Gestational zinc deprivation in mice: persistence of immunodeficiency for three generations.

Pregnant Swiss Webster mice were fed a diet moderately deficient in zinc from day 7 of gestation until parturition. Offspring of these mice showed depressed immune function through 6 months of age. In addition, the second and third filial generations, all of which were fed only the normal control diet, continued to manifest reduced immunocompetence, although not to the same degree as in the first generation.

Specific nutrient abnormalities in asymptomatic HIV-1 infection.

OBJECTIVE: To determine whether specific nutrient abnormalities occur in earlier stages of HIV-1 infection, thereby preceding the marked wasting and malnutrition that accompany later stages of the infection. DESIGN: A longitudinal investigation to determine biological, psychological and social factors thought to influence the progression and outcome of HIV-1 infection. Nutritional status was assessed using biochemical measurement of nutrient levels, dietary history, anthropometry and clinical examination for the signs and symptoms of nutritional deficiency or excess. SETTING: The study was performed on an outpatient basis at the University of Miami School of Medicine. PARTICIPANTS: One hundred homosexual men, aged between 20 and 55 years, who were asymptomatic other than persistent generalized lymphadenopathy (Centers for Disease Control stage III) and 42 age-matched homosexual men demonstrated to be free of HIV-1 infection at two 6-month intervals. MAIN OUTCOME MEASURES: Biochemical measurement of nutrient status, dietary history, anthropometry, clinical signs or symptoms of nutritional excess or deficiency were obtained for all participants. RESULTS: Despite few differences in mean blood levels of specific nutrients, prevalence of specific nutrient abnormalities was widespread among HIV-1-infected subjects, compared with non-infected male homosexual controls. Overtly and marginally low blood levels of vitamins A (18%), E (27%), riboflavin (26%), B6 (53%), and B12 (23%), together with copper (74%) and zinc (50%) were documented in HIV-1-seropositive subjects. With the exception of riboflavin, zinc, and copper, a similar prevalence of abnormalities among HIV-1-seronegative controls was not observed. CONCLUSION: Specific nutrient abnormalities occur with relative frequency in asymptomatic HIV-1 infection and may contribute to the rate and form of HIV-1 disease progression.

Persistent immunological consequences of gestation zinc deprivation.

Recent work has shown that offspring of outbred mice deprived of adequate dietary zinc during the latter two-thirds of gestation exhibited a defective direct plaque-forming cell response to immunization with heterologous erythrocytes, as well as impaired ontogenesis of serum IgM. Moreover, such aberrant immunological measurements continued to be observed, although to a lesser degree, in F2 and F3 progeny. We now demonstrate that offspring of mice moderately deprived of zinc (5 ppm zinc diet) between days 7 and 20 of gestation also show an aberrant pattern of development of serum levels of IgG2a and IgA, despite complete nutritional rehabilitation beginning at birth. Only by 6 months of age were concentrations of these serum immunoglobulins similar to those in offspring of control dams. In contrast, levels of IgG1 and IgG2b were within normal ranges by 6 wk of age. Cross-fostering of zinc-deprived offspring to dams adequately nourished during pregnancy did little to ameliorate their aberrant pattern of serum immunoglobulin development. Defective maturation of serum IgG2a and IgA did not persist in F2 and F3 progeny. Nonetheless such 2nd and 3rd generation offspring continued to have higher than normal perinatal mortality. The alterations of immune ontogenesis in these mice could not be attributed to the persistence of abnormal plasma zinc levels, as these were within normal ranges. It would appear that zinc deficiency during gestation may alter the basic mechanism of development of immunological competence.

Use of an expanded-whole-wheat product in the reduction of body weight and serum lipids in obese females.

To achieve weight reduction and alter serum lipid profiles, an air-expanded whole-wheat protein product (SNW) was used by moderately obese women as a meal substitute for 12 wk. Results were compared with those from a standard low-calorie diet (LCD). The SNW group lost 3.9 kg (means) over the first 6 wk and a further 1.6 kg between weeks 6 and 12. In contrast, the LCD group lost 2.8 kg during the initial 6 wk but failed to achieve weight loss during the second 6 wk. Consequently, the SNW group lost nearly twice as much weight over the 12-wk period as did LCD participants. A beneficial effect of SNW on serum cholesterol and triglycerides was noted; both measures declined in conjunction with the weight loss. Such alterations were greater in the SNW group than in LCD participants. Both schemes proved safe. SNW is safe and effective in weight reduction and serum lipid modification in moderately obese women.

Plasma vitamin B12 level as a potential cofactor in studies of human immunodeficiency virus type 1-related cognitive changes.

Studies of cognitive function in subjects with human immunodeficiency virus type 1 (HIV-1) infection who remain relatively asymptomatic (ie, Centers for Disease Control stages II and III) have provided widely variable estimates of cognitive impairment. In view of the finding that approximately 25% of asymptomatic HIV-1-infected subjects demonstrate either marginal or overt vitamin B12 deficiency, we have investigated plasma vitamin B12 status as a potential cofactor in studies of HIV-1-related cognitive impairment. When cognition was assessed in asymptomatic (Centers for Disease Control stages II and III) HIV-1-infected participants taking into consideration vitamin B12 status, those subjects with low plasma vitamin B12 levels (less than 180 pmol/L) performed more poorly than did those with normal (greater than or equal to 180 pmol/L) vitamin B12 status on specific measures of information processing speed and visuospatial problem-solving skills. These findings suggest that concurrent vitamin B12 deficiency may be a cofactor in subtle cognitive changes observed in the asymptomatic stages of HIV-1 infection. These differences in prevalence of low plasma vitamin B12 levels may help to explain differences among studies in the proportion of HIV-1-infected subjects showing cognitive impairment.

Association of vitamin B6 status with parameters of immune function in early HIV-1 infection.

Nutritional deficiencies have been documented to affect immune function. The present study indicates that vitamin B6 deficiency is prevalent in CDC stage III HIV-1-infected subjects, despite adequate dietary vitamin B6 intake. As vitamin B6 deficiency has been previously shown to affect immune function, these relatively asymptomatic HIV-1-infected patients were examined for evidence of a relationship between vitamin B6 deficiency and immune dysregulation. Vitamin B6 status in HIV-1-infected subjects was significantly associated with functional parameters of immunity [multivariate F(3,36) = 3.70, p less than or equal to 0.02]. Additional analyses indicated that overtly deficient participants exhibited significantly decreased lymphocyte responsiveness to the mitogens phytohemagglutinin and pokeweed, and reduced natural killer cell cytotoxicity, compared to subjects with clearly adequate vitamin B6 status (chi 2 = 8.78, df = 3, p less than 0.04). Vitamin B6 status was not related to immune cell subpopulations, e.g., CD4, CD8 cell number, or level of serum immunoglobulins. The results of this study indicate that while vitamin B6 status is not a primary etiological factor in HIV-1-related immunological dysregulation, it appears to be an important cofactor of immune function.

Zidovudine-associated adverse reactions in a longitudinal study of asymptomatic HIV-1-infected homosexual males.

Chemotherapeutic regimens frequently interact with and may influence nutritional factors. To determine the possible effects of zidovudine (ZDV) treatment on nutrient status, this study examined and compared the nutritional, immunological, and hematological status of asymptomatic, CDC stage III, HIV-1-seropositive males (n = 15) provided with ZDV (500-1,200 mg/day) and 22 nontreated, CD4-matched HIV-1-seropositive subjects. Prior to ZDV administration, hematological and plasma nutrient levels were similar in both groups. Following ZDV treatment, drug-treated subjects demonstrated alterations in hematological and nutritional parameters. A large proportion of the ZDV-treated participants exhibited decreased levels of zinc and copper along with a significant increase in red cell folate. The level of plasma zinc appeared to be particularly important in maintaining immune function in the ZDV-treated group. Whereas ZDV-treated subjects with adequate zinc levels displayed a significant increase in the response of peripheral blood lymphocytes to mitogens, this enhancement was not demonstrated in zinc-deficient, ZDV-treated participants or in untreated individuals whose lymphocyte response significantly declined over time, despite adeqaute zinc status. The findings of this study reveal a zidovudine-induced effect on nutritional parameters, indicating the importance of monitoring nutritional status with drug therapeutic regimens.

Nutritional status of institutionalized elderly in south Florida.

To assess the nutritional status of an elderly nursing home population of South Florida, forty-seven persons with ages ranging from 65 to 96 years were studied. Complete clinical examination and anthropometric measures were performed, along with blood cell count, biochemical blood parameters and assessment of water-soluble vitamins levels. The most common clinical finding were edentulous (67%), general pallor (44%), hyperpigmentation (33%), dry skin (26%) and arcus corneitis (26%). Thirty-five percent of the studied population had cholesterol levels greater than 220 mg/dl. Triglyceride levels were also significantly elevated in a considerable subset of our subjects, with 30% having levels above threshold value of 150 mg/dl. Small proportions of subjects showed low levels of albumin (6%), total protein (28%), ascorbic acid (2%), and thiamin (9%). Forty-five percent of males were pyridoxine deficient, while 63% of the females presented such deficiency. This study underscores the need to define, with greater precision, the nutritional status of aged populations as well as improve our inadequate standards associated with the "normal" aging process. Nutritional intervention--only possible when appropriate standards are defined--can potentially serve not only to prevent the occurrence of significant morbidity and mortality, but can also be employed to enhance quality of life in the elderly individuals.

Vitamin A augments collagen production by corneal endothelial cells.

When isolated confluent corneal endothelial cells were cultured in delipidized serum, a marked reduction in collagen production was observed. Supplementation of such cultures with vitamin A as either retinol or retinoic acid at concentrations of 10(-6)-10(-7) M was capable of significantly increasing collagen production. In addition, when cultured in normal (non-delipidized) serum, both retinol and retinoic acid were capable of further increasing collagen production by corneal endothelial cells. Such augmentation of collagen production was relatively specific as total protein synthesis was not altered to the same extent, nor was it merely a reflection of changes in total cell number, as such cell numbers were similar in all treatment groups.

Zinc, copper, and manganese in immune function and experimental oncogenesis.

Dietary deficiency of trace metals among human populations, once thought to be exceedingly rare, has recently gained attention as a potential public health problem. The consumption of highly refined and heavily processed foods reduces the trace element content of the diet. The higher trace element requirements of pregnancy, lactation, growth, development, and chronic disease may further contribute to states of marginal trace metal nutriture. Experimental animal studies have demonstrated that even marginal trace element deprivation during critical periods of growth and development or, alternately, during prolonged deficiency in adults can significantly alter immunologic function. Furthermore, trace metal nutriture has been shown to affect initiation and progression of a large variety of neoplasia. Studies of the interaction of trace metal nutriture and cancer have, however, suffered from many methodological inconsistencies as well as failures to define and quantitate the trace element content of diets and the host alterations in response to neoplastic challenge. Similarly, there has been little information in the critical area of marginal and moderate trace metal deficiency, i.e., those experimentaL situations most analogous to deficiencies that may occur in human populations. In this review, an attempt is made first to place in perspective experimental data relevant to these issues, and second to emphasize the desirability of further investigation in this critical area of human nutrition.

Nutritional factors and autoimmunity. III. Zinc deprivation versus restricted food intake in MRL/1 mice--the distinction between interacting dietary influences.

To investigate further the modulation of autoimmune disease by nutritional means, the influence of zinc deprivation upon the development of the immunopathology of MRL/I mice was studied. Because some effects of zinc deficiency may be due to associated inanition and consequent caloric deprivation, mice with similarly restricted food intake but adequate zinc intake were also studied. Zinc restriction was introduced at either 4 or 10 wk of age and was continued throughout the study. When zinc deficiency was introduced at 4 wk of age, a significant delay in the appearance of the physical findings of MRL/I mice, including open sores, necrotic ears, arthritis, and end-stage cachexia, was noted. In addition, zinc deficiency introduced at this age resulted in a lower incidence and titer of antibodies to dsDNA and less severe glomerulonephritis than control mice. Furthermore, the immune response of zinc-deprived MRL/I mice was better preserved than control animals, and most importantly, survival was significantly prolonged. Pair-fed controls also showed delayed progression of their disease, but animals restricted isocalorically from 4 wk of age experienced a more rapid onset of the lupus-like syndrome than did their zinc-deprived counterparts. In contrast, when zinc deprivation was introduced at 10 wk of age, it had little beneficial effect upon disease progression. Indeed, caloric restriction introduced at this age had a greater impact than did zinc deficiency. Nonetheless, despite the variable influence of zinc deprivation and pair-feeding on autoimmune disease, zinc deprivation, whether introduced at 4 or 10 wk of age, resulted in a significantly greater reduction of lymphoproliferation. Successful modulation of disease activity by nutritional changes will depend on understanding the mechanisms of these differential pathologic processes.

Reversibility of development retardation following murine fetal zinc deprivation.

To investigate the effects and reversibility of moderate prenatal zinc deprivation, pregnant mice were fed, beginning on day 7 of gestation, a diet containing either 100 ppm (control) or 5 ppm zinc; pair-fed controls were also studied. Nutritional manipulation was limited to the prenatal period. Zinc-deprived dams had significantly smaller litters than did controls, and postnatal survival was markedly compromised. Progeny of zinc-deprived dams displayed significant growth retardation, as reflected by lower body weight and length than controls, whether ad libitum-fed or pair-fed. Growth of spleen and thymus was affected by zinc deprivation to a significantly greater extent than was growth of heart, kidney or brain. Cross-fostering of control pups to zinc-deprived dams resulted in delayed growth; however, retardation was not as great as that observed in deprived pups allowed to suckle their natural mothers. Cross-fostering of zinc-deprived pups to control dams improved growth of most organs, but did little to improve growth of spleen and, most notably, thymus. Zinc-deprived pups exhibited considerable "catch up" growth following neonatal zinc repletion, and by 6-8 weeks of age, no significant differences between control and deprived offspring were observed.

Growth and development in postnatally zinc-deprived mice.

The influence of postnatal zinc deprivation upon the growth and development of outbred mice was investigated by feeding groups of animals, during the suckling period, one of four diets: 100 ppm zinc (control); 9 ppm zinc (marginal deficiency); 5 ppm zinc (moderate deficiency), and 2.5 ppm zinc (severe deficiency). In addition to control for inanition caused by zinc deprivation, a group of mice were fed the control diet but in amounts equal by weight to the measured intake of the moderately deprived animals (5 ppm zinc). A variety of developmental anomalies was observed in the zinc-deprived animals, including alopecia, extensive dermatitis, delayed opening of eyes and incoordination. Furthermore, growth in body weight and length were reduced. Similarly, on the basis of absolute net weight, heart, kidney and liver all demonstrated a significant stunting, and there was a direct relationship between the magnitude of organ growth retardation and the degree of zinc deprivation. However, when examined on a relative basis as a percentage of total body weight, only liver growth was significantly retarded. The heart and, most notably, the kidney represented an even greater proportion of body weight in the zinc-deprived mice than in the controls. We conclude that, in the mouse, the heart and kidney were affected to a lesser extent by zinc deficiency than was the whole animal. This observation is in contrast to the extreme lack of growth, but absolute and relative, of the spleen and especially the thymus, previously described by us in mice deficient in zinc during the suckling period.

Impaired immunologic ontogeny in postnatal zinc deprivation.

The effects of zinc deprivation upon the normal immunologic ontogeny of outbred N:NIH(S) mice was investigated by feeding lactating dams, from the day of parturition, and their pups to 8 weeks of age, a diet containing EDTA-washed isolated soy protein and 9 ppm (marginal zinc deficiency), 5 ppm (moderate zinc deficiency) or 2.5 ppm (severe zinc deficiency) zinc. Two groups of controls were provided with the same diet, but containing 100 ppm zinc; one group was fed ad libitum, the other was pair-fed to the level of food intake observed in the moderately deprived animals (5 ppm zinc). Severe growth retardation of lymphoid tissues, most notably thymus, was observed in all mice deprived of zinc. Indeed, the magnitude of splenic and thymic hypogenesis was directly dependent upon the severity of the dietary zinc deficit. Furthermore, zinc-deprived pups exhibited a significantly decreased splenic cellularity whether assessed per spleen or as a function of spleen weight, including a sharp reduction in both red and white cell counts. Similarly, at 4 weeks of age direct splenic plaque-forming cell responses to sheep erythrocyte immunization were dramatically diminished in mice that were moderately and severely deprived of zinc during the postnatal period. Finally, a striking and indicative feature of the critical import of zinc in immune maturation was the observation that these zinc-deficient mice at 4 weeks of age exhibited a highly disordered serum immunoglobulin profile, with absence of detectable IgM, IgG2a and IgA along with greatly elevated serum levels of IgG1. We suggest that deficiency of zinc during growth and development may predispose in a major way to acquired immune deficiency and opportunistic infection.