New Tools For Intermodal Analysis And Association Testing In Neuroimaging

In the field of neuroimage analysis two key goals are to understand the association of a high- dimensional imaging variable with a phenotype, and to understand relationships between several high-dimensional imaging variables. Several recent studies have shown that the standard “mass- univariate” methods to test an association of an image with a phenotype have inflated type 1 error rates due to invalid assumptions. Here, we propose two new methods to perform association testing in neuroimaging and illustrate the method in two stages of the lifespan. The first is a para- metric bootstrap testing procedure that estimates the joint distribution of test statistical parametric map in order to control the voxel-wise family-wise error rate (FWER). We illustrate the method by identifying sex differences in nonlinear developmental trajectories of cerebral blood flow through adolescence using the Philadelphia Neurodevelopmental Cohort. The second testing procedure is a generalization of Rao’s score test based on projecting the score statistic onto a linear sub- space of a high-dimensional parameter space. The approach provides a way to localize signal in the high-dimensional space by projecting the scores to the subspace where the score test was performed. This allows for inference in the high-dimensional space to be performed on the same degrees of freedom as the score test, effectively reducing the number of comparisons. We illus- trate the method by analyzing a subset of the Alzheimer’s Disease Neuroimaging Initiative dataset. Finally, we propose a new tool to study relationships between neuroimaging modalities that we to describe how the spatial association between cortical thickness and sulcal depth changes in adolescent development

Ocjena ekspozicije pesticidima i njihove opasnosti za ljude

Although mammalian toxicity studies are essential in assessing the hazard of any candidate pesticide, the ultimate assessment of the safety in its intended use depends upon studies on exposed people. Those compounds introduced for public health purposes undergo a thorough toxicological scrutiny, and assessment of their safety is made concurrently with their development for a particular use. There is an obvious need to carry out a similar evaluation of hazard to users of agricultural pesticides, in particular those handling pesticides in tropical climates.Premda su u ocjeni opasnosti svakog novog pesticida toksikološka proučavanja na pokusnim životinjama od bitne važnosti, konačna ocjena njegove sigurnosti za predstojeću široku upotrebu zasniva se na rezultatima proučavanja njegovih mogućih učinaka na eksponiranim ljudima. Spojevi što se uvode u upotrebu u javnom zdravstvu podliježu veoma temeljitom toksikološkom proučavanju i njihova sigurnost pri upotrebi ocjenjuje se uporedo s njihovim usavršavanjem za određenu primjenu. Postoji očita potreba da se sličan postupak ocjene moguće opasnosti uvede i za one pesticide što se upotrebljavaju u poljoprivredi a napose za one što se primjenjuju u tropskim klimatskim uvjetima

Toxicology of organophosphorus insecticides

Prikazana je biokemija, farmakologija, eksperimentalna i klinika toksikologija, terapija i prevencija otrovanja organofosfornim insekticidima. Opširnije su iznijeta današnja shvaćanja o mehanizmu djelovanja organofosfornih inhibitora na kolinesterazu i istraživanja s područja reaktivacije inhibirane kolinesteraze pomoću nukleofilnih reagensa.A review of the biochemistry, pharmacology, experimental and clinical toxicology, therapy, and prevention of poisonings due to organophosphorus insecticides. The present-day concepts of the mechanism of the effect of organophosphorus inhibitors on cholinesterase are described more in detail, as well as the investigations in the field of the reactivation of inhibited cholinesterase by nucleophilic reagents

Toxicology of dieldrin I. studies of acute toxicity

Određena je peroralna, intraperitonealna i intravenozna LD50 vrijednost za dieldrin na bijelim štakorima. Istražen je utjecaj gladovanja u odnosu na brzinu javljanja simptoma nakon peroralne aplikacije dieldrina. Određena je ukupna tolerirana doza otrova pri različitim brzinama intravenozne infuzije dieldrina štakorima. Dobiveni rezultati su prodiskutirani, a napose s obzirom na pojavu »zakašnjelih« simptoma nakon jednokratne aplikacije otrova.The peroral, intraperitoneal and intravenous LD50 values of dieldrin are determined in albino rats. The effect of starving in relation to the time of the onset of symptoms after peroral application of dieldrin is studied. The total tolerated dose of dieldrin at various intravenous infusion rates is determined. The results obtained are discussed, particularly with regard to the appearance of »delayed« symptoms after a single application of the poison

Study of dermal toxicity of organophosphorus compounds. I. Parathion toxicity in relation to the skin surface and the technique of application

Istražen je učinak pripreme površine kože štakora kao i pokrivanje kontaminirane površine na perkutanu otrovnost parationa. Uklanjanje masnog sloja s ošišane kože leda 24 sata prije aplikacije otrova nije utjecalo na otrovnost parationa. Pokrivanje kontaminiranog mjesta politenskim listićem smanjilo je otrovnost parationa za oko 2 puta, a pokrivanje kontaminiranog mjesta leukoplastom za oko 3,5 puta. Pokusi u kojima je mogućnost ingestije otrova kod nepokrivenih štakora bila djelomično ili potpuno spriječena pokazali su da veće LD50 vrijednosti dobivene pokrivanjem kontaminiranog mjesta nisu rezultat spriječenog unošenja otrova peroralnim putem, već su posljedica smanjenog prodiranja parationa kroz kožu. To se može tumačiti adhezijom otrova na politenski listić, odnosno leukoplast, kojima je kontaminirano mjesto bilo pokriveno.The effect of the preparation of the rat\u27s skin surface and the covering of the contaminated area on dermal Parathion toxicity was investigated. The removal of the fatty layer from the clipped back skin area 24 hours prior to the application of the poison had no effect on Parathion toxicity. Parathion toxicity was reduced to about twice when the contaminated area was covered with a polythene sheet, and to about three and a half times when cevered with a leukoplast. The experiments, in which the possibility of ingestion of the poison in uncovered rats was partly or completely avoided, have shown that higher LD50 values obtained by covering the contaminated area were not due to the prevented introduction of the poison by ingestion but to a reduced penetration of Parathion through the skin. This may be explained by the adhesion of the poison to the polythene sheet or leukoplast by which the contaminated area was covered

Warburg apparatus

Prikaz sadržava opis i teoriju Warburgova aparata. U drugom dijelu opširnije su iznijete praktičke upute za rad kao i primjer kalibracije aparata i mjerenja aktivnosti enzima.The description and theory as well as methods of calibration of the Warburg apparatus are given. The review includes a detailed description of Iaboratory techniques and an example of calibration of the apparatus and determination of the enzyme activity

Protection of agricultural workers against pesticide poisoning

Izneseni su specifični uvjeti i priroda ekspozicije pesticidima u poljoprivredi i mjere za sprečavanje profesionalnih i akcidentalnih otrovanja. U zasebnom poglavlju predložen je nacrt higijensko-tehničkih propisa za bezopasnu primjenu pesticida. Na kraju autori daju konkretne prijedloge za rješavanje aktuelnih problema u preventivi otrovanja pesticidima.Conditions under which pesticides are used in agriculture, the nature of exposure, and the measures for the prevention of hazards are presented. A draft of suggested safety regulations is given in a separate chapter. The authors also make proposals for the solution of current problems in the prevention of pesticide poisonings

Faster Family-wise Error Control for Neuroimaging with a Parametric Bootstrap

In neuroimaging, hundreds to hundreds of thousands of tests are performed across a set of brain regions or all locations in an image. Recent studies have shown that the most common family-wise error (FWE) controlling procedures in imaging, which rely on classical mathematical inequalities or Gaussian random field theory, yield FWE rates that are far from the nominal level. Depending on the approach used, the FWER can be exceedingly small or grossly inflated. Given the widespread use of neuroimaging as a tool for understanding neurological and psychiatric disorders, it is imperative that reliable multiple testing procedures are available. To our knowledge, only permutation joint testing procedures have been shown to reliably control the FWER at the nominal level. However, these procedures are computationally intensive due to the increasingly available large sample sizes and dimensionality of the images, and analyses can take days to complete. Here, we develop a parametric bootstrap joint testing procedure. The parametric bootstrap procedure works directly with the test statistics, which leads to much faster estimation of adjusted \emph{p}-values than resampling-based procedures while reliably controlling the FWER in sample sizes available in many neuroimaging studies. We demonstrate that the procedure controls the FWER in finite samples using simulations, and present region- and voxel-wise analyses to test for sex differences in developmental trajectories of cerebral blood flow

Analysing spatial point patterns in digital pathology: immune cells in high-grade serous ovarian carcinomas

Multiplex immunofluorescence (mIF) imaging technology facilitates the study of the tumour microenvironment in cancer patients. Due to the capabilities of this emerging bioimaging technique, it is possible to statistically analyse, for example, the co-varying location and functions of multiple different types of immune cells. Complex spatial relationships between different immune cells have been shown to correlate with patient outcomes and may reveal new pathways for targeted immunotherapy treatments. This tutorial reviews methods and procedures relating to spatial point patterns for complex data analysis. We consider tissue cells as a realisation of a spatial point process for each patient. We focus on proper functional descriptors for each observation and techniques that allow us to obtain information about inter-patient variation. Ovarian cancer is the deadliest gynaecological malignancy and can resist chemotherapy treatment effective in cancers. We use a dataset of high-grade serous ovarian cancer samples from 51 patients. We examine the immune cell composition (T cells, B cells, macrophages) within tumours and additional information such as cell classification (tumour or stroma) and other patient clinical characteristics. Our analyses, supported by reproducible software, apply to other digital pathology datasets

Factors influencing the variability of results in the assessment of acute toxicity

U uvodu je raspravljeno značenje novosintetiziranih supstancija s obzirom na njihovu toksičnost i opasnost po zdravlje za ljude i domaće životinje. Analizirajući korištenje eksperimentalnih podataka o toksičnosti, autori ističu, da je primjena tih podataka na ljude i domaće životinje moguća tek onda, kad dobro poznajemo mehanizam djelovanja istraživane supstancije. Izneseni su faktori, koji uvjetuju varijabilnost rezultata pri ocjeni akutne toksičnosti, s naročitim osvrtom na određivanje toksičnosti organofosfornih spojeva. Autori temelje svoja izlaganja na podacima drugih autora i na vlastitim zapažanjima. Faktore, od kojih zavisi varijabilnost rezultata, autori dijele na one, koji se odnose (1) na istraživanu supstanciju, (2) na pokusnu životinju i (3) na put unošenja otrova. Od faktora, koji se odnose na istraživanu supstanciju, autori ističu nedovoljnu čistoću spoja i razgradnju uzorka u toku njegova pripremanja ili pohranjivanja. S obzirom na pokusnu životinju prodiskutiran je utjecaj vrste, dobi, spola i genetskih faktora, kao i utjecaj faktora, od kojih zavisi kondicija eksperimentalne životinje. Naročito je istaknuto od kojeg je značenja za konačan ishod rezultata postupak s tretiranim životinjama u toku opservacije simptoma. Zbog različite brzine apsorpcije put unošenja često uvjetuje vrlo velike razlike u toksičnosti nekog spoja. I medij, u kojem se istraživana supstancija primjenjuje, može znatno utjecati na brzinu apsorpcije otrova. Autori zaključuju, da eksperimentalni podaci o akutnoj toksičnosti nekog spoja imaju svoju punu vrijednost tek onda, kad uz osnovne statističke karakteristike sadržavaju i sve podatke o eksperimentalnim uvjetima, koji mogu biti od značenja u vezi s istraživanom supstancijom, putom unošenja i pokusnom životinjom.The significance of newly synthetized compounds with regard to their toxicity and health hazards both for humans and domestic animals is discussed. It is pointed out that the extrapolation of experimental toxicity data on humans and domestic animals is not possible without a thorough understanding of the mechanism of the action of the substances tested. The factors influencing the variability of results in the assessment of acute toxicity are presented, with special reference to the determination of the toxicity of organophosphorus compounds. The autors\u27 discussion is based on literature data and their own experience. The factors influencing the variability of results are divided into those relating (1) to the test substance, (2) to the experimental animal, and (3) to the route of administration. Amongst the factors relating to the test substance, the presence of impurities and the conversion of the sample in the course of its preparation and storage are specially emphasized. With regard to the factors relating to the experimental animal, the effect of the species, age, sex, and genetic factors is discussed. as well as the effect of the factors influencing the condition of the experimental animal. In this connection it is pointed out that in the assessment of results the treatment of animals under observation plays an important part. Different routes of administration may also be the cause of great variability of the results. They determine how long it will take the poison to attain a certain level in the blood, what kind of the detoxifying mechanism will be put in action and to what extent, and by which route and rate the poison will be eliminated from the body. The vehicle used in the application of the test substance may also produce a considerable effect on the absorption rate of the poison. The authors conclude that experimental data on the acute toxicity of .a compound cannot be considered satisfactory, unless besides basic statistical data they contain all the information on the experimental conditions that may be of significance either to the substance tested, or the experimental animal, or the route of administration