Rh disease (also Rhesus disease, Haemolytic Disease of the Newborn (HDNB) or Morbus haemolyticus neonatorum or erythroblastosis) is a condition that occurs when a Rh negative mother has given birth to a Rh positive baby and subsequently becomes pregnant with another Rh positive child. About 5% of at-risk pregnancies would result in still births or extremely sick babies. Many who managed to survive would be severely retarded. Once a woman gives birth to a baby with the disease, all subsequent babies would also have it. The connection between the Rh antigen and erythroblastosis was made in 1941 by Dr. Philip Levine. The treatment that came to be developed for the disease was blood transfusion, which was often ineffective or only partially ameliorative because the damage had already been done. Severely retarded children often resulted.

During the first pregnancy and the act of birth a small amount of the baby's blood may enter the mother's body. If the mother is Rh negative, her body produces antibodies (including IgG) against the Rhesus antigens on her baby's erythrocytes, if the baby is Rh positive. During the second pregnancy the IgG is able to pass through the placenta into the fetus, where it leads to agglutination and destruction of erythrocytes. The means to prevent this harmful disease is to vaccinate the mother immediately after the birth of her first child: she is treated with anti-Rh antibodies, so that the fetal erythrocytes are destroyed before her immune system can discover them.

This explanation of the etiology of the disease was first worked in 1960 out by Dr. Ronald Finn, a Liverpool, England native, who applied a microscopic technique for detecting fetal cells in the mother's blood. It lead him to propose that the disease might be prevented by injecting the at-risk mother with an antibody against fetal red blood cells. He proposed this for the first time to the public on February 18, 1960. A few months later, he proposed at a meeting of the British Genetical Society, that the antibody be anti-Rh. Nearly simultaneously with him, a group of researchers from New York City Columbia-Presbyterian Medical Center, John Gorman, Vince Freda, and Bill Pollack came to the same realization, and set out to prove it by injecting a group of male prisoners at Sing Sing Correctional Facility with anti-body supplied by Ortho Pharmaceutical Corporation. Dr. Gorman's daughter-in-law was the first at risk woman to receive a prophylactic injection on January 31, 1964. Clinical trials by the two rival groups, and others quickly confirmed their hypothesis, and the vaccine was finally approved in England and the United states in 1968. Within a year or so, it had been injected with great success into more than 500,000 women. Time magazine picked it as one of the top ten medical achievements of the 1960's. By 1973, it was estimated that in the US alone, over 50,000 baby's lives had been saved.

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Hunger Disease and Pulmonary Alveoli
From American Journal of Respiratory and Critical Care Medicine, 10/1/04 by Massaro, Donald

Non omnis moriar

["I shall not wholly die"]

- Dr. Israel Milejkowski

"The time was 1940, the place the Jewish ghetto in Warsaw, Poland. The Nazis had sealed several hundred thousand people off from the outside world, determined to starve them to death" (1). Remarkable Jewish physician-scientists, themselves starving, conceived and completed a clinicopathologic study and smuggled the manuscript out of the ghetto to Professor Orlowski of Warsaw University. He buried it until it could be safely reclaimed (1). The diet in the ghetto was 800 calories per day (2), body temperature about 35°C, chests typanitic, chest X-rays showed hyperlucent lungs, O2 consumption was diminished by 30 to 40%. Histologically, "emphysema" was diagnosed in 13.5% of cases examined (2).

In this issue of the Journal (pp. 748-752), Coxson and coworkers show that undernourished women with anorexia nervosa (AN) exhibit computed tomographic evidence of enlarged gas-exchange units (3). Their studies could have implications for the development of emphysema in humans. Indeed, they previously reported the presence of bullae and bronchiectasis in a woman with AN (4).

As an alternative to the hypothesis that undernourishment leads to the development of emphysema, they acknowledge (3) that the lung's response to calorie restriction could reflect an evolutionarily conserved adaptation to diminished O2 consumption during food scarcity (5, 6). Although available evidence precludes a firm choice between alternatives, we favor the latter. Why? In part, because lung function studies in AN (7) do not support the presence of emphysema as the term is used clinically. In addition, a series of papers demonstrates that calorie restriction in rats, hamsters, and mice (5, 6, 8-11) causes gas-exchange unit enlargement and alveolar loss (5, 6); refeeding results in a decrease in size of the gas-exchange units (8) and alveolar regeneration (5, 6). Like Coxson and colleagues, the authors of the earlier papers considered that calorie restriction causes emphysema (8-11). Even though such a conclusion about emphysema is literally correct, we do not believe it has the same meaning as used in pulmonary medicine because there was no evidence of alveolar destruction (5, 6, 8-11). However, we admit that studies of long-term calorie restriction in animals whose lungs have been appropriately fixed to enable detection of destructive emphysema are not available.

What is the basis for our "adaptative" interpretation of the findings? Periods of food unavailability occurred, and continue to occur, in the wild and to humans. Air-breathers have suffered episodes of diminished food intake since the Devonian, when lungfish estivated during periods of drought. Extreme food scarcity is life threatening, and the organism's metabolism adjusts, seemingly to diminish energy need while simultaneously maintaining the brain. During starvation, in addition to lowering body temperalure (2), thereby decreasing heat loss and energy needed to maintain a higher temperature, the organism destroys unessential functional capacity and unneeded tissue. Tissue destruction generates substrate for gluconeogenesis, which provides glucose for the brain, and diminishes the cost of maintaining unneeded tissue.

O2 need determines alveolar architecture. Calorie restriction diminishes organismal and lung (14) O2 consumption and, in adult mice, causes loss of alveoli and alveolar surface area within 3 days (6); ad libitum refeeding increases O2 consumption and induces alveolar regeneration (5, 6). Iguana shrink long bones during food scarcity; those that shrink the most have the greatest rate of survival (13). This loss presumably provides substrate for gluconeogenesis.

The lung's preferred substrate is glucose, but during calorie restriction the use of glucose by the lung is markedly diminished; lipid is used instead (14). Calorie restriction diminishes the rate of protein synthesis by lung, thereby lowering the lung's use of energy, and doubles the rate of proteolysis in the lung (15). The diminished use of glucose makes more glucose available to brain; doubling proteolysis provides substrate for gluconeogenesis and maintains muscle, another key organ for survival.

In animals with elastase-induced emphysema (16), and in human COPD, alveolar loss and diminished tissue elastic recoil persist after the initiators of these losses are gone; in neither is spontaneous alveolar regeneration known to occur. Calorie restriction does not diminish lung elastic tissue recoil (11, 12) and alveolar loss is regulated, ending after about 3 days even in the presence of continued calorie restriction (5, 6). Ad libitum refeeding after alveolar loss results in spontaneous alveolar regeneration (5, 6). Thus, regulated alveolar loss is followed by alveolar regeneration, whereas unregulated alveolar loss seemingly is not. Calorie restriction and refeeding of rats with preexisting elastase-induced emphysema results in a return of the size and surface area of the lung's gas exchange units but only to the dimensions present before the onset of calorie restriction (16). This suggests that, to the extent alveolar and extracellular matrix destruction are initiated in an unregulated manner by exogenous agents, spontaneous alveolar regeneration does not occur.

Molecular changes, which may mediate alveolar destruction during calorie restriction, precede the decline of lung (6), and organism O2 consumption. Granzymes, produced only by cytotoxic lymphocytes (CTL) and natural killer (NK) cells, and caspase expression are elevated within 2 to 3 hours of the onset of calorie restriction (6); this indicates that calorie restriction activates these cells and initiates events resulting in regulated alveolar destruction. CTL and NK cells are thought to be involved in the alveolar inflammation of COPD. Explication of the signaling that activates and turns off these cellular populations in the lung during calorie restriction may shed light on the persistent alveolar inflammation and destruction in COPD. Understanding the signaling associated with alveolar regeneration, which ad libitum refeeding induces, may provide clues to the induction of alveolar regeneration in humans. Computed tomographic evidence of alveolar regeneration upon refeeding in AN would provide proof of principle in adult humans. Perhaps the lung "shall not wholly die" (1).

References

1. Winick M. Preface. In: Winick M, editor. Hunger Disease: Studies by the Jewish Physicians in the Warsaw Ghetto. New York: John Wiley & Sons; 1979. p. ii.

2. Fliederbaum J. Clinical aspects of hunger disease in adults. In: Winick M, editor. Hunger Disease: Studies by the Jewish Physicians in the Warsaw Ghetto. New York: John Wiley & Sons; 1979. p. 11-36.

3. Coxson H, Chan IHT, Mayo JR, Hlynsky J. Nakano Y, Birmingham CL. Early emphysema in patients with anorexia nervosa. Am J Respir Crit Care Med 2004;170:748-752.

4. Cook VJ, Coxson HO, Mason AG, Bai TR. Bullae, bronchiectasis and nutritional emphysema in severe anorexia nervosa. Can Respir J 2001; 8:361-365.

5. Massaro GD, Radaeva S, Clerch LB, Massaro D. Lung alveoli: endogenous programmed destruction and regeneration. Am J Physiol 2002;283: L305-L309.

6. Massaro D, Massaro GD, Baras A, Hoffman EP, Clerch LB. Calorie-related rapid onset of alveolar loss, regeneration, and changes in mouse lung gene expression. Am J Physiol 2004;286:L896-L906.

7. Pieters T, Boland B, Beguin C, Veriter C, Stanescu D, Frans A, Lambert M. Lung function study and diffusion capacity in anorexia nervosa. J Intern Med 2000;248:137-142.

8. Sahebjami H, Wirman JA. Emphysema-like changes in lungs of starved rats. Am Rev Respir Dis 1981;124:619-624.

9. Harkema JR, Mauderly JL, Gregory RE, Pickrell JA. A comparison of starvation and elastase models of emphysema in rats. Am Rev Respir Dis 1984;129:584-591.

10. Kerr JS, Riley DJ, Lanza-Jacoby S, Berg RA, Spilker HC, Yu SY, Edelman NH. Nutritional emphysema in the rat: influence of protein depletion and impaired lung growth. Am Rev Respir Dis 1985;131:644-650.

11. Karlinsky JB, Goldstein RH, Ojserkis B, Snider GL. Lung mechanics and connective tissue levels in starvation-induced emphysema in hamsters. Am J Physiol 1986;251:R282-R288.

12. Gail DB, Massaro GD, Massaro D. Influence of fasting on the lung. J Appl Physiol 1977;42:88-92.

13. Wikelski M, Thom C. Marine iguanas shrink to surivive El Nino. Nature 2000;403:37-38.

14. Gregorio CA, Gail DB, Massaro D. Influence of fasting on lung oxygen consumption and respiratory quotient. Am J Physiol 1976;230:291-294.

15. Thet LA, Delaney MD, Gregorio CA, Massaro D. Protein metabolism by rat lung: influence of fasting, glucose, and insulin. J Appl Physiol 1977;43:463-467.

16. Sahebjami H, Domino M. Effects of starvation and refeeding on elastase-induced emphysema. J Appl Physiol 1989;66:2611-2616.

DOI: 10.1164/rccm.2408002

Conflict of Interest Statement: D.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; G.D.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

DONALD MASSARO, M.D.

GLORIA DEUARLO MASSARO, M.D.

Georgetown University School of Medicine

Washington, DC

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