic pancreatitis (n=117), alcoholic liver cirrhosis (n=217), combined liver cirrhosis and pancreatitis (n=17) and in alcoholics without gastrointestinal organ damage (n=174). The ADH1C*1 allele and genotype ADH1C*1/1 were significantly more frequent in patients with alcohol-related cancers than that in individuals with nonmalignant alcohol-related organ damage. Using multivariate analysis, ADH1C*1 allele frequency and rate of homozygosity were significantly associated with an increased risk for alcohol-related cancers (p<0.001 in all instances). The odds ratio for genotype ADH1C*1/1 regarding the development of esophageal, hepatocellular and head and neck cancer were 2.93 (CI, 1.84-4.67), 3.56 (CI, 1.33-9.53) and 2.2 (CI, 1.11-4.36), respectively. The data identify genotype ADH1C*1/1 as an independent risk factor for the development of alcohol-associated tumors among heavy drinkers, indicating a genetic predisposition of individuals carrying this genotype.

TAFI and PAI-1 levels in human sepsis

BACKGROUND: Plasminogen activator inhibitor type-1 (PAI-1) is considered to be the main inhibitor of fibrinolysis in sepsis. However, the contribution of TAFI to the inhibition of fibrinolysis in sepsis is currently unknown. METHODS: TAFI antigen and PAI-1 levels were measured in severe sepsis (n = 32) and septic shock (n = 8) patients. In addition, TAFI antigen levels had been determined in 151 controls. RESULTS: Septic patients had significantly (p < 0.0001) decreased TAFI levels (median: 78.9% [range: 32.4-172.6]) as compared to controls (108.1% [35.9-255.4]). TAFI levels were equal in septic shock and severe sepsis (68.9% [32.4-172.6] vs. 82.5% [32.7-144.9], p = 0.987) as well as in survivors and non-survivors (87.1% [32.7-172.6] vs. 65.8% [32.4-129.5], p = 0.166). PAI-1 levels were significantly (705.5 ng/ml [131-5788]) higher in septic shock as in severe sepsis patients (316.5 ng/ml [53-1311], p = 0.016) and were equal in survivors and non-survivors (342 ng/ml [53-1311] vs. 413 ng/ml [55-5788], p = 0.231). TAT/PAP ratio (R((TAT/PAP))) reflecting the dysbalance between coagulation and fibrinolysis was calculated. R((TAT/PAP)) significantly increased with fatality and was significantly dependent on PAI-1, but not on TAFI. PAI-1 levels (570.5 ng/ml [135-5788]) and R((TAT/PAP)) (1.6 [0.3-6.1]) were significantly (p = 0.008 and p = 0.047) higher in patients with overt DIC as compared to patients without overt DIC (310 ng/ml [53-1128] and 0.6 [0.1-4.3]), whereas no difference was found for TAFI levels (68.9% [32.7-133.2] vs. 86.4% [32.4-172.6], p = 0.325). CONCLUSIONS: Although inhibition in sepsis is mediated by both, PAI-1 might be involved early in the sepsis process, whereas TAFI might be responsible for ongoing fibrinolysis inhibition in later stages of sepsis.

Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia

RATIONALE: Nighttime agitation occurs frequently in patients with dementia and represents the number one burden on caregivers today. Current treatment options are few and limited due to substantial side effects. OBJECTIVES: The aim of the study was to measure the effect of the cannabinoid dronabinol on nocturnal motor activity. METHODS: In an open-label pilot study, six consecutive patients in the late stages of dementia and suffering from circadian and behavioral disturbances-five patients with Alzheimer's disease and one patient with vascular dementia-were treated with 2.5 mg dronabinol daily for 2 weeks. Motor activity was measured objectively using actigraphy. RESULTS: Compared to baseline, dronabinol led to a reduction in nocturnal motor activity (P=0.028). These findings were corroborated by improvements in Neuropsychiatric Inventory total score (P=0.027) as well as in subscores for agitation, aberrant motor, and nighttime behaviors (P<0.05). No side effects were observed. CONCLUSIONS: The study suggests that dronabinol was able to reduce nocturnal motor activity and agitation in severely demented patients. Thus, it appears that dronabinol may be a safe new treatment option for behavioral and circadian disturbances in dementia.

Prognostic importance of anaemia in HIV type-1-infected patients starting antiretroviral therapy: collaborative analysis of prospective cohort studies

BACKGROUND: In HIV type-1-infected patients starting highly active antiretroviral therapy (HAART), the prognostic value of haemoglobin when starting HAART, and of changes in haemoglobin levels, are not well defined. METHODS: We combined data from 10 prospective studies of 12,100 previously untreated individuals (25% women). A total of 4,222 patients (35%) were anaemic: 131 patients (1.1%) had severe (<8.0 g/dl), 1,120 (9%) had moderate (male 8.0-<11.0 g/dl and female 8.0- < 10.0 g/dl) and 2,971 (25%) had mild (male 11.0- < 13.0 g/ dl and female 10.0- < 12.0 g/dl) anaemia. We separately analysed progression to AIDS or death from baseline and from 6 months using Weibull models, adjusting for CD4+ T-cell count, age, sex and other variables. RESULTS: During 48,420 person-years of follow-up 1,448 patients developed at least one AIDS event and 857 patients died. Anaemia at baseline was independently associated with higher mortality: the adjusted hazard ratio (95% confidence interval) for mild anaemia was 1.42 (1.17-1.73), for moderate anaemia 2.56 (2.07-3.18) and for severe anaemia 5.26 (3.55-7.81). Corresponding figures for progression to AIDS were 1.60 (1.37-1.86), 2.00 (1.66-2.40) and 2.24 (1.46-3.42). At 6 months the prevalence of anaemia declined to 26%. Baseline anaemia continued to predict mortality (and to a lesser extent progression to AIDS) in patients with normal haemoglobin or mild anaemia at 6 months. CONCLUSIONS: Anaemia at the start of HAART is an important factor for short- and long-term prognosis, including in patients whose haemoglobin levels improved or normalized during the first 6 months of HAART.

Pharmacogenetics-based population pharmacokinetic analysis of etravirine in HIV-1 infected individuals

Objectives: Etravirine (ETV) is metabolized by cytochrome P450 (CYP) 3A, 2C9, and 2C19. Metabolites are glucuronidated by uridine diphosphate glucuronosyltransferases (UGT). To identify the potential impact of genetic and non-genetic factors involved in ETV metabolism, we carried out a two-step pharmacogenetics-based population pharmacokinetic study in HIV-1 infected individuals. Materials and methods: The study population included 144 individuals contributing 289 ETV plasma concentrations and four individuals contributing 23 ETV plasma concentrations collected in a rich sampling design. Genetic variants [n=125 single-nucleotide polymorphisms (SNPs)] in 34 genes with a predicted role in ETV metabolism were selected. A first step population pharmacokinetic model included non-genetic and known genetic factors (seven SNPs in CYP2C, one SNP in CYP3A5) as covariates. Post-hoc individual ETV clearance (CL) was used in a second (discovery) step, in which the effect of the remaining 98 SNPs in CYP3A, P450 cytochrome oxidoreductase (POR), nuclear receptor genes, and UGTs was investigated. Results: A one-compartment model with zero-order absorption best characterized ETV pharmacokinetics. The average ETV CL was 41 (l/h) (CV 51.1%), the volume of distribution was 1325 l, and the mean absorption time was 1.2 h. The administration of darunavir/ritonavir or tenofovir was the only non-genetic covariate influencing ETV CL significantly, resulting in a 40% [95% confidence interval (CI): 13–69%] and a 42% (95% CI: 17–68%) increase in ETV CL, respectively. Carriers of rs4244285 (CYP2C19*2) had 23% (8–38%) lower ETV CL. Co-administered antiretroviral agents and genetic factors explained 16% of the variance in ETV concentrations. None of the SNPs in the discovery step influenced ETV CL. Conclusion: ETV concentrations are highly variable, and co-administered antiretroviral agents and genetic factors explained only a modest part of the interindividual variability in ETV elimination. Opposing effects of interacting drugs effectively abrogate genetic influences on ETV CL, and vice-versa.

Where to find 1.5 million yr old ice for the IPICS "Oldest-Ice" ice core

The recovery of a 1.5 million yr long ice core from Antarctica represents a keystone of our understanding of Quaternary climate, the progression of glaciation over this time period and the role of greenhouse gas cycles in this progression. Here we tackle the question of where such ice may still be found in the Antarctic ice sheet. We can show that such old ice is most likely to exist in the plateau area of the East Antarctic ice sheet (EAIS) without stratigraphic disturbance and should be able to be recovered after careful pre-site selection studies. Based on a simple ice and heat flow model and glaciological observations, we conclude that positions in the vicinity of major domes and saddle position on the East Antarctic Plateau will most likely have such old ice in store and represent the best study areas for dedicated reconnaissance studies in the near future. In contrast to previous ice core drill site selections, however, we strongly suggest significantly reduced ice thickness to avoid bottom melting. For example for the geothermal heat flux and accumulation conditions at Dome C, an ice thickness lower than but close to about 2500 m would be required to find 1.5 Myr old ice (i.e., more than 700 m less than at the current EPICA Dome C drill site). Within this constraint, the resolution of an Oldest-Ice record and the distance of such old ice to the bedrock should be maximized to avoid ice flow disturbances, for example, by finding locations with minimum geothermal heat flux. As the geothermal heat flux is largely unknown for the EAIS, this parameter has to be carefully determined beforehand. In addition, detailed bedrock topography and ice flow history has to be reconstructed for candidates of an Oldest-Ice ice coring site. Finally, we argue strongly for rapid access drilling before any full, deep ice coring activity commences to bring datable samples to the surface and to allow an age check of the oldest ice.

Na 1 Nachlass Max Horkheimer, 691 - "Materialien zum Antisemitismus", "Die deutschen Arbeiter und Angestellten", "Neue Enquêten über Folgen der Arbeitslosigkeit" (p. IX 164 - IX 166.1-13)

"Materialien zum Antisemitismus" (1940-65): Zeitungsausschnitte, Broschüren, Drucksachen; "Die deutschen Arbeiter und Angestellten" (1930-38):; 1. Inhaltsverzeichnisse, Typoskripte, 5 Blatt; 2. Fragebogen zur Erhebung, Druck, 4 Blatt; 3. Statistische Auswertung der Fragebögen; 4. Max Horkheimer: eigenhändige Notzizen zur Erhebung, 1 Blatt; 5. Robert S. Lynd: 1 Brief (Abschrift) an Erich Fromm, New York, 7.2.1938; 6. "Arbeiter und Angestellten-Enquête". Zum Stand der Ausarbeitung, 1937, Typoskript, 3 Blatt; 7. Bibliographien, Typoskripte, 42 Blatt; "Neue Enquêten über Folgen der Arbeitslosigkeit" (1936-37):; 1. Liste der Erhebungen in Österreich, Palestina, USA, 5 Blatt; 2. "Remarque générale sur l'enquête". Typoskript mit eigenhändigen Korrekturen, 9 Blatt; 3. - 6. Protokolle von Familieninterviews in Wien, 1937; 7. "Literatur über die psychologischen Wirkungen der Arbeitslosigkeit" (1936). Typoskript, 15 Blatt; 8. Hilde Oppenheimer-Bluhm: 1 Brief mit Unterschrift an Friedrich Pollock, Jerusalem, 7.12.1936, 1 Blatt; 9. Paul F. Lazarsfeld: "Memorandum Subject: Remarks on the French Questionaire" (12.3.1937). Typoskript, 1 Blatt; 10. Paul F. Lazarsfeld: "Report on the University of Newark Research Center". Als Typoskript vervielfältigt, 9 Blatt; 11. "Publications Directed and Distributed by Bureau of Social Research, Municipal University of Omaha, Omaha, Nebraska". Als Typoskript viervielfältigt, 3 Blatt; 12. Programm zur Conférence Internationale des Sciences Sociales, Paris, 1937, Drucksachen, 3 Blatt; 13. The American Sociological Society: Rundschreiben, Drucksache, 2 Blatt;

Na 1 Nachlass Max Horkheimer, 711 - Zu "Image de la France. Un sondage de l'opinion publique allemande" und "Enquête sur l'écoute et les conditions d'efficacité des émissions en langue allemande de la Radiodiffusion Francais à destination de l'Allemangne" sowie "The Effectiveness of Candid versus Evasive German-Language Broadcasts of the Voice of America. Final Report" (p. IX 185.3-22 - IX 186)

3. "Plan d'ensemble d'une enquête sur les attitudes generales de la population allemande a l'egard de la France et leurs consequences en ce qui concerne l'orientation des emissions en langue allemande de la radiodiffusion francaise", 18.05.1953. Typoskript, 7 Blatt; 4. "Note" Über Methode, Forschungsrichtung und Reichweite der Ergebnisse der Untersuchung; 18.05.1953; Typoskript, 7 Blatt; 5. "Note" Über Geschichte und Tätigkeit des Instituts für Sozialforschung; 18.05.1953; Typoskript, 5 Blatt; 6. Memorandum des Instituts zu Verfahren und ergebnissen der Untersuchung; 1954 [?]; Typoskript, 2 Blatt; 7.-17. Décamps, Jacques: Memoranden; 7. Memorandum, 12.09.1953; Typoskript, 1 Blatt; 8. "Memorandum re: Besprechung in Bad Godesberg in Bezug auf die französische Studie, am 04.September 1953", 10.09.1953. Typoskript, 1 Blatt; 9. "Memorandum re: Vorhaben des 'Centre d'Etudes Sociologiques, Paris', eine deutsch-französische Arbeitsgemeinschft für die Durchführung von Gemeindestudien zu gründen", 15.06.1953. Typoskript, 1 Blatt; 10. "Memorandum über den Besuch von M. Jean L. Pelosse, Centre d'Etudes sociologiques Paris", 12.06.1953. Typoskript, 3 Blatt; 11. "Bericht über die 'Journées d'Etudes eurropéennes sur la Population' Paris, 21., 22. und 23. Mai 1953", 01.06.1953; 12. "Bericht über den Stand der Verhandlungen mit dem Französischen Auswärtigen Amt und dem französischem Rundfunk. Besprechungen in Paris am 27. und 28. Mai 1953", 01.06.1953. Typoskript, 2 Blatt; 13. Angaben für Max Horkheimer zur Übergabe von Memoranden, Projektbeschreibungen und Briefentwürfen, Mai 1953; Typoskript, 1 Blatt; 14. "Bericht über das 'Institut National d'Etudes Démographiques'", 07.05.1953. Typoskript, 4 Blatt; 15. "Memorandum re: Methode der Gruppendiskussion", 04.05.1953. Typoskript, 1 Blatt; 16. "Besprechung im 'Institut francaise d'Opinion Publique, Paris' und bei der hohen Behörde Luxemburg" 30.04.1953; 17. "Besprechung im Auswärtigen Amt und bei dem französischen Rundfunk", 29.04.1953. Typoskript, 6 Blatt; 18. Horkheimer, Max: 1 Brief an den französischen Botschafter in der Bundesrepublik Deutschland, ohen Ort, ohne Datum; Typoskript, 1 Blatt; 19. Radiodiffusion-Télévision Francaise, le Directeur: 1 Briefabschrift an Jacques Décamps, Paris, 09.03.1954; 1 Blatt; 20. Plessner, Helmuth: 1 Brief an den französischen Außenminister, ohne Ort, 18.05.1953; 1 Blatt; 21. Plessner, Helmuth: 1 Brief an Radiodiffusion Francaise, ohne Ort, 18.05.1953; 1 Blatt; 22. Plessner, Helmuth: 1 Brief an den Ministerialrat der Sektion "Agences et Radio" im französischem Außenministerium, ohne Ort, 18.05.1953; 1 Blatt; "The Effectiveness of Candid versus Evasive German-Language Broadcasts of the Voice of America. Final Report", 1953. Typoskript, gebunden, 432 Blatt;

The last occurrence of Proboscia curvirostris in the North Atlantic marine isotope stage 9-8

Well-preserved diatoms are present in high sedimentation rate Pleistocene cores retrieved on Ocean Drilling Program (ODP) Legs 151, 152, 162 and IMAGES cruises of R/V Marion Dufresne from the North Atlantic. Investigation of the stratigraphic occurrence of diatom species shows that the youngest diatom event observed in the area is the last occurrence (LO) of Proboscia curvirostris (Jousé) Jordan and Priddle. P. curvirostris is a robust species that can easily be identified in the sediments, and therefore can be a practical biostratigraphic tool. We have mapped its areal distribution, and found that it stretches from 40°N to 80°N in the North Atlantic. Further, we have correlated the LO P. curvirostris to the oxygen isotope records of six cores to refine the age of this biostratigraphic event. The extinction of P. curvirostris is latitudinally diachronous through Marine Isotope Stages (MIS) 9 to 8 within the North Atlantic. This is closely related to the paleoceanography of the area. P. curvirostris first disappeared within interglacial MIS 9 (324 ka) from the northern areas that are most sensitive to climatic forcing, like the East Greenland current and the sea-ice margin. It survived in mid-North Atlantic until the conditions of the MIS 8 (glaciation) became too severe (260 ka). In the North Pacific at ODP Site 883 the LO P. curvirostris falls within MIS 8. The observed overlap in age between the North Atlantic and the North Pacific strongly suggests that the extinction of P. curvirostris is synchronous between these oceans.

Fatty acid and stable isotope composition of calanoid copepods in the open eastern Atlantic Ocean during POLARSTERN cruise ANT-XXIX/1

The majority of global ocean production and total export production is attributed to oligotrophic oceanic regions due to their vast regional expanse. However, energy transfers, food-web structures and trophic relationships in these areas remain largely unknown. Regional and vertical inter- and intra-specific differences in trophic interactions and dietary preferences of calanoid copepods were investigated in four different regions in the open eastern Atlantic Ocean (38°N to 21°S) in October/November 2012 using a combination of fatty acid (FA) and stable isotope (SI) analyses. Mean carnivory indices (CI) based on FA trophic markers generally agreed with trophic positions (TP) derived from d15N analysis. Most copepods were classified as omnivorous (CI ~0.5, TP 1.8 to ~2.5) or carnivorous (CI >=0.7, TP >=2.9). Herbivorous copepods showed typical CIs of <=0.3. Geographical differences in d15N values of epi- (200-0 m) to mesopelagic (1000-200 m) copepods reflected corresponding spatial differences in baseline d15N of particulate organic matter from the upper 100 m. In contrast, species restricted to lower meso- and bathypelagic (2000-1000 m) layers did not show this regional trend. FA compositions were species-specific without distinct intra-specific vertical or spatial variations. Differences were only observed in the southernmost region influenced by the highly productive Benguela Current. Apparently, food availability and dietary composition were widely homogeneous throughout the oligotrophic oceanic regions of the tropical and subtropical Atlantic. Four major species clusters were identified by principal component analysis based on FA compositions. Vertically migrating species clustered with epi- to mesopelagic, non-migrating species, of which only Neocalanus gracilis was moderately enriched in lipids with 16% of dry mass (DM) and stored wax esters (WE) with 37% of total lipid (TL). All other species of this cluster had low lipid contents (< 10% DM) without WE. Of these, the tropical epipelagic Undinula vulgaris showed highest portions of bacterial markers. Rhincalanus cornutus, R. nasutus and Calanoides carinatus formed three separate clusters with species-specific lipid profiles, high lipid contents (>=41% DM), mainly accumulated as WE (>=79% TL). C. carinatus and R. nasutus were primarily herbivorous with almost no bacterial input. Despite deviating feeding strategies, R. nasutus clustered with deep-dwelling, carnivorous species, which had high amounts of lipids (>=37% DM) and WE (>=54% TL). Tropical and subtropical calanoid copepods exhibited a wide variety of life strategies, characterized by specialized feeding. This allows them, together with vertical habitat partitioning, to maintain high abundance and diversity in tropical oligotrophic open oceans, where they play an essential role in the energy flux and carbon cycling.