IGF-I, IGF-I-binding proteins and GH-binding protein in malnourished elderly patients with inflammation receiving refeeding therapy.

OBJECTIVE: To investigate the mechanisms determining the success or failure of refeeding therapy in malnourished elderly patients with inflammation by studying changes in plasma IGF-I, GH-binding protein (GHBP) and IGF-binding protein (IGFBP) levels and IGFBP-3 proteolysis. DESIGN AND METHODS: We studied 15 severely malnourished hospitalized elderly patients. Weight, food intake, plasma albumin, transthyretin, C-reactive protein (CRP), orosomucoid, interleukin-6 (IL-6), IGF-I, intact and proteolytically degraded IGFBP-3 and GHBP levels were determined on admission and during refeeding therapy designed to increase food intake to 40 kcal/kg body weight per day (15% protein). RESULTS: Plasma IGF-I, IGFBP-3 and GHBP levels were significantly low for age on admission in all malnourished elderly patients. They increased in nine patients as nutritional status improved (albuminemia >30 g/l; transthyretinemia >200 mg/l or weight gain >5% of initial body weight) and levels of inflammation markers decreased (group 1). In contrast, plasma IGF-I, IGFBP-3 and GHBP levels remained low in six patients in whom nutritional status failed to improve and levels of inflammation markers increased (group 2). IGF-I showed greater variations than IGFBP-3 or GHBP with respect to nutritional status. High plasma CRP and IL-6 levels were associated with high levels of IGFBP-3 proteolysis. CONCLUSION: Efficient refeeding therapy was associated with a significant increase in IGF-I plasma levels. In patients with severe and persistent inflammation, high levels of proteolysis of IGFBP-3 may have contributed to the low plasma IGF-I levels, persistence of hypercatabolism and lack of improvement in nutritional status.

Pregnancies modulate B lymphopoiesis and myelopoiesis during murine ageing.

We recently reported that pregnancy affects age-related changes in the distribution of lymphoid and macrophage populations in the spleen of C57Bl/6 mice. In the present study, we examined the influence of pregnancies on the generation of various developmental B-cell subsets and granulocyte/macrophage lineage cells during murine ageing. Using flow cytometry, changes in lymphoid (mature and early B-cell precursors: B220high, B220low, surface immunoglobulin M (sIgM) mu chain +/-) and myeloid (monocyte/macrophage Mac-1/CD11b, granulocyte Gr-1/Ly-6G) compartments were monitored in the bone marrow of young (2 months) and 15- and 23-month-old mice including male, multiparous and virgin female mice. Pregnancies delayed the age-related decline in murine B lymphopoiesis and maintained B-cell reserve capacity during ageing. We also found an increased production of myeloid cells induced by pregnancies at middle (15 months) and advanced (23 months) ages. This comparative study provides new information on changes in marrow lymphopoiesis and myelopoiesis with age. Our data emphasizes that the onset, magnitude and kinetics of age-related changes in the haematopoietic marrow are parity dependent. These changes could influence the incidence of age-related diseases and may account for the greater longevity of females.

Nutrition and immunity in the elderly.

Immune function declines with age, leading to increased infection and cancer rates in aged individuals. In fact, recent progress in the study of immune ageing has introduced the idea that rather than a general decline in the functions of the immune system with age, immune ageing is mainly characterized by a progressive appearance of immune dysregulation throughout life. Changes appear earlier in life for cell-mediated immunity than for humoral immunity. Thus, age-related modifications in cell-mediated immunity, i.e. changes in naive : memory T-cells, mature : immature T-cells, T-helper 1 : T-helper 2 cells are more important in the elderly than changes in humoral immunity, i.e. CD5 : CD5+ cells or length of antibody responses. Such evolution of the immune system has been linked to declining thymus function and to accumulative antigenic influence over the lifespan. In contrast, innate immunity (macrophage functions) is preserved or even increased during the ageing process. This finding shows that the 'primitive' immune system is less affected by the ageing process than the sophisticated specific immune system. The present review focuses on innate and cell-mediated immune changes with ageing. It provides evidence that primary changes (intrinsic modifications in the immune system) and secondary changes (resulting from environmental influences during the lifespan) exert different influences on the immune system. Primary changes, occurring in healthy individuals, seem less important nowadays than they were considered to be previously. For example, interleukin 2 secretion in some very healthy aged individuals is comparable with that in younger adults. Primary immune changes may not explain the increased incidence and severity of infections observed in the elderly population. Secondary immunological changes are far more frequent and are certainly responsible for most of the immune modifications observed in the elderly population. Environmental factors leading to secondary immune dysfunctions include not only antigenic influence, which is a reflection of diseases experienced over the lifespan, but also many other factors such as drug intake, physical activity and diet; factors for which important changes occur in the elderly population. Nutritional factors play a major role in the immune responses of aged individuals and the present review shows that nutritional influences on immune responses are of great consequence in aged individuals, even in the very healthy elderly.

[Aging and the immune system. Experimental aspects]. / Vieillissement et système immunitaire. Quelques aspects expérimentaux.

So far no comparative studies have been conducted to know whether physiological influences related to sex hormonal differences affect the age-related changes of the immune system. The aim of this study was to investigate whether pregnancies and sex influence the age-related changes in the peripheral lymphoid compartment and functions of T cells in mice. Using flow cytometry, we examined changes in (Thy1.2+) T cells, (B220+) B cells and (CD11b/Mac-1+) macrophages in the spleen of multiparous and virgin females and males at 2, 8, 15 and 23 months of age. The development of naive (CD44low) and memory (CD44high) cells were investigated in CD4+ and CD8+ T cell subsets. To analyze the age-related changes in functions of T cells, we examined the secretion of some T cell immunoregulatory cytokines (IL-2, IL-4, gamma-interferon and GM-CSF) of in vitro Concanavalin A-activated spleen cells of C57BL/6 mice. Both short term (8 months) and long term (15-23 months) effects of pregnancies were obvious in the age-related changes of the immune system. Short term effect included delayed appearance of memory CD4+ cells and the preserved IL-2 production. At eight months, shortly after pregnancies, both parameters were higher in multiparous females. Later effects of pregnancies were evidenced by a higher level of macrophages (Mac-1+) than in other groups throughout life. The increased gamma-interferon, IL-4 and GM-CSF productions appeared earlier, at 15 months, IL-4 and GM-CSF levels remained higher in multiparous females than in virgin females and males in late adulthood. Sex differences were also noticed: males exhibited lower macrophage levels after one year and gamma-interferon secretion capacity than females in late life. This study underlines that the onset, magnitude and kinetics of the age-related changes in the distribution of immune cells and T cell functions are parity- and sex-dependent. These changes may influence the incidence of age-related diseases and may explain the greater longevity of women, especially the multiparous ones.

[An unusual variant of urothelial carcinoma: the "nested variant of urothelial carcinoma." Report of two cases]. / Une variante particulière de carcinome urothélial: le "nested variant of urothelial carcinoma". A propos de deux cas.

We report two cases of a poorly known variant of transitional cell carcinoma, the "nested variant of urothelial carcinoma". This tumor is composed of small islands or nests of transitional cells, presenting little atypia and mimicking von Brünn's nests. This low grade tumoral variant seems to behave as a high grade tumor of the same stage. Deep biopsies are necessary to display tumoral invasion, which allows the diagnosis. Importance of the knowledge of this entity is highlighted in order to avoid misdiagnoses that could delay appropriate therapy.

Immune response during disease and recovery in the elderly.

The present article reviews immune ageing and its relationship with nutritional ageing, with a particular insight into the influences of disease on both ageing processes. Immune ageing can be described primarily as the progressive appearance of immune dysregulations, mainly acquired immunity (mature: immature, naive: memory T lymphocyte subset decreases) leading to gradual increases in T-helper 2: T-helper 1 cells. This change is due initially to decreased thymic function, and later to accumulative antigen pressure over the lifespan. In contrast, innate immunity (macrophage functions) is preserved during the ageing process and in the elderly this leads to macrophage-lymphocyte dysequilibrium, which is particularly critical during on-going disease. Indeed, any disease induces long-lasting acute-phase reactions in aged patients and leads to body nutritional reserve (mainly protein) losses. Episodes of disease in the aged patient progressively deplete body nutritional reserves and lead to protein-energy malnutrition, undernutrition-associated immunodeficiency, and finally cachexia. Undernutrition is a common symptom in the elderly; protein-energy malnutrition is found in more than 50% of hospitalized elderly patients and in most elderly diseased subjects. In addition, micronutrient deficit or low levels are common in home-living self-sufficient apparently-healthy elderly subjects. All these nutritional deficits induce decreased immune responses, and micronutrient deficits are now thought to be partly responsible for the decreased immune responses (immune ageing?) observed in the apparently-healthy elderly. Indeed, several studies have shown that micronutrient supplements induce increased immune responses in the healthy elderly. The progression of infectious diseases depends on immune responses and on nutritional status before the onset of illness in aged subjects. In addition, recovery depends on the intensity of acute-phase responses in the undernourished elderly. In fact, chronic acute-phase responses, commonly associated with diseases in aged patients, lead to progressive lowering of metabolic responses in the undernourished elderly. This can be quantified by increased production of free radicals during treatment and these increases may explain the difficulty in successfully treating aged patients. Nutritive therapy in order to improve metabolic processes and also to maintain body reserves should be considered as a necessary adjuvant therapy in the treatment of elderly patients.

Nutritional influences on immune response in healthy aged persons.

Healthy elderly (80+/-5 years) with different nutritional status were compared to young healthy adults (25+/-5 years) to quantify the relative influences of aging and nutrition on immune response. Aged persons, without alteration of their nutritional status, had lower CD3+, CD8+, and CD45RA+ as well as higher CD2+CD3-, CD2+CD4-CD8-, and CD45RO+ T cell subsets and IL-6 release than their younger counterparts. T cell proliferation and IL-2 production were comparable in the two healthiest groups. Aged subjects with low nutritional status expressed similar but more marked changes in immune response while nutritional status did not influence the immune response in young subjects. Furthermore, lower nutritional status was associated with lower CD4+ counts and lower T cell functions in aged persons. These results indicate that the influences of aging and undernutrition in humans are cumulative and suggest that some changes in immune response that have been attributed to aging may, in fact, be related to nutrition and not aging.

[Discovery of a renal chromophobe cell carcinoma in a pregnant woman. Apropos of a case]. / Découverte d'un carcinome rénal à cellules chromophobes chez une femme enceinte. A propos d'un cas.

We report the case of a young pregnant woman with a malignant tumour of the kidney suggestive of oncocytoma. Because of the pregnancy, preoperative staging consisted of abdominal ultrasound and magnetic resonance imaging. Caesarean section was performed. Several days later, surgical exploration of the kidney was performed with tumourectomy and frozen section analysis: radical nephrectomy was finally performed. The definitive histology was chromophobe renal cell carcinoma. This is a rare tumour of the kidney, with its own characteristics allowing histopathological diagnosis and with a better prognosis than renal cell carcinoma. In the literature, pregnancy, a situation of immune depression, does not increase the prevalence of malignant neoplasms.

Sex and parity modulate cytokine production during murine ageing.

We have previously shown that physiological hormone differences related to pregnancy or sex affect the age-related distribution of mononuclear cell populations during murine ageing. To determine whether such changes are involved in the age-related changes in functions of T cells, we examined the secretion of major T cell immunoregulatory cytokines (IL-2, IL-4, interferon-gamma (IFN-gamma), IL-3, IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF)) of in vitro concanavalin A-activated spleen cells of C57B1/6 mice. The study included multiparous and virgin females and males at 2, 8, 15 and 23 months of age. Short-term effects of parity (8 months) were evidenced by the decrease of IFN-gamma and the preserved IL-2 production in multiparous females (8 months), while IFN-gamma was unchanged and IL-2 decreased in virgin mice. The increase in IL-4 production appeared earlier in multiparous females (15 months) than in virgin mice (23 months). The increase in IL-4/IFN-gamma and IL-4/IL-2 ratios at 8 and 15 months, respectively, in multiparous females, suggests that pregnancy modifies the Th1/Th2 equilibrium. In late adulthood (15 months), IL-6 and GM-CSF production was higher in multiparous females than in virgin males or females. Sex differences were also noticed: IFN-gamma secretion capacity was lower in males than in females during ageing. This study underlines that the onset, magnitude and kinetics of the age-related changes in cytokine production are parity- and sex-dependent. These changes probably influence the incidence of age-related diseases and may explain the greater longevity of females.

Effects of trace element and/or vitamin supplementation on vitamin and mineral status, free radical metabolism and immunological markers in elderly long term-hospitalized subjects. Geriatric Network MIN. VIT. AOX.

A randomized double-blind trial was performed in order to assess the efficacity of differing combinations of antioxidant nutrients on biochemical parameters of vitamin and trace element status, immunological parameters and free radical metabolism in elderly long term hospitalized subjects. A total of 756 institutionalized elderly subjects were recruited in 26 nursing homes in different areas of France. Four groups were constituted, receiving daily, for 1 year, either vitamins (beta-carotene, 6 mg; vitamin C, 120 mg; and vitamin E, 15 mg), trace elements (zinc, 20 mg and selenium, 100 micrograms), trace elements associated with vitamins, or a placebo. Biochemical indicators of trace elements and vitamin status and free radical parameters were measured before and after 6 months and 1 year of supplementation. Some immunological markers were investigated initially and after 6 months of supplementation on a subsample of 134 subjects. Mean plasma levels of alpha-tocopherol, gamma-tocopherol, vitamin C, alpha-carotene, beta-carotene and copper increased significantly after 6 months of supplementation in groups receiving vitamins alone or associated with trace elements. Serum selenium concentrations were significantly increased at 6 months of supplementation, and serum zinc only after one year in the trace element groups. Serum lycopene levels were significantly decreased by trace element supplementation. A significant increase in Se-glutathione peroxidase (GPx) levels was observed in groups receiving trace elements alone or associated with vitamins. No effect was noted on superoxide dismutase (SOD) activity or TBARs production. No effect of supplementation was found for in vitro lymphocyte proliferative responses or most lymphocyte subsets, except for a significantly lower percentage of CD2 subsets observed in groups receiving mineral supplementation either alone or associated with vitamins. A significant difference in CD19 subsets was found in groups receiving trace elements. Mean IL-1 production was significantly higher after 6 months of supplementation in the vitamin groups.

[Nephrectomy for cancer in pregnant women. Apropos of a case]. / Néphrectomie pour cancer chez la femme enceinte. A propos d'un cas.

We report on the case of a young pregnant woman who had a malignant tumor of the kidney. The pregnancy did not change the gold standard therapy: radical nephrectomy. Because of the pregnancy the preoperative staging consisted of an abdominal ultrasound and a magnetic resonance imaging for the local extension, and of a chest X-ray looking for pulmonary metastases. According to the literature pregnancy, a situation of immune depression, does not increase the prevalence of malignant neoplasms.

Longitudinal changes in iron and protein status of elderly Europeans. SENECA Investigators.

OBJECTIVE: Describe the iron and protein status of European elderly people studied in 1993, together with changes observed in the previous four years. DESIGN: Two optional designs: (1) A transversal study from a randomly selected group of female and male elderly subjects born between 1913 and 1914. (2) A longitudinal study including base-line measurements in 1988/1989 in subjects born in 1913-1918, which were repeated and extended in 1993. SETTING: Nineteen towns in 12 European countries participated in the baseline study in 1988/ 1989. Eleven centres in nine countries completed the follow-up study in 1993, and two new towns joined in 1993. The study included blood sampling for analysis of markers of nutritional status. RESULTS: The mean haemoglobin (Hb) values during the follow-up study for the different town populations ranged from 142 to 159 g/l for men and from 129 to 146 g/l for women. Prevalences of anaemia, based on WHO criteria (Hb < 130 g/l for men, and Hb < 120 g/l for women), amounted to 6.0% and 5.0% for men and women, respectively, and were very close to the baseline prevalences of 5.6% and 5.5%. A small decrease in Hb was observed after 4y in men. The mean haematocrit (Hct) values for the different towns ranged from 42% to 48% in men and from 39% to 44% in women. For both sexes, a decrease in Hct was observed. White blood cell (WBC) counts and differentials were measured in the follow-up study only. Mean WBC counts ranged from 5.8 x 10(3)/microliter to 7.1 x 10(3)/microliter in men and from 5.6 x 10(3)/microliter to 6.7 x 10(3)/microliter in women. Mean lymphocyte counts ranged from 1.6 x 10(3)/microliter to 2.4 x 10(3)/microliter in men and from 1.7 x 10(3)/microliter to 2.3 x 10(3)/microliter in women and mean neutrophile counts ranged from 3.4 x 10(3)/microliter to 4.4 x 10(3)/microliter and from 3.1 x 10(3)/microliter to 4.0 x 10(3)/microliter, respectively. The mean serum albumin values for the different towns varied from 39.9 g/l to 43.2 g/l for men, and from 39.3 g/l to 42.4 g/l for women, quite similar to the baseline study. In 25 subjects (2.2%) only serum albumin level was below 35 g/l and five subjects (0.4%) had a serum albumin level below 30 g/l. No albumin changes were detected for either sex over the four year period. The group of survivors in the follow-up study had higher mean albumin concentrations at baseline than the group of subjects who had died between the baseline and the follow-up study. CONCLUSION: In this population of elderly subjects in their seventies, Hb, Hct and albumin showed little change over the 4 year follow-up period. The prevalence of anaemia and low serum albumin values was relatively low, which is indicative of a relatively good health.

[The frequency of surgery of benign prostatic hypertrophy]. / Fréquence de la chirurgie de l'hypertrophie bénigne de la prostate.

OBJECTIVES: To calculate the incidence of surgical treatment of benign prostatic hyperplasia (BPH) in two French departments, Indre-et-Loire and C her, in order to deduce the incidence in France. METHODS: All patients operated for BPH by transurethral resection or transvesical prostatectomy were counted prospectively over a 6-month period by all surgeons of the Indre-et-Loire and Cher departments. Collection of case files was complete and based on BPH resection specimens sent to pathology. 506 patients were included in this survey. RESULTS: The mean age of the patients was 71.8 years. 78% of patients were operated by a private urologist, and 93% by a specialist urologist. The mean postoperative stay was 7.1 days and varied according to the patient's age, the weight of the prostate and the site of the operation (university hospital, private establishment and general hospital). This study allowed calculation of the annual incidence of surgery for BPH in these 2 departments: 822/100,000 men over the age of 50 years. The maximal incidence was observed during the 7th decade of life: 1,742/100,000. In our study, private urologists operated 76 patients for BPH per year. CONCLUSION: Extrapolation of these results to the French population indicates an annual incidence of surgery for benign prostatic hyperplasia in France of 776/100,000 men over the age of 50 years. On the basis of this incidence, an estimated 55,000 to 65,000 men are operated for BPH per year in France.

Cell mediated immunity changes in ageing, relative importance of cell subpopulation switches and of nutritional factors.

Decreased T-cell functions with ageing have been extensively described. This review focuses on recent data on changes in T-cell subpopulations related to ageing and their consequences on T-cell proliferation. Increase of immature T cells CD2+ CD3- is an ageing phenomenon related to T-cell declining proliferation. Recently it was shown that increase of immature T cells was due to an increase in different subtypes of the CD2+ CD3- population, double-negative CD2+ CD4- CD8- and double-positive CD2+ CD4+ CD8+ subpopulations, the former being associated with nutritional deficit, the latter with associated diseases. Other authors have focused on decreases of native T cells with parallel increase of memory T cells; such a switch is also relevant to declining T-cell proliferation. This review focuses on two major factors which influence immune ageing; nutritional parameters and antigen exposure.

Multitest CMI for standardized measurement of delayed cutaneous hypersensitivity and cell-mediated immunity. Normal values and proposed scoring system for healthy adults in the U.S.A.

The Multitest CMI system, a disposable device that simultaneously applies seven standardized preloaded antigens and diluent control, is a major advance for measurement of delayed type hypersensitivity (DTH) in assessment of cell-mediated immunity (CMI). The system was tested in 402 healthy adults, aged 17 to 92 years, to determine normal values for incidence and size of DTH responses. Incidence of positive responses to individual antigens varied from 85% to 46%, with great variability related to age and sex. To better assess CMI, a two-part score based on 48-hour readings was employed. The mean number of positive antigens ranged between four and five, and the mean sum of their mm induration ranged between 18 and 25, with both scores increasing with advancing age. A statistical zone of reduced DTH scores (hypoergy) was identified. The Multitest CMI system appears to be a practical means of reproducibly assessing CMI in subjects with immunologic, metabolic, infectious, or neoplastic disorders. The scores in our population may serve as reference values to which results from any tested adult can be compared.

Characterization of human dialyzable transfer factor from normal and chronic lymphoid leukemia sources.

Dialysates of lymphomonocytes can be roughly quantified through the use of optical density and measurements of RNA and protein contents. Dialysates of normal lymphocytes (N-TFd) contain about 224 +/- 67 mug of RNA-like material per 10(8) cells, 75 to 90% of which is eluted in fractions II and III on Biogel P10 chromatography. In contrast, dialysates of lymphocytes from patients suffering chronic lymphoid leukemia (CLL-TFd) contain approximately 12 times less RNA-like material (about 27 +/- 11 mug per 10(8) lymphocytes) and have a different characteristic chromatographic pattern. Bioassays with crude dialysates confirm (a) that N-TFd increases 3H-thymidine incorporation by nonsenstitized lymphocytes "in vitro" in the presence of PPD, and (b) that inbred Lewis rats develop positive skin tests (systemic transfer) after receiving injections of N-TFd or of fractions II and III from Biogel fractionation of N-TFd. Neither test gives positive results when CLL-TFd is used.