Bernard Kennes

Effect of Vitamin C Supplements on Cell-Mediated Immunity in Old People

Both ageing and vitamin C (VC) deficiency result in immune defect. Since low serum and tissue levels of VC are found in the elderly, we have in a placebo-controlled study, tested the effect of VC supplements (500 mg/day i.m. for 1 month) on various immune parameters. Indeed, VC enhances the proliferative response of T lymphocytes in vitro, and the tuberculin skin hypersensitivity in vivo. Neither the serum concentrations of IgA, IgG and IgM, nor the proportion of E-rosette-forming cells were modified. No significant change was observed in the placebo-treated group.

Biochemical events associated with lymphocyte activation in aging ☆: K+ transport and sensitivity of the Na+K+ pump to digoxine

The present investigation was directed toward answering the question of whether some age-related changes of membrane dependent triggering mechanisms during lymphocyte activation could account for the depressed T cell response to mitogens in aging. For this purpose, the K+ movements were analyzed in PHA-stimulated peripheral blood lymphocytes (PHA-PBL) from old humans (O) compared to adult (A). Indeed, plasma membrane Na+, K+, ATPase activation plays an essential role in cell proliferation and results from direct interaction between the loaded mitogen receptor and the enzyme. No difference could be found in the magnitude and the timing of the PHA-induced increase of K+ fluxes between PHA-PBL from O and A despite a higher K+ inflow in unstimulated but 20-hour preincubated PBL from O. Further experiments showed that the lectin-induced triggering mechanism of cation transport resulted from digoxine (DGX: a glycosid cardiotonic) sensitive ATPase. Moreover, whereas PBL from O exhibited a decreased PHA-induced DNA synthesis, DGX depressed the thymidine incorporation by 72-hour cultured PHA-PBL within the same inhibitory dose-related pattern in both O and A. We conclude that the triggering mechanism of Na+, K+-ATPase induced by PHA occurs adequately in early stimulated PBL from old subjects. In addition, digoxine sensitive structures work freely during PHA-induced lymphocyte proliferation in aging, thereby supporting further arguments for adequate Na+, K+-ATPase activity.

Lymphocyte subsets in major depressive patients. Influence of anxiety and corticoadrenal overdrive.

We studied 26 inpatients (17 females; mean age +/- SD: 41.2 +/- 14.3 years) who met the DSM III criteria for a major depressive episode and had a mean (+/- SD) Hamilton Depression Score of 19.3 +/- 8.0. All patients were drug free and medically healthy at the time of experimentation. We found a significant correlation between the CD4/CD8 ratio and the Hamilton Anxiety Score (r = 0.57, p less than 0.005). When splitting our sample in dexamethasone suppression test suppressors (DST-S) and nonsuppressors (DST-NS), this relationship appeared only in DST-NS (DST-NS: r = 0.81, p less than 0.005; DST-S: r = 0.20, p = NS). These results are discussed in terms of heterogeneity among major depressive disorders and possible relationships between catecholaminergic activity and the immune system.

Biochemical events associated with PHA-induced lymphocyte activation in human ageing II. Characteristics of the early Ca2+ uptake

Abstract Since the early biochemical changes are critical in defining the triggering mechanism of a mitogen-induced lymphocyte activation, their study could provide a good understanding of the processes that might be relevant to the immune deficiency associated with ageing. The increase of Ca 2+ influx appears to be one of these earliest events which takes place in the first minutes following the contact with stimulating agents, as a consequence of membrane activation. Therefore, the timing and the magnitude of Ca 2+ influx were analyzed in unstimulated and PHA-stimulated peripheral blood lymphocytes (PBL) from old and adult subjects. Whereas PBL from elders exhibited a decrease in DNA synthesis, the characteristics of Ca 2+ accumulation into unstimulated and PHA-stimulated PBL were found unaltered in the elderly. The data support the evidence that the cellular defect relevant to the depressed response to T-mitogens associated with ageing, does not result from the defect of Ca 2+ transport induced by membrane activation.

Changing pattern of CD5+ CD20+ double positive lymphocytes with ageing and cytotoxic chemotherapy.

In this cross-sectional clinical study, it was found that two subtypes of CD5+ B-lymphocytes existed either with CD5-high and CD20-low or CD5-low and CD20-high expression, as determined by dual fluorescence analysis with fluorochrome-labeled monoclonal antibodies on a FACScan flowcytometer. In the normal healthy subjects (n = 20), the CD20 positive cells could be broken down into 3 subsets: CD5(2+) CD20+, 25.4 +/- 3.0% (mean +/- S.E.M.), CD5+ CD20(2+), 18.4 +/- 2.4% and CD5- CD20(2+), 56.2 +/- 2.7%. Similar values were observed in a group of patients (n = 29) suffering from a wide variety of benign or untreated malignant disorders. The CD5(2+) CD20+ subset was typically related to age (Spearman coefficient of correlation rho = 0.77, P less than 0.001 in healthy subjects and rho = 0.46, P = 0.02 in pathological cases). The CD5+ CD20(2+) subpopulation was a salient feature of newborns and little infants (n = 6, 75.4 +/- 2.4%, P less than 0.01). The CD5- CD20(2+) subset was characteristically depressed in patients treated with cytotoxics (n = 21, 41.2 +/- 3.6%, P = 0.001). As far as cytotoxic chemotherapy may represent a model of accelerated ageing, it is worth noting that, in patients treated with cytotoxics, the CD5 CD20 pattern was frequently disturbed in a hyperyoung or hyperaged picture. That age and cytotoxics can affect CD5 expression on CD20+ lymphocytes, suggests some specific B-dysregulation and should be put together with the known emergence of autoantibodies, paraproteinemias and lympho-plasmocytic tumors with age and chemotherapy.

Comprehensive geriatric assessment and comorbidities predict survival in geriatric oncology

Objectives: The comprehensive geriatric assessment (CGA) can detect geriatric problems and potentially improve survival, physical, and cognitive state of patients, as well as increase an older person’s chances of staying at home longer. In older people, the number and severity of comorbidity increase with age and are an important determinant of survival. The aim of the study was to assess to which extent CGA and comorbidities could be seen as determinants of survival. Materials and methods: This study analyzed data from two hospitals that included geriatric assessments of patients aged 70 years and more with cancer linked to mortality. Logistic regression was used to model survival predictors. Results: Two hundred and five various cancer patients (47% females) with a median age of 79 were included. They presented with a lot of undiagnosed geriatric problems. Screening scales (G8, SEGA), cognitive, and psychological disorders, and low albumin levels appeared to be independent survival factors. A frailty profile classification was associated with higher mortality. The average comorbidity was graded 2 according to the Charlson scale. By the geriatric cumulative illness rating scale (CIRS-G), the arithmetic average number of affected organ systems was 5 (range 0–10) in all patients. Cardiovascular disorders were the most common comorbidity. Renal insufficiency and anaemia were negatively associated with survival. Conclusion: Old cancer patients present a lot of comorbidities and newly diagnosed geriatric problems. Several tools provide determinants of survival in old cancer patients. Prospective trials evaluating the utility of a CGA to guide interventions to improve quality of cancer care in older adults are justified.

Effect of dipyridamole upon thymidine incorporation and capping in human lymphocytes

Dipyridamole is a potent inhibitor of tritiated thymidine incorporation by PHA-stimulated human lymphocytes. This effect is unrelated to the length of culture, to the level of response in untreated cultures, or to the proliferative index. This suggests that dipyridamole principally effects the membrane transport of thymidine. Dipyridamole inhibits sheep-erythrocyte-capping by E-rosettes. This effect cannot be mimicked by theophylline or cyclic nucleotides and cannot be reverted by adenosine. Pharmacological studies with colchicine and cytochalasin B suggest interference with cytoskeletal functions, probably of microtubules. This could be another site of action of dipyridamole beyond phosphodiesterase inhibition and adenosine metabolism.

Stability of E-rosettes in aged humans: Effect of cytochalasin B and colchicine

A greater stability of E-rosettes and a reduced rate of capping of sheep erythrocytes are observed in elderly people. The lack of qualitative changes in the sensitivity of these processes to colchicine and cytochalasin B suggests that the function of the microfilaments and the microtubules is not primarily affected by ageing. The density and the affinity of the lymphocytes for sheep erythrocytes do not decrease in aged subjects. So the defective rearrangement of the E-receptors cannot be accounted for by some receptor alteration but points to a possible hindrance of their cross-linking in the membrane or their submembrane connection to the cytoskeleton.

Thiobarbiturate and fructosamine assays: significance and interest of the borohydride blank

The acute-phase reaction (APR) induces the production by the liver of short-lived glycoproteins. The carbohydrate moiety of these proteins is thought to interfere with the thiobarbiturate (TBA) and nitroblue tetrazolium colorimetric tests which are used for assaying non-enzymatic glycosylation (NEG) of serum proteins. The aim of the present study was to assess the effect of the APR on the specificity of the colorimetric tests in non-diabetic and diabetic subjects. A positive correlation was found between C-reactive protein (CRP), an APR glycoprotein, and non-specific TBA reactivity as determined after borohydride reduction (BH4-resistant TBA, BR-TBA), both in non-diabetics (r=0.61;P<0.01) and diabetics (r=0.68;P<0.01). The BH4-sensitive specific TBA (SP-TBA) was not influenced by glycoproteins, and its increase in diabetics was correlated with the nitroblue tetrazolium assay (r=0.89;P<0.01). An independant effect of diabetes and APR on non-specific TBA was also demonstrated, suggesting an effect of hyperglycaemia on both protein glycation and glycosylation. TBA with borohydride reduction is an attractive tool for the study of complex glycoproteins in diabetes.

Sheep-erythrocyte-capping by human T-lymphocytes. Pharmacological inhibition by phenothiazine drugs

In our previous studies it was found that E-rosette dissociation and sheep-erythrocyte capping were active processes involving the cytoskeleton. These cellular functions are now shown to be very sensitive to phenothiazine-drugs whose activities can be differentiated as follows: trifluoperazine greater than chlorpromazine greater than sulfoxide derivatives, suggesting a role for calmodulin-mediated events. These findings are in contradiction to prior reports pointing to the inefficacy of chlorpromazine to inhibit slow kinetic capping. However, no co-capping of trifluoperazine fluorescence (as a probe of calmodulin) and sheep erythrocytes could be observed. No requirement in extracellular calcium was evident for E-rosette formation and dissociation.