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Histopathological diagnosis of brain tumours with the help of a computer: mathematical fundaments and practical application.

With the help of a personal computer we have subjected 1684 tumours of the central and peripheral nervous systems to a discriminant analysis to test whether the different brain tumours can be classified. By ascribing a coefficient value which belongs to a linear function to the objective criteria for each tumour these can be ordered in groups, and a classification is then possible. This has been termed discriminant analysis. Fifty histological characteristics were the criteria taken into consideration for each tumour. By using Bayes' formula with a correction for binomial distribution we obtained a correct diagnosis in 98% of the cases studied. The differential diagnosis with its percentage of probabilities is given by the computer. The mathematical fundaments are given. The valuability and precision of this method are discussed.

Brain Neoplasms↗

Exponential kinetics of formation or organic microstructures.

Organic microstructure production in Miller-Urey spark discharge flasks in an energy-dependent, autocatalytic process which follows first order kinetics similar to microbial growth curves. These relationships hold for all three major morphological types of microstructures observed. The three types are assembled from smaller precursor subunits which associate according to a binomial distribution. These structures could have formed bounded systems in which pre-biological processes might have occurred.

Ammonia↗

Evaluation of potential interactions involving trichothecene mycotoxins using the chick embryotoxicity bioassay.

The Chick Embryotoxicity Screening Test (CHEST) was used to examine possible interactions between different trichothecenes. Combinations of deoxynivalenol (DON), 15-acetyldeoxynivalenol (15-ADON) and HT-2 toxin were tested at various concentrations and the effects were determined based on percent mortality. The combined toxicity of any two trichothecenes was found to be additive. Discrepancies between observed and expected mortality values seldom differed by more than 10%, well within sampling error for the binomial distribution. Several limitations of the CHEST assay are discussed.

Animals↗

Tables of critical values for examining compositional non-randomness in proteins and nucleic acids.

A binomially distributed statistic pchi2i is defined which in conjunction with a set of critical tables permits, for peptides or proteins of arbitrary lengths, a well-defined answer to the question: Does the proportion of a particular amino acid iota present in that protein deviate significantly from random expectation? An analogous statistic is defined for nucleic acids. This statistic is simply related to the classical chi-squared test. The classical chi2 and the pchi2i are supplementary in that the former permits one to determine that a non-randomness in amino acid composition exists in a protein, while the latter permits one to localize that non-randomness to particular amino acids. The pchi2i statistic takes into account explicity the compositional fluctuations imposed by the finite length of proteins. The tables are more exact than any hitherto existing, and require no intermediate calculations for their use: from the direct experimental measurement of the number of residues of amino acid iota, one immediately reads from the tables whether the number observed is within random expectation or not. These statistics are used to analyze eight proteins of diverse length, function, and origin in an accompanying paper.

Amino Acids↗

Colorectal adenocarcinoma: quality of the assessment of lymph node metastases.

PURPOSE: We have studied 193 cases of colorectal adenocarcinoma from a population-based register to determine the minimum number of lymph nodes to be examined to provide an accurate assessment of the presence of nodal metastases. METHODS: The mean total number of lymph nodes identified per surgical specimen was 11 +/- 6.8 (range, 1-36) using traditional dissection. One hundred eighteen specimens (61 percent) were classified as Dukes B. Seventy-five (39 percent) had lymph node metastases (Dukes C) with a mean of 3.3 +/- 4.7 positive lymph nodes per specimen. With binomial distribution we calculate the probability to find at least one positive node in a sample size n with a determined proportion of positive nodes. RESULTS: The error probability in the ganglionar assessment by traditional dissection was 0.05 with 6 examined lymph nodes and 0.01 with 10 examined nodes. CONCLUSION: We must provide the pathologist with a minimum of six examined lymph nodes per surgical specimen for an optimal Dukes B assessment.

Adenocarcinoma↗

Cryotherapy for active retinopathy of prematurity.

Twenty-eight patients with bilateral symmetrical stage-III retinopathy of prematurity and plus disease had one eye treated using cryotherapy, while the other acted as a control. Eleven patients showed improvement in both the treated and untreated eye, while 11 others were noted to improve in the treated eye while demonstrating deterioration in the untreated eye. The P value obtained by applying binomial distribution tests suggested that, in the sampled population, cryotherapy was preferable to no treatment.

Clinical Trials as Topic↗

Evolution of the cytochrome b gene of mammals.

With the polymerase chain reaction (PCR) and versatile primers that amplify the whole cytochrome b gene (approximately 1140 bp), we obtained 17 complete gene sequences representing three orders of hoofed mammals (ungulates) and dolphins (cetaceans). The fossil record of some ungulate lineages allowed estimation of the evolutionary rates for various components of the cytochrome b DNA and amino acid sequences. The relative rates of substitution at first, second, and third positions within codons are in the ratio 10 to 1 to at least 33. For deep divergences (greater than 5 million years) it appears that both replacements and silent transversions in this mitochondrial gene can be used for phylogenetic inference. Phylogenetic findings include the association of (1) cetaceans, artiodactyls, and perissodactyls to the exclusion of elephants and humans, (2) pronghorn and fallow deer to the exclusion of bovids (i.e., cow, sheep, and goat), (3) sheep and goat to the exclusion of other pecorans (i.e., cow, giraffe, deer, and pronghorn), and (4) advanced ruminants to the exclusion of the chevrotain and other artiodactyls. Comparisons of these cytochrome b sequences support current structure-function models for this membrane-spanning protein. That part of the outer surface which includes the Qo redox center is more constrained than the remainder of the molecule, namely, the transmembrane segments and the surface that protrudes into the mitochondrial matrix. Many of the amino acid replacements within the transmembrane segments are exchanges between hydrophobic residues (especially leucine, isoleucine, and valine). Replacement changes at first and second positions of codons approximate a negative binomial distribution, similar to other protein-coding sequences. At four-fold degenerate positions of codons, the nucleotide substitutions approximate a Poisson distribution, implying that the underlying mutational spectrum is random with respect to position.

Amino Acid Sequence↗

Patients with aortic stenosis: cardiac complications in non-cardiac surgery.

PURPOSE: To reassess the risk of patients with aortic stenosis (AS) undergoing non-cardiac surgery. METHODS: Following institutional approval, a retrospective chart audit of all patients with AS who underwent non-cardiac surgery in Hamilton between 1992 and 1994 was performed. For each AS case, a matching control was randomly selected. Data pertaining to pre-operative cardiac risk factors, intra-operative, and post-operative management were recorded. Complications were defined as the onset of congestive heart failure (CHF), myocardial infarction (MI), or dysrhythmias requiring cardioversion within seven post-operative days; unplanned or prolonged intensive care unit (ICU) stay due to cardiac cause; and cardiac death. Categorical data were compared using discordant data pairs and binomial distribution, with theta = 0.5. Parametric data were compared using students' t test. All comparisons were two-tailed, with alpha < 0.05 considered significant. RESULTS: 55 patients (32 male, 23 female, mean age 73 yr) with AS (mean aortic valve area 0.9 cm2) were studied. Cases and controls were identical for eight of nine pre-operative risk factors. Differences in perioperative management were found. Cardiac complications occurred in five cases and six control patients (P = 1.00). CONCLUSIONS: The current study, involving 55 patients with AS undergoing non-cardiac surgery, showed no difference in the risk of cardiac complications compared with matched controls. However, the intensification of management in the AS patients may have attenuated the risk in this group. The sample size was adequate to detect a fourfold increase in risk.

Aged↗

The effectiveness of insect-pollination test to evaluate the level of self-incompatibility and their genetic analysis in radish (Raphanus sativus L.).

We have tried an insect-pollination self-incompatibility (SI) test to strictly evaluate the level of SI as a model for the actual F(1) seed production field using radish as experimental material. Twelve inbred lines, homozygous for the S-alleles, were used in the artificial self-pollination and the insect-pollination SI test. There was a positive correlation ( r = 0.606) between the results by these two methods. Some lines showed a low level of SI in the insect-pollination test despite showing a high level of SI in the artificial self-pollination test. On the other hand, no lines showing a low level of SI in artificial self-pollination had a high level of SI in insect-pollination. These results show that the insect-pollination SI test can be considered to be a more reliable and stricter method than the artificial self-pollination test with respect to an evaluation of SI levels. We have raised and analyzed an F(2) population and F(3) lines derived from an F(1) cross between a line showing a high level of SI (R00-04) and one showing a low level. The rate of self-seed settings of the F(2) population showed a binomial distribution. There were 39 high-level SI plants to 15 low-level SI plants. This result and F(3) progeny tests suggested that the high level of SI which R00-04 showed is controlled by a dominant gene.

Animals↗

Persistent trigeminal artery associated with trigeminal neuralgia: hypothesis of neurovascular compression.

INTRODUCTION: The aim of this study was to determine the prevalence of persistent trigeminal artery (PTA) associated with trigeminal neuralgia (TN). METHODS: From January 1998 to January 2004, 288 MRI scans of patients examined for trigeminal deficits were retrospectively evaluated. MRI was performed at 1.5 T. Scan protocols included cerebral TSE T2-weighted imaging, contrast enhanced SE T1-weighted imaging and thin-section 3D T2-weighted imaging of the temporal bones, 3D TOF pre- and postcontrast MR angiography. TN was defined as episodes of intense stabbing, electric shock-like pain in areas of the face supplied by the trigeminal branches. Neurovascular compression (NVC) was assumed to be present if the patient showed clinical features of TN, if there was contact between an artery and the trigeminal nerve on the affected side, and if other pathology had been excluded. The prevalence and confidence intervals were calculated (95% CI of the prevalence was based on the exact binomial distribution). RESULTS: Of 288 patients, 136 matched the criteria for TN. In this series a PTA was detected in three patients, which in all patients was on the same side as the TN. The prevalence of a PTA in patients presenting with TN was 2.2% (CI 0.005-0.06). CONCLUSION: Previous studies have shown PTA as an incidental finding in 0.1-0.6% of cerebral angiograms. The prevalence of a PTA in patients with TN was 2.2%. With respect to the clinical significance, a PTA has to be considered in TN and the diagnosis of a PTA can easily be made using MR imaging/angiography.

Arterio-Arterial Fistula↗

Steal phenomenon through the anterior communicating artery in Moyamoya disease.

Branch occlusion of the anterior cerebral artery (ACA) is regarded as a part of Moyamoya disease. The purpose of this study is to define the ACA steal phenomenon (SP) in Moyamoya disease and to evaluate temoporal changes according to the disease progression. From 139 Moyamoya patients we defined ACASP as narrowing of the ipsilateral A1-2 junction while preserving the anterior communicating artery and supplying the contralateral ACA cortical branches with the development of leptomeningeal collaterals by the ipsilateral middle cerebral artery into the hypoperfused ipsilateral ACA territory. Direction of the steal related to the stage in both hemispheres by Suzuki classification was statistically analyzed using the binomial test based on binomial distribution. Follow-ups of ACASP were evaluated in five patients. We identified ACASP in 13 (9%) patients (male:female=7:6, mean age 18 years, range: 2-58 years) of the 139 study patients. The presenting pattern was ischemic in 12 and hemorrhagic in one. The direction of SP occurred from the hemisphere in the lower to the higher stage of Suzuki classification (two-tail P value=0.0002). After revascularization surgery, ACASP disappeared or diminished. ACASP may occur in bilaterally different stages of Moyamoya disease as a transient self-adaptive process. It regresses after revascularization surgery.

Adolescent↗

Presynaptic effects of biogenic amines modulating synaptic transmission between identified sensory neurons and giant interneurons in the first instar cockroach.

Intracellular recording was used to investigate the modulatory effects of serotonin and octopamine on the identified synapses between filiform hair sensory afferents and giant interneurons in the first instar cockroach, Periplaneta americana. Serotonin at 10(-4) mol l(-1) to 10(-3) mol l(-1) reduced the amplitude of the lateral axon-to-ipsilateral giant interneuron 3 excitatory postsynaptic potentials. and octopamine at 10(-4) mol l(-1) increased their amplitude. Similar effects were seen on excitatory postsynaptic potentials in dorsal giant interneuron 6. Several lines of evidence suggest that both substances modulate the amplitude of excitatory postsynaptic potentials by acting presynaptically, rather than on the postsynaptic neuron. The fitting of simple binomial distributions to the postsynaptic potential amplitude histograms suggested that, for both serotonin and octopamine, the number of synaptic release sites was being modulated. Secondly, the amplitudes of miniature excitatory postsynaptic potentials recorded in the presence of tetrodotoxin were unaffected by either modulator. Finally, recordings from contralateral giant interneuron 3, which has two identifiable populations of synaptic inputs, showed that each modulator had a more pronounced effect on excitatory postsynaptic potentials evoked by the lateral axon than on those evoked by the medial axon. Immunocytochemistry confirmed that neuropilar processes containing serotonin are present in close proximity to these synapses.

Animals↗

Cooperative mechanism for improving the discriminating ability in the chemoreceptor neuron binomial case.

The discriminating ability (selectivity) of the chemoreceptor neuron is compared with that of its receptor proteins. The process of neuronal triggering is expected to be cooperative and threshold type in a sense that the neuron fires a spike if and only if the number of receptor proteins which are bound with odor molecules is above a definite threshold. The binomial distribution is utilized to estimate the firing probability if a definite odor is applied. It is established that a chemoreceptor neuron can have a much higher selectivity than its individual receptor proteins, provided that the chemical stimuli are presented at low concentrations. A possibility for the above mechanism to be valid in other sensory systems is discussed.

Animals↗

[Hemostatic wound management in marcumar patients. Collagen fleece vs. tranexamic acid].

A total of 124 patients on oral anticoagulation therapy with coumarin were treated by orosurgical procedures and entered into a study to determine the hemostatic efficiency of different methods. The therapeutic anticoagulation level was determined in accordance with the recommendations of the American Heart Association (low risk: 2.0 < INR < 3.0; high risk: 2.5 < INR < 3.5) and maintained during treatment. In one group, the alveoli were treated with collagen, in a second group a mouthrinse regime with tranexamic acid was implemented. Twenty-three patients had to be excluded because anticoagulation levels differed from the recommended values. The group treated with collagen included 31 patients, the group with tranexamic acid mouthwashes, 32 patients. A third group was analyzed in which a controlled change in the anticoagulation level had been performed and all treated alveoli had been covered by mucosal flaps (n = 38); they were compared to the other two groups. The surgical proceedings were outlined precisely. Patients treated with collagen had a bleeding rate of 19%, patients with tranexamic acid mouthwash 6%, and those treated with mucosal flaps 40%. The data were not suited for statistical evaluation, they were objected to a descriptive analysis: the confidence intervals were determined by tables for binomial distributions. These did confirm the difference in the frequency of bleeding for the tranexamic acid and mucosal flap groups.

Adult↗

SISE matters: the sum of information on seventy-yr-old equivalents measures pedigree information content when assessing the risk of HNPCC in a family.

Hereditary non-polyposis colon cancer (HNPCC) is a significant cause of colorectal and other malignancies. Due to the lack of features that reliably differentiate between a sporadic case and an inherited case of colon cancer, it is likely that HNPCC is under reported. The diagnosis of HNPCC relies heavily on finding multiple cases of colorectal or other specific cancers within a family. In the absence of a significant family history, a diagnosis of HNPCC is seldom considered. We postulate that small kinships--or, more specifically, kinships with a low information content--are more likely to be designated as having a low risk of an inherited cancer predisposition than are large kinships. This has the potential to exacerbate the under-diagnosis of HNPCC in small families, leading to inadequate treatment, follow-up and family counselling. We have developed an objective measure of the information content of individual pedigrees called the Sum of Information on Seventy-yr-old Equivalents (SISE) coefficient. The SISE coefficient is a function of the number of relatives in a kinship and their relationship to the proband, of their ages and of the age-dependent penetrance of HNPCC mutations. A population-based series of colorectal cancer cases was assessed, by currently accepted methods, for the likelihood of there being an HNPCC mutation segregating in each family. We observed that families with a low SISE coefficient were significantly more likely to be designated at low risk of HNPCC (P< or =0.001). Using a cumulative binomial distribution function, we estimated the likelihood of observing multiple cancers in families of different SISE coefficients.

Adult↗

Logarithmic growth in surface adsorption.

A review is made of experimental data on surface adsorption of particles and polymers from water solutions, their analysis and interpretation in terms of general theoretical models of surface adsorption. A characteristic isotherm and kinetics is found and defined as logistic growth. The discussion is focused on literature indicating a possibility of describing logistic growth by using statistical (probabilistic) models based on the mean stay time of molecules on the surface. The statistical approach is further elaborated as follows: ligands arriving at a surface have a binary choice-to bind or to become reflected. Since the number of attempts to bind, n, will be high we can use the true mean of the binomial distribution to describe the reaction and write: S = n a; where S is the number of successful attempts and a is the probability of binding. The probability, a, will depend on the site density and on the sticking probability of the ligand at the binding site. Several experimental studies show that surface reactions have a nonlinear time- and concentration dependence and can be described by a Boltzmann factor of the form, I(1-e-t/tau); where I is the flux of ligands to the surface and tau = stay-time. The exponential form indicates that the reactions are self-dependent, and a statistical model for description of such reactions will be of the form: S(t) = N(o)(1-2-alpha t) (2-beta t); where N(o) is the number of molecules present in the system, alpha relates to the probability of positive cooperativity or t-dependent binding, and beta relates to the probability of desorption.

Adsorption↗

Statistical comparison of Pearl rates.

Statistical procedures for hypothesis testing and interval estimation of the difference in a pair of Pearl rates are presented. The p value of the test statistic is evaluated exactly from the binomial distribution or approximately from the standard normal distribution. Interval estimation is provided by the test-based method of Miettinen. The procedures are applied to two published data sets, and the conceptual link between the Pearl rate and life-table methods is discussed.

Actuarial Analysis↗

Molecular fragments associated with non-genotoxic carcinogens, as detected using a software program based on graph theory: their usefulness to predict carcinogenicity.

We assembled 390 chemicals with a structure non-alerting to DNA-reactivity (145 carcinogens and 245 non-carcinogens) for which rodent carcinogenicity data were available. These non-alerting chemicals were defined by the absence in their molecules of DNA-reactive (directly or after metabolic activation) alerting structures, as described by Ashby and coworkers (Mutat. Res., 204 (1988) 17-115; Mutat. Res., 223 (1989) 73-103; Mutat. Res., 257 (1991) 209-227; Mutat. Res., 286 (1993) 3-74). Using our software program based on graph theory we analyzed the compounds in order to estimate the program's ability to predict nonalerting carcinogens. Our software fragmented the structural formula of the chemicals into all possible fragments of contiguous atoms with size between 2 and 8 (non-hydrogen) atoms and learned about statistically significant fragments from a training set of chemicals. These fragments were used to predict carcinogenicity or lack thereof in a verification set of compounds. For 390 runs of the software program we used (n - 1) of the chemicals as a training set, to predict the excluded chemical at each run (as a test set). Using two different probability thresholds to select significant fragments (P = 0.05 and P = 0.125 1-tailed according to binomial distribution), we performed two analyses: in the better one (P = 0.05) 19% of the molecules tested lacked significant fragments, for the remaining 81% the observed level of accuracy of the prediction was 66.0% against an expected level of accuracy of 51.7%. The difference was highly significant (P < 0.0001). We also examined the more significant activating fragments (biophores) and discussed at length both their biological plausibility and the working hypothesis that additional alerting structures for carcinogenicity (not only those related to genotoxicity) can be detected using this type of SAR approach. This new class of alerting structures could identify subfamilies of congeneric analogs active through mechanisms of receptor mediated carcinogenesis.

Carcinogens↗