The Vibratome-Ralph knife combination: a useful tool for immunohistochemistry

A modified immunohistochemical technique is described for the improved detection of antigens. The method involves the use of the Vibratome combined with Ralph knives, which are easily manufactured with an LKB 2078 Histoknifemaker. The sectioning procedure was used with the peroxidase-antiperoxidase method of Sternberger and his collaborators for demonstrating growth hormone release-inhibiting hormone (somatostatin) and noradrenaline N-methyltransferase in neurones in the central nervous system of the rat. The morphological preservation of the tissue was good and cytological details were easily seen, especially in the thin sections (5-10 microns thick).     

Mean inactivation dose: a useful concept for intercomparison of human cell survival curves

The mean inactivation dose (D?) is calculated for published in vitro survival curves obtained from cell lines of both normal and neoplastic human tissues. Cells belonging to different histological categories (melanomas, carcinomas, etc.) are shown to be characterized by distinct values of D? which are related to the clinical radiosensitivity of tumors from these categories. Compared to other ways of representing in vitro radiosensitivity, e.g., by the multitarget parameters D(0) and n, the parameter D? has several specific advantages: (i) D? is representative for the whole cell population rather than for a fraction of it; (ii) it minimizes the fluctuations of the survival curves of a given cell line investigated by different authors; (iii) there is low variability of D? within each histological category; (iv) significant differences in radiosensitivity between the categories emerge when using D?. D? appears to be a useful concept for specifying intrinsic radiosensitivity of human cell lines.     

Transient binding patches: a plausible concept for drug binding

Dose–response curves for inhibitors (drugs) generally are analyzed by means of four-parameter fits, yielding IC₅₀, background, amplitude, and Hill coefficient. Hill coefficients ≠1 contradict 1:1 competition. If binding of substrates to proteins is a stepwise process where initial binding to initial locations (patches) leads to strong binding on defined sites, then drugs (non-endogenous inhibitors) may bind to those presumably larger patches and need not follow a 1:1 stoichiometry for specific inhibition. This concept was translated into three computable models and successfully fitted to 1,282 phosphatase dose–response curves. The models only required four parameters, namely, the equilibrium dissociation constant K _D(1) of the first inhibitor binding step, background, amplitude, and a compound interaction factor to quantify the interaction of inhibitors on those patches. Binding of one established inhibitor to the vaccinia virus VH1-related (VHR) phosphatase was directly measured with microcalorimetry, confirming multiple inhibitor binding with equilibrium constants obtained from corresponding inhibition curves.     

The continuum concept remains a useful framework for studying mycorrhizal functioning

Background

Recent studies have questioned the validity of the mutualism-parasitism continuum of mycorrhizal function. This paper re-evaluates the continuum model and analyzes these concerns.

Scope and Conclusions

Three insights arise from this analysis. First, the continuum model defines mycorrhizal function as an emergent property of complex interactions. The model identifies resource trade and symbiotic control as key determinants of the costs and benefits of the symbiosis for plants and fungi, and the interaction of these factors with the environment ultimately controls mycorrhizal function. Second, analysis of carbon costs and phosphorus benefits is too narrow a focus to accurately predict mycorrhizal function. Analysis of plant and fungal fitness responses in ecologically and evolutionarily relevant systems are required to elucidate the full range of nutritional and non-nutritional factors embodied within mycorrhizal functioning. Finally, the definition of the term ‘parasitism’ has evolved. Some fields of science maintain the original definition of a nutritional relationship between host and parasite while other fields define it as a +/- fitness relationship. This has generated debate about whether the continuum of mycorrhizal functioning should properly be called a positive–negative response continuum or a mutualism-parasitism continuum. This controversy about semantics should be resolved, but it does not overturn the continuum concept.     

The concept of a changing receptor concentration: implications for the theory of drug action

Drugs are considered to produce their effects on biological tissues either by altering some physical property of cells or by interacting with specific cellular components, called receptors. Most drugs and endogenous neurotransmitters act on highly selective receptors located on the outer surface membrane of cells. These receptors were believed, until recently, to be stationary on the cell surface and to be present in unvarying numbers. Consequently, most early theorists modeled the drug-receptor interaction on the basis of stationary and static receptor molecules. The substantial advances in our understanding of drug action based on these models have partly justified this view. However, recent electron microscopic studies have revealed the presence of structures, including "coated" pits and vesicles, that appear to provide a mechanism by which cell surface receptors might be internalized in a process of endocytosis. The precise intracellular fate of these internalized receptors is unknown, but based on present understanding, it seems reasonable to believe that some are destroyed intracellularly whereas others are recycled to the cell surface. The importance of such processes to pharmacologic theory is a new awareness of a cellular pathway that is capable of internalizing drugs, receptors, or both. The implications of such a process to the theory of drug action extends to some unexplained drug phenomena such as down regulation, drug tolerance, tachyphyllaxis, and partial agonism. We present herein the theoretical framework for a model of drug action that incorporates the possibility of receptor internalization and subsequent degradation, recycling, or replacement.     

The concept of the effective dose a proposal for the combination of organ doses

Irradiation of the human body by external or internal sources leads mostly to a simultaneous exposure of several organs. However, so far no clear and consistent recommendations for the combination of organ doses and the assessment of an exposure limit under such irradiation conditions are available. Following a proposal described in ICRP-publication 14 one possible concept for the combination of organ doses is discussed in this paper. This concept is based on the assumption that at low doses the total radiation detriment to the exposed person is given by the sum of radiation detriments to the single organs. Taking into account a linear dose-risk relationship, the sum of weighted organ doses leads to the definition of an "Effective Dose". The applicability and consequences of this "Effective Dose Concept" are discussed especially with regard to the assessment of the maximum permissible intake of radionuclides into the human body and the combination of external and internal exposure.     

How useful is the concept of habitat? – a critique

The following argument regarding the quantitative value of the habitat concept is presented for discussion purposes. The discussion is not intended as a review of the habitat-population literature (which is immense for any class of organism) and so does not include an exhaustive appeal to authority. Instead, the arguments are, largely, intended to stand or fall on their own merit, and the literature is used selectively to demonstrate a point.     

The economics of drug abuse: a quantitative assessment of drug demand

Behavioral economic concepts have proven useful for an overall understanding of the regulation of behavior by environmental commodities and complements a pharmacological perspective on drug abuse in several ways. First, a quantitative assessment of drug demand, equated in terms of drug potency, allows meaningful comparisons to be made among drug reinforcers within and across pharmacological classes. Second, behavioral economics provides a conceptual framework for understanding key factors, both pharmacological and environmental, that contribute to reductions in consumption of illicit drugs. Finally, behavioral economics provides a basis for generalization from laboratory and clinical studies to the development of novel behavioral and pharmacological therapies.     

Peroral peptide delivery: Peptidase inhibition as a key concept for commercial drug products

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