Calculation of clinical r.b.e. values for neutrons

A method is described for calculating r.b.e. values for normal tissues at risk in clinical neutron beam therapy. This is based on the assumption that with high l.e.t. radiations the slope of the cell survival curve is steeper, mainly in the initial or low-dose region. This effect is quantified by using two coefficients, one (epsilon) to produce a proportionate increase in the initial slope, and a second (eta) determining the change in the terminal slope (D0) of the survival curve. Analysis of published experimental data shows epsilon to be a variable quantity, different for different tissues; epsilon is larger when the survival curve has a large shoulder or slope ratio (rho). By contrast, eta is relatively constant (for a given beam) and less dependent on the tissue or end-point studied. For low doses, the r.b.e. approaches epsilon, which can be calculated given eta (characteristic of the beam) and rho (characteristic of the relevant tissue) [epsilon = eta + rho(eta - 1)]. This provides a useful approximation to the clinical r.b.e. for specific tissues relative to conventionally fractionated low-l.e.t. photons.     

Debendox in early pregnancy and fetal malformation.

During the mid-1960s, 22 977 pregnant women in Scotland and England were followed up prospectively for the incidence of malformations in their infants evident at birth or within six weeks. During the first 13 weeks of gestation 620 of these women had been prescribed Debendox (dicyclomine-doxylamine-pyridoxine) and 743 other women agents other than Debendox containing pyridoxine. Of the 620 women given Debendox, 589 (95%) had a normal outcome of pregnancy, 8 (13%) delivered a malformed infant, and 23 (3.7%) had other outcomes. Of the 22 357 women who were given Debendox, 445 (2.0%) produced infants with malformation; and the rates for all abnormal outcomes among women given Debendox and those not given the drug were 5.0% and 5.4% respectively. These results support the hypothesis that Debendox is not teratogenic.     

Effect of a single treatment with the alkylating carcinogens dimethylnitrosamine and methyl methanesulphonate on liver regenerating after partial hepatectomy. III. Effect on DNA synthesis in vivo and on DNA polymerase activity assayed in vitro.

A single treatment with dimethylnitrosamine (DMN) but not with methyl methanesulphonate (MMS) induces liver cell carcinoma if given during the period of restorative hyperplasia following partial hepatectomy, a higher incidence of tumours being induced if the carcinogen is given during the period of DNA synthesis (24 h after the operation) than if given early in the prereplicative stage (at 6 h). To study the effect of treatment with DMN and with MMS on the regenerating liver, DNA replication was measured in vivo in partially hepatectomised animals treated with the methylating agents, and DNA polymerase activity was assayed in vitro.     

Effect of a single treatment with the alkylating carcinogens dimethylnitrosamine, diethylnitrosamine and methyl methanesulphonate, on liver regenerating after partial hepatectomy. II. Alkylation of DNA and inhibition of DNA replication.

Experiments were carried out to determine whether replication of alkylated DNA could be involved in the initiation of hepatocellular carcinoma which results from a single administration of dimethylnitrosamine (DMN) given after partial hepatectomy. The incidence of tumours is higher when DMN is given during the wave of DNA synthesis induced by the operation than when given in the early prereplicative stage. Therefore the alkylation of DNA in the regenerating liver by DMN given at these times and the effect of DMN on DNA synthesis were investigated. The extent, duration and pattern of alkylation of DNA, including the formation of 0-6-methylguanine, were similar whether DMN was given in the early pre-replicative stage (6 h after the operation) or during the period of DNA synthesis (at 24 h). DMN given a 6 h very greatly reduced the wave of DNA replication which would otherwise have ensued. When given at 24 h, by which time DNA synthesis was already taking place, DMN reduced the rate of incorporation of (-3H)thymidine after 1-2 h delay. However, in neither case was DNA synthesis reduced to the level occurring in normal intact liver. Treatment with diethylnitrosamine (DEN) at 6 h or at 24 h had a similar effect to DMN on the wave of DNA replication induced by partial hepatectomy. Methyl methanesulphonate (MMS given in the early pre-replicative stage delayed the wave of DNA synthesis by about 8 h, but when it did take place the extent of synthesis was as great as in untreated animals. When given during the period of DNA replication, MMS rapidly reduced the rate of synthesis. As in the case of the nitrosamines, synthesis was not reduced to the level occuring in normal intact animals. The difference from the nitrosamines lies in the nature of the alkylated bases formed in DNA. The fact that a single treatment with DMN induces cancer in partially hepatectomised animals but not in intact adult animals is not considered to be due to a gross difference in the nature of the alkylation of DNA. The experiments described support the concept that replication of DNA containing bases which are likely to mispair during replication may be necessary to 'fix' the lesion and thus cause a permanent inheritable change in the genetic material.     

913. MEEHANIA FARGESII var. PEDUNCULATA

Meehania fargesii var. pedunculata (Hemsley) C. Y. Wu, from the mountains of western China, is illustrated. The history and variation in the species is discussed, and suggestions for its successful cultivation are given.     

Prostaglandins, cyclic AMP and the mechanism of opiate dependence.

Further evidence is given that dependence arises from the agonist action of opiates. From this and our previous propositions assigning a fundamental role to neuronal cyclic AMP in (i) the agonist action of opiates and (ii) the expression of the abstinence syndrome, it follows that opiate dependence is a state of heightened potential activity of a neuronal cyclic AMP mechanism, initiated and maintained by the blockade of an adenylate cyclase. Various possible mechanisms are discussed by which this potential is heightened. New evidence is given that morphine and naloxone stimulate prostaglandin biosynthesis without mutual antagonism. Preliminary evidence also is given that (i) the formation of cyclic AMP is enhanced in brain homogenates from heroin-dependent rats, and (ii) an acidified ethylacetate extract of brains of morphine-dependent rats induces quasi-abstinence effects when injected into a lateral cerebral ventricle of naive rats.     

Bleeding varices: 1. Emergency management.

The aim of the emergency management of bleeding varices is to stop the hemorrhage nonoperatively if possible, avoiding emergency shunt surgery, an operation that has a higher mortality than elective shunt surgery. Patients with an upper gastrointestinal hemorrhage should undergo endoscopy immediately to verify the diagnosis of bleeding varices. They can then be categorized according to whether they stop bleeding spontaneously (group 1), continue to bleed slowly (group 2) or continue to bleed rapidly (group 3). Group 1 patients are discussed in the second part of this two-part series. Group 2 patients are initially treated with vasopressin given intravenously; those who fail to respond should undergo emergency angiography and receive vasopressin intra-arterially. If this fails, patients at low surgical risk should undergo urgent shunt surgery; those at high risk do better with endoscopic sclerotherapy. Group 3 patients are also given an intravenous infusion of vasopressin. Patients at low surgical risk who continue to bleed then receive tamponade with a Sengstaken--Blakemore tube. If this fails, they undergo emergency creation of an H-shaped mesocaval shunt. Patients at high surgical risk who fail to respond to vasopressin given intravenously are next treated intra-arterially. If this fails they are given either endoscopic or transhepatic sclerotherapy.     

Adverse reactions to frusemide in hospital inpatients.

Out of 2580 medical inpatients included in a drug-surveillance programme, 585 (22.7%) were treated with frusemide. Of these, 123 (21.0%) had a total of 177 adverse reactions. The most common were hypovolaemia (85 cases), hyperuricaemia (54), and hypokalaemia (21). Most reactions were mild, and only three patients had potentially life-threatening effects. The incidence of adverse reactions increased significantly with daily dose, occurring in 47 patients (13.5%) given up to 40 mg, 42 (26.3%) given up to 80 mg, and 34 (43.6%) given over 80 mg (P less than 0.001). There was no clear association between side effects and a raised blood urea concentration on admission, confirming that treatment with frusemide is not more hazardous in patients with renal failure. Frusemide is a safe and highly effective diuretic. Nevertheless, in view of the potential seriousness of volume depletion, dosage should probably begin at 20 rather than 40 mg daily.     

Sample size considerations in genetic polymorphism studies.

OBJECTIVES: Molecular studies for genetic polymorphisms are being carried out for a number of different applications, such as genetic disorders in different populations, pharmacogenomics, genetic identification of ethnic groups for forensic and legal applications, genetic identification of breed/stock in animals and plants for commercial applications and conservation of germ plasm. In this paper, for a random sampling scheme, we address two questions: (A) What should be the minimum size of the sample so that, with a prespecified probability, all alleles at a given locus (or haplotypes at a given set of loci) are detected? (B) What should be the sample size so that the allele frequency distribution at a given locus (or haplotype frequency distribution at a given set of loci) is estimated reliably within permissible error limits? METHODS: We have used combinatorial probabilistic arguments and Monte Carlo simulations to answer these questions. RESULTS: We found that the minimum sample size required in case A depends mainly on the prespecified probability of detecting all alleles, while in case B, it varies greatly depending on the permissible error in estimation (which will vary with the application). We have obtained the minimum sample sizes for different degrees of polymorphism at a locus under high stringency, as well as a relaxed level of permissible error. We present a detailed sampling procedure for estimating allele frequencies at a given locus, which will be of use in practical applications. CONCLUSION: Since the sample size required for reliable estimation of allele frequency distribution increases with the number of alleles at the locus, there is a strong case for using biallelic markers (like single nucleotide polymorphisms) when the available sample size is about 800 or less.     

Cytogenetic studies in Cochlearia L. (Cruciferae). The origins of C. officinalis L. and C. micacea Marshall

Genome analysis has been used to investigate the evolutionary relationships of the tetraploid species in the genus Cochlearia. The results indicate that both C. officinalis L. (2n=24) and C. micacea Marshal (2n=26) are essentially autotetraploid in origin and that C. scotica Druce is simply a morphological variant of C. officinalis. The chromosomal relationships of the tetraploids to each other and to the diploids in the genus are discussed and the possible routes for the formation of all the species from a single, 2n=12, basic taxon are given. Evidence for the existence of a genic mechanism causing C. officinalis to form only bivalents is given and the mode of evolution of such a mechanism discussed.     

Glycogen metabolism: the integrated cellular response to a bi-directional metabolic stimulus.

The control exerted by phosphorylase a over the I-conversion of glycogen synthase (1) does not apply to glycogen synthesis, as judged from experiments with intact human leucocytes. 1. In incubated leucocytes conversion of glycogen synthase (GS) (E.C.2.4.1.11) to GS-I is preceeded by inactivation of glycogen phosphorylase a (GPh-a). 2. By the addition of latex particles a flash-activation of GPh-a can be elicited within 10–30 sec. in the intact cells. 3. GPh is inactivated when a glucose load is given. 4. When, in glycogen depleted cells, glucose is given immediately after latex the I-conversion of GS is completely abolished, and GS-I remains low for 20 min although GPh is rapidly inactivated after the glucose is given. 5. However, glycogen synthesis as compared with a control in which only glucose is given, and in which a large I-conversion occurs, is not the least depressed. 6. This apparent contradiction is completely resolved taking into account a newly discovered, intermediate form of GS (2) (GS-R). 7. An important physiological role can be proposed for GS-R.     

General continuum analysis of transport through pores. II. Nonuniform pores.

A general continuum derivation of the nonelectrolyte (Js) and volume (Jv) flux through a pore whose cross section is a function of axial position (nonuniform) is given. In general, the flux equations cannot be reduced to the same form as for a uniform pore and it is not possible to characterize the pore kinetics by three constants as in the uniform pore case. However, it is shown that under certain conditions, the nonuniform pore equations can be approximated by the uniform pore form and can be characterized by three constants (omega, sigma, Lp). The only condition needed to reduce the Jv equation to the uniform form is that the solution be dilute. The deviation of the Js equation from the uniform form is characterized by an asymmetrical function of Jv whose maximum value is estimated. It is shown that the maximum posible fractional deviation of the Js equation from the uniform form is given by the parameter: 0:5sigmaJv/omegaRT. Since this parameter is less then 0.15 for most membrane studies, the nonuniform Js equation can usually be approximated by the uniform pore form. The general results are illustrated by explicit calculations on several models of nonuniform pores. It is shown, for example, that the "equivalent pore radius" defined in the usual way is a function of the experimental parameter that is measured and is not unique.     

How to read a paper. Statistics for the non-statistician. II: "Significant" relations and their pitfalls.

It is possible to be seriously misled by taking the statistical competence (and/or the intellectual honesty) of authors for granted. Some common errors committed (deliberately or inadvertently) by the authors of papers are given in the final box.     

Estimation of viable airborne microbes downwind from a point source.

Modification of the Pasquill atmospheric diffusion equations for estimating viable microbial airborne cell concentrations downwind form a continuous point source is presented. A graphical method is given to estimate the ground level cell concentration given (i) microbial death rate, (ii) mean wind speed, (iii) atmospheric stability class, (iv) downwind sample distance from the source, and (v) source height.     

Sorting by short swaps.

A short swap is an operation on a permutation that switches two elements that have at most one element between them. This paper investigates the problem of finding a minimum-length sorting sequence of short swaps for a given permutation. A polynomial-time 2-approximation algorithm for this problem is presented, and bounds for the short-swap diameter (the length of the longest minimum sorting sequence among all permutations of a given length) are also obtained.