Novel DNA methylation signatures of tobacco smoking with trans-ethnic effects.

BACKGROUND: Smoking remains one of the leading preventable causes of death. Smoking leaves a strong signature on the blood methylome as shown in multiple studies using the Infinium HumanMethylation450 BeadChip. Here, we explore novel blood methylation smoking signals on the Illumina MethylationEPIC BeadChip (EPIC) array, which also targets novel CpG-sites in enhancers. METHOD: A smoking-methylation meta-analysis was carried out using EPIC DNA methylation profiles in 1407 blood samples from four UK population-based cohorts, including the MRC National Survey for Health and Development (NSHD) or 1946 British birth cohort, the National Child Development Study (NCDS) or 1958 birth cohort, the 1970 British Cohort Study (BCS70), and the TwinsUK cohort (TwinsUK). The overall discovery sample included 269 current, 497 former, and 643 never smokers. Replication was pursued in 3425 trans-ethnic samples, including 2325 American Indian individuals participating in the Strong Heart Study (SHS) in 1989-1991 and 1100 African-American participants in the Genetic Epidemiology Network of Arteriopathy Study (GENOA). RESULTS: Altogether 952 CpG-sites in 500 genes were differentially methylated between smokers and never smokers after Bonferroni correction. There were 526 novel smoking-associated CpG-sites only profiled by the EPIC array, of which 486 (92%) replicated in a meta-analysis of the American Indian and African-American samples. Novel CpG sites mapped both to genes containing previously identified smoking-methylation signals and to 80 novel genes not previously linked to smoking, with the strongest novel signal in SLAMF7. Comparison of former versus never smokers identified that 37 of these sites were persistently differentially methylated after cessation, where 16 represented novel signals only profiled by the EPIC array. We observed a depletion of smoking-associated signals in CpG islands and an enrichment in enhancer regions, consistent with previous results. CONCLUSION: This study identified novel smoking-associated signals as possible biomarkers of exposure to smoking and may help improve our understanding of smoking-related disease risk.

Trials and Tribulations in the First Three Years in Operation of the SSAMS for Biomedical 14C-AMS at LLNL.

We report on the first several years of operation of our recently installed 250 kV SSAMS at LLNL, purchased to replace our 1-MV AMS system for the measurement of 14C from labeled biochemical samples. We have modified the ion source region to improve ion output. Additionally, the SSAMS required significant software modifications to the data acquisition system in order to accurately measure 14C at the high-count rates typically encountered with labeled biochemical samples. We found that the data can be corrected assuming a nonparalyzable dead time response with a single event dead time of 6 µs. Since operation began, we have measured over 13,000 graphitic unknowns and over 1900 standards with an overall precision of 1.0%. We have optimized our system for the analysis of CO2 gas samples. We compared aliquots of identical samples measured as solid graphite and as liquid drops. Excellent agreement was found between the two, although the average precision of the graphite targets was an order of magnitude better than the liquid drop analysis due to the much larger number of 14C atoms available for measurement.

Síndrome de Nicolau: A propósito de un caso / Nicolau syndrome: About a case

Se evaluó paciente femenino de 51 años, con antecedentes de diabetes mellitus tipo II e infecciones urinarias a repetición, procedente de la comunidad Mario Briceño Iragorry, quien acude al ambulatorio centro de especialidades "Los Grillitos", de la Corporación de Salud del Estado de Aragua - Venezuela, presentando lesión ulcerada a nivel de hemicadera izquierda, posterior a la colocación vía intramuscular de diclofenac sódico el 28/03/17, el que fue indicado por facultativo para tratar dolor por infección urinaria alta. Posteriormente, a las 24 horas presenta en la zona de la inyección una coloración violácea, induración y mucho dolor, motivo por el que acude nuevamente al facultativo. Se le realizó ecosonograma de partes blandas en región glútea izquierda, reportando imagen heterogénea a predominio hipoecoico con ecos internos de mediana intensidad, que genera reforzamiento posterior de 49x39 mm, con aproximadamente 30 cc de líquido, que correspondería a un proceso inflamatorio e infeccioso (absceso). Posteriormente a la evaluación, se indica antibiótico terapia a base de oxacilina 1 g cada 8 horas vía endovenosa por siete días, además 100 mg cada 12 horas vía oral de nitrofurantoína para el proceso infeccioso urinario, que el urocultivo indica ser sensible a la E. Coli. Al tercer día de la enfermedad actual, se le drena absceso con material purulento aproximadamente 20 cc y cura sucesiva por cinco días, evolucionando satisfactoriamente del proceso infeccioso de partes blandas e infección urinaria.

A 51-year-old female patient with a history of type II diabetes mellitus and recurrent urinary tract infections from the Mario Briceño Iragorry community, attended the outpatient clinic "Los Grillitos" of the health corporation of Aragua Venezuela, with an ulcerated lesion at the left hemi-hip level, following the intramuscular placement of diclofenac sodium on 03/28/17, which was indicated by facultative to treat pain due to high urinary tract infection, afterwards approximately 24 hours presents at the injection site a violet coloration, induration and a lot of pain, which is why she returned to facultative, she performed a soft-tissue echosonogram in the left gluteal region reporting a heterogeneous image to hypoechoic predominance with internal echoes of medium intensity that generates posterior reinforcement which measures 49x39 mm with approximately 30 cc of liquid that could correspond to an inflammatory and infectious process (abscess), post-evaluation is indicated antibiotic therapy based on oxacillin 1 g every 8 hours intravenous route for seven days plus 100 mg every 12 hours oral route of nitrofurantoin for the urinary infectious process that the urine culture indicates to be sensitive E. coli, the third day of illness is drained abscess purulent material approximately 20 cc and successive cure for five days. Satisfactory evolution of the infectious process of soft tissue and urinary tract infection.

Cadmium body burden and increased blood pressure in middle-aged American Indians: the Strong Heart Study.

Cadmium (Cd) is an environmental pollutant that has been associated with cardiovascular disease in populations, but the relationship of Cd with hypertension has been inconsistent. We studied the association between urinary Cd concentrations, a measure of total body burden, and blood pressure in American Indians, a US population with above national average Cd burden. Urinary Cd was measured using inductively coupled plasma mass spectrometry, and adjusted for urinary creatinine concentration. Among 3714 middle-aged American Indian participants of the Strong Heart Study (mean age 56 years, 41% male, 67% ever-smokers, 23% taking antihypertensive medications), urinary Cd ranged from 0.01 to 78.48 µg g-1 creatinine (geometric mean=0.94 µg g-1) and it was correlated with smoking pack-year among ever-smokers (r2=0.16, P<0.0001). Participants who were smokers were on average light-smokers (mean 10.8 pack-years), and urinary Cd was similarly elevated in light- and never-smokers (geometric means of 0.88 µg g-1 creatinine for both categories). Log-transformed urinary Cd was significantly associated with higher systolic blood pressure in models adjusted for age, sex, geographic area, body mass index, smoking (ever vs never, and cumulative pack-years) and kidney function (mean blood pressure difference by lnCd concentration (ß)=1.64, P=0.002). These associations were present among light- and never-smokers (ß=2.03, P=0.002, n=2627), although not significant among never-smokers (ß=1.22, P=0.18, n=1260). Cd was also associated with diastolic blood pressure among light- and never-smokers (ß=0.94, P=0.004). These findings suggest that there is a relationship between Cd body burden and increased blood pressure in American Indians, a population with increased cardiovascular disease risk.

[Care Provided to Psychopaths in Rostock]. / Psychopathenfürsorge in Rostock.

In the first decades of the 20th century stations for observing "psychopathological" children and adolescents were established at a number of psychiatric facilities in the German Reich. Often they functioned as the nucleus for future psychiatric clinics for children and adolescents. Using primary sources of the Landeshauptarchiv Schwerin (main land archive in Schwerin), the local development of the neuropsychiatric clinic in Rostock-Gehlsheim is illustrated in this paper, exploring the question to what degree it caused the specific development of psychiatry in the child and adolescent age group.

Operation of the "Small" BioAMS Spectrometers at CAMS: Past and Future Prospects.

A summary of results from the solid samples run on our compact 1 MV AMS system over its 13.5 years of operation is presented. On average 7065 samples per year were measured with that average dropping to 3278 samples per year following the deployment of our liquid sample capability. Although the dynamic range of our spectrometer is 4.5 orders in magnitude, most of the measured graphitic samples had 14C/C concentrations between 0.1 and 1 modern. The measurements of our ANU sucrose standard followed a Gaussian distribution with an average of 1.5082 ± 0.0134 modern. The LLNL biomedical AMS program supported many different types of experiments, however, the large majority of samples measured were derived from animal model systems. We have transitioned all of our biomedical AMS measurements to the recently installed 250 kV SSAMS instrument with good agreement compared in measured 14C/C isotopic ratios between sample splits. Finally, we present results from replacement of argon stripping gas with helium in the SSAMS with a 22% improvement in ion transmission through the accelerator and high-energy analyzing magnet.

[University professors in the Soviet Occupation Zone and the German Democratic Republic up to 1961: Academic alternation of generations at university psychiatric hospitals]. / Hochschullehrer in der Sowjetischen Besatzungszone und DDR bis 1961 : Der akademische Generationswechsel an den Universitätsnervenkliniken.

After WWII a politically guided staffing policy foresaw an exchange program for professors from the Soviet Occupation Zone and the German Democratic Republic (GDR). In the field of medicine this initiative was not successful. With respect to university psychiatric/neurological hospitals this experiment failed as a result of a shortage of personnel due to the consequences of war, denazification and people migrating into western occupation zones. Criteria for politically selecting promising young talent which had been propagated by the Socialist Unity Party of Germany (Sozialistische Einheitspartei Deutschlands, SED) were thus not relevant in academic medicine until 1961; however, the communist rulers had great interest in bringing professional and academic resources up to date. Politically implicated representatives in the field were also included in this process. At the forefront was the interest in functioning medical care and education in order to be able to train much needed health professionals. At the end of the 1950s a new generation of professors was established at the university hospitals. This generation rotation demonstrated the politically intended replacement of the "old" professor generation and the transition to a new GDR generation that had been trained after 1945. This second generation of professors inherited vacant professorships and defined and shaped research and academia until the end of the GDR much more than the previous generation had and also more than the one that followed. The generation of professors continued to feel a strong affiliation with their academic teachers and consequently continued their tradition in the sense of a school, for the most part independent of political circumstances.

Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants.

BACKGROUND: In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown. OBJECTIVE: The objective of this study is to compare BDNF concentrations of subjects with loss-of-function (LOF) and gain-of-function (GOF) MC4R variants with those of controls with common sequence MC4R. METHODS: Circulating BDNF was measured in two cohorts with known MC4R sequence: 148 subjects of Pima Indian heritage ((mean±s.d.): age, 15.7±6.5 years; body mass index z-scores (BMI-Z), 1.63±1.03) and 69 subjects of Hispanic heritage (10.8±3.6 years; BMI-Z, 1.57±1.07). MC4R variants were characterized in vitro by cell surface expression, receptor binding and cyclic AMP response after agonist administration. BDNF single-nucleotide polymorphisms (SNPs) rs12291186, rs6265 and rs7124442 were also genotyped. RESULTS: In the Pima cohort, no significant differences in serum BDNF was observed for 43 LOF subjects versus 65 LOF-matched controls (age, sex and BMI matched; P=0.29) or 20 GOF subjects versus 20 GOF-matched controls (P=0.40). Serum BDNF was significantly associated with genotype for BDNF rs12291186 (P=0.006) and rs6265 (P=0.009), but not rs7124442 (P=0.99); BDNF SNPs did not interact with MC4R status to predict serum BDNF. In the Hispanic cohort, plasma BDNF was not significantly different among 21 LOF subjects, 20 GOF subjects and 28 controls (P=0.79); plasma BDNF was not predicted by BDNF genotype or BDNF-x-MC4R genotype interaction. CONCLUSIONS: Circulating BDNF concentrations were not significantly associated with MC4R functional status, suggesting that peripheral BDNF does not directly reflect hypothalamic BDNF secretion and/or that MC4R signaling is not a significant regulator of the bulk of BDNF expression in humans.

Epidemiology and genetic determinants of progressive deterioration of glycaemia in American Indians: the Strong Heart Family Study.

AIMS/HYPOTHESIS: Type 2 diabetes is a chronic, heterogeneous disease and a major risk factor for cardiovascular diseases. The underlying mechanisms leading to progression to type 2 diabetes are not fully understood and genetic tools may help to identify important pathways of glycaemic deterioration. METHODS: Using prospective data on American Indians from the Strong Heart Family Study, we identified 373 individuals defined as progressors (diabetes incident cases), 566 individuals with transitory impaired fasting glucose (IFG) and 1,011 controls (normal fasting glycaemia at all visits). We estimated the heritability (h(2)) of the traits and the evidence for association with 16 known variants identified in type 2 diabetes genome-wide association studies. RESULTS: We noted high h(2) for diabetes progression (h(2) = 0.65 ± 0.16, p = 2.7 × 10(-6)) but little contribution of genetic factors to transitory IFG (h(2) = 0.09 ± 0.10, p = 0.19) for models adjusted for multiple risk factors. At least three variants (in WFS1, TSPAN8 and THADA) were nominally associated with diabetes progression in age- and sex-adjusted analyses with estimates showing the same direction of effects as reported in the discovery European ancestry studies. CONCLUSIONS/INTERPRETATION: Our findings do not exclude these loci for diabetes susceptibility in American Indians and suggest phenotypic heterogeneity of the IFG trait, which may have implications for genetic studies when diagnosis is based on a single time-point measure.

[Disciplinary differentiation under socialist conditions--the establishment of neurology at the University of Rostock in East Germany]. / Fächerdifferenzierung unter sozialistischen Bedingungen--Die Etablierung der Neurologie an der Universität Rostock.

The move towards disciplinary independence in Germany turned out to be more troublesome than in France or Great Britain and real institutional independence was not established at German universities until the 1970s of the 20th century, and this in the Federal Republic of Germany only. In East Germany (German Democratic Republic--GDR), a division into Chairs of Psychiatry and Neurology took place at individual universities and medical colleges only. Nevertheless, in exceptional circumstances, neurology did gain academic autonomy in the GDR. One such exception was the University of Rostock, where as early as 1958, the Chair of Psychiatry had been divided into three independent Chairs of Psychiatry, Neurology and Child Psychiatry. Besides internal scientific factors, socio-political constraints played a particular role here and had an influence on the disciplinary differentiation.

Activated coagulation times in normal cats and dogs using MAX-ACT tubes.

OBJECTIVE: To establish reference values for activated coagulation time (ACT) in normal cats and dogs, by visual assessment of clot formation using the MAX-ACT(TM) tube. SUBJECTS: We recruited 43 cats and 50 dogs for the study; 11 cats and 4 dogs were excluded from the statistical analysis because of abnormalities on clinical examination or laboratory testing including anaemia, prolonged prothrombin time (PT) or activated partial thromboplastin time (APTT), or insufficient plasma volume for comprehensive laboratory coagulation testing. PROCEDURE: Blood samples were collected via direct venipuncture for MAX-ACT, packed cell volume/total solids, manual platelet estimation and PT/APTT measurement. Blood (0.5 mL) was mixed gently in the MAX-ACT tube at 37 degrees C for 30 s, then assessed for clot formation every 5 to 10 s by tipping the tube gently on its side and monitoring for magnet movement. The endpoint was defined as the magnet lodging in the clot. The technique was tested with 10 dogs by collecting two blood samples from the same needle insertion and running a MAX-ACT on each simultaneously. RESULTS: In normal cats the mean MAX-ACT was 66 s (range 55-85 s). In normal dogs the mean was 71 s (range 55-80 s). There was no statistical difference between the first and second samples collected from the same needle insertion. CONCLUSIONS: and Clinical Relevance In both cats and dogs, a MAX-ACT result >85 s should be considered abnormal and further coagulation testing should be performed. Additionally, failure to discard the first few drops of the sample does not appear to significantly affect results.

[Franz Günther von Stockert between politics and science--a study in the history of the neurology and psychiatry in the GDR]. / Franz Günther von Stockert im Spannungsfeld von Politik und Wissenschaft--Ein Beitrag zur Geschichte der Nervenheilkunde in der DDR.

1945 marked the beginning of the so-called anti-fascist democratic transformation in the Soviet occupied zone and later GDR, which also included radical reforms in the higher education system. The aim of these reforms was to establish a "new intelligence" that was to spread Marxist-Leninist teaching in universities and colleges. However, in practice the new rulers had to rely on the old "erudite elite" which led to considerable problems. Against this socio-political background this study analyses the affairs at the neuropsychiatric clinic Gehlsheim at Rostock University, in particular those around Franz Günther von Stockert (1899-1967), who was head of the department between 1954 and 1958. Archival sources, not accessible till now, shed light on the background and motives that finally led to his dismissal and short-term imprisonment, and the consequences for the clinic. The analysis of this example also shows how external factors can influence science and the disciplinary differentiation. This case from the field of psychiatry and neurology is a contribution to the broader history of science in the GDR until 1961.

Genome-wide linkage scan for plasma high density lipoprotein cholesterol, apolipoprotein A-1 and triglyceride variation among American Indian populations: the Strong Heart Family Study.

BACKGROUND: Recent studies have identified chromosomal regions linked to variation in high density lipoprotein cholesterol (HDL-C), apolipoprotein A-1 (apo A-1) and triglyceride (TG), although results have been inconsistent and previous studies of American Indian populations are limited. OBJECTIVE: In an attempt to localise quantitative trait loci (QTLs) influencing HDL-C, apo A-1 and TG, we conducted genome-wide linkage scans of subjects of the Strong Heart Family Study. METHODS: We implemented analyses in 3484 men and women aged 18 years or older, at three study centres. RESULTS: With adjustment for age, sex and centre, we detected a QTL influencing both HDL-C (logarithm of odds (LOD) = 4.4, genome-wide p = 0.001) and apo A-1 (LOD = 3.2, genome-wide p = 0.020) nearest marker D6S289 at 6p23 in the Arizona sample. Another QTL influencing apo A-1 was found nearest marker D9S287 at 9q22.2 (LOD = 3.0, genome-wide p = 0.033) in the North and South Dakotas. We detected a QTL influencing TG nearest marker D15S153 at 15q22.31 (LOD = 4.5 in the overall sample and LOD = 3.8 in the Dakotas sample, genome-wide p = 0.0044) and when additionally adjusted for waist, current smoking, current alcohol, current oestrogen, lipid treatment, impaired fasting glucose, and diabetes, nearest marker D10S217 at 10q26.2 (LOD = 3.7, genome-wide p = 0.0058) in the Arizona population. CONCLUSIONS: The replication of QTLs in regions of the genome that harbour well known candidate genes suggest that chromosomes 6p, 9q and 15q warrant further investigation with fine mapping for causative polymorphisms in American Indians.

[Autism: exploring historical psychiatric and psychological concepts]. / Betrachtungen zum Autismus. Ein historischer Streifzug durch psychiatrisch-psychologische Konzepte.

Autism today is a widely used term, yet what is understood by autism has changed considerably since first being introduced in scientific discourse almost 100 years ago. Autism is one example for the influence of the psychoanalytic school of Sigmund Freud on scientific psychiatry at the beginning of the 20th century. In particular psychoanalysis had an impact on Eugen Bleuler's concept of schizophrenia. The Swiss psychiatrist did not only acknowledge and follow a biological, but also a psychological approach to psychiatry and thus opened up his subject to psychoanalytic thoughts. This paper provides insights into the term's conceptual history--or, more specifically and precisely--sheds light on the expansion of the term's scope, which has gotten to be used for more and more symptoms and phenomena. When Bleuler first presented the term autism, he used it to refer to a classical schizophrenic symptom. Since, however, Bleuler was not very specific and exclusive in his definition, the term was soon used for other phenomena as well, such as to describe a schizoid symptom in the sense of today's schizoid personality disorder (schizoid autism). The concepts of autistic hebephrenia and depressive autism are further examples how the term was used and give insight into how the contents behind the term changed, got less and less specific and widened its scope. Due to its growing vagueness its suitability and usability as a psychopathological term decreased. This process further was strengthened when the word autism got more and more widely used in colloquial language for different aspects of day-to-day routine and thinking. Thus in psychiatry today, autism is exclusively used in connection with the so-called autism spectrum disorders, but has, as other formerly exclusively technical terms, different and rather unspecific meanings in everyday communication.

[The case of Sefeloge: a contribution to the history of forensic psychiatry]. / Der "Fall Sefeloge". Ein Beitrag zur Geschichte der forensischen Psychiatrie.

In 1850 the mentally disordered Sergeant Maximilian Joseph Sefeloge (1821-1859) tried to assassinate the Prussian King Friedrich Wilhelm IV (1795-1861). Besides clarification of the political background to the assassination, the question of the delinquent's criminal responsibility has been posed from the very beginning. For the first time Sefeloge's case is examined from a medicohistorical perspective. Due to the importance of the circumstances, a forensic scientist and three well-known psychiatrists made this forensic examination. These medical professionals seemed particularly competent because of their common experience with psychiatric patients. This unique case from nineteenth century Germany is exemplary in that the psychiatrist was generally accepted as an expert witness to evaluate crimes in the context of unclear mental conditions. From there the development of forensic psychiatry could proceed without hindrance.

[Considerations on the work of the neuropsychiatrist Gabriel Anton (1858-1933)]. / Uberlegungen zum Wirken des Neuropsychiaters Gabriel Anton (1858-1933).

Gabriel Anton (1858-1933) attained fundamental clinical neuropathological results. His scientific career and research were highly influenced by Theodor Meynert. However, in contrast to Meynert, Anton sought not only descriptions of pathological changes but also their therapy. The surgical treatment of hydrocephalus was one of his most important achievements. With this, he gave important impetus to the still new science of neurosurgery. Nowadays, Anton is still known in medical nomenclature by Anton's syndrome. The detailed description and explanation of visual anosognosia and asomatoagnosia and furthermore his emphasis on their importance can be regarded as Anton's most notable contribution to science. However, his research on basal ganglia disorders is not as well-known, although Anton's thoughts mark the beginning of further systematic research on these disorders. In addition, he did preliminary work in the development of child and adolescent psychiatry. Today, some of his work in the field of eugenics is controversial.

[Heinrich Damerow (1798-1866). Comments on the title page]. / Heinrich Damerow (1798-1866). Anmerkungen zum Titelbild.

Heinrich Philipp August Damerow was one of the most important German psychiatrists of the nineteenth century. His most notable achievements were in the field of institutional psychiatry. With the construction of a clinic for the mentally ill in Halle-Nietleben, Germany, he realized the concept of a "relatively integrated Mental Hospital and Asylum." As an editor of the Allgemeine Zeitschrift für Psychiatrie und psychischgerichtlichen Medicin (Journal of Psychiatry and Psychic-Legal Medicine), he exerted considerable influence. Ideologically, Damerow was a representative until about the mid-nineteenth century of the holistic approach of medicine during the Romantic period, and he was largely influenced by the ideas of Hegel. He found justification for his service to the then ruling Prussian state in the concept of the state as manifestation of divine reason. He supported a holistic approach to treating the mentally ill in which the patient is viewed as a union of body, soul, and mind. This viewpoint was evident in his critical stance toward Esquirol's concept of monomania.