Practical guidelines for action regarding application of CPR/DNR

Technological advances in the field of medicine have resulted in the prolongation of lives that under ordinary conditions would have terminated. Such advances, though calling attention to the wonders of modern technology, are not without significant complications. The injudicious application of extraordinary procedures for extending life highlights problems that affect medical, social, and psychological as well as moral and ethical realms. The complexity of the problems has long since perplexed health/human service practitioners charged with effecting and/or assisting in the implementation of the critical life-death decisions on which this paper focuses.

A systematic strategy is outlined to guide human service providers in making decisions regarding the application or withholding of life-sustaining procedures. Emphasis is placed upon the integrity of self-determination as it relates to competency. Procedures for the incompetent patient are recommended.     

New evidence for a gating action of norepinephrine in central neuronal circuits of mammalian brain

Many previous studies have examined the effects of norepinephrine (NE) on neuronal responsiveness to synaptic inputs and putative transmitter substances and have described differential depressant actions of NE on stimulus evoked versus spontaneous discharge such that the "signal to noise" ratio of threshold responses was increased. In the present studies, similar experimental strategies employing a combination of microiontophoresis, single unit recording and afferent pathway stimulation in intact anesthetized and brain tissue slice preparations have revealed noradrenergic "gating" actions whereby weak or subthreshold synaptic stimuli can evoke threshold neuronal responses in the presence of iontophoretically applied NE or following electrical stimulation of the locus coeruleus. Overall, these results suggest that potentially threshold excitatory and inhibitory synaptic inputs may normally arrive at central neurons but appear weak or absent except during behavioral conditions favoring the synaptic release of NE. As such, these findings provide evidence that signal to noise ratio may not be the only potential modulatory action expressed by NE in noradrenergic target circuits of the mammalian brain.     

Structure-activity relationships for epidermal ornithine decarboxylase induction and skin tumor promotion by anthrones

The present study was designed to compare the skin tumor promotingand epidermal ornithine decarboxylase (ODC) inducing activitiesof various structural analogs of anthralin (1, 8-dihydroxy-9-anthrone)and chrysarobin (1, 8-dihydroxy-3- methyl-9-anthrone). Groupsof 30 SENCAR mice each were initiated with 7, 12-dimethylbenz[a]anthraceneand 2 weeks later promoted with once- or twice-weekly applicationsof various doses of these anthrone derivatives. Carbon-10 (C₁₀)-acylderivatives of anthralin were active skin tumor promoters inthe range of 25–440 nmol per mouse. 10-Acetylanthralinwas significantly more active than 10-myristoyl-anthralin atlow doses (e.g. 25 and 50 nmol per mouse) and nearly as potentas the unsubstituted compound. Higher doses ( 100 nmol per mouse)of this derivative were toxic, hence, reducing the final papillomaresponse. On a relative activity scale where anthralin is 1.0,these derivatives had activities that were 0.7 and 0.2, respectively.10, 10-Dipropylanthralin was totally inactive at the doses tested.C⁶-Substituted derivatives of chrysarobin demonstrated diversetumor promoting activities when tested in the range of 25–440nmol per mouse. On a relative activity scale where chrysarobinis 1.0, 6-methoxychrysarobin (physcion anthrone) was 0.9, whereas6-hydroxychrysarobin (emodin anthrone) had no activity. Chrysophanicacid (1, 8-dihydroxy-3-methyl-9, 10-anthraquinone) was alsoinactive as a tumor promoter at the doses tested. In general,the tumor promoting activities of these anthrone derivativescorrelated very well with their ability to induce epidermalODC after a single topical application indicating an importantrole for this enzyme in skin tumor promotion by anthones. Theability of C₁₀-substituted derivatives of anthralin to undergobase catalyzed oxidation in vitro correlated with both ODC inducingand tumor promoting activities. In addition, copper(II) bis(diisopropylsalicylate)was found to inhibit both ODC induction and skin tumor promotionby chrysarobin. These latter data, when taken together, suggesta role for oxidation at C₁₀ in skin tumor promotion by anthronederivatives.     

Regulatory developmental neurotoxicity and human risk assessment.

A number of efforts, in the last 15 years, have been directed at developing protocols to assess the potential developmental neurotoxicity (DN) of test agents. Japan and the United Kingdom have general protocols that describe the behavioral parameters that should be evaluated as part of other types of testing protocols, such as standard developmental and/or reproductive toxicity studies. In 1986, EPA published a proposed separate guideline for the testing of glycol ethers. Since then, this protocol has undergone extensive review and comment by an agency-wide workgroup, participants of a workshop sponsored by EPA and NIDA, EPA's Scientific Advisory Panel, and the public. Comments were taken into consideration and the final DN testing protocol has been published recently by EPA's Office of Pesticide Programs. This protocol provides specific guidance on issues of study design, aspects of CNS function to be evaluated and criteria for selection of testing procedures. It is designed to be a "generic" protocol could be applied to testing of pesticides and other chemicals and that could be modified on a case-by-case basis depending on the data available on a specific agent of concern. With the development of testing protocols for assessing DN, there comes a need for the development of guidance as to how the data should be interpreted and applied toward conducting a risk assessment for extrapolation to humans. Some guidance was developed at the EPA-NIDA Workshop. EPA has published specific risk assessment guidelines in the area of developmental toxicity that include a section on interpretation of data on functional deficits, including DN.(ABSTRACT TRUNCATED AT 250 WORDS)     

Seasonal prevalence of major congenital malformations in the Fylde of Lancashire 1957-1981.

The seasonal prevalence of major congenital malformations was studied in a prospective survey of 88,449 children born in the circumscribed Fylde of Lancashire to residents there over 25 years. Ascertainment was thought to be as complete as was practically possible because cases were recorded daily by one, and for 17 years the only, paediatrician and a very high rate of necropsies was maintained. The number of malformations were classified by month of maternal last menstrual period and seasonal variation was assessed by three statistical models. Neural tube defects showed a significant seasonal variation in month of last menstrual period but not in month of birth. From May 1956 to April 1968, when the prevalence of neural tube defects was high (5.5 per 1000 total births), conceptions were significantly more common in December to May. For anencephaly alone the figures were not significant, but spina bifida and cranium bifidum were more common in March to May. From May 1968 to April 1981, when the prevalence of neural tube defects fell below the national average, the significant variations disappeared. Seasonality for spina bifida and cranium bifidum was seen only in "singles" (cases with no other major lesion), but for anencephaly it was seen only in "multiples" (cases with other lesions). The three types of cardiac septal defect and persistent ductus each showed a higher prevalence of conceptions at some time during May to October. In contrast the commonest group of cyanotic cases showed no such pattern but with greater numbers in winter. There was evidence of a seasonal variation for bilateral renal agenesis and for vesicoureteric reflux as ascertained. Seasonal prevalence in an aetiological factor for certain malformations of the central nervous system, cardiac and urinary systems.     

Novel mutations in type 2 Gaucher disease in Chinese and their functional characterization by heterologous expression

We investigated 10 unrelated Chinese patients with type 2 Gaucher disease and performed ex vivo expression for the novel mutations to characterize their functional defects. These patients were diagnosed by enzymatic assays and clinicopathologic features over the past five years in a national centre in China. Genomic DNA was sequenced by a two-stage PCR approach for mutations in the functional GBA gene. Novel mutations were expressed with baculovirus-transfected Sf21 cells. Six novel mutations were found (in traditional nomenclature): P122L, Y363C, N382K, L383R, L385P, and M416V. Review of reported mutations indicated clustering of type 2 mutations in three regions of the GBA gene. Expression of novel mutations revealed that the enzyme defect could arise from one of two mechanisms: loss of catalytic activity (Y363C and M416V) or enzyme instability (P122L and N382K).     

The atheroprotective effect of 17beta-estradiol depends on complex interactions in adaptive immunity

Estradiol prevents fatty streak formation in chow-fed atherosclerosis-prone apolipoprotein E (ApoE)-deficient mice. We previously reported that fatty streak development of immunodeficient ApoE(-/-)/recombination activating gene 2 (RAG-2(-/-)) double-deficient mice was insensitive to estradiol. In the present work, we demonstrate that the reconstitution of ApoE(-/-)/RAG-2(-/-) with bone marrow from immunocompetent ApoE(-/-)/RAG-2(+/+) mice restores the protective effect of estradiol on fatty streak constitution. We extended this demonstration to the model of low-density lipoprotein receptor-deficient mice, establishing the obligatory role of mature lymphocytes in this process. We then investigated whether the protective effect of estradiol was mediated by a specific lymphocyte subpopulation by studying the hormonal effect on fatty streak constitution in recently developed models of ApoE(-/-) mice deficient in selective T-lymphocyte subsets (either TCRalphabeta+, CD4+, CD8+, or TCRgammadelta+ lymphocytes) or B lymphocytes. In all these specifically immunodeficient mice, estradiol administration to ovariectomized mice conferred protection as in immunocompetent ApoE(-/-) mice, clearly demonstrating that no single lymphocyte subpopulation was specifically required for this effect. These results point to additional lymphocyte-dependent mechanisms such as modulating the interactions among lymphocytes and between lymphocytes and endothelial and/or antigen-presenting cells.     

Evaluation of the association of nine Helicobacter pylori virulence factors with strains involved in low-grade gastric mucosa-associated lymphoid tissue lymphoma

Helicobacter pylori has been associated with the development of two malignant diseases: gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Although the cag pathogenicity island, especially the cagA gene, has been linked with adenocarcinoma, few data concerning H. pylori pathogenic factors involved in low-grade gastric MALT lymphoma are available. The goal of this study was to analyze the prevalence of and correlation between genes coding for seven H. pylori virulence factors (cagA, cagE, vacA, iceA, babA, hopQ, and oipA) and two novel adhesins (sabA and hopZ) by comparing a collection of 43 H. pylori strains isolated from patients with low-grade gastric MALT lymphoma to 39 strains isolated from age-matched patients with gastritis only. Our results show that taken individually, none of the nine genes tested can be considered associated with MALT strains and allow us to conclude that MALT pathogenesis is not linked with more proinflammatory H. pylori strains. We demonstrated that in patients infected with strains harboring the iceA1 allele, sabA functional status, and hopZ "off" status, the odds of developing a MALT lymphoma were 10 times higher. However, the low prevalence of such strains (10 of 43 MALT strains) renders this triple association a low-sensitivity marker for MALT strains. Our data confirmed that H. pylori virulence factors are correlated with one another. If the involvement of H. pylori in MALT lymphoma is well established, the pathomechanism by which gastric lymphoma occurs remains to be identified.     

Pathogenesis of fever in delayed hypersensitivity: factors influencing release of pyrogen-inducing lymphokines.

In continuing studies on the pathogenesis of fever in states of delayed hypersensitivity, we have investigated the conditions for the release of an endogenous pyrogen (EP)-inducing lymphokine from draining-lymph-node lymphocytes of rabbits with delayed hypersensitivity to bovine gamma globulin. Using doses of 4 X 10(7) to 5 X 10(7) blood leukocytes (BL) as a source of EP, we found that ratios of about 5:1 of viable lymphocytes to BL were required to stimulate the BL to produce detectable amounts of EP in vitro. Both irradiated lymphocytes (1,700 R) as well as those from steroid-treated donors retained their ability to activate BL when incubated with antigen, properties consistent with activated "T" lymphocytes. In experiments to determine effects of temperature and duration of incubation on lymphokine release, the maximum EP-releasing activity was found to be present in supernatants of sensitized lymphocytes incubated with antigen for 18 h at 37 degrees C. These studies have confirmed that sensitized lymphocytes release a soluble, pyrogen-inducing lymphokine when incubated with antigen and further demonstrate that tissue macrophages (Kupffer cells) as well as BL can be activated to produce EP in vitro by this agent.