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The probability distributions of population size are derived for populations living in randomly varying environments for both density-dependent and density-independent population growth. The effects of random variation in the rate of increase, the carrying capacity, and sampling variation in numbers are examined.
A model of group selection is constructed for the case of differential extinction acting on small boundary populations of a large, fixed population. Consideration is restricted to extinction operators acting at or near to carrying capacity. Under the assumption that the extinction rate is large relative to individual genetic parameters affecting gene frequencies in boundary populations, we discuss the conditions under which differential extinction is most likely to produce a significant effect. In particular, a condition for bimodality in the distribution of gene frequencies in boundary populations (population polymorphism) is that there be some critical allele frequency at which the extinction rate jumps from high to low. An extinction operator linear in allele frequency produces no qualitative effect of this kind. In consequence, we are able to make precise rather limited circumstances under which group selection is likely to have a significant effect.
Genetic analysis for group selection is developed for the case of a biallelic locus (A, a) undergoing group selection of founder populations only. By contrast to R. Levins"E = E(x) models, extinction now depends on genetics at the propagule stage but acts uniformly on larger populations. Biological evidence supports this hypothesis, which also allows mathematical treatment at once simpler and biologically more general than the Fokker-Planck partial differential equation formalism adopted by Levins. It is presently possible to handle cytogenetics of both diploid and haplodiploid type. The model is set up as a quasideterministic recursion in the 5-simplex Sigma(5), collapsing both drift and mendelian selection effects into a single parameter u, which is a Fisher-Kimura-Ohta fixation probability. In the analysis, it is shown that the stability of the fixed points is determined by the convexity of the extinction operator acting on propagules, assumed to be of size 2.THUS, [FORMULA: see text] in which E(1) and E(3) are extinction probabilities for phenotypically uniform founder populations and E(2) is the corresponding probability for founder populations of mixed phenotype. Further parameter regions are defined where fixation of the group-selected gene is globally stable, and this is still possible even when extinction pressure acting on carrying capacity populations becomes weak relative to a fixed mendelian selection strength.
In one specific model of a density-regulated population undergoing natural selection in a fluctuating environment there is a systematic evolutionary pressure favoring a lower intrinsic rate of increase, which can sometimes even overcome an evolutionary pressure favoring a higher carrying capacity.
Immunoliposomes (antibody-directed liposomes) were used in the present study for delivery of the antineoplastic agent daunomycin to the rat brain. A coupling procedure was introduced, which allows conjugation of a thiolated antibody to maleimide-grafted 85-nm liposomes sterically stabilized with PEG. Antibody was thereby coupled to the terminal end of a PEG-conjugated linker lipid. No brain uptake of PEG-conjugated liposomes carrying [3H]daunomycin was observed. However, brain targeting of immunoliposomes carrying [3H]daunomycin was mediated by the OX26 monoclonal antibody to the rat transferrin receptor, which is selectively enriched at the brain microvascular endothelium that comprises the blood-brain barrier in vivo. Coupling of 30 OX26 antibodies per liposome resulted in optimal brain delivery. Saturation of delivery was observed at higher antibody densities. Determination of brain levels of immunoliposomes over 24 h revealed that immunoliposomes accumulate in brain tissue. Brain targeting of immunoliposomes was not observed in immunoliposomes conjugated with a mouse IgG2a isotype control. In addition, coinjection of free OX26 saturated plasma clearance of immunoliposomes. Since a single liposome may carry > or = 10,000 drug molecules, the use of PEG-conjugated immunoliposomes increases the drug carrying capacity of the monoclonal antibody by up to 4 logarithmic orders in magnitude. In summary, specific OX26-mediated targeting of daunomycin to the rat brain was achieved by the use of an immunoliposome-based drug delivery system.
alpha-Nitrosyl hemoglobin, alpha(Fe-NO)2beta(Fe)2, which is frequently observed upon reaction of deoxy hemoglobin with limited quantities of NO in vitro as well as in vivo, has been synthetically prepared, and its reaction with O2 has been investigation by EPR and thermodynamic equilibrium measurements. alpha-Nitrosyl hemoglobin is relatively stable under aerobic conditions and undergoes reversible O2 binding at the heme sites of its beta-subunits. Its O2 binding is coupled to the structural/functional transition between T- (low affinity extreme) and R- (high affinity) states. This transition is linked to the reversible cleavage of the heme Fe-proximal His bonds in the alpha(Fe-NO) subunits and is sensitive to allosteric effectors, such as protons, 2,3-biphosphoglycerate, and inositol hexaphosphate. In fact, alpha(Fe-NO)2beta(Fe)2 is exceptionally sensitive to protons, as it exhibits a highly enhanced Bohr effect. The total Bohr effect of alpha-nitrosyl hemoglobin is comparable to that of normal hemoglobin, despite the fact that the oxygenation process involves only two ligation steps. All of these structural and functional evidences have been further confirmed by examining the reactivity of the sulfhydryl group of the Cysbeta93 toward 4, 4'-dipyridyl disulfide of several alpha-nitrosyl hemoglobin derivatives over a wide pH range, as a probe for quaternary structure. Despite the halved O2-carrying capacity, alpha-nitrosyl hemoglobin is fully functional (cooperative and allosterically sensitive) and could represent a versatile low affinity O2 carrier with improved features that could deliver O2 to tissues effectively even after NO is sequestered at the heme sites of the alpha-subunits. It is concluded that the NO bound to the heme sites of the alpha-subunits of hemoglobin acts as a negative allosteric effector of Hb and thus might play a role in O2/CO2 transport in the blood under physiological conditions.
In 1984-1985 insecticide-treated targets were deployed in the 600-km2 Rifa Triangle, Zambezi Valley, Zimbabwe. Trap catches of Glossina pallidipes Austen were modelled using a function combining logistic growth with diffusive movement. A simulation routine was linked to a non-linear least-squares optimization programme and fits optimized with respect to population carrying capacities, rates of growth and movement, and to levels of imposed mortality. In March-September 1984, the overall additional mortality was 2% per day of adult female G. pallidipes, increasing thereafter to 8% per day, due to the deployment of more targets, the onset of the hot, dry season and the ground-spraying of the adjoining Zambezi escarpment with DDT. For G. m. morsitans Westwood the corresponding estimates were 1 and 2% per day. For both species, the deployment of four targets km(-2) in a closed population will ensure eradication. For G. m. morsitans a halving of target efficacy would reduce the killing rate to the point where eradication would be unlikely. Estimated daily displacements were c. 200 m for G. m. morsitans and 660 m for G. pallidipes. The lower rate for G. m. morsitans means that, while targets kill this species less effectively, re-invasion of cleared areas is slower. Targets do not markedly affect robust populations outside the deployment area. The Zambian tsetse population adjacent to the Rifa Triangle declined markedly during the experiment, however, suggesting that it is largely maintained by immigration. The methods developed here will be applied to data from other campaigns with the aim of improving the efficiency of tsetse control programmes.
The generation of the free radical reaction in the ischaemic and hypoxic brain has been demonstrated using the chemiluminescence and the ESR techniques. The effects of various drugs, thought to be free radical scavengers were then tested in the ischaemic brain of dogs. It was found that not only mannitol, but also vitamin E, dexamethasone and other drugs have significant cerebral protective effects--particularly when administered together. Moreover, remarkable improvements were found when these 3 drugs were administered with the artificial blood substitute, PFC, which is known to have a high oxygen-carrying capacity. Finally, using the chemiluminescence and the ESR method, we have demonstrated that mannitol, vitamin E and glucocorticoids act as free radical scavengers and particularly mannitol acts as a scavenger of the hydroxy radical.
The purpose of this study was to determine the vitamin A status of alcoholics upon admission and after a brief in-patient stay. Fasting blood was drawn from 28 randomly selected subjects who were presumed to represent a wide range of liver disease severity. Admission laboratory tests revealed hypozincemia in 14.8% of subjects, while serum retinol and retinol-binding protein (RBP) were depressed below normal range in 15 (57.1%) and 7 (25%) of the subjects, respectively. Significant linear correlations were found between serum retinol and RBP (r = 0.90, p < or = 0.0001), serum retinol and albumin (r = 0.76, p < or = 0.0001), serum retinol and serum zinc (r = 0.56, p < or = 0.0003), and serum retinol and serum triglycerides (r = 0.42, p < or = 0.006). All subjects with elevated serum bilirubin levels demonstrated depressed serum retinol levels. However, elevated molar ratios of retinol to RBP suggest that the carrying capacity of RBP was at times exceeded, even with low serum retinol levels. Follow-up of 12 subject after 2 weeks of hospitalization revealed significant individual changes in blood chemistry, but no general trends. Although this study emphasizes the need for individual evaluation and treatment, elevated bilirubin levels may be indicative of low serum retinol levels in the alcoholic. Caution in levels of vitamin A therapy in these cases is advised, and consideration should instead be given to beta-carotene supplementation.
Hypoxic cells in human tumours probably contribute to the failure of radiotherapy in some sites. Changes in the oxygen carrying capacity of the blood, such as in anaemia, have been shown to influence tumour response. The effect of acute and chronic changes in haematocrit on the radiosensitivity of three mouse tumours (EMT6, KHT and RIF-1) were studied. Alterations in haematocrit were achieved by bleeding followed by retransfusion. When radiation was preceded immediately by an acute reduction in haematocrit (anaemia), radiosensitivity was markedly reduced in each tumour. An acute rise in haematocrit (polycythaemia) increased or decreased X-ray sensitivity depending on its severity. The optimum haematocrit for maximum sensitivity was always found to be at a level 5-10 per cent above normal. When the time between induction of anaemia and irradiation was increased, simulating a progressively longer duration of anaemia, marked changes in radiosensitivity of all the tumours were observed. A short duration of anaemia resulted in a resistant tumour with each cell line, but the resistance was gradually lost as the anaemia was prolonged, even though no recovery in haematocrit occurred. The rate of recovery to normal radiosensitivity varied from 24 to 72 hours in the different tumours. Therefore, only haematocrit changes which occurred within 1-3 days of a dose of radiation affect the radiosensitivity of these tumours.
The effects of FMIQ, a perfluorochemical emulsion based on perfluoro-N-methyldecahydroisoquinoline, were examined using BALB/c mice and EMT6 mammary carcinomas. The radiobiological effects of FMIQ were similar to those found previously for Fluosol in the same tumour/host system. Although the perfluorochemical content (20% w/v) and oxygen-carrying capacity of FMIQ are similar to those of Fluosol, the formulation of FMIQ offers some advantages over that of Fluosol. For example, FMIQ has greater stability during storage. FMIQ also is formulated without pluronic F-68 and is based on a perfluorochemical (FMIQ) having a shorter tissue dwell time than the perfluorotripropylamine in Fluosol; it therefore may produce fewer side-effects than Fluosol. The lifetime of the circulating perfluorochemical droplets in BALB/c mice was longer than FMIQ than for Fluosol; this could offer an advantage in fractionated radiotherapy. These findings give reason to expect that FMIQ may prove to be a better emulsion than Fluosol for clinical use as an adjunct to cancer therapy.
Aquasomes, a new drug delivery system comprised of surface-modified nanocrystalline ceramic carbohydrate composites, was developed to serve as haemoglobin carrier for oxygen delivery. The hydroxy-apatite ceramic core was prepared by coprecipitation and self-precipitation and coated with various sugars like cellobiose, maltose, sucrose, and trehalose. The effect of drying methods, i.e., air drying, vacuum drying, and lyophilization, on the degree of binding was studied by concanavalin-induced aggregation method. Haemoglobin was adsorbed over the sugar-coated ceramics, and percent loading was estimated by benzidine method. The adsorption of sugars on calcium hydro-apatite powder and haemoglobin adsorption on sugar-adsorbed ceramic followed both Freundlich and Langmuir isotherm. The haemoglobin aquasome formulations (equivalent to 7.5% Hb) were suspended in a phosphate buffer containing 7.5% w/v albumin and 0.01% w/v lecithin, and they were evaluated for oxygen-carrying capacity, which was found to be similar to fresh blood. The Hill coefficients were found to be fairly good for its use as oxygen carrier. The haemoglobin aquasome formulations did not induce haemolysis of red blood cells nor alter the blood coagulation time. The haemoglobin content of the formulation remained unchanged on storage for 30 days. The haemoglobin desorption was fairly low under shear conditions, indicating good stability of formulation in biological system. During in vivo study in rats the survivals were monitored as function of hematocrit in rats receiving isovolemic exchange transfusion. Arterial blood pressure and heart rate did not change significantly in animals transfused with aquasomal suspension on 50% exchange transfusion.
BACKGROUND: Hemoglobin based oxygen carrying solutions (HBOC) have been designed to combine the beneficial effects of colloidal solutions with oxygen carrying capacity. Clinical trials in humans using HBOCs have had variable results. METHODS: We used a rodent 50% exchange model to compare Hemolink and Hemopure HBOC to autologous blood and Pentastarch solution. We monitored hemodynamic parameters, hemoglobin clearance, weight gain and hematocrit over a five-day period. RESULTS: Acute hemodynamic effects between the two HBOCs were similar with mild vasoconstriction. Cardiac output, systemic vascular resistance and renal function were similar to that seen with blood. HBOC's were associated with hemoglobinuria with a half-life in the circulation of 13.8 hrs for Hemolink and 19.2 hrs for Hemopure. Animals resuscitated with HBOCs exhibited delayed weight gain. CONCLUSION: Hemodynamic effects in rodents exchange-transfused with blood, Hemolink, or Hemopure were similar. The delayed weight gain observed with the HBOCs must be investigated.
The optimum population of the world is the one that is most likely to make the option of a good quality of life available to everyone everywhere, both now and in the future. Establishing a consensus about the size of such a population would be an important step towards achieving it. Estimates of an optimum involve three main steps. First, estimate the maximum (carrying capacity) assuming a specified lifestyle. The main criteria are the maintenance of biodiversity, the availability of freshwater, and the availability of land--for agriculture, forestry and artificial systems but above all for the conversion of energy. (In applying the criteria, there are always two questions to ask: 'What is the maximum amount of consumption that the biosphere can stand?' and 'What is an adequate share of such consumption per person?') Second, convert the maximum (two to three billion) into an optimum by applying a far wider range of criteria, including personal liberty, mobility, recreation and political representation. Third, consider just two criteria (economies of scale and technological innovation) in order to ensure that the optimum (one to two billion) has not fallen below the minimum (half to one billion). The estimates are so low because of the need for a huge increase in median per capita consumption if everyone is to have the option of an adequate material standard of living. Opinion-formers are likely not to take much notice of such estimates, but it is probable that minds will be concentrated by an energy shock some time during the next decade. Achieving an optimum world population will not solve the world's major problems, but it would make them solvable.
The explosion of the population bomb has long been predicted to cause massive famine in overpopulated countries. Rising consumption, even in a time of decreasing population growth rates, now threatens adverse global health effects more severe than localised famines. The world faces potential ecological entrapment. This has two dimensions: planetary eco-impoverisation and planetary eco-pathology. Eco-impoverisation, the depletion of natural capital, arises as the limit of the global human carrying capacity approaches. Eco-pathology, the disruption of ecological support systems, arises because of the way the biosphere has been modified by human activity and is caused particularly by unsustainable consumption for human purposes. Despite encroaching ecological entrapment, the dominant economic paradigm claims record levels of growth; a paradox that needs recognition. Reasons for denial of the gravity of ecological entrapment are discussed. Ways are suggested to defuse the consumption bomb and avert ecological entrapment.
We have prepared human erythrocytes that contain exclusively alpha-nitrosyl hemoglobin (Hb), i.e., alpha(Fe-NO)2beta(Fe-O2)2, by incorporating nitric oxide (NO) into erythrocytes in a well-controlled nitrosylation process. The amount of alpha(Fe-NO) corresponding to 50% of the total heme content of the erythrocytes and exclusive binding of NO to alpha-subunits of intraerythrocytic Hb were confirmed by EPR. Oxygenation experiments on the intraerythrocytic alpha-nitrosyl Hb over a wide range of pH showed that: (1) the oxygen affinity of cell-free and intraerythrocytic alpha-nitrosyl Hbs were much lower than native Hb in their respective environments; (2) the oxygenation characteristics of the intraerythrocytic alpha-nitrosyl Hb in the acidic range was similar to that of the cell-free alpha-nitrosyl Hb in the presence of 2,3-diphosphoglycerate; and (3) the apparent Bohr effect in the intraerythrocytic alpha-nitrosyl Hb was dramatically diminished. This can be due to a restricted variation in intraerythrocytic pH in the alkaline region and the presence and/or production of endogenous 2,3-diphosphoglycerate. By comparing oxygen saturation characteristics, it was found that the intraerythrocytic alpha-nitrosyl Hb, despite its halved oxygen carrying capacity, could deliver more oxygen than DPG-depleted erythrocytes under similar experimental conditions. This makes alpha-nitrosyl Hb-containing erythrocytes a promising candidate for blood transfusant.
Gossypol prevents the liberation of oxygen from oxyhemoglobin and exerts a hemolytic effect on erythrocytes. In excessive dosages of gossypol, an extreme burden is placed upon the respiratory and circulatory organs owing to the reduced oxygen carrying capacity of blood. Chromium protoporphyrin (CrPP) has been shown to either competitively suppress or to significantly ameliorate a variety of naturally occurring or experimentally induced forms of jaundice in animals and man. In this communication, a novel tissue dependent response to gossypol (50 micromol/kg bw) and gossypol in association with CrPP (50 micromol/kg bw) is described. Our results revealed that gossypol stimulated the hepatic, splenic, and renal delta-aminolevulinic acid synthase (ALA-S) activity, the heme biosynthetic enzyme, and simultaneous administration of CrPP and gossypol synergized the gossypol-mediated increase of ALA-S activity. Gossypol was found to be a potent stimulator of heme oxygenase (HMOX) activity in rat liver and kidney to varying degrees. This tissue response contrasted with that of the spleen, where gossypol decreased the activity of the enzyme. In consonance with the increased hepatic and renal HMOX activity, a marked increase was observed in total serum bilirubin concentration in gossypol treated rats. When rats were given CrPP simultaneously with gossypol, the gossypol mediated increase in hepatic and renal HMOX activity was effectively blocked. Furthermore, the increase in enzymatic activity was accomplished by a decline in the total microsomal protein content on gossypol administration. These findings emphasize the toxic effect of gossypol in eliciting increased heme degradation by stimulating HMOX activity in the liver and the kidney and the potential usefulness of CrPP in experimental and perhaps clinical conditions in which hyperbilirubinemia occurs.
Artificial blood substitutes (ABS) offer an alternative to donated blood. Increasing the oxygen carrying capacity of blood plasma through the addition of a Perfluorocarbon emulsion (PFE) is one approach in creating a blood substitute. The peripheral resistance of the circulatory system may be altered depending on the rheological properties of the ABS. Measurements of the rheological behavior of mixtures of a PFE, Oxygent, and erythrocyte suspensions were conducted at room temperature at different hematocrits using sheep (nonaggregating) and swine (aggregating) erythrocytes. The pure PFE was found to be shear thinning. Adding 6 and 12 g per 100 mL of sheep blood at the various hematocrits increased the viscosity of the suspension from as low as 4% (6 g PFE/40% Hct) to as high as 26.5% (12 g PFE/plasma). The nonaggregating sheep erythrocyte and PFE mixtures exhibited Newtonian behavior. Shear thinning behavior continued upon addition of 6 and 12 g per 100 mL of swine blood at the various hematocrits, with a slight increase in viscosity in most cases. It was observed that adding 12 g of PFE (approximately 3 x intended clinical dose) to 40% Hct swine blood at room temperature led to a significant decrease in viscosity.