Soft X-Ray Second Harmonic Generation as an Interfacial Probe.

Nonlinear optical processes at soft x-ray wavelengths have remained largely unexplored due to the lack of available light sources with the requisite intensity and coherence. Here we report the observation of soft x-ray second harmonic generation near the carbon K edge (∼284 eV) in graphite thin films generated by high intensity, coherent soft x-ray pulses at the FERMI free electron laser. Our experimental results and accompanying first-principles theoretical analysis highlight the effect of resonant enhancement above the carbon K edge and show the technique to be interfacially sensitive in a centrosymmetric sample with second harmonic intensity arising primarily from the first atomic layer at the open surface. This technique and the associated theoretical framework demonstrate the ability to selectively probe interfaces, including those that are buried, with elemental specificity, providing a new tool for a range of scientific problems.

Correlation between myocardial perfusion abnormalities detected with intermittent imaging using intravenous perfluorocarbon microbubbles and radioisotope imaging during high-dose dipyridamole stress echo.

BACKGROUND: The clinical accuracy of myocardial contrast echocardiography (MCE) using intermittent harmonic imaging and intravenous perfluorocarbon containing microbubbles during dipyridamole stress has not been evaluated in a multicenter setting. HYPOTHESIS: The accuracy of dipyridamole stress contrast echo in the detection of coronary artery disease (CAD) using myocardial perfusion images is high in comparison with technetium-99 (99Tc) sestamibi single-photon emission computed tomography (MIBI SPECT) and increases the accuracy of wall motion data. METHODS: In 68 consecutive nonselected patients (46 men; mean age 66 years) from three different institutions in two countries. dipyridamole stress echo and SPECT with 99mTc MIBI were compared. Continuous intravenous (IV) infusion of perfluorocarbon exposed sonicated dextrose albumin (PESDA) (2-5 cc/min) was administered for baseline myocardial perfusion using triggered harmonic end systolic frames. Real-time digitized images were used for wall motion analysis. Dipyridamole was then injected in two steps: (1) 0.56 mg/kg for 3 min, (2) 0.28 mg/kg for 1 min, if the first step was negative for an inducible wall motion abnormality. After dipyridamole injection, myocardial contrast enhancement and wall motion were analyzed again by the same methodology. RESULTS: There were 35 patients with perfusion defects by SPECT. Wall motion was abnormal in 22, while MCE was abnormal in 32. Wall motion and MCE each had one false positive. The proportion of correctly assigned patients was significantly better with MCE than with wall motion (p = 0.03; chi square test). CONCLUSIONS: Myocardial contrast echocardiography, using intermittent harmonic imaging and intravenous perfluorocarbon containing microbubbles, is a very effective method for detecting coronary artery disease during dipyridamole stress echo.

Role of zinc and alpha2 macroglobulin on thymic endocrine activity and on peripheral immune efficiency (natural killer activity and interleukin 2) in cervical carcinoma.

Decreased natural killer (NK) activity as well as interleukin 2 (IL-2) are risk factors for the progression of cervical carcinoma. NK activity and IL-2 may be thymus controlled. Plasma levels of active thymulin, a zinc-dependent thymic hormone (ZnFTS), are reduced in cancer because of the low peripheral zinc bioavailability. Zinc and thymulin are relevant for normal immune functions. Alpha2-macroglobulin is an inhibitor of matrix metalloproteases (MMPs) against invasive tumour proliferation. Because alpha2-macroglobulin has a binding affinity (Kd) for zinc that is higher than does thymulin, it may play a key role in immune efficiency in cancer. Plasma samples of 22 patients (age range 35-60 years) with locally advanced squamous cervical carcinoma and with FIGO stage Ib2-IIb were examined. They showed reduced active thymulin, decreased NK activity and IL-2 production, increased soluble IL-2 receptor (sIL-2R) and augmented alpha2-macroglobulin in the circulation, whereas plasma zinc levels were within the normal range for age. Significant positive correlations were found between zinc or active thymulin and alpha2-macroglobulin (r = 0.75, P < 0.01, r = 0.78, P < 0.01, respectively) in cancer patients. In vitro zinc increases IL-2 production from peripheral blood mononuclear cells (PBMCs) of cancer patients. These data suggest that an increase in alpha2-macroglobulin, which competes with thymulin for zinc binding, may be involved in causing a thymulin deficit with a consequent decrease of IL-2 and NK cytotoxicity. Thus, physiological zinc treatment in cervical carcinoma maybe restores impaired central and peripheral immune efficiency.

Presence of links between zinc and melatonin during the circadian cycle in old mice: effects on thymic endocrine activity and on the survival.

Links between zinc and melatonin in old melatonin treated mice with a reconstitution of thymic functions have been recently documented. Concomitant increments of the nocturnal peaks of zinc and melatonin, with a synchronization of their circadian patterns, are achieved in old mice after melatonin treatment. A recovery of the nocturnal peaks of thymulin plasma levels and of the number of thymulin-secreting cells with a synchronization of their circadian patterns are also achieved. The existence of significant positive correlations between melatonin and zinc and between melatonin and thymulin or the number of thymulin-secreting cells supports the presence of links between zinc and melatonin also during the circadian cycle with a beneficial effect on thymic functions. The altered circadian pattern of corticosteron in old mice is normalized by melatonin. The existence of inverse correlations between corticosteron and melatonin, between corticosteron and zinc and between corticosteron and thymulin or the number of thymulin-secreting cells during the whole circadian cycle, suggests the involvement of glucocorticoids pathway in the melatonin thymic reconstitution, via zinc. The presence of an interplay among zinc, melatonin, glucocorticoids and thymulin may be, therefore, supported during the circadian cycle. 'In vitro' experiments from old thymic explants show a direct action of zinc, rather than melatonin, on thymulin production, further suggesting that the action of melatonin on the thymic efficiency is mediated by the zinc bioavailability. The beneficial effect of the links between zinc and melatonin on thymic functions during the circadian cycle, may be extended to a prolonged survival in aging, where, however, zinc may be more involved.

Zinc, thymic endocrine activity and mitogen responsiveness (PHA) in piglets exposed to maternal aflatoxicosis B1 and G1.

Growth retardation, thymic involution and impaired peripheral immune efficiency are constant events in piglets exposed to maternal aflatoxicosis. Zinc may play a key role because of its requirement for good immune responses, including thymic endocrine activity. Zinc is required to activate a thymic hormone, i.e. thymulin (ZnFTS), which is responsible for cell-mediated immunity. Zinc deficiency and decreased thymic endocrine activity are present in piglets fed from sows exposed to aflatoxins (AF) B1 and G1 as compared with healthy control piglets. In particular, active ZnFTS is decreased while concentrations of inactive thymulin (FTS) are high. The in vitro addition of zinc up to the plasma samples induces a reduction of inactive thymulin. The lymphocytes mitogen responsiveness (PHA) is decreased and a thymic cortical lymphocyte depletion is also present. These data suggest that the thymic defect, followed by impaired peripheral immune efficiency, may largely depend by the low peripheral zinc bioavailability to saturate all thymulin molecules produced.

Generation of human lymphokine-activated killer cells following an IL-2 pulse in elderly cancer patients.

The toxicity of high-dose interleukin 2 (IL-2) treatments limits its use in tumour therapies, particularly in older age groups, characterized by a reduced tolerance to antineoplastic therapies. Here, we evaluated the possibility to induce cytotoxic lymphokine-activated killer (LAK) cells through a brief exposure (1-h pulse) of peripheral blood mononuclear cells (PBMC) from elderly cancer patients to high concentrations of IL-2. The cytotoxic activity, phenotype, apoptosis, and cell cycle phase of IL-2 pulsed PBMC were determined and compared with those of non-pulsed PBMC cultured continuously in IL-2. Significant levels of LAK cytotoxicity were obtained in pulsed PBMC from all patients examined. The mean values of lytic activity on day 6 of culture were lower, even if not significantly, in pulsed than non-pulsed cultures. The pulsed cells were phenotypically similar to non-pulsed lymphocytes with regards to the expression of CD3, CD4, CD8, CD16, and CD56 antigens. The induction of activation markers, like CD25 and CD122 IL-2 receptors and CD71 transferrin receptor, was also comparable in pulsed and non-pulsed cultures. When a lower cytotoxicity was found in pulsed cultures, a lower number of CD54+ (ICAM-1) cells was also found. LAK cell cytotoxicity and number of CD54 cells were significantly correlated. No difference was found between pulsed and non-pulsed cultures in their cell cycle phase or in the percentage of apoptotic cells. Autologous plasma did not inhibit the differentiation of pulsed PBMC into LAK cells. The IL-2 pulse of PBMC from healthy young donors resulted in the induction of LAK cytotoxicity as observed in elderly cancer patients. The results demonstrate the effectiveness of IL-2 pulse to generate cytotoxic LAK cells in elderly cancer patients suggesting the potential application of pulsing procedures to treatment of older age groups.

Effect of zinc or zinc plus arginine supplementation on antibody titre and lymphocyte subsets after influenza vaccination in elderly subjects: a randomized controlled trial.

OBJECTIVE: to evaluate whether oral supplementation with zinc or zinc/arginine increases the antibody response to influenza vaccine or modulates the lymphocyte phenotype in elderly subjects. DESIGN: a randomized controlled trial with two supplemented groups and one control group. SETTING: a community nursing home. PARTICIPANTS: 384 subjects aged 64-100 (mean age 82 years) examined in three separate studies. INTERVENTION: oral supplementation with zinc (400 mg/day) or zinc plus arginine (4 g/day) for 60 days starting 15 days before influenza vaccination. The control groups received vaccine only. MEASUREMENTS: haematological and nutritional indices, antibody titre against influenza viral antigens, lymphocyte phenotype. RESULTS: supplementation with zinc or zinc plus arginine increased zinc plasma concentrations restoring the age-related impairment in zinc concentrations to values found in younger people. The antibody titre against influenza viral antigens was not increased in zinc or zinc/arginine supplemented groups in comparison with subjects receiving vaccine alone. The number of CD3, CD4 or CD8 lymphocytes was not affected by zinc or zinc/arginine supplementation. CONCLUSION: prolonged supplementation with zinc or zinc/arginine restores zinc plasma concentrations but is ineffective in inducing or ameliorating the antibody response after influenza vaccination in elderly subjects.

Altered thymic endocrine activity along with impairments of peripheral zinc metabolism and T-lymphocyte populations are associated with myasthenia gravis: a follow-up study.

Thymic endocrine activity was assessed by a bioassay to determine the basal activity of thymulin (TH), a zinc dependent hormone, and its in vitro reactivation in two different age groups of patients with myasthenia gravis (MG). Before thymectomy, basal TH plasma levels were increased in patients over the age of 50 years. Plasma zinc levels were increased in all patients, this increment being very high in old patients. One year after thymectomy both TH and zinc plasma levels decreased. While zinc plasma levels were within the normal ranges for their respective ages, TH levels were lower in young and higher in old patients than in age comparable controls. Young patients with MG showed increased CD3,DR positive peripheral T-cells as well as lymphocytes with the CD16,CD56 phenotype. An increment of CD3 positive cells along with CD4 and CD16,CD56 positive cells were found in older patients. Thymectomy partially affected blood lymphocyte representation only in young patients, since CD3,DR T-cells decreased one year after surgery. No significant variations in T-cell representation were found in old patients after thymectomy. Immunosuppression in thymectomized patients did not significantly affected TH and zinc plasma levels. Very high levels of TH and the presence of additional alterations in T-lymphocyte subsets in old patients suggested that differential age related pathogenetic immunological mechanisms might be associated with the disease.

Plasticity of neuroendocrine-thymus interactions during aging.

Thymic regrowth and reactivation of thymic endocrine activity may be achieved even in old animals by different endocrinological or nutritional manipulations such as, (a) intrathymic transplantation of pineal gland or treatment with melatonin, (b) implantation of a growth hormone (GH) secreting tumor cell line or treatment with exogenous GH, (c) castration or treatment with exogenous luteinizing hormone-releasing hormone (LH-RH), (d) treatment with exogenous thyroxine or triiodothyronine, and (e) nutritional interventions such as arginine or zinc supplementation. These data strongly suggest that thymic, involution is a phenomenon secondary to age-related alterations in neuroendocrine-thymus interactions and that it is the disruption of such interactions in old age that is responsible for age-associated dysfunction. With regard to the mechanisms involved in hormone-induced thymic reconstitution, it is at present, difficult to draw any definitive conclusions. The effect of GH, thyroid hormones, and LH-RH may be due to the presence on thymic epithelial cells supposed to produce thymic peptides, of the specific hormone receptors. Melatonin or other pineal factors may also act through specific receptors, but experimental evidence is still lacking. The role of zinc, whose turnover is usually reduced in old age, is diverse. The effects range from the reactivation of zinc-dependent enzymes, required for both cell proliferation and apoptosis, to the reactivation of thymulin, a zinc-dependent thymic hormone. The role of zinc may even be more crucial. According to recent preliminary data obtained both in animal and human studies, it appears that the above reported endocrinological manipulations capable of restoring thymic activity in old age, may act also by normalizing the altered zinc pool.

Plasticity of neuro-endocrine-thymus interactions during aging--a minireview.

Thymic regrowth and reactivation of thymic endocrine activity may be achieved even in old animals by different endocrinological or nutritional manipulations. In particular: a) intrathymic transplant of pineal gland or treatment with melatonin; b) implantation of a growth hormone secreting tumor cell line or treatment with exogenous growth hormone; c) castration or treatment with exogenous LH-RH; d) treatment with exogenous thyroxine or triiodothyronine, and e) nutritional interventions such as arginine or zinc supplementation. These data strongly support the idea that thymic involution is a phenomenon secondary to age-related alterations in neuroendocrine-thymus interactions and that it is the disruption of such interactions in old age which is responsible for most of age-associated dysfunctions. With regard to the mechanisms involved in hormone-induced thymic reconstitution, it is, at present, difficult to draw any definitive conclusion. The effect of GH, thyroid hormones and LH-RH may be due to the presence on thymic epithelial cells, supposed to produce thymic peptides, of the specific hormone receptors. Melatonin or pineal derived factors may as well act through specific receptors but experimental demonstration is still lacking. The role of zinc, whose turnover is usually reduced in old age, is of quite wide-range: from the reactivation of zinc-dependent enzymes, required for both cell proliferation and apoptosis, to the reactivation of thymulin, a zinc-dependent thymic hormone. The role of zinc may be even more crucial. According to recent preliminary data obtained both in animal and in man, it appears that the above reported endocrinological manipulations, capable of restoring thymic activity in old age, may act also by normalizing the altered zinc pool.

Long-term melatonin supplementation does not recover the impairment of natural killer cell activity and lymphocyte proliferation in aging mice.

In this study we evaluated the effect of long-term melatonin (MEL) treatment on the cytotoxic activity and number of natural killer (NK) cells and the proliferative response of spleen lymphocytes to phytohemagglutinin (PHA) or interleukin-2 (IL-2) in old mice. Seventeen-eighteen month-old Balb/c mice were supplemented with MEL (40-50 microg/day/mouse) and sacrificed after eight months. The MEL supplementation was unable to recover the low levels of both endogenous and IL-2-induced NK cell activity found in old untreated mice. Also the NK cell number was unaffected by MEL treatment. The spleen lymphocyte proliferative response to both PHA and IL-2 was not different in old MEL-treated compared to old untreated mice. These results indicate that long-term MEL supplementation does not recover the age-related deterioration of NK cell activity and lymphocyte proliferative capacity.

Thymulin, zinc and insulin-like growth factor-I (IGF-I) activity before and during recombinant growth hormone (rec-GH) therapy in children and adults with GH deficiency.

Plasma thymulin (active and total) levels; IGF-I and zinc concentrations were evaluated in 9 children and in 8 adults with GH-deficiency (GHD) before and after 3-6 months of recombinant-GH treatment. Before therapy, GH deficient children had lower plasma active thymulin levels (1.0 +/- 0.3 log-2), not due to a peripheral defect in zinc saturation since plasma zinc levels were within the normal range, and total thymulin levels (1.3 +/- 0.3 log-2) than in the age-matched control group. GH therapy significantly increased active thymulin (3rd month: 3.0 +/- 0.2 log-2, 6th month: 4.0 +/- 0.2 log-2), total thymulin (3rd month: 3.3 +/- 0.3 log-2, 6th month: 4.3 +/- 0.2 log-2) and IGF-I levels (3rd month: 283.3 +/- 7.2 micrograms/L, 6th month: 411.2 +/- 44.2 micrograms/L, vs basal: 144.3 +/- 11.5 micrograms/L); at the 6th month of therapy, thymulin levels (active and total) were comparable to those found in controls. A positive correlation existed between zinc and plasma IGF-I levels (r = 0.66, p < 0.05). In adults with GHD, plasma active (1.9 +/- 0.3 log-2) and total thymulin levels (3.9 +/- 0.1 log-2), significantly lower (p < 0.01 and 0.05, respectively) than in controls before treatment, increased after GH therapy (active thymulin, 3rd month: 3.0 +/- 0.2 log-2, 6th month: 4.4 +/- 0.3 log-2; total thymulin, 3rd month: 3.9 +/- 0.3 log-2, 6th month: 4.7 +/- 0.2 log-2), being at 6th month of therapy no more different from the values recorded in the age-matched control group. In conclusion, children and adults with GHD have a marked impairment of the thymic endocrine activity, which can be restored by six months of GH treatment. The effects of GH on thymic functions may be mediated by IGF-I, through the modulation of zinc turnover, suggesting the possible existence of an interplay among GH, zinc, IGF-I and thymulin both in children and adults with GHD.

Role of prolactin in the modulation of NK and LAK cell activity after short- or long-term morphine administration in neoplastic patients.

In a previous work we demonstrated that chronic in vivo antalgic therapy of cancer patients with morphine reduced the endogenous cytotoxic activity of natural killer (NK) cells, while increasing the development of lymphokine activated killer (LAK) cell cytotoxicity. In order to investigate the mechanisms by which morphine affects NK and LAK cell function further, we evaluated the modulation exerted by short- or long-term morphine administration on either NK/LAK cell cytotoxicities or plasma levels of prolactin (PRL) and other immunomodulating neurohormones. An intravenous morphine injection (10 mg) significantly increased the plasma levels of PRL, reduced the cytotoxic activity of NK cells, and increased the development of LAK cell activity 30 min after drug injection in neoplastic patients. The administration of bromocriptine before the injection of morphine prevented both PRL augmentation and the increase in LAK cell activation, although it did not prevent the inhibition of NK cytotoxicity. The chronic oral administration of morphine (90 +/- 30 mg/day for 1 month) also resulted in higher PRL levels; the NK and LAK cell activities were, respectively, lower than or higher than those found in neoplastic patients untreated with morphine. The plasma levels of thyrotropin (TSH), adrenocorticotropic hormone (ACTH) and cortisol were not significantly modified in either short- or long-term experiments. The absolute number and the percentages of lymphocyte populations, as well as the percentage of IL-2 receptors, were not modified after short-term morphine administration whereas little changes of T lymphocyte populations and NK cell number were observed after oral treatment with morphine. In vitro morphine did not affect the development of LAK cell activity. In conclusion, our findings indicate that morphine reduces NK cytotoxicity and increases the development of LAK cell cytotoxicity after short- and long-term administration. The effect of morphine on LAK cell activation but not on NK cell reduction is related to the modulation of PRL levels determined by the opioid drug.

Effect of melatonin and pineal grafting on thymocyte apoptosis in aging mice.

We have evaluated the effect of chronic melatonin (MEL) treatment or pineal grafting (PG) in old mice on the apoptosis of both thymocytes and spleen lymphocytes under conditions of either serum deprivation or glucocorticoid or zinc administration. The apoptosis was correlated with the modulation of thymus and adrenal weight and corticosterone and zinc plasma levels induced by MEL treatment or PG in old mice. Balb/c mice (17-18 months old) were given supplements of MEL (40-50 micrograms/day/mouse) or grafted with a young pineal gland and then sacrificed after 8 months. Both the MEL treatment and PG partially prevented thymic involution in very old mice. Both treatments protected the thymic and spleen lymphocytes in old mice from the apoptosis induced by serum deprivation and recovered the reduced thymocyte sensitivity to the apoptosis induced by dexamethasone (DEX), present in old untreated animals, to the values found in young mice. DEX caused a bigger loss of G D /G 1 phase cells in MEL treated mice than in old untreated mice. The protective action of MEL treatment or PG on serum deprivation induced apoptosis was correlated with increased thymus weight, reduced adrenal weight and corticosterone levels and increased zinc plasma levels. The greater DEX-induced apoptosis found in MEL treated and PG mice was correlated with reduced adrenal weight and function. In vitro MEL did not affect thymocyte apoptosis in young or old mice. These results suggest that MEL treatment or PG prevent age-related thymus involution through regulation of thymocyte apoptosis which, in turn, occurs through modulation of the pituitary-adrenal axis and zinc turnover determined by the pineal hormone.

Natural cytotoxicity and GnRH agonist administration in advanced endometriosis: positive modulation on natural killer activity.

OBJECTIVE: To investigate the effects of pharmacologic suppression of ovarian function on the immune system, with respect to the clinical outcome of endometriosis and the possibility of an immunoendocrine combined treatment. METHODS: After informed consent, 25 of 37 patients with revised American Fertility Society stage III and IV endometriosis who underwent postoperative medical treatment were selected and enrolled for this immunoendocrine longitudinal study. Medical treatment consisted of tryptorelinum depot injection, 3.75 mg/month for 24 weeks. Blood samples were collected before the first injection in the early follicular phase, day 2-3 of the cycle, and during medical treatment (every 4 weeks) and follow-up (every 6 months). At the end of the study, we had ten blood samples per patient to evaluate the cytotoxic activity, the number of natural killer cells, and the serum levels of estradiol. Natural killer activity was determined against the K562 cell line by target cell retention of the fluorescent dye carboxyfluorescein diacetate. RESULTS: A positive immunomodulating effect was observed during GnRH agonist administration. In particular, a significant progressive increase in natural killer cell activity was defined within the first 12 weeks of medical treatment; after three injections, we observed the highest values of cytotoxicity, with a median of 7.1 lytic units (range 0.3-14.0; P = .02). Natural cytotoxicity then decreased toward a plateau, which persisted during therapy completation and follow-up, with slight fluctuations. In patients who had recurrence, the values of natural killer cell activity were constantly lower than those in patients with disease-free follow-up, particularly within the first 12 weeks of medical treatment.

The zinc pool is involved in the immune-reconstituting effect of melatonin in pinealectomized mice.

Melatonin (MEL) affects the immune system by direct or indirect mechanisms. An involvement of the zinc pool in the immune-reconstituting effect of MEL in old mice has recently been documented. An altered zinc turnover and impaired immune functions are also evident in pinealectomized (px) mice. The present work investigates further the effect of "physiological" doses of MEL on the zinc pool and on thymic and peripheral immune functions in px mice. Daily injections of MEL (100 micrograms/mouse) for 1 month in px mice restored the crude zinc balance from negative to positive values. Thymic and peripheral immune functions, including plasma levels of interleukin-2, also recovered. The nontoxic effect of MEL on immune functions was observed in sham-operated mice. Because the half-life of MEL is very short (12 min), interruption of MEL treatment in px mice resulted, after 1 month, in a renewed negative crude zinc balance and a regression of immune functions. Both the zinc pool and immunological parameters were restored by 30 further days of MEL treatment. The existence of a significant correlation between zinc and thymic hormone after both cycles of MEL treatment clearly shows an involvement of the zinc pool in the immunoenhancing effects of MEL and thus suggests an inter-relationship between zinc and MEL in px mice. Moreover, the existence of significant positive correlations between zinc or thymulin and interleukin-2 suggests that interleukin-2 may participate in the action of MEL, via zinc, on thymic functions in px MEL-treated mice.

Impaired peripheral zinc metabolism in patients with senile dementia of probable Alzheimer's type as shown by low plasma concentrations of thymulin.

Plasma concentrations of a zinc carrier peptide, namely thymulin, were measured according to a bioassay in young donors, healthy elderly, and patients with senile dementia of Alzheimer's type (SDAT). Thymulin is a hormone released by thymic epithelial cells and its biological activity on cells of immune system is dependent on the presence of one molecule of zinc bound to the peptide. Plasma from different subjects were fractionated by gel filtration to yield protein-bound thymulin and free thymulin. The biological activity of the peptide was then assessed in the two different fractions. The activity of protein-bound thymulin was higher in young donors than in elderly or SDAT patients, being the lowest in SDAT. Addition of zinc ions to plasma fractions increased the thymulin activity of samples from elderly and SDAT patients to levels observed in young donors. Thymulin activity in free thymulin fractions was lower in the elderly than in the young and was practically undetectable in SDAT patients. The addition of zinc ions normalized the activity of thymulin in these fractions from both the elderly and SDAT patients. These findings confirm the presence of an altered zinc status in the elderly and suggest that an impaired zinc metabolism may be present in SDAT patients.

Relationship between 17-beta-estradiol and prolactin in the regulation of natural killer cell activity during progression of endometriosis.

Endometriosis is an estrogen-dependent disease affecting women during their reproductive years. An abnormal immune function and, in particular, a decreased natural killer (NK) cell activity have been found in endometriosis, suggesting a role of the immune system in the pathophysiology of the disease. We have recently evidenced a significant inverse relationship between 17-beta-estradiol plasma levels and NK cytotoxicity in endometriosis patients. In this study we have investigated the combined role of 17-beta-estradiol (E2) and prolactin (PRL) in the regulation of NK cell activity during the progression of endometriosis, by evaluating the correlation among E2, PRL, and other immunomodulating neurohormones on both the cytotoxic activity and the number of NK cells in women at different stages of endometriosis. The early stages (I/II) of endometriosis are characterized by increased plasma levels of either E2 or PRL without significant alterations of NK cell activity in comparison with healthy subjects. The progression to advanced stages (III/IV) of the disease is associated with a further increase of E2 levels, a decrease of PRL plasma concentrations (with an increase of E2/PRL ratio), and an impairment of NK cytotoxicity. The plasma levels of both E2 and PRL and the E2/PRL ratio are significantly correlated with the values of NK cytotoxicity in advanced stages of endometriosis. Either the absolute number or the relative percentage of CD16+ or CD56+ peripheral lymphocytes are not significantly different between patients at either stages I/II or III/IV and healthy controls. Plasma levels of progesterone (P) and luteinizing hormone (LH), are not significantly changed in different stages of endometriosis with respect to healthy controls. The significant decrease of follicle-stimulating hormone (FSH) plasma levels found in either stages I/II or III/IV endometriosis patients is not correlated with the NK cell activity. In conclusion, at advanced stages of endometriosis the impairment of NK cell activity occurs with increased E2, and decreased PRL plasma levels. Additional studies are required to determine whether the E2/PRL ratio represents a possible biochemical marker of endometriosis.

Reversibility of the thymic involution and of age-related peripheral immune dysfunctions by zinc supplementation in old mice.

With advanced ageing the zinc pool undergoes progressive reduction as shown by the low zinc plasma levels and the negative crude zinc balance, both in humans and in rodents. It has been suggested that such zinc deficiency might be involved in many age-related immunological dysfunctions, including thymic failure. The relevance of zinc for good functioning of the entire immune system is, at present, well documented. In particular, zinc is required to confer biological activity to one of the best-known thymic peptides, thymulin, which is responsible for cell-mediated immunity. In deep zinc deficiencies, in humans and other animals, the low thymulin levels are due not to a primary failure of the thymus, but to a reduced peripheral saturation of thymic hormones by zinc ions. In aged mice both a reduced peripheral saturation of the hormone and a decreased production by the thymus were present. Oral zinc supplementation in old mice (22 months old) for 1 month induced a complete recovery of crude zinc balance from negative (-1.82) to positive values (+1.47), similar to those of young animals (+1.67). A full recovery of thymic functions with a regrowth of the organ and a partial restoration of the peripheral immune efficiency, as measured by mitogen responsiveness (PHA and ConA) and natural killer cell (NK) activity, were observed after zinc supplementation. These findings clearly pin-point for relevance of zinc for immune efficiency and suggest that the age-related thymic involution and peripheral immunological dysfunctions are not intrinsic and irreversible events but are largely dependent on the altered zinc pool.