Sudden infant death syndrome: selenium administered above dietary needs stabilizes the electrocardiograms of subjects deprived of exercise stimuli to the brain.

The human foetus begins preparation for extrauterine life in the 26th week of gestation. Victims of sudden infant death syndrome (SIDS) were described as having less-intensive reactions to environmental stimuli than their siblings. They were described as less-active physically and more breathless and exhausted during feeding. These foetal-like qualities are similar to the microgravity deconditioning of the space traveller and the autonomic dysfunction of hypokinetic humans. During quiet sleep, a group of near-miss SIDS victims displayed a faster heart-rate and a decreased movement-time, compared to controls. Another group of SIDS victims linked delayed repolarisation and sympathetic overactivity of the nervous system. The excessive Q-T wave intervals, cardiac instability and autonomic dysfunction tended to coincide with the peak incidence of SIDS which is the normal period of autonomic transformation at 2-3 months of age. Sympathetic hyperactivity transforms the subject into an energy-intensive species with an accelerated heartbeat, intensive vasoconstriction and general reactions to a hostile environment. Energy-intensive species (flight-oriented species) were sensitive to selenium (Se) deficiency. Altered mitochondrial structure and defective electron transport of heart mitochondria were features of this syndrome. Runaway excessive sympathetic autonomic activity transforms the subject into an energy-intensive species responsive to selenium. Groups of Se-deficient lambs confined for eight weeks developed abnormal electrocardiograms (ECGs). Groups exercised daily on a treadmill or Se-supplemented groups retained virtually normal ECGs. Foetuses and subjects unreactive to the environment are space travellers lacking parasympathetic stimuli to the brain. Decreased movement-time deprives the brain receptors of the stimulus induced by gravity.

Postnatal hypokinesia and the delayed time frame of sudden infant death syndrome.

The sudden infant death syndrome peaks in the second and third month of life. This is the period of the "two-month transformation of the central nervous system" in the human infant. Studies of 120 days of imposed hypokinesia in man demonstrated that the maximum period of autonomic dysfunction was delayed until the beginning of the second month through to the fourth month of the experiment. Hypokinesia also impaired sleep mechanisms and induced polymorphic changes in almost all systems of the human body. These studies suggest that prolonged postnatal hypokinesia in infants may induce autonomic dysfunction in the CNS, especially during the "two-month transformation period" of major postnatal neural development.

Sudden infant death syndrome (SIDS): microgravity and inadequate sensory stimulation.

In early gestation, the human foetus develops in a buoyant environment, which is similar to the near-weightlessness of space flight. After the 26th week of gestation, the foetus gradually becomes exposed to gravitational forces. The influence of fluid immersion declines as the weight of the foetus increases. In this way, the foetus adapts and trains for the gravity environment after birth. Failure of gravitational loading in the last trimester of pregnancy delays development and maintains the pathophysiological environment of microgravity as experienced by the astronaut in space flight. The deconditioning effects of microgravity during space flight are the reverse processes of intrauterine development after the 26th week when the foetus begins training body processes for adaptation to an earthly environment. Growth requires space and movement, which suggests that a growth-retarded foetus may have been deprived of the mechanical dimension of uterine wall pressure, and, in twins, the smaller sibling may have been deprived of space. The behaviour of a study group of sudden infant death syndrome infants suggested a continuation of the effects of the foetal akinesia syndrome during the third trimester period of gestation. NASA research into the pathophysiology of microgravity was based on a simple insight: that the physiological effects of human space travel were virtually identical to the adjustments the body makes when lying down. This is the same environment as that of the human foetus in the first 22 weeks of gestation after which the uterine environment becomes a prelude to adaptations to the force of gravity.

Sudden infant death syndrome: is it a transepithelial transport disorder?

The first limiting factor of dietary zinc deficiency has been described as a loss of the protective role of zinc against auto-oxidation of membrane sulfhydryl (SH) compounds. It has now been established that the prohormones (nutriuretic peptides) of the intestinal guanylin family are activated extracellularly by conversion of cysteines in the peptide to disulfide bridges. The induction of uroguanylin mRNA is elevated in intestinal zinc deficiency and nutriuretic peptides regulate epithelial transport of salt and water. Nitric oxide (NO) is also a modulator of salt and water transport. The constitutive forms of nitric oxide synthase (cNOS) in neurons and endothelial cells are calcium-dependent. The inducible form of nitric oxide synthase (iNOS) is activated by bacterial entero-toxins and damaged mucosa with NO penetrating the cell and acting directly on guanylate cyclase. The activated receptor-guanylate cyclases initiating the intracellular cycle 3'-5' guanasine monophosphate (cyclic GMP) cascade in target cells results in a flux of chloride and water into the intestinal lumen. Most of the actions of NO are mediated by activation of cyclic GMP. High-altitude pulmonary edema (HAPE) is associated with a defect in transepithelial water transport. It is suggested that dietary zinc, by modulating thiol oxidation to disulfides in guanylin prohormones to active hormones, is associated with salt and water secretion such that the overworked heart in hypoxemia increases the production and release of natriuretic peptides to activate guanylate cyclase receptors in target tissue in sudden infant death syndrome.

Sudden infant death syndrome and enteric infection.

The association of Helicobacter pylori in the stomach, trachea and lungs with the incidence of SIDS, gastric ulcers and cancer may have a counterpart in animals. In field studies of white muscle disease (WMD) and hepatic necrosis in selenium-deficient pigs dying suddenly, veterinarians identified gastric ulcers in 40% of inspected piglets. The lesion was also commonly observed by researchers in experimentally produced vitamin E-selenium deficiency and other researchers suspected that gastric ulcers in swine may be associated with vitamin E-selenium deficiency. Mice preferentially concentrated (75)selenium in peritoneal exudative cells (PEC) when (75)selenium as selenium selenate was administered by stomach tube to selenium-deficient mice. Selenium concentrated in PECs as glutathione peroxidase (GSHP(x)). GSHP(x)-deficient leucocytes in peritoneal exudate failed to kill yeast cells. GSHP(x) deficiency has also been associated with decreased microbicidal activity of leucocytes in patients with chronic granulomatosis. The selenium-deficient swine were usually growing rapidly in crowded conditions, and, apart from WMD and hepatic necrosis, edema was prominent in the spiral colon, subcutaneous tissues, lungs and submucosa of the stomach. The elevated immunological response in the spleen and lungs of SIDS victims suggests an initial defective microbicidal propensity of the peritoneal exudative cells.

Sudden infant death syndrome (SIDS): T-cell immunodeficiency--Part 1.

It is hypothesized that SIDS mimics AIDS and atopic eczema in that defective T lymphocytes and overactive B cells overstimulate pro-inflammatory cytokines in the mucosal immune system. Virally infected cells are unable to convert linoleic acid (LA) into gamma-linolenic acid (GLA) which eventually leads to defective T lymphocyte production. Abnormal lung cytokine synthesis by virus-induced immunodeficient T lymphocytes is associated with the murine AIDS-related complex (ARC). Adenosine triphosphate (ATP) deficient anaerobic cells cannot convert LA to GLA. It is hypothesized that, in SIDS victims, elevated levels of hypoxanthine and immunoglobulins are evidence of chronic hypoxemia and ATP catabolism, and an inability to convert LA to GLA, leading to defective T lymphocytes in the mucosal immune system.

Sudden infant death syndrome Part 2: the response of the reticuloendothelial system to hypoxemia and infection.

The incidence of ascites in chicks raised in a high-altitude chamber doubled from 6500 feet to 8000 feet. A similar condition developed in calves transported to pasture at high altitude. Chicks raised in a high-altitude chamber (compared to controls) produced more plasma cells in the germinal centres of the spleen about four days after an antigen challenge. Children usually suffering from a mild respiratory infection at sea level often developed pulmonary edema (HAPE) on transfer to high altitude. Sudden infant death syndrome (SIDS) victims produced more plasma cells in the germinal centers of the spleen. In one survey of SIDS, about half of the infants suffered an upper respiratory tract infection in the two weeks prior to death and the lungs were filled with fluid at autopsy. Elevated levels of hypoxanthine indicated hypoxemia before death, and a presumed response to hypoxemia in SIDS was the presence of extramedullary hematopoiesis in the liver. The effect of prolonged hypoxemia and infection are additive in increasing vascular permeability and the accumulation of edema fluid. The preferential uptake of zinc by edema fluid proteins at the expense of inflammatory cells increases the motility and metabolism of zinc-deprived activated macrophages. Activated macrophages release cytokines which in turn stimulate the release of pro-inflammatory peptides which increase vascular permeability and mortality. These inflammatory peptides are under proteolytic control. The neutral endopeptidase (NEP) is a cell-surface zinc metalloproteinase which modulates toxic shock.Zinc also modulates the inflammatory response of the activated macrophage. Interleukin-12 (IL-12), predominantly a product of macrophages, is involved in regulating both hematopoiesis and the adaptive immune response. IL-12 promotes interferon gamma (IFNgamma) production by T cells. IFNgamma acts on macrophages to release large amounts of nitric oxide (NO). An elevated immune response leads to NO overload, dilation of the cardiovascular system and toxic shock. A mechanism resulting in cardiovascular failure and a shock-like sequence is described in some cases of SIDS.Bradycardia, recorded on cardiorespiratory monitors in six SIDS infants, was considered a late event. Cytokines regulate all aspects of the immune response. Extramedullary hematopoiesis in the liver was one anatomical marker of hypoxemia in SIDS. This survey traces the function of the activated macrophage with the cytokines regulating extramedullary hematopoiesis and the precocious immune response in SIDS.

Sudden infant death syndrome: neonatal hypodynamia (reduced exercise level).

Sudden infant death syndrome (SIDS) has been described as a silent unexpected death during sleep. Infants with near-miss SIDS have shown a higher heart rate and diminished heart rate variability during sleep. Non-rapid-eye-movement (NREM) sleep rate variability was related to respiration. A decreased heart rate variability was also observed in infants with respiratory distress syndrome (RDS) or prenatal hypoxia. It was hypothesized that decreased heart rate variability and decreased body measurement during sleep were related to a decreased arousal response. Cardiac output is greater in the supine position. Acetylcholine slows the heart beat. Postural changes modify the acute baroreflex control of the heart rate. The cerebellum also contributes to the reflex anti-orthostatic (supine) cardiovascular response to postural change. Delayed myelination of various areas of the brain occurred in SIDS victims and it was suggested that the defect in central respiratory control could be a motor rather than a sensory problem, and that the search for abnormalities should be extended to regions in the cerebellum and pre-frontal-temporal-limbic systems. The cerebellum exercises control over motor neuron impulses from the cerebral cortex to lower structures. An extended period of neonatal decreased body movement has its counterpart in the astronaut exposed to the deconditioning effect of zero gravity. Hypodynamia induces hyperglycemia, insulin resistance, renal inositoluria and impaired nerve conduction. Myoinositol is 20 times higher in fetal-like tissue than in adults. The insecticide lindane (gammexane) is an inositol antagonist. Lindane administration to neonatal rats induced low levels of specific components of myelin proteins in oligodendrocytes in the brain. The activity of these specific enzymes was reduced in oligodendrocytes in the brain of SIDS victims. It is hypothesized that lindane administration to laboratory neonatal animals is a laboratory model for studying delayed development of the brain in SIDS.

Sudden infant death syndrome: a preconditioning approach to acute arterial hypoxemia.

The blood hemoglobin F (HbF) concentration increases in response to chronic arterial hypoxemia and is abnormally elevated in sudden infant death syndrome (SIDS) post-mortem indicating a need for greater oxygen affinity of hemoglobin (Hb) or diminished oxygen usage by tissues or both. Modifying Hb oxygen affinity in rats revealed that increased, rather than decreased, hemoglobin-oxygen affinity permitted survival at greatly reduced environmental oxygen pressures equivalent to high altitude. Decreased Hb-oxygen affinity resulted in bradycardia 5-10 minutes before death. Cardiorespiratory recordings from infants dying suddenly and unexpectedly at home demonstrated cardiovascular failure with hypotension and bradycardia, rather than a cessation of breathing.A fall in blood pressure and acidosis due to hypoxemia in combination with reduced arterial oxygen saturation leads to circulatory failure, heart failure and death. It is speculated that the final mechanism of SIDS mimics failure to survive at high altitudes and very low environmental oxygen pressures when low arterial oxygen pressures combine with decreased Hb-oxygen affinity lead to severe hypoxemia and death.

Sudden infant death syndrome: oxidative stress.

In studies of oxidative stress in sudden infant death syndrome (SIDS) there were two major findings: (1) During normal post-natal development, there was a gradual decline in the number of Cu/Zn superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) immunoreactive neurons in the hippocampus and parahippocampus gyrus in the brain; (2) The total number of immunoreactive neurons was elevated in SIDS victims compared to age-matched controls in infants 6 months of age and under (1). SOD and neuronal aging and degeneration in the hippocampus and neocortex were features of SIDS, Alzheimer's disease and Down's syndrome. In the SIDS study of infants from 3-6 months of age, the elevation of SOD in SIDS victims was significant, whereas no significant elevation of GSHPx was detected. An imbalance between SOD and GSHPx was said to be crucial in the prevention of toxicity of free radicals (1). Zinc-deficient cells cannot up-regulate gene expression of the scavenger enzymes SOD and GSHPx in cells exposed to high levels of superoxide and hydrogen peroxide (2). GSHPx coupled to reduced nicotine adenine diphosphate (NADPH) regenerating systems via glutathione reductase is virtually able to guarantee an effective protection of biological structures against oxidative attack (22). When the capacity of the cell to regenerate GSH is exceeded - primarily due to an insufficient supply of NADPH-oxidised glutathione (GSSG) is released from the cell and protein synthesis turns off (20). We hypothesize that the increased incidence of aging and neuronal death and increased incidence of SOD and GSHPx reactive neurons in early post-natal development indicates an increased up-regulation of gene expression of scavenger enzymes during high exposure to oxidative stress after birth. GSH-dependent peroxide metabolism is linked to the pentose phosphate shunt via NADPH-dependent glutathione reductase (GR). GSHPx is a selenium containing enzyme which together with catalase (CAT) SOD and vitamin E protects cells in the free radical chain. Zinc upregulates gene expression of these antioxidants.

Sudden infant death syndrome: hypothalamic failure to sense elevated blood pyrogens.

Sudden infant death syndrome (SIDS) is frequently associated with a mild infection, the incidence peaking during the third month of life. We hypothesize that the neonatal immaturity of both the acute febrile response and hypothalamus promote neonatal protection from SIDS. Vagal afferents modify the febrile response. Vagotomized rodents displayed a loss of febrile responsiveness in a 'non-sensing' brain. The failure of a 'non-sensing' brain to react to elevated blood pyrogens leads to failure of the febrile response and to a shock-like state. SIDS infants may appear well yet, within hours of this observation, may be found dead. There is a mismatch between the acute febrile response and hypothalamic hypoactivation. The discrepancy increases with development. There is an elevated cytokine response in endothelial cells which induces nitric oxide (NO) production and retarded development of the hypothalamus. Cigarette smoke also induces NO production and retards hypothalamic development by augmented apoptosis. Zinc inhibits this effect in mouse thymocytes. Fetal haemoglobin (HbF) induces hypoxia, which is a stimulator of the immune response while vasodilator gases (carbon monoxide (CO), NO) reduce hypothalamic function. The hypothalamic failure to sense elevated blood pyrogens induces toxic shock - a feature of SIDS.

Sudden infant death syndrome and the modulation of neuropeptides released during shock.

It is generally accepted that sudden infant death syndrome (SIDS) victims fail to survive relatively minor stress in infancy. My hypothesis is that failure to orchestrate the endocrine response in stress leads to excessive release of neutral-endopeptidase-sensitive peptide substrates that enhance lethality. The 'quick zinc' response Reid recorded in livestock with circulatory shock is described. It is concluded that the failure to mount an endocrine response leads to SIDS.

Sudden infant death syndrome and placental disorders: the thyroid-selenium link.

Placental insufficiency, inducing hypoxia-ischaemia, is considered a major cause of neuronal injury and impaired post natal development. Placental insufficiency alters the metabolism of arachidonic acid and its oxidation products. Premature labour and low-birth-weight infants are associated with reduced intrauterine blood-flow and infections of the reproductive tract. Thyroidal activity is depressed in undernutrition (placental insufficiency). Premature infants require extra vitamin C for normal tyrosine metabolism (tyrosine is the thyroxine precursor). Among the symptoms indicating infantile cretinism, which appear during 3-5 months of age are: delayed union of skull bones, torpid behaviour, slow feeding, cyanosis during feeding, excessive sleepiness, enlarged tongue, umbilical herniation, flabby musculature, short stature and delayed development. These symptoms have all been described in low-birth-weight infants and sudden infant death syndrome victims by various authors. Bacteria utilize selenium (at the expense of host tissue). Escherichia coli is among the bacteria invading the reproductive tract. E. coli produce thiouracil and are goitrogenic. Some strains of E. coli produce phospholipase A2 which releases arachidonic acid from phospholipids for prostaglandin synthesis. Phospholipase A2 is more active against peroxidized than non-peroxidized lipids. Bacterial competition for intrauterine selenium and goitrogenic bacterial infections of the reproductive tract during pregnancy, depress thyroid function in the fetus but not in the mother.

Sudden infant death syndrome: near-weightlessness and delayed neural transformation.

Dilation of the pulmonary arteries and increased pulmonary blood volume are recorded in sudden infant death syndrome and in infants living at low barometric pressures (high altitude). Low barometric pressure leads to chronic alveolar hypoxia (1,2). There is diversion and loss of body-fluid under conditions of microgravity (near-weightlessness) encountered in human space-travel and prolonged bedrest (3). The condition mimics shock and oligemia (4,5). The human neonate has underdeveloped postural mechanisms and low muscle-power. A transformation begins at about two months of age, which enables the human infant to adapt to the extrauterine environment (6). The neonate resembles the space traveller who, in a near-weightlessness antigravity environment, develops baroreceptor incompetence, visceral and venous congestion and oliguria. The low birthweight infant displays many of the disorders of the space traveller, viz. poor circulation, high blood-glucose, insulin resistance, weak muscles, slow gut absorption and bone demineralization (7-10). These conditions are virtually identical with the internal adjustments the body makes on lying down (negative gravity or near-weightlessness). We discuss the similarities of sudden infant death syndrome to low barometric pressure environment, orthostatic intolerance, the Pickwickian syndrome and X disease.

Sudden infant death syndrome and superoxide/nitric oxide.

In a sudden infant death syndrome review Valdès-Dapena describes Naeye's report of increased medial muscle mass in walls of small pulmonary arteries and increased weight of cardiac right ventricles. These findings point to cardiorespiratory insufficiency, a problem in fast growing chicks raised at high altitudes. The vascular epithelium lining all blood vessels synthesises nitric oxide which induces relaxation of smooth muscle in vessel walls, and is possibly an important neurotransmitter. Others demonstrate that nitric oxide is involved in regulating vessel calibre, blood pressure and blood flow, as well as falls in ventricular outputs. Superoxide interacts with nitric oxide and removes it from the circulation. Superoxide is thus a vasoconstrictor. Superoxide is produced by activated phagocytes and possibly lymphocytes and other cell types in the immune response. Elevated immunoglobulins in mucus secretions are a hallmark in sudden infant death syndrome and hypoxic chicks. Our approach therefore is that cardiorespiratory insufficiency may be induced by superoxide in small pulmonary arteries preventing nitric oxide from acting as a muscle relaxant in vascular walls.

Children's occupational sex-role stereotyping in 1994.

To update the basis of the explanation of how elementary children evaluate the capability of males versus females to perform occupations which are dominated by males, females, or are gender balanced (neutral) in the workforce 180 girls and 200 boys in Grades 1, 2, and 3 completed a questionnaire indicating which of 39 occupations were mostly done by women, by either, or by men on a 5-point scale. The most and least stereotyped occupations were very like gender-occupational data from 1972 and 1983 and reflected the actual sex-typing in the labor force. Sex and grade differences were noted for male occupations but not for female occupations. Some differences from 1977 data of Garrett, et al. were noted. The neutral status of some occupations appeared to assume a male worker.

Sudden infant death syndrome (SIDS): immunoglobulins and hypoxia.

A body of opinion suggests that immunological overstimulation of the gastrointestinal and respiratory mucosa is involved in SIDS. The local stimulation of immunoglobulin concentration in the respiratory mucosa is said to be the consequence of an accentuated reaction to a trivial infection (1-4). One hypothesis is that an accentuated airways reactivity plays a key role in the events leading to SIDS and cites the final insult as oxygen lack, low oxygen stores, high oxygen usage and cardiorespiratory failure (5). We hypothesize that hypoxia and antioxidants exacerbate disorders of the paracrine interaction in the airways mucosa leading to overproduction of immunoglobulins. Administration of vitamin E above dietary needs to hypoxic chicks increased the immune response. The effects were considered synergistic in elevated production of immunoglobulins, and in their function as antioxidants (6). The oxygen lack, low oxygen stores, high oxygen usage and cardiorespiratory failure (5) are factors capable of provoking an overstimulated immune response in the respiratory mucosa. When levels of T-helper/inducer cells are maintained in AIDS patients' blood plasma, survival time is extended (7). This paper investigates the role of 1,25 (OH) 2D3 in suppression of T-helper/inducer lymphocyte activity in vitro (8,9,34,36), and the failure of activated pulmonary alveolar macrophages (PAM) to produce sufficient 1,25(OH)2D3 to inhibit beta-cell proliferation before differentiation to immunoglobulin secreting cells (4,36).

Maternal sex-stereotyping of newborns.

Gender as a social category playing a role in the process of how mothers perceive their newborns was investigated. 94 primiparous mothers completed a survey that included a physical and an emotional scale on their newborn infants. Neither scale as a whole discriminated between the male and female newborns; however, a one-way analysis of variance did identify four statistically discriminating items. The four items evidence maternal perceptions that sex-stereotype males as having broad, wide hands, looking tall and large, looking athletic, and being mostly serious--not smiling but not crying. Maternal sex-stereotyped perceptions for daughters would be the inverse of these. 30 items gave similar maternal ratings between the two gender sets. These confirmed prior work in 1974 showing sex-stereotyped physical characteristics outnumber the emotional characteristics. The similarity of current conclusions to the 1974 data suggests less than expected fundamental parental attitudinal change due to increased societal interest and attention to gender and sex-stereotyping.