N. Nagelkerke

Consanguineous marriages and endemic malaria: can inbreeding increase population fitness?

BackgroundThe practice of consanguineous marriages is widespread in countries with endemic malaria. In these regions, consanguinity increases the prevalence of α+-thalassemia, which is protective against malaria. However, it also causes an excessive mortality amongst the offspring due to an increase in homozygosis of recessive lethal alleles. The aim of this study was to explore the overall effects of inbreeding on the fitness of a population infested with malaria.MethodsIn a stochastic computer model of population growth, the sizes of inbred and outbred populations were compared. The model has been previously validated producing results for inbred populations that have agreed with analytical predictions. Survival likelihoods for different α+-thalassemia genotypes were obtained from the odds of severe forms of disease from a field study. Survivals were further estimated for different values of mortality from malaria.ResultsInbreeding increases the frequency of α+-thalassemia allele and the loss of life due to homozygosis of recessive lethal alleles; both are proportional to the coefficient of inbreeding and the frequency of alleles in population. Inbreeding-mediated decrease in mortality from malaria (produced via enhanced α+-thalassemia frequency) mitigates inbreeding-related increases in fatality (produced via increased homozygosity of recessive lethals). When the death rate due to malaria is high, the net effect of inbreeding is a reduction in the overall mortality of the population.ConclusionConsanguineous marriages may increase the overall fitness of populations with endemic malaria.

New K-Oximes (K-27 and K-48) in Comparison with Obidoxime (LuH-6), HI-6, Trimedoxime (TMB-4), and Pralidoxime (2-PAM): Survival in Rats Exposed IP to the Organophosphate Paraoxon

ABSTRACT Oximes are cholinesterase reactivators used in organophosphorus compound poisoning. The purpose of the study was to compare the protective effect of the K-oximes (K-27 and K-48) in male rats with that of obidoxime (LuH-6), trimedoxime (TMB-4), and HI-6, using paraoxon (POX) as a cholinesterase inhibitor. Pralidoxime (2-PAM) was also retested. Seven groups of six rats each were used. Group 1 (G1) received 1 μmol/rat POX (≈ LD75), the other groups (G2–7) received 1 μmol/rat POX + one of the six reactivators. The animals were monitored for 48 h and time of mortality was recorded. The procedure was repeated seven times. Subsequently, experiments as described were repeated using 10 and 15 μmol/rat POX. Mortality data were compared and hazards ratios (relative risks) ranked with the Cox proportional hazards model using the POX dose and group (reactivator) as time-independent covariables. K-27 followed by K-48 were the most potent reactivators. K-27 was statistically significantly superior to all other reactivators except K-48. The relative risk of death estimated by Cox analysis in K-27– and K-48–treated animals when compared with untreated animals, adjusted for the POX dose, was 0.22 (95% confidence interval [CI], 0.15 to 0.31) and 0.26 (95% CI, 0.18 to 0.37), respectively. We concluded that in the animal model used K-27 and K-48 are superior to older oximes in their ability to protect from paraoxon effects. They should be tested further using methyl- and propyl-organophosphates as toxic agents.

Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System

Our objectives were to compare the levels of circulating electrolytes, hormones, and renal function during 20 days of dehydration in camels versus the level in non-dehydrated camels and to record the effect of blocking angiotensin II AT1 receptors with losartan during dehydration. Dehydration induced significant increments in serum sodium, creatinine, urea, a substantial fall in body weight, and a doubling in plasma arginine vasopressin (AVP) levels. Plasma aldosterone, however, was unaltered compared with time-matched controls. Losartan significantly enhanced the effect of dehydration to reduce body weight and increase serum levels of creatinine and urea, whilst also impairing the rise in plasma AVP and reducing aldosterone levels. We conclude that dehydration in the camel induces substantial increments in serum sodium, creatinine, urea and AVP levels; that aldosterone levels are altered little by dehydration; that blockade of angiotensin II type 1 receptors enhances the dehydration-induced fall in body weight and increase in serum creatinine and urea levels whilst reducing aldosterone and attenuating the rise in plasma AVP.

On Some Novel Aspects of Consanguineous Marriages

Consanguineous marriages, often viewed as incestuous and objectionable, are more widespread than commonly perceived. They integrate multiple facets of human adaptation: economic, cultural and genetic. The widely touted explanation for the origin and persistence of consanguinity is that it provides many socioeconomic benefits; however, this view may be too simplistic. The bias against consanguinity may preclude an objective understanding of this sociobiological puzzle. Inbreeding increases the speed of selection of beneficial recessive and co-dominant alleles, e.g. those that protect against diseases. In populations endemic with malaria, the prevalence of consanguineous marriages and the frequency of alleles protective against malaria are both very high. Thus, consanguinity could theoretically increase the relative fitness of a population under specific ecological conditions; sometimes, the overall genetic benefits may exceed genetic costs of inbreeding. We discuss some recent evidence from studies on inbreeding along with the reasons responsible for the mating strategy found in some human populations. We contend that a better appreciation of our inherent biases and potential genetic benefits of inbreeding in specific ecological conditions would help us to appreciate the wider picture of consanguinity.

Consanguinity affects selection of alpha-thalassemia genotypes and the size of populations under selection pressure from malaria

Background: In populations with α+-thalassemia gene deletion, the practice of consanguineous marriages is common. Aim: The study explored the impact of consanguinity (inbreeding) on the selection of α+-thalassemia genotypes in a computer model. Method: In a population under selection pressure from malaria, a single protective mutation (–α/αα genotype) was introduced among normal genotypes (αα/αα), and mating allowed to proceed. Heterozygote (–α/αα) and homozygote (–α/–α) children were 1.5 and 2.5 times more likely to survive malaria than those with normal genotypes. Using different coefficients of inbreeding (F, range 0–0.12), we examined the effect of population size, and the mean number of generations required for the homozygote frequency to reach 0.5. Results: On average, consanguineous populations were larger than randomly mating populations and the size was directly proportional to F. In more inbred populations,–α/–α homozygotes reached a frequency of 0.5 faster than in less inbred populations. As the frequency of the α+-thalassemia allele in a population increases, however, the positive effect of inbreeding on the population growth decreases. Conclusion: Under selection pressure from malaria, consanguinity may increase the speed of selection of–α/–α homozygotes and provide an advantage regarding population growth over non-consanguineous populations.

ANP and BNP Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System

The objectives of this study were to investigate and compare the responses of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in the circulation of hydrated, dehydrated, and dehydrated losartan - treated camels; and to document the cardiac storage form of B-type natriuretic peptide in the camel heart. Eighteen male camels were used in the study: control or hydrated camels (n = 6), dehydrated camels (n = 6) and dehydrated losartan-treated camels (n = 6) which were dehydrated and received the angiotensin II (Ang II) AT-1 receptor blocker, losartan, at a dose of 5 mg/kg body weight intravenously for 20 days. Control animals were supplied with feed and water ad-libitum while both dehydrated and dehydrated-losartan treated groups were supplied with feed ad-libitum but no water for 20 days. Compared with time-matched controls, dehydrated camels exhibited a significant decrease in plasma levels of both ANP and BNP. Losartan-treated camels also exhibited a significant decline in ANP and BNP levels across 20 days of dehydration but the changes were not different from those seen with dehydration alone. Size exclusion high performance liquid chromatography of extracts of camel heart indicated that proB-type natriuretic peptide is the storage form of the peptide. We conclude first, that dehydration in the camel induces vigorous decrements in circulating levels of ANP and BNP; second, blockade of the renin-angiotensin system has little or no modulatory effect on the ANP and BNP responses to dehydration; third, proB-type natriuretic peptide is the storage form of this hormone in the heart of the one-humped camel.

Effect of Dehydration in the Presence and Absence of the Angiotensin Receptor Blocker Losartan on Blood Constituents in the Camel

Aim: Dromedary camels are extremely well adapted to periods of water deprivation. The physiological mechanisms underlying this adaptation, however, are imperfectly understood. It is likely that the renin-angiotensin system plays an important role although few studies have addressed this possibility in the camel. Accordingly, the effects of long term dehydration alone and with angiotensin II type 1 receptor blocker, losartan, on whole blood and serum constituents were studied in camels. Methods: Twenty eight male camels 3-4 years old were studied while under shade during summer in the Gulf-region, where the ambient temperature was above 40 degree Celsius. The camels were divided into three groups: a control group (n=6) was allowed free access to feed and water, a dehydration group (n=16) was given food ad-lib during 20 days of total water deprivation, and a dehydration plus losartan (losartan) group (n=6) which received losartan 5 mg/Kg daily by intravenous injection during 20 days of dehydration. Results: The body weight of the losartan group decreased by nearly 39.1% across dehydration whereas the reduction in body weight for the dehydration group was nearly 34.5% compared to controls. There was a significant increase in the packed cell volume (p<0.05) and leucocytes count (p<0.01) in the losartan group compared to controls. However, the mean corpuscular volume was significantly higher (p<0.05) in the dehydration group compared to controls. We observed major, statistically significant increases in serum urea (p<0.01) and creatinine (p<0.05) levels in the dehydration and losartan groups compared to controls. By the end of the period of water restriction, serum levels of gamma glutamyl transferase were significantly (p<0.01) lower in the losartan group compared to controls. Conclusion: The results of our experiment show that dehydration alone or in combination with Angiotensin II receptor blocker has major effects on the biochemical and hematological parameters of the camel blood.

Effect of intrathecal pralidoxime administration upon survival of rats exposed to the organophosphate paraoxon

The therapeutic results of systemic administration of pralidoxime (2-PAM) in the treatment of poisoning with organophosphate-type cholinesterase inhibitors are disappointing. It has been hypothesized that this is due to poor entry of 2-PAM into the brain. To test if survival rates can be improved by direct administration of 2-PAM into the cerebrospinal fluid (CSF), the effect of intrathecal 2-PAM injections upon mortality after paraoxon intoxication was examined. Eight groups of rats (n=30 each) were examined, all of which received paraoxon (1 micromol=272 microg, 3 micromol=816 microg, or 5 micromol=1.36 mg) intraperitoneally (i.p.). One group received no further treatment; the other groups were given 50 micromol (=8.63 mg) 2-PAM i.p., 5 micromol (=863 microg) 2-PAM intrathecally and pentobarbital/lidocaine in various combinations. Results were compared with the no treatment group and the control groups that did not receive any paraoxon injections, but were given intrathecal injections of saline or 2-PAM. The relative risk of death was estimated by Cox survival analysis. Mortality was lowest after treatment with a combination of both i.p. and intrathecal 2-PAM plus pentobarbital, and with 2-PAM i.p. alone plus pentobarbital. Both treatments were significantly better than 2-PAM i.p. alone (p<or=0.0001). Mortality of intrathecal 2-PAM plus either pentobarbital or lidocaine was in the same order of magnitude as 2-PAM i.p. without pentobarbital/lidocaine, which was significantly (p<or=0.05) lower than that of the no treatment group and of the groups that had only been given pentobarbital or lidocaine. Our results indicate that i.p. injections of 2-PAM insufficiently protect the CNS against the effect of paraoxon. Supplementary injection of pentobarbital, presumably by its anticonvulsive action, has a superior efficacy compared to 2-PAM i.p. alone, irrespective of additional intrathecal 2-PAM administration.

On Some Novel Aspects of Consanguineous Marriages: Response to A.H. Bittles

guinity. All we can do is express uncertainty. More puzzling, however, is his criticism of a 7-year-old paper by one of us [3] , which was not the subject of the review and yet, at the time, was already commented by A.H. Bittles himself [4] ; the paper was published in the discontinued journal Medical Hypotheses and was characterized as speculative and ‘too much’. Indeed, the paper was somewhat speculative and was therefore published in the journal of Medical Hypotheses . When further tested, we obtained negative result [5] , the inevitable fate of a majority of hypotheses. We are very grateful for the insightful comments of the reviewer. We are pleased with his sympathetic response to our thesis that inbreeding can have beneficial effects and are thankful for providing references of widespread homozygosity in the human genome. We agree that the genetic benefits of inbreeding were indeed previously considered in animals and plants, but to a lesser extent in humans, likely because of negative attitudes towards consanguineous unions. Similarly, we agree that the true incidence of congenital malformations may exceed the 2.0% mentioned by us. Reported frequencies of congenital malformations depend on definition criteria and thoroughness of ascertainment, and not all such malformations may significantly affect relative fitness. Certainly, human consanguinity is a complex sociobiological phenomenon. Many studies that one would like to conduct are simply not feasible for various reasons. What happened during human evolution is by and large uncertain. Thus, essentially, stochastic computer modeling and analytical investigations are the only available tools, no matter how unrealistic model may be at times. Yet, these tools suggest new hypotheses and insights, such as that consanguineous unions may act as evolutionary catalysts by accelerating selection of alleles [1, 2] . We accept to the reviewer’s criticism regarding our skepticism about the economic nature of human consanReceived: June 7, 2010 Accepted after revision: October 6, 2010 Published online: December 10, 2010