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Metabolic gradients are known to influence cellular differentiation at critical junctures of development. The existence of these gradients will stimulate variations in the rate of generation of active oxygen metabolites by metabolic pathways. Recent evidence suggests that cellular oxidation can induce changes in gene expression during normal development. Conversely, antioxidants such as ascorbate, alpha-tocopherol and beta-carotene are inhibitory to differentiation in many types of cells. One basis of oxidative influence on gene expression stems from changes in cellular calcium distribution.

The activities of superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione S-transferases, GSSG reductase, thiol transferases, gamma glutamyl-cysteine synthetase, and glucose-6-phosphate dehydrogenase, and the concentrations of H2O2 and reduced and oxidized glutathione were determined in the various developmental stages of houseflies. Housefly development was correlated with a progressive increase of cellular oxidizing equivalents and a loss of cellular reducing capacity. The loss of reducing equivalents appeared to result from a decrease in the activity of enzymes involved in glutathione and NADPH synthesis and a concomitant increase in glutathione-oxidizing enzymes. Relatively little change was observed in SOD activity during housefly development; however, the electrophoretic pattern of MnSOD varied in a manner specific to developmental stage. A striking increase in H2O2 concentration occurred prior to pupation possibly due to changes in substrate catabolism. These results support the hypothesis that the cellular environment becomes progressively more oxidizing during development.

Metabolic gradients are established during early phases of development and their existence influences subsequent developmental events. Variations in oxygen supply and oxygen metabolism associated with the gradation of metabolic rate in embryos appear to form one basis for the influence of metabolic gradients on development. The rate of oxygen metabolism affects the rate of oxidant generation by various cellular biochemical pathways. Cells contain antioxidant defenses that respond to variations in cellular oxidant production. Large changes in the activity of the antioxidant enzyme superoxide dismutase and changes in cellular redox state occur during the differentiation of many types of cells. These changes correspond to an increased rate of oxidant production; the cellular environment becomes more prooxidizing during differentiation. Evidence is presented that implicates oxidants as a factor that can stimulate alterations in gene expression. Possible mechanisms by which oxidants influence gene expression are also discussed.

Fanconi anemia (FA) is an autosomal recessive disorder characterized clinically by a progressive pancytopenia, diverse congenital abnormalities, and increased predisposition to malignancy. Although a variable phenotype makes accurate diagnosis on the basis of clinical manifestations difficult in some patients, the unique sensitivity of FA cells to the clastogenic effect of DNA cross-linking agents such as diepoxybutane (DEB) can be used to facilitate the diagnosis. We review all cases of FA reported to have leukemia, preleukemia, or a bone marrow (BM) clonal chromosomal abnormality and include for the first time an analysis of these conditions observed in patients in the International Fanconi Anemia Registry (IFAR). The incidence of acute myelogenous leukemia (AML) in FA patients is more than 15,000 times that observed in children in the general population. Cytogenetic studies of FA-associated leukemias disclose a high frequency of monosomy 7 and duplications involving 1q. There were no occurrences of t(8;21), t(15;17), or abnormalities of 11q, which are associated with M2, M3, and M5 leukemias, respectively, but not with preleukemia. Development of leukemia in FA patients was associated with an exceedingly poor prognosis, with a mean age of death of 15 years. We suggest that all FA patients may be considered preleukemic and that this disorder presents a model for study of the etiology of AML.

Free radicals are believed to play a fundamental role in a wide variety of biological phenomena, including aging. The involvement of free radicals in aging has usually been attributed to the destabilizing effects of structural damage. Recent evidence has indicated, however, that there are at least two other mechanisms by which free radicals may influence the aging process. Specific free radical reactions and their effects in biological systems have been reviewed by several authors and will not be extensively examined here to avoid redundancy. Instead, the mechanisms by which free radicals are postulated to influence the aging process shall be the focus of this discussion. It should be noted that none of the mechanisms to be discussed are exclusive of the others and, in fact, all of these explanations may ultimately prove to be necessary to understand fully the role of free radicals in the aging process.

We present new ultraviolet (UV) polarimetry of the well-studied interstellar line of sight toward HD 204827 obtained with the Faint Object Spectrograph on Hubble Space Telescope. HD 204827 is of great interest because the dust along this line of sight has extremely low values of both lambda(sub max) and R(sub V). Its far-UV extinction is very large, reflecting its small R(sub V) value. In addition, we reexamine the entire sample of 14 interstellar lines of sight for which there are now UV polarization data. We find that the previously suggested relationship between lambda(sub max) and the wavelength dependence of the polarization in the UV is strongly supported by the data for this larger sample including HD 204827. Seven stars with lambda(sub max) greater than or equal to 0.54 micron agree well with an extrapolation of the Serkowski relation into the UV while seven stars with lambda(sub max) less than or equal to 0.53 micron show polarization in excess of the Serkowski extrapolation (super-Serkowski). However, the division of the observed lines of sight into Serkowski and super-Serkowski categories is artificial. In fact, the amount of polarization in the UV is correlated with a single parameter, lambda(sub max). This may indicate that there is a mean interstellar polarization law analogous to the mean interstellar extinction law of Cardelli, Calyton, & Mathis which is based on R(sub V). The data are consistent with a linear relationship between 1/lambda(sub max) and rho(UV)/rho(sub max) but more data are needed to define the functional form. We suggest that the Serkowski and super-Serkowski designations be replaced by high and low lambda(sub max) which are more physically descriptive. At the same time, we note that all seven super-Serkowski (low lambda(sub max)) stars lie in a relatively small region of the sky between l(sup II) = 90 deg - 150 deg and b = -5 deg - 15 deg. These stars all lie in or behind a spur of the local Orion spiral arm. Similarly, most of the Serkowski (high lambda(sub max) stars lie in or near the Scorpio-Centaurus OB Association. So lines of sight covering larger areas of the sky are needed to test the universality of the lambda(sub max)/UV polarization relationship. The recent discovery of warm dust near HD 197770 suggests the possibility that a mechanism other than the traditional alignment to the Galactic magnetic field may be invoked to explain its 2175 A polarization bump.

We have used the Faint Object Spectrograph of the Hubble Space Telescope to observe interstellar linear polarization from 1300 to 3300 A in two stars with well-studied interstellar polarization at visible wavelenths. The wavelength dependence of linear polarization declines smoothly with decreasing wavelength and is devoid of structure associated with the prominent 2175 A absorption bump in the interstellar extinction curve. The data for one star (HD 161056) are consistent with an extrapolation based on the Serkowski formula of a fit to the ground-based polariztion; the other star (HD 7252) shows excess (super-Serkowski) polarization relative to the extrapolation. Out of a total of 10 stars now studied by means of spectropolarimetry in the satellite ultraviolet, including eight obseved with the Wisconsin Ultraviolet Photopolarimeter, five (those of longest lambda (sub max)) show Serkowski behavior, and four others show super-Serkowski behavior; only one (HD 197770) shows evidence for polarization associated with the 2175 A bump. These results place important constraints on the nature of the bump feature.

We have previously reported that calcium is required for the starvation-induced differentiation of the slime mold, Physarum polycephalum. With the exception of calcium, each component of the complex starvation medium may be withheld and the organism will still differentiate into spherules. The results of the present study reveal that spherulation will proceed normally when the microplasmoidal cells are transferred from nutrient medium to a citrate buffer containing only 8 mM Ca CI2. Electron microscopy and X-ray microprobe analysis reveal that there is an initial increase in the population of calcium-containing mitochondrial granules when the microplasmodia are induced to differentiate. However, as differentiation proceeds, these granules decrease in number and are virtually absent from the mitochondria of mature spherules. The accumulation and depletion of calcium-containing granules is not observed in a nondifferentiating strain of Physarum cultured under standard conditions, but is observed when this strain is first treated with a calcium-enriched nutrient medium that conditions it for spherulation. Changes in the cellular concentrations of NADH and lipid peroxides, and in the activity of superoxide dismutase, correspond temporally to the pattern of increase and depletion of the calcium-containing inclusions. The oxidative stress associated with starvation-induced spherulation may be a consequence of the active accumulation of calcium; the mobilization of this calcium may then be the event that initiates differentiation.

The effects of total inhibition of catalase, induced by 3-amino-1,2,4-triazole, on the adult housefly (Musca domestica) were examined. The lack of catalase activity had no effect on the longevity of the houseflies. Inorganic-peroxide concentration was elevated at younger ages, but declined in older flies. The rate of oxygen consumption by the flies was greatly decreased and the levels of oxidized as well as reduced glutathione were augmented. Superoxide dismutase activity showed a slight increase. This study suggests that loss of catalase activity does not affect survival of houseflies due to adaptive responses.

Confluent cultures of human skin fibroblast lines established from fetal and postnatal donors were exposed to a broad range of oxygen tensions (10-600 mmHg) for 1 wk; superoxide dismutase (SOD) activity was subsequently determined. Hyperoxia increased SOD activity slightly in postnatal lines but not in fetal lines. The magnitude of the increase in postnatal lines was not significant. Fetal lines exhibit only about one-fifth the SOD activity observed in postnatal lines. The results indicate that, while development-associated changes in SOD do occur in human cells, these alterations do not result from variations in ambient oxygen tension.

Glycerol starvation of an Escherichia coli glycerol auxotroph results in a specific inhibition of membrane phospholipid synthesis. Mindich ((1972) J. Bacteriol. 110, 96-102) observed only a trace accumulation of free fatty acid following glycerol deprivation. We have repeated these experiments using glycerol auxotrophs which also possess a lesion in beta oxidation. This defect was introduced in order to control fatty acid degradation. In contrast to the previous results, we find free fatty acid does accumulate during glycerol starvation. Similar results were found using beta oxidation-defective (fadE-) derivatives of both gpsA and plsB glycerol auxotrophs. Upon glycerol starvation of a plsB- fadE- strain, phospholipid synthesis is 90 percent inhibited. Following a lag of 20 to 40 min, free fatty acid synthesis begins and proceeds at a rate that steadily increases until the rate of fatty acid synthesis is equal to that found in glycerol-supplemented cultures. The accumulation of free fatty acid is the result of de novo synthesis. The average chain length of the fatty acid in the unesterified fraction is abnormally long. Two 20-carbon fatty acids, cis-13-eicosenoic acid and arachidic acid, are found in this frction. Furthermore, a greatly increased level of stearic acid and a small amount of a C-22 (behenic) acid are found in the free fatty acid fraction. These data indicate that acyl transfer into phospholipid is a major determinant of phospholipid acyl moiety chain length. Other experiments have shown that the free fatty acid fraction in glycerol-starved cells is metabolically active. This fraction turns over despite the defective beta oxidation system. Restoration of glycerol to starved cells allows the incorporation of the unesterified fatty acids into phospholipid.

The authors outline the progression of thought on the mechanism of the aging process, giving emphasis to environmental factors that influence genetic events. Discussion is limited to those theories that explain fundamental causes of aging and have a firm thermodynamic basis. The authors propose that the cumulative result of continual oxidative stress and other thermodynamic processes (such as aminoacid racemization and nonenzymatic glycosylation), resulting in altered function and increasing the net entropy of living systems, governs the rate of the aging process.

Microplasmodia of Physarum polycephalum differentiate into spherules when the CaCI2 concentration of their nutrient medium is increased to 54mM (high- calcium). The salts starvation medium routinely used to induce differentiation contains 8mM CaCI2. This medium will not induce spherulation in the ab- sence of a calcium salt; no other metal is essential. High-calcium also induces the spherulation of a strain of Physarum that had not been previously ob- served to spherulate. The striking increase in superoxide dismutase activity (SOD) and the decrease in glutathione concentration (GSH) that are charac- teristic of salts-induced spherulation do not occur in salts media containing high-calcium. In the absence of calcium, no significant change in SOD is observed and very little change in GSH occurs. The immediate effect of the oxidative stress associated with spherulation may be the release of calcium stores into the cytosol. The parameters modulating this stress are, in turn, sensitive to exogenous calcium concentrations. Cellular differentiation is ultimately due to qualita- tive and quantitative alterations in gene expression. At present the nature of the mechanisms governing devel- opmental changes in gene expression remains obscure. Cytoplasmic fields, gradients, and morphogenetic deter- minants are widely believed to modulate the transition of embryonic tissues into differentiated cell types (Na- menwirth, 1974; Summerbell, 1979; Summerbell et al., 1973; Wolpert, 1978). Among the factors which appear to play a role in development are the metabolic and chemical gradients observed in developing organisms; these arise from regional variations in surfaceholume ratio and from differential vascularization of the embry- onic tissues (Boveri, 1901; Browder, 1980; Caplan and Ordahl, 1978; Child, 1915). The effects of metabolic gra- dients on development may be partly due to differential nutrient supply; however, there is also evidence that variations in molecular oxygen concentration play a role in the regulation of developmental processes (Jargiello and Caplan, 1983; Caplan and Koutroupas, 1973). The mechanism by which oxygen and its metabolites affect gene expression is presently unknown.

The authors outline the progression of thought on the mechanism of the aging process, giving emphasis to environmental factors that influence genetic events. Discussion is limited to those theories that explain fundamental causes of aging and have a firm thermodynamic basis. The authors propose that the cumulative result of continual oxidative stress and other thermodynamic processes (such as aminoacid racemization and nonenzymatic glycosylation), resulting in altered function and increasing the net entropy of living systems, governs the rate of the aging process.

The maculae of rhesus monkeys were exposed for 120/s to Nd-YAG and argon laser radiation at wavelengths of 1060 and 514.5 nm, respectively. Histopathology of lesions associated with a thermal and a nonthermal damage mechanism were compared. Differences were observed for both lesion development and retinal layers affected, depending upon the damage mechanism involved.

Sixteen patients with transposition of the great arteries, 8 days to 2 1/2 years of age, underwent intra-atrial transposition of venous return by the modified Shumacker technique. A bipedicle flap of right atrial wall was used to direct vena caval return to the mitral valve, and a hinged viable flap of pericardium was used to form the lateral wall of the pulmonary venous pathway. Thirteen patients survived operation and are well to date. Two of the three nonsurvivors were less than 1 month of age at operation, and the third had an associated inlet ventricular septal defect and a straddling tricuspid valve. Early postoperative chest radiographs were compared with preoperative films in each patient. Postoperative findings included minor right pleural effusion in four, minor pneumothorax in two, and paralyzed right hemidiaphragm in one. Two patients required a permanent pacemaker because of the development of sick sinus syndrome 2 and 4 years postoperatively. Each preoperative angiocardiogram was reviewed and compared with postoperative studies in nine patients. The latter demonstrated absence of caval gradients in each, trivial baffle leaks in four, a moderate baffle leak in one, small residual ventricular septal defects in two, and mild tricuspid regurgitation in two patients.

We have studied the post-translational processing of POMC-derived peptides during fetal monkey development using immunoassay and reverse-phase high-performance liquid chromatography (RP HPLC). Pituitary tissues obtained from fetal monkeys ranging from Gestational Day 50 to 155 were fractionated and analyzed for ACTH- and alpha-MSH-related peptides and compared to adult forms. Extracts of whole pituitary from Fetal Days 50 and 55 contained ACTH(1-39) and very small amounts of CLIP (corticotropin-like intermediate-lobe peptide; ACTH(18-39))-like immunoactivity. Acetylated alpha-MSHs were not detectable at Day 50. alpha-MSHs were barely detectable at Day 55. By Day 65, when pituitary lobes were separable, small amounts of des-, mono-, and diacetyl alpha-MSH were detectable in NIL extracts, but not in anterior lobe extracts. ACTH(1-39) levels were negligible when compared to increasing alpha-MSHs through Fetal Day 80 to 155 in the intermediate lobe. The CLIP immunoactivity was negligible in Day 80 and adult anterior lobe extracts. Thus, lobe-specific proteolytic processing of ACTH-related peptides was well established by midterm gestation. Marked increases of alpha-N- and alpha-N,O-acetylated forms of alpha-MSHs were detected during middle and late stage fetal development. Diacetyl alpha-MSH was the predominant form of alpha-MSH in adult NIL extracts. No acetylated alpha-MSHs were found in anterior lobe tissues, thus adult anterior lobe extracts contained almost exclusively ACTH(1-39). However adult NIL extracts contained two distinct forms of CLIP-related immunoactivity. Therefore changes in post-translational processing patterns of ACTH-related and alpha-MSH-related peptides continued to some extent, postnatally. These data indicate that marked changes in post-translational processing of POMC-derived ACTH-related products occur during the first half of monkey gestation.

We have studied the post-translational processing of POMC-derived peptides during fetal monkey pituitary development using immunoassay and reverse-phase high-performance liquid chromatography (RP HPLC). Whole pituitary glands obtained from Day 50 and 55 fetal monkeys and separated lobes From Day 65 to 155 were extracted, fractionated, and analyzed for beta-melanotropin (beta-MSH), midportion beta-endorphin (beta-EP), and acetylated beta-EP immunoactivity. Separated adult pituitary lobes were analyzed for comparison. At Day 50, POMC-containing cells were located in both the anterior and intermediate pituitary lobes by immunofluorescence staining, the majority of these cells were localized in the anterior lobe. The Day 50 and 55 whole pituitaries contained predominantly beta-lipotropin (beta-LPH), gamma-lipotropin (gamma-LPH), beta-EP(1-31), and 2.2-kda beta-MSH. No acetylated products were found in Day 50 whole pituitary extracts. By Day 55, carboxy-shortened and acetylated beta-EPs were barely detectable in whole pituitary extracts. These forms were more apparent in the Day 65 separated neurointermediate lobe (NIL) extracts, and were similar to adult proportions by Day 80. The adult anterior lobe contained predominantly beta-LPH, beta-EP, and gamma-LPH. Adult NILs contained almost exclusively 2.2-kda beta-MSH, alpha-N-acetyl beta-EP(1-31) and alpha-N-acetyl beta-EP(1-27). The production of 2.2-kda beta-LPH in the monkey NIL indicates that monkey beta-LPH is different from rat beta-LPH in that it must contain the paired-basic cleavage site required for the formation of 2.2-kda beta-MSH that is known to be lacking in rat beta-LPH. Another finding was that monkey beta-EP contains a Tyr residue at position 27 as found in human beta-EP but appears to have the rat Gln substitution at position 31. The post-translational processing patterns characteristic of each lobe were well established by midterm fetal development (Day 80).

The syncytial slime mold Physarum polycephalum has been widely employed as a model for the study of a variety of cellular events; however, the overwhelming emphasis in modern Physarum research has been on those areas directly related to growth and differentiation (22). Mitosis is synchronous following an interphase period of 8–10 h and mitotic synchrony implies metabolic synchrony (13). All events involved in the regulation of differentiation are therefore presumed to be amplified since they should occur simultaneously. This hypothesis has been the basis for intensive efforts to identify the role of specific enzymes (15), nucleic acids (2,8), and nuclear proteins (17) in the developmental processes of eucaryotes. A considerable volume of literature concerning developmental processes in Physarum has accumulated since Rusch (22) first introduced the organism as a model system for probing the events that govern the life cycle of cells. At this time little conclusive information has resulted; endogenous events and factors which induce specific cell state transitions have not been identified. A perennial problem has been to distinguish between the events that are causative and the events which are the consequence of differentiation. For example, when Physarum differentiates into groups of dormant spherules (sclerotia) dramatic changes occur in the electrophoretic profile of the nonhistone chromosomal proteins; however, it has not been possible to determine whether these changes induce differentiation or are a parallel response to the inductive treatment (17).

Thresholds for retinal vitreal and contained hemorrhages were determined for 1064 nm laser light at 30-nsec and 4-nsec pulsewidths. Rhesus monkeys received graded exposures from a neodymium-yag laser onto either the macular or extramacular region of the retina. Contained hemorrhages appeared as concentric ring structures with white punctate centers. The vitreal hemorrhage was characterized by the presence of choroidal blood in the vitreal chamber at the exposure site. The 30-nsec contained hemorrhage threshold (ED50) was 1.7 mJ on the macula and 2.1 mJ for an extramacular exposure. The 30-nsec vitreal hemorrhage macular threshold was 2.3 mJ, and the extramacular threshold was 6.6 mJ. The threshold for the 4-nsec pulsewidths to produce a hemorrhage (vitreal or contained) on the retina (macula or extramacular) was 340 microJ.

The authors outline the progression of thought on the mechanism of the aging process, giving emphasis to environmental factors that influence genetic events. Discussion is limited to those theories that explain fundamental causes of aging and have a firm thermodynamic basis. The authors propose that the cumulative result of continual oxidative stress and other thermodynamic processes (such as amino-acid racemization and nonenzymatic glycosylation), resulting in altered function and increasing the net entropy of living systems, governs the rate of the aging process.

Metabolic gradients exist in developing organisms and are believed to influence development. It has been postulated that the effects of these gradients on development result from differential oxygen supplies to tissues. Oxygen has been found to influence the course of development. Cells and tissues in various stages of differentiation exhibit discrete changes in their antioxidant defenses and in parameters of oxidation. Metabolically generated oxidants have been implicated as one factor that directs the initiation of certain developmental events. Also implicated as factors that modulate developmental processes are the cellular distribution of ions and the cytoskeleton both of which can be influenced by oxidants. The interaction of oxidants with ion balance and cytoskeleton is discussed.

This study from Frankfurt, although similar to other reports with respect to clinical findings, presents further evidence of a varied etiology for hand, foot and mouth disease (HFMD). Of the 6 patients with HFMD, 5 had virologic evidence of coxsackievirus B5 infection, and 1 had definite evidence of coxsackievirus B2 infection. Our data suggest an etiologic association of coxsackievirus group B with HFMD.

The maculae of rhesus monkeys were exposed to an argon-ion lazer operated in the TEM00 continuous wave mode at a wavelength of 514.5 nm. Both ophthalmoscopic and histopathologic evaluations of exposure sites were obtained. Threshold (ED50) values were obtained for 0.5, 5, 30, 120, and 1,000 sec. exposure times. Presence of minimum visible lesions was assessed ophthalmoscopically at both 1 hour and 24 hours after exposure. With increasing exposure times, a 24 hr. lesion-appearance criterion resulted in ED50 values too low to be consistent with a thermal damage mechanism. In contrast, exposure to neodymium laser radiation at a 1,060 nm. wavelength for 120 sec. produced only ED50 values consistent with those associated with thermal injury. These results suggest that the damage mechanisms for long-duration exposures to visible light may involve photochemical processes initiated by the interaction of visible light with the retinal photopigments.

Evidence is presented that supports a role for the enzyme superoxide dismutase (SOD) in the differentiation of the slime mold, Physarum polycephalum. SOD activity increases 46-fold during differentiation. A strain of Physarum that does not differentiate exhibits no change in SOD activity. Addition of SOD, via liposomes, to the nondifferentiating strain induces differentiation; this effect is enhanced by an inhibitor of glutathione synthesis. Other antioxidants selected for study failed to induce differentiation. Conversely, oxidative treatments including introduction of d -amino acid oxidase, via liposomes, induced differentiation. Cellular oxidation is the probable cause of the SOD effect.

There is presently no single, widely accepted, unifying theory of aging that is applicable to a wide spectrum of organisms. This fact has led many gerontologists to believe that mechanisms of aging may differ in various phylogenetic groups, albeit no compelling evidence or a priori reason has been forwarded to support this view. Given the basic similarity of molecular and cellular processes in living systems, it is indeed more probable that the contrary may be true, and that the underlying causal mechanisms of aging are essentially similar in all organisms. Conceptually, theories of aging can be assigned to two fundamentally different schools. One view regards aging as a continuation of the process of differentiation involving a programmed “shutdown” of genomic activity or a sequential activation of specific genes whose products have deleterious effects on cellular functions. Alternatively, aging is postulated to be a direct or indirect product of metabolic damage arising from the inadequacy of protective and reparative mechanisms.

Glutathione is a tripeptide consisting of glutamic acid, cysteine and glycine moieties, and is found in all aerobes (Kosower and Kosower 1976). Glutathione may exist in the reduced form (GSH) or as an oxidized dimer (GSSG). More than 90% of the glutathione contained in cells is in the form of GSH; the oxidized form, GSSG, is rapidly reduced to GSH by glutathione reductase or is extruded from the cells (Meister and Anderson 1983). The cellular concentration of GSH is usually high, exceeding one millimolar in many tissues (Meister and Anderson 1983). Glutathione plays an important role in multiple physiological processes, due mainly to its ability to donate reducing equivalents; indeed, most of the reducing equivalents in cells are contained in GSH (Chance et al. 1979). Although the principle role of glutathione is to detoxify potentially deleterious substances, including oxygen free radicals, it strongly modulates the redox state of cells, which is a function of the ratio of oxidizing to reducing equivalents (Chance et al. 1979).

Metabolic rate is a major factor governing the rate of aging in both homeotherms and poikilotherms and is inversely related to life span. Homeotherms exhibit stable basal metabolic rates and species-specific life spans. Conversely, in poikilotherms, both basal metabolic rate and life span vary greatly. Metabolic potential (total energy consumed/g/life span) is a species-specific characteristic in Homoetherms and poikilotherms. Length of life is dependent upon the rate at which this fixed metabolic potential is expended, that is, metabolic rate. Oxygen-free radicals produced by metabolism can cause molecular damage. Accumulation of lipofuscin granules, Schiff-base-like, fluorescent material and thiobarbituric acid-reactants, as well as increased exhalation of pentane with age are indicative of free, radical-induced molecular damage. Metabolic rate influences the rate of age-related changes. There is an overlapping compensatory balance between various components of the antioxidant defense system. The total antioxidant capacity of cells tends to decline with age. A dynamic equilibrium may exist between the rate of free radical generation and antioxidant levels. The establishment of this equilibrium is associated with differentiation. It is hypothesized that loss of the equilibrium between free radical generation and antioxidant defenses results in dysdifferentiation, aging and cancer.

Sir--I wish to record a case of sudden death in a young woman of 23 who had been taking an oral contraceptive containing mestranol and ethynodiol diacetate for three months. I might add that this was not prescribed by me. Post-mortem examination revealed a large pulmonary embolus and loosely adherent antemortem thrombus was found in both iliac veins adn their tributaries. There was no other lesion present which might have predisposed to thrombosis. The facts have been reported to the Dunlop Committee.(Full text)