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Despite the tendency to a normocytic picture for the red cells, a wide range of changes has been described, in terms of the shape and size of the red cells or their relative fragility (1, 2, 4, 5). There may be varying degrees of reticulocytosis, but in more severe cases reticulocytosis may be absent. Anemia represents a reduction in the circulating red cell mass, which must be the result of blood loss or a change in the balance between the rates of red cell synthesis and red cell degradation. Alterations in the rate of degradation are most likely to lead to a shortened life span of the red cell, either because the cells are of poor quality and more vulnerable, or because they exist in a challenging environment produced by infection or nutritional Figure 14. Fondu considered that the diminished erythrocyte survival time resulting from increased hemolysis was more likely to be due to poor vitamin E or selenium status than to a limitation of standard hematinics such as iron, folate, or B12 (1, 2, 15) (Figure 14. Malnourished individuals are highly susceptible to infection and also frequently have multiple deficiencies of specific nutrients. It is not easy to determine the extent to which this variability can be accounted for by adaptive responses, more complex nutrient deficiencies or the impact of concurrent infection. Therefore, in an established case of severe malnutrition, with or without edema, it can be difficult to differentiate the relative contribution of these multiple potential causes or the extent to which the relative overall effect represents some more complex interaction. Notwithstanding these complexities, an appreciation of the role of different components is of considerable importance since an injudicious approach to the treatment of anemia is one of the principle causes of excess mortality (22). During the early stages of treatment of severe undernutrition, the administration of supplemental iron can contribute to a significant increase in mortality (6, 7, 8). In more extreme situations, the adipose tissue in marrow is lost and is replaced with gelatinous, ground substance or mucopolysaccharides. Erythroid precursors are maintained to a varying extent and may appear to be more active than usual in some situations, but may show a preterminal decrease in activity. A series of case reports characterizes the abnormal marrow in patients with anorexia nervosa. The main characteristic is serous or gelatinous change in which atrophy of fat is associated with an increase in ground substance or acid mucopolysaccharides. This gelatinous change may be associated with atrophy and significant reduction of erythroblasts and hypocellularity of the other blood forming tissues. The drive to erythropoiesis might be enhanced, as determined by increased levels of erythropoietin (24), and there may be evidence of increased iron storage, despite a low hemoglobin level (30). The pattern of change is similar to that in severe undernutrition under other circumstances. Although the changes can be severe, it appears that they are potentially completely reversible with successful treatment and recovery (30, 34, 35). The erythropoietin level tends to be higher than normal during the acute stages, and reduces towards normal with recovery. Nevertheless, even when other measures such as the regaining of weight indicate recovery, this does not necessarily mean that there is complete recovery of the red cells or a higher than usual drive to red cell formation. For example, the systematic autopsies carried out where possible for those who died in the Warsaw Ghetto (5) identify that, in the most severely malnourished, marrow changes might be varied. This picture is in many respects similar to that reported for individuals with severe anorexia as a result of psychological disturbances, or the more complex 220 A. If, in the absence of evident blood loss, and despite increased levels of erythropoietin, the red cell mass remains lower than would be expected, this strongly suggests a limitation to red cell production. Thus, a demonstrated increase in the stored iron in the marrow, liver and spleen, despite the increased erythropoietin providing a drive to utilization of this iron for enhanced red cell formation, suggests a constraint on the effective utilization of the available iron (37, 42, 43). And the other possibility remains: an increased rate of red cell loss or excessive red cell breakdown. The marrow changes are usually reflected in changes in peripheral blood where, although the erythrocytes often appear normocytic with a near normal hemoglobin content, they may appear hypochromic, microcytic or megaloblastic. With successful treatment even the most severe changes appear to be reversible, although the timescale of improvement lags behind that of other systems.

However, this observation clearly indicated the importance of the balanced adequacy of micronutrients in resisting potentially toxic environmental challenge (7, 8). Further, it made clear the way in which the multiple layers of protection against free radical induced damage are fundamental to maintaining cellular protection, its structure and its function. Of critical importance, it raised the question of the extent to which the red cell plays an important, if not central and specific role, in the progressive pathophysiology of edematous malnutrition. To an extent, the pathology of the red cell can be taken to mark the pathology of other cells in the body. Jackson will predispose it to a shortened life span, a critical basis for an increase in stored and/or free intracellular iron and the establishment of ensuing cellular pathology. An increased loss of red cells in the face of any limitation on red cell production inevitably leads to a reduction in red cell mass. The lowered hemoglobin will be one important, potential consequence, but of much greater significance is the fate of the iron which can no longer be returned to the synthesis of red cells and has to be handled and stored. Moreover, it has to be stored in a form in which free iron is unlikely to be generated to act catalytically as a centre for Fenton and HaberWeiss reactions, the focus of radical induced molecular and cellular damage (43). The evidence from studies where the excess burden of iron has been removed by chelation therapy provides support for the proposal that free iron is causative for some of the features of severe malnutrition, and contributes directly to enhanced mortality (7, 8, 45). The demonstration that reduced glutathione is usually, if not always, associated with edematous malnutrition, and that this is directly associated with increased susceptibility to free radical induced damage, has been demonstrated in many but not all studies. The cellular content of reduced glutathione plays a fundamental role in normal cellular function and it is critically involved in a range of functions related to cellular integrity. If the glutathione content of cells cannot be maintained then cells fail to survive. Antioxidant protection is one important function and, importantly, free radical challenge is a major process through which cellular glutathione can be depleted (7, 8). Thus, cellular glutathione has to be placed in the context of the other cellular antioxidant protective mechanisms and processes. For these reasons, single or multiple micronutrient deficiencies or altered membrane structure and function interact with impaired ability to maintain cellular glutathione status in determining cellular survival (77). Although glutamic acid, cysteine and glycine, the three amino acids which go on to form glutathione, are not essential dietary components, the ability to maintain their synthesis at an adequate level is of critical importance (75, 76, 78). This is determined by the integrity of the control and regulatory systems on cells and tissues, the adequacy of dietary micronutrients, and the amount and quality of dietary nitrogen or protein (75, 76, 78). Thus, the quality of red cell synthesis and the life span of the red cell in a harsh circulatory environment mark the wider stresses placed upon the cells of the body in the undernourished state. The effectiveness of antioxidant protection is directly related to the magnitude of the challenges imposed, either as a consequence of normal cellular metabolism, the oxidant burst associated with infection, or other pathological processes. The increase in stored iron as an integral feature of reductive adaptation may well go on to play a critical role in determining the magnitude of prooxidant stress in severe malnutrition. A randomized controlled trial of a supplement of antioxidants in children at risk of developing edematous malnutrition failed to demonstrate any protective effect (95). It is important to determine whether this should be taken as evidence to support rejection of the idea that free radical damage plays a role in the etiology and pathogenesis of the process, or whether the particular choice of intervention was not suitable for the context (94). Infection adds to the problem by increasing specific nutrient losses and the associated reductive adaptation increases individual vulnerability. Anemia is one manifestation of this complex process, and is usually associated with an inability to effectively utilize iron, leading to enhanced iron both in stored and free form. The likelihood of an individual dying from a period of severe undernutrition, or surviving with a reasonable chance of recovery, not only depends upon what is done in terms of immediate care but, critically, on the order in which different interventions are carried out (97). The systems for classifying malnutrition place emphasis on two characteristics: loss of relative weight and the presence of edema (6). Based on standard approaches in nutrition, the impetus is to correct the edema directly, frequently by the use of diuretics, to correct wasting through the generous provision of food, and to treat abnormal blood biochemistry by direct provision of single nutrients. Each treatment runs the risk of contributing to increased mortality unless at least equal attention is given to correcting the associated cellular damage, the result of multiple nutrient deficiencies (21). Although anemia might be a common presenting feature, and has many of the characteristics of an iron-deficient picture, the problem in the short term is an inability to effectively utilize the iron that is in the body, rather than any immediate shortage. With appropriate treatment, as infections are treated and specific nutrient deficiencies corrected, cellular competence returns.

Isolated ageusia is most commonly encountered as a transient feature associated with coryzal illnesses of the upper respiratory tract, as with anosmia. Indeed, many complaints of loss of taste are in fact due to anosmia, since olfactory sense is responsible for the discrimination of many flavours. Central processes run in the solitary tract in the brainstem and terminate in its nucleus (nucleus tractus solitarius), the rostral part of which is sometimes called the gustatory nucleus. Fibres then run to the ventral posterior nucleus of the thalamus, hence to the cortical area for taste adjacent to the general sensory area for the tongue (insular region). Lesions of the facial nerve proximal to the departure of the chorda tympani branch in the mastoid (vertical) segment of the nerve. Ageusia as an isolated symptom of neurological disease is extremely rare, but has been described with focal central nervous system lesions (infarct, tumour, demyelination) affecting the nucleus of the tractus solitarius (gustatory nucleus) and/or thalamus and with bilateral insular lesions. As a corollary of this last point, some argue that there should be no language disorder (aphasia) to permit the diagnosis of agnosia. Intact perception is sometimes used as a sine qua non for the diagnosis of agnosia, in which case it may be questioned whether apperceptive agnosia is truly agnosia. However, others retain this category, not least because the supposition that perception is normal in associative visual agnosia is probably not true. Moreover, the possibility that some agnosias are in fact higher-order perceptual deficits remains: examples include some types of visual and tactile recognition of form or shape. The difficulty with definition perhaps reflects the continuing problem of defining perception at the physiological level. Theoretically, agnosias can occur in any sensory modality, but some authorities believe that the only unequivocal examples are in the visual and auditory domains. With the passage of time, agnosic defects merge into anterograde amnesia (failure to learn new information). Anatomically, agnosias generally reflect dysfunction at the level of the association cortex, although they can on occasion result from thalamic pathology. The neuropsychological mechanisms underpinning these phenomena are often ill understood. Cross References Agraphognosia; Alexia; Amnesia; Anosognosia; Aprosodia, Aprosody; Asomatognosia; Astereognosis; Auditory agnosia; Autotopagnosia; Dysmorphopsia; Finger agnosia; Phonagnosia; Prosopagnosia; Pure word deafness; Simultanagnosia; Tactile agnosia; Visual agnosia; Visual form agnosia Agrammatism Agrammatism is a reduction in, or loss of, the production or comprehension of the syntactic elements of language, for example articles, prepositions, conjunctions, verb endings. Cross References Aphasia; Aprosodia, Aprosody Agraphaesthesia Agraphaesthesia, dysgraphaesthesia, or graphanaesthesia is a loss or impairment of the ability to recognize letters or numbers traced on the skin, i. Cross References Agnosia; Tactile agnosia Agraphia Agraphia or dysgraphia is a loss or disturbance of the ability to write or spell. Since writing depends not only on language function but also on motor, visuospatial, and kinaesthetic function, many factors may lead to dysfunction. From the linguistic viewpoint, two types of paragraphia may be distinguished as follows: Surface/lexical/semantic dysgraphia: misspelling of irregular words, producing phonologically plausible errors. Writing disturbance due to abnormal mechanics of writing is the most sensitive language abnormality in delirium, possibly because of its dependence on multiple functions. Akathisia Akathisia is a feeling of inner restlessness, often associated with restless movements of a continuous and often purposeless nature, such as rocking to and fro, repeatedly crossing and uncrossing the legs, standing up and sitting down, and pacing up and down (forced walking, tasikinesia). Treatment of akathisia by reduction or cessation of neuroleptic therapy may help, but may exacerbate coexistent psychosis. Centrally acting -blockers such as propranolol may also be helpful, as may anticholinergic agents, amantadine, clonazepam, and clonidine. Cross References Parkinsonism; Tasikinesia; Tic Akinesia Akinesia is a lack of, or an inability to initiate, voluntary movements. More usually in clinical practice there is a difficulty (reduction, delay), rather than complete inability, in the initiation of voluntary movement, perhaps better termed bradykinesia, or reduced amplitude of movement or hypokinesia. These difficulties cannot be attributed to motor unit or pyramidal system dysfunction.

Reduced birth weight was reported in offspring from Rhesus monkeys treated before mating and during gestation with 0. Reduced mean birth weight also was reported in monkeys exposed to Aroclor 1248 (Allen and Barsotti 1976; Allen et al. End points that have been examined in these studies include gene mutations in bacteria and Chinese hamster V79 cells, chromosomal aberrations in human lymphocytes and rat and mouse bone marrow cells and spermatogonia, micronuclei in mouse bone marrow cells, and dominant lethal mutations in rat sperm cells. Although control and exposed groups were matched regarding smoking and alcohol drinking habits, the exposed workers were also exposed to benzene and formaldehyde. The authors also observed that the number of chromosome breaks per cell was often higher in the exposed subjects than in unexposed controls. Additionally, lymphocytes from the exposed workers appeared to be more fragile than those from unexposed individuals. However, exposure to toxic chlorinated dioxins and/or furans generated during the fire may have occurred. Six of 16 workers engaged in cleaning oil from old transformers showed abnormal banding pattern for fes oncogene-related proteins; all of the 6 were smokers (Brandt-Rauf and Niman 1988). Single doses #5,000 mg/kg of Aroclor 1242 administered by gavage did not induce chromosome abnormalities in bone marrow cells or spermatogonial cells of rats (Green et al. In the same study, doses #750 mg/kg/day Aroclor 1254 administered for a 5-day period did not increase the incidence of chromosomal abnormalities in rat bone marrow cells. Genotoxicity of Polychlorinated Biphenyls In Vivo Species (test system) Mammalian cells: Rat spermatogonia Rat spermatogonia Rat hepatocytes Rat spermatogonia Rat bone marrow cells Rat bone marrow cells Rat sperm cells Rat sperm cells Mouse bone marrow cells Mouse sperm cells Nonmammalian cells: Chicken embryos Ring dove Drosophila melanogaster D. Lack of dominant lethality was indicated by no consistent changes in numbers of implantations and dead implantations per pregnant untreated female. The 70-day duration of the feeding study covered the spermatogenic cycle of the rat. Gene mutations also were not induced by Aroclor 1242 or Clophen A60 in Chinese hamster V79 cells (Hattula 1985). Varying results were found in two assays for Aroclor 1254-induced chromosomal damage in cultured human lymphocytes, but the different findings may be the consequence of a higher test concentration in the positive study (Hoopingarner et al. Genotoxicity of Polychlorinated Biphenyls In Vitro Results Species (test system) Prokaryotic organisms: Salmonella typhimurium (plate incorporation) S. A report of liver cancer in Yusho victims appears to support the occupational hepatocarcinogenicity data. A small excess risk of liver-related cancer was found in studies of workers from two capacitor manufacturing plants in New York and Massachusetts (Brown 1987b; Brown and Jones 1981). Aroclor 1254 was used at first, but usage was later changed to Aroclor 1242, and finally to Aroclor 1016. The workers were also exposed to additional chemicals, including trichloroethylene, toluene, and methyl isobutyl ketone. The first study (Brown and Jones 1981) included 2,567 total subjects comprised of 968 workers (583 males, 385 females) in Plant 1 and 1,599 workers (675 males and 924 females) in Plant 2. The second study (Brown 1987b) was conducted after 7 additional years of observation on 2,588 total subjects, comprised of 981 workers (593 males, 388 females) in Plant 1 and 1,607 workers (677 males and 930 females) in Plant 2. A slight increase in mortality due to cancer of the liver, biliary tract, or gall bladder (3 observed/1. The follow-up study (Brown 1987b) identified two additional cases of liver/biliary tract/gall bladder cancer, which made the excess statistically significant (5 observed/1. Four of the five cancer cases occurred in women who worked in Plant 2 (4 observed/0. Although the four cases in women occurred in the plant with the higher exposure range, there was no clear increase in the risk of liver/biliary tract/gall bladder cancer with increasing latency (time from start of exposure to end of observation) or length of employment; however, the confidence in this analysis is low due to the small numbers of deaths. Reclassification of the data showed that only two of the five deaths were from liver cancer and the remaining three were in the biliary tract (two cases) or gall bladder (one case) (Brown 1987b). Additionally, one of the two liver cancers was not a primary carcinoma as it metastasized from another site (unknown). Other findings included a slight increase in rectal cancer in the first study, but not in the follow-up (see Section 3.