Search

Because of the importance of accurate data for fission chain yields (FCYs) for many applications, we present a rigorous “clean sheet” evaluation of all available data to provide an accurate set of ...

Summary Purpose Within this phase II EORTC trial, we have investigated the safety and efficacy of pentostatin in lymphoid malignancies. We have previously reported the results in T-and B-cell prolymphocytic leukemia, B-cell chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia. This report focuses on the outcome in T-cell malignancies: T-CLL, Sezary syndrome (Sezary), mycosis fungoides (MF) and T-zone lymphoma (TZL). Patients and methods Of the 92 patients with these diagnoses enrolled, 76 were evaluable for response and toxicity, i.e., 25 of 28 with T-CLL, 21 of 26 with Sezary, 22 of 26 with MF, and 8 of 12 with TZL. All patients had progressive and advanced disease. Pentostatin was administered at a dosage of 4 mg/m2 every week for the first 3 weeks, then 4 mg/m2 every 14 days for another 6 weeks, followed by maintenance therapy of 4 mg/m2 monthly for a maximum of 6 months. Results Response rates (complete and partial responses) in patients with Sezary (n = 22) or MF (n = 21) were 33% and 23%, respectively, and in patients with T-CLL (n = 21) or TZL (n = 8) 8% and 25%, respectively. Sixteen (21%) patients died during the first ten weeks of treatment: twelve of progressive disease, two of infectious complications with progressive disease, one of myocard infarction and one of renal failure related to administration of i.v. contrast. Major toxicity (grade 3–4) included infection in 11% of patients, nausea/vomiting in 4%, diarrhea in 3%. Hematologic toxicity was mild to non-existent. Conclusions We conclude that pentostatin is active in Sezary and MF but showed marginal activity in T-CLL or TZL. Toxicities are mild to moderate at the dose schedule administered. Due to its relatively specific lympholytic effect and its favorable toxicity spectrum, pentostatin might be especially useful for the palliative treatment of T-cell malignancies.

In the AML 8A study patients were treated with remission-induction therapy followed by one consolidation course. Patients in complete remission (CR) were randomised between autologous bone marrow transplantation (ABMT) and a second intensive consolidation course, except for those with a histocompatible sibling donor, who received allogeneic bone marrow transplantation (alloBMT). This analysis was performed to determine whether centres which only performed induction and consolidation therapy, achieved similar results as centres who also performed transplantation. 542/676 (80%) from transplantation centres and 150/194 (77%) from referring centres achieved CR, with an early death rate of 5% and 11%, respectively (P = 0.01). 66% of patients with a donor from transplantation centres received alloBMT in first CR compared with 57% from referring centres (P = 0.2). Transplantation centres randomised 64% of patients without a donor, referring centres 47% (P = 0.04). The full protocol treatment was completed by 275/542 (51%) and 61/150 (41%) patients, respectively (P = 0.04). The overall survival rate at 6 years from diagnosis was 34% and 36%, respectively (P = 0.9). In conclusion, the type of centre did not appear to have an influence on overall survival. The feasibility of the study was acceptable for both types of centres. The referring centres applied more selection for transplantation. Despite a more intensive second-line treatment at transplantation centres, the overall outcome remained similar to that of referring centres.

To determine whether patients with a HLA-identical sibling donor have a better outcome than patients without a donor, an analysis on the basis of intention-to-treat principles was performed within the framework of the EORTC-GIMEMA randomized phase III AML 8A trial. Patients in complete remission (CR) received one intensive consolidation course. Patients with a histocompatible sibling donor were then allocated allogeneic bone marrow transplantation (alloBMT). the patients without a donor were randomized between autologous BMT (ABMT) and a second intensive consolidation (IC2). 831 patients 8 weeks from diagnosis were included. HLA typing was performed in 672 patients. AlloBMT was performed during CR1 in 180 (61%) out of 295 patients with a donor. Another 38 patients were allografted: ave in resistant disease, 14 during relapse and 19 in CR2, ABMT was performed in 130 (34%) out of 377 patients without a donor in CR1, in six: (2%) patients during relapse and in 38 (10%) patients during CR2. The disease-free survival (DFS) from CR for patients with a donor was significantly longer than for patients without a donor (46% v 33% at 6 years; P = 0.01, RR 0.78, 95% confidence interval 0.63-0.96). The overall survival from diagnosis for patients with a donor was longer, but not statistically significant, than for patients without a donor (48% v 40% at 6 years; logrank P= 0.24). When patients were stratified according to prognostic risk groups, the same trend in favour of patients with a donor was seen for survival duration and the DFS remained significantly longer for this group of patients.

Extracellular matrix ligands and receptors have been identified as determining in vivo lymphocyte positioning and activation, including effector functions in alloreactive responses. Herein we evaluated the involvement of laminin and its receptor, the very late antigen 6 (VLA-6) integrin, in CD4+ T cell-dependent autoreactivity, using a transplantation model for the autoimmune myocarditis occurring in mice chronically infected with Trypanosoma cruzi. Previous work showed that syngeneic mouse hearts grafted in the ears of chronic chagasic recipients were rejected through a CD4+ T cell-dependent mechanism. Rejection also occurred when cells from chagasic animals were transferred adjacent to hearts transplanted into naive recipients. Here, we observed the formation of a thick laminin network during rejection, with donor-derived CD4+ T cells concentrated in the laminin-rich areas. Most importantly, anti-laminin as well as anti-laminin receptor Ab inhibited the rejection of syngeneic hearts by T cells from chagasic animals. Our results suggest that interaction of the VLA-6 molecule with laminin is involved in triggering the antimyocardial autoreactive process by driving the influx of CD4+ T cells to the heart. They also support the concept that an Ag-specific T cell response, even an autoreactive one, can be modulated by in vivo interactions involving extracellular matrix ligands and receptors. In this regard, our study represents, to our knowledge, the first in vivo evidence for laminin-mediated T cell echotaxis, with simultaneous experimental demonstration of ligand and receptor involvement. Lastly, our findings indicate that treatment with anti-VLA-6 Abs can be effective in suppressing autoimmune disease activity.

Twenty-one patients with acute myeloid leukemia (AML) who failed to enter complete remission (CR) after first-line standard-dose remission-induction therapy with 7 days of cytarabine and 3 days of daunorubicin were treated with a salvage regimen containing intermediate-dose cytosine arabinoside (Ara-C) 2 x 500 mg/m2/day during 7 days in combination with continuous infusions of idarubicin 12 mg/m2/day on days 1, 3, and 5. Twenty patients were considered primary resistant, and one patient had a partial remission after two remission-induction courses. Overall, 11 patients (52%, 95% confidence interval: 30-74%) entered CR. Three patients died during hypoplasia and seven patients had resistant disease or a partial remission. The remission rate in this study compares favorably with the results obtained in similar patient categories. The toxicity of this salvage regimen was remarkably mild. No extramedullary toxicity was observed except for hepatic dysfunction in seven patients. The median duration of remission was 8.5 months, and ultimately, all complete remitters have relapsed except the patient who died from infectious complications after allogeneic bone marrow transplantation (BMT). This study shows that new intensive chemotherapy regimens may be effective after failure of primary treatment. Salvage regimens containing intermediate/high-dose Ara-C and/or alternative anthracyclines or anthracenes should be induced in the treatment of young patients with de novo AML.

Background Allogeneic or autologous bone marrow transplantation and intensive consolidation chemotherapy are used to treat acute myelogenous leukemia in a first complete remission. Methods After induction treatment with daunorubicin and cytarabine, patients who had a complete remission received a first course of intensive consolidation chemotherapy, combining intermediate-dose cytarabine and amsacrine. Patients with an HLA-identical sibling were assigned to undergo allogeneic bone marrow transplantation; the others were randomly assigned to undergo autologous bone marrow transplantation (with unpurged bone marrow) or a second course of intensive chemotherapy, combining high-dose cytarabine and daunorubicin. Comparisons were made on the basis of the intention to treat. Results A total of 623 patients had a complete remission; 168 were assigned to undergo allogeneic bone marrow transplantation, and 254 were randomly assigned to one of the other two groups. Of these patients, 343 completed the treatment assi...

This paper discusses the insulin utilization kinetics and the effect of its concentration during batch and continuous mass cultures of the murine VO208 hybridoma cells, using a home-made serum-free medium. Our results show that insulin is utilized by the cells, with a specific rate of 1 relative units (RU) per 10(9) cells per h in batch culture. In continuous reactor running at different insulin levels, this consumption rate is observed to vary from 0.13 to 0.55 RU per 10(9) cells per h when the insulin activity increases from 0.3 to 35 RU l-1 and then to stabilize for higher insulin levels until 110 RU l-1. A low insulin amount in the medium around 0.01 RU l-1, which is near physiological levels, is found sufficient to promote the cell growth. Interestingly, we observe that too high insulin levels, above 25 RU l-1, induce a reduction of the cell density due to an inhibitory effect on the maximal specific cell growth rate. Furthermore, the specific rate of MAb production is found to be independent of the insulin amount in the medium.

Expression of diabetes susceptibility genes at the hemopoietic stem cell level is sufficient for the development of the disease in nonobese diabetic (NOD) mice. This work investigated whether the defects that reside within the stem cells have consequences on the homeostasis of the stem and progenitor cell compartments. The fraction of cyclically active stem cells, or spleen colony-forming units (CFU-s), is enlarged, and their differentiation toward megakaryocytopoiesis seems to be enhanced in NOD mice at 3 and 10 weeks of age as compared to C57BL/6 mice. Whereas colony-forming unit assay (CFU-A) numbers are normal in the bone marrow, they are significantly increased in the spleen of NOD mice. A strain-dependent difference in granulocyte-macrophage colony-forming cell (GM-CFC) numbers was observed; they were higher in NOD mice than in B6 mice of three and ten weeks of age. These results suggest that autoimmune type 1 diabetes mellitus of the NOD mouse is accompanied by disorders of myelopoiesis and megakaryopoiesis. This observation is in keeping with the role of macrophages in the development of diabetes and with the hyperactivity of diabetic platelets.

In the Pontal auriferous lode, dominant saccharoidal quartz is associated with oligoclase, biotite, hornblende, tremolite-actinolite, sulphides (less than 2%), and disseminated native gold. Four main types of fluid inclusion have been distinguished based on their habit, distribution and spatial relation-ship with gold particles. Type S are primary multiphase large sized (100 to 200 µm) inclusions with homogenization temperatures (V + L → L) between 350 and 450°C. They contain siderite and/or calcite and graphite-like microcrystals as daughter phases. Commonly associated with these inclusions are tiny (50 to 100 µm) solid inclusions of biotite or actinolite. In most of these inclusions, only CH4 has been detected in the vapour phase. However some noticeable exceptions were observed (CO2/CH4 ratio near 0.85). Type C inclusions are later than gold and occur disseminated in quartz or along trails that crosscut quartz grain boundaries. They may contain nahcolite daughter crystals. CO2/CH4 ratios range from 0.0 to 0.5. Homogenization temperatures vary from 150 to 300°C. Type V are mainly gaseous CH4-H2O inclusions. They may occur as small-sized inclusions directly associated with gold particles. Type L are aqueous two-phase inclusions of late secondary origin.The scattering of the CO2/CH4 ratios could be related to fluctuations of the oxygen fugacity that triggered gold precipitation at the time of trapping. These variations of fO2 with time could reflect unbuffered fluid-rock interaction with respect to redox conditions during quartz deposition.Finally, gold deposition is interpreted to have occurred at elevated temperature (500°C) and pressure, compatible with boundary conditions between greenschist and amphibolites facies.

It is well recognized that zinc is an essential trace element, influencing growth and affecting the development and integrity of the immune system. Research has begun to clarify the molecular mechanisms underlying the action of zinc on the immune function. It is clear that this trace element has a broad impact on key immunity mediators, such as enzymes, thymic peptides and cytokines, explaining the paramount importance of zinc's status on the regulation of lymphoid cell activation, proliferation and apoptosis. Ongoing and future studies regarding the immunological status of zinc deficiency 'at risk' groups could lead to public health interventions with nutritional doses of zinc supplements to prevent alteration of the immune system and improve resistance to infections.

Increasing evidence has placed hormones and neuropeptides among potent immunomodulators, in both health and disease. Herein, we focus on the effects of growth hormone (GH) upon the thymus. Exogenous GH enhances thymic microenvironmental cell-derived secretory products such as cytokines and thymic hormones. Moreover, GH increases thymic epithelial cell (TEC) proliferation in vitro, and exhibits a synergistic effect with anti-CD3 in stimulating thymocyte proliferation, which is in keeping with the data showing that transgenic mice overexpressing GH or GH-releasing hormone exhibit overgrowth of the thymus. GH also influences thymocyte traffic: it increases human T-cell progenitor engraftment into the thymus; augments TEC/thymocyte adhesion and the traffic of thymocytes in the lymphoepithelial complexes, the thymic nurse cells; modulates in vivo the homing of recent thymic emigrants, enhancing the numbers of fluroscein isothiocyanate (FITC)+ cells in the lymph nodes and diminishing them in the spleen. In keeping with the effects of GH upon thymic cells is the detection of GH receptors in both TEC and thymocytes. Additionally, data indicate that insulin-like growth factor (IGF)-1 is involved in several effects of GH in the thymus, including the modulation of thymulin secretion, TEC proliferation as well as thymocyte/TEC adhesion. This is in keeping with the demonstration of IGF-1 production and expression of IGF-1 by TEC and thymocytes. Also, it should be envisioned as an intrathymic circuitry, involving not only IGF-1, but also GH itself, as intrathymic GH expression is seen both in TEC and in thymocytes, and that thymocyte-derived GH could enhance thymocyte proliferation. Finally, the possibility that GH improve thymic functions, including thymocyte proliferation and migration, places this molecule as a potential therapeutic adjuvant in immunodeficiency conditions associated with thymocyte decrease and loss of peripheral T cells.

Most patients with MDS are treated with supportive care only, mainly in view of the average advanced age in MDS and the poor response to more intensive therapy. Allogeneic stem cell transplantation is today the treatment of choice in the majority of young patients with histocompatible siblings. The results of treatment with allogeneic stem cell transplantation depend on the stage of disease at the time of transplantation and various clinical factors, such as the presence of cytogenetic abnormalities, age, and the percentage of blasts in the bone marrow at time of transplantation. Most patients may benefit optimally from an allogeneic stem cell transplantation when the transplant is performed as soon as an HLA-identical family member has been identified. Progression to more advanced leukemic conditions is associated with a higher failure rate mainly due to an increased incidence of relapse after transplantation. Delay of the transplant may be justified in a minority of patients with refractory anemia without cytopenias or complex cytogenetic abnormalities.

Within this phase II trial of the European Organization for Research and Treatment of Cancer, we have investigated the safety and efficacy of pentostatin (Nipent; SuperGen, San Ramon, CA) in refractory lymphoid malignancies. Pentostatin was administered at a dosage of 4 mg/m2 every week for the first 3 weeks, then every 14 days, followed by maintenance therapy of 4 mg/m2 monthly for a maximum of 6 months. We have previously reported the results in T- and B-cell prolymphocytic leukemia, B-cell chronic lymphocytic leukemia, and hairy cell leukemia This report focuses on the outcome in T-cell malignancies: T-cell chronic lymphocytic leukemia, Sézary syndrome, mycosis fungoides, and T-zone lymphoma. Of 92 patients with these diagnoses enrolled, 76 were evaluable for response and toxicity, ie, 25 of 28 with T-cell chronic lymphocytic leukemia, 21 of 26 with Sézary syndrome, 22 of 26 with mycosis fungoides, and eight of 12 with T-zone lymphoma. All patients had progressive and advanced disease. Sixteen patients (21%) died during the first 9 weeks of treatment: 12 of progressive disease, two of infectious complications thought to be unrelated to treatment, one of myocardial infarction, and one of renal failure related to administration of intravenous contrast. Major toxicity (grades 3 and 4) included infection in 10.5% of patients, nausea/vomiting in 5%, and hepatotoxicity in 3%. One patient (1.3%) achieved a complete remission and 15 (19.7%) a partial remission. Better results were achieved in patients with Sézary syndrome or mycosis fungoides (complete remission + partial remission = 33.4% and 22.7%, respectively) than in patients with T-cell chronic lymphocytic leukemia (8%) or T-zone lymphoma (25%). We conclude that pentostatin is active in low-grade T-cell malignancies. Toxicities are mild to moderate at the dose schedule administered. Severe hematologic toxicity has not been observed. The efficacy at the present dose level is moderate. A higher dose might be necessary for some T-cell malignancies.

In the AML 8A study patients were treated with remission-induction therapy followed by one consolidation course. Patients in complete remission (CR) were randomised between autologous bone marrow transplantation (ABMT) and a second intensive consolidation course, except for those with a histocompatible sibling donor, who received allogeneic bone marrow transplantation (alloBMT). This analysis was performed to determine whether centres which only performed induction and consolidation therapy, achieved similar results as centres who also performed transplantation. 542/676 (80%) from transplantation centres and 150/194 (77%) from referring centres achieved CR, with an early death rate of 5% and 11%, respectively (P = 0.01). 66% of patients with a donor from transplantation centres received alloBMT in first CR compared with 57% from referring centres (P = 0.2). Transplantation centres randomised 64% of patients without a donor, referring centres 47% (P = 0.04). The full protocol treatment was completed by 275/542 (51%) and 61/150 (41%) patients, respectively (P = 0.04). The overall survival rate at 6 years from diagnosis was 34% and 36%, respectively (P = 0.9). In conclusion, the type of centre did not appear to have an influence on overall survival. The feasibility of the study was acceptable for both types of centres. The referring centres applied more selection for transplantation. Despite a more intensive second-line treatment at transplantation centres, the overall outcome remained similar to that of referring centres.

Within this phase II EORTC trial, we have investigated the safety and efficacy of pentostatin in lymphoid malignancies. We have previously reported the results in T- and B-cell prolymphocytic leukemia, B-cell chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia. This report focuses on the outcome in T-cell malignancies: T-CLL, Sézary syndrome (Sézary), mycosis fungoides (MF) and T-zone lymphoma (TZL).Of the 92 patients with these diagnoses enrolled, 76 were evaluable for response and toxicity, i.e., 25 of 28 with T-CLL, 21 of 26 with Sézary, 22 of 26 with MF, and 8 of 12 with TZL. All patients had progressive and advanced disease. Pentostatin was administered at a dosage of 4 mg/m2 every week for the first 3 weeks, then 4 mg/m2 every 14 days for another 6 weeks, followed by maintenance therapy of 4 mg/m2 monthly for a maximum of 6 months.Response rates (complete and partial responses) in patients with Sézary (n = 22) or MF (n = 21) were 33% and 23%, respectively, and in patients with T-CLL (n = 21) or TZL (n = 8) 8% and 25%, respectively. Sixteen (21%) patients died during the first ten weeks of treatment: twelve of progressive disease, two of infectious complications with progressive disease, one of myocard infarction and one of renal failure related to administration of i.v. contrast. Major toxicity (grade 3-4) included infection in 11% of patients, nausea/vomiting in 4%, diarrhea in 3%. Hematologic toxicity was mild to non-existent.We conclude that pentostatin is active in Sézary and MF but showed marginal activity in T-CLL or TZL. Toxicities are mild to moderate at the dose schedule administered. Due to its relatively specific lympholytic effect and its favorable toxicity spectrum, pentostatin might be especially useful for the palliative treatment of T-cell malignancies.

Thymic peptides, a heterogenous family of polypeptidic hormones synthesized within the thymus, not only exert important regulatory effects within both the immune and neuroendocrine systems but are also themselves subject to control by hormones derived from the hypothalamic-pituitary-adrenal axis (HPA) and other endocrine glands. Regarding thymic hormonal function, thymulin production is up-regulated by several hormones, including prolactin, growth hormone and thyroid hormones. Other aspects of the physiology of thymic epithelial cells can also be modulated by hormones and neuropeptides, particularly cytokeratin expression, cell growth and production of extracellular matrix proteins, thus characterizing the pleiotrophic action of these molecules on the thymic epithelium. Conversely, thymic-derived peptides also regulate hormone release from the HPA axis and may act directly on target endocrine glands of this axis, modulating gonadal tissues. In addition, it has recently been shown that thymulin can modulate some peripheral nervous sensory functions, including those related to sensitivity to pain. According to the dose given, thymulin induces or reduces hyperalgesia related to both mechanical and thermal nociceptors and thus represents an important interface between the immune, endocrine and nervous systems.

To determine whether patients with a HLA-identical sibling donor have a better outcome than patients without a donor, an analysis on the basis of intention-to-treat principles was performed within the framework of the EORTC-GIMEMA randomized phase III AML 8A trial. Patients in complete remission (CR) received one intensive consolidation course. Patients with a histocompatible sibling donor were then allocated allogeneic bone marrow transplantation (alloBMT), the patients without a donor were randomized between autologous BMT (ABMT) and a second intensive consolidation (IC2). 831 patients46 years old and alive8 weeks from diagnosis were included. HLA typing was performed in 672 patients. AlloBMT was performed during CR1 in 180 (61%) out of 295 patients with a donor. Another 38 patients were allografted: five in resistant disease, 14 during relapse and 19 in CR2. ABMT was performed in 130 (34%) out of 377 patients without a donor in CR1, in six (2%) patients during relapse and in 38 (10%) patients during CR2. The disease-free survival (DFS) from CR for patients with a donor was significantly longer than for patients without a donor (46% v 33% at 6 years; P=0.01, RR 0.78, 95% confidence interval 0.63-0.96). The overall survival from diagnosis for patients with a donor was longer, but not statistically significant, than for patients without a donor (48% v 40% at 6 years; logrank P=0.24). When patients were stratified according to prognostic risk groups, the same trend in favour of patients with a donor was seen for survival duration and the DFS remained significantly longer for this group of patients.

GH has been shown to modulate various functions of the thymus. We now demonstrate the production of human GH (hGH) by human thymic cells, and the expression of GH receptors in thymic epithelial cells (TEC) and in thymocytes at different stages of differentiation. The presence of hGH messenger RNA was shown by RT-PCR in both human thymocytes and in primary cultures of TEC. Moreover, immunoreactive hGH material was detected in culture media of thymocytes and TEC with the use of a sensitive immunoradiometric assay. GH receptor gene expression was shown in TEC in primary cultures and in fetal and postnatal TEC lines as well as in thymocytes. By immunocytochemistry, the presence of GH receptors in the various TEC preparations was confirmed. In cytofluorometric studies with the use of a biotinylated anti-GH receptor monoclonal antibody, we could show that GH receptors are predominantly expressed by immature thymocytes: over 90% of CD3- CD4- CD8- CD19- CD34+ CD2- cells (a phenotype characterizing the most immature T cell progenitors in the thymus) were GH receptor positive. Our results provide a molecular basis for an autocrine/paracrine mode of action of GH in the human thymus.

Because few data were available on glucose homeostasis at the early prediabetic stage in the nonobese diabetic (NOD) mouse, we investigated glycemia, insulinemia, and pancreatic insulin content under basal conditions in both sexes of 4-, 6-, and 8-week-old fed NOD mice, compared with sex- and age-matched fed C57BL/6 mice. We also investigated glucose tolerance in both sexes of fasting 8-week-old NOD and C57BL/6 mice. The main results obtained under basal fed conditions, when comparing both strains, were lower glycemia and higher insulinemia in NOD females at all ages investigated and in NOD males (particularly at 6 weeks of age). Glucose tolerance tests showed that: 1) the blood glucose response to 1 g/kg i.p. glucose was less sustained in both sexes of 8-week-old NOD mice than in their control counterparts; 2) the blood insulin response to glucose (1 g/kg i.p.) appeared earlier in both sexes of NOD mice than in sex-matched C57BL/6 mice; 3) an unusual sexual dimorphism existed in NOD mice, compared with controls, with females secreting, in response to glucose, twice as much insulin as males; 4) dose-response studies (1-6 g/kg glucose) confirmed the lower increase in blood glucose levels in both sexes of NOD mice and their unusual sexual dimorphism in insulin secretion; and 5) glucose tolerance tests in 4- to 8-week-old NOD mice showed that although the sexual dimorphism in insulin secretion was not observed in 4-week-old mice, it was particularly striking at 6 weeks of age. Taken together, these results suggest that beta-cell hyperactivity exists in the NOD mouse at the early prediabetic stage, especially in NOD females.

We conducted a prospective randomized multicenter clinical trial comparing the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjunct to intensive chemotherapy in patients of 61 years and older with untreated newly diagnosed acute myeloid leukemia (AML). Patients were randomized to either receive daunomycin-cytosine arabinoside with GM-CSF or daunomycin-cytosine arabinoside (control arm). Based on the rationale that GM-CSF might sensitize the leukemic cells to the cytotoxicity of chemotherapy as well as enhance white blood cell regeneration, GM-CSF was given during chemotherapy as well as after chemotherapy. Patients were treated with one, and in case of a partial response, with two remission induction cycles. When a complete remission was attained they received one additional cycle of consolidation therapy. Of 318 evaluable patients with a median age of 68 years, 157 were randomized to receive GM-CSF and 161 were assigned to control therapy. The effect of GM-CSF on treatment was evaluated according to intention-to-treat. Complete remission was achieved in 56% of the patients in the GM-CSF group and 55% of the control patients (P = .98). Recovery of neutrophils was significantly faster in GM-CSF-treated patients. The median time of recovery of neutrophils towards 0.5 x 10(9)/L was 23 days in the GM-CSF group versus 25 days in the control group (P = .0002) with the percentages of patients who recovered being 81% and 71%, respectively. With a median follow-up of 36 months, the probabilities of survival at 2 years after randomization were estimated at 22% for individuals assigned to the GM-CSF treatment as well as for control patients (P = .55). Disease-free survival at 2 years compared 15% and 19% for the two treatment groups (P = .69). The number of nights spent in the hospital, number of transfusions, and frequencies and types of hemorrhages and infections did not differ either. The cytogenetic results at diagnosis of this study in elderly AML shows that there is a relatively high numerical representation of patients with abnormal cytogenetics (55% of documented cases), who showed significantly inferior response rates and survival duration. We conclude that, except for a faster neutrophil recovery, GM-CSF during and after induction chemotherapy does not improve the clinical outcome of elderly patients with AML.

5-Aza-2'-deoxycytidine combined with either amsacrine or idarubicin has been applied in a treatment protocol for patients with a relapse of acute myeloid or lymphocytic leukemia. Sixty-three patients received 5-Aza-2'-deoxycytidine 125 mg/m2 as a 6 h infusion every 12 h for 6 days in combination with either amsacrine 120 mg/m2 as a 1 h infusion on days 6 and 7 (n=30) or idarubicin 12 mg/m2 as a 15 min infusion on days 5, 6 and 7 (n = 33). Twenty-three patients (36.5%) obtained a complete remission (CR); eight of 30 patients treated with amsacrine and 15 of 33 treated with idarubicin. Patients with an interval of more than 1 year between initial diagnosis and start of the protocol achieved CR in 51.4%, compared to 15.4% for patients with an interval of less than 1 year. Patients with normal cytogenetics had a higher CR rate (61%) than those with abnormal cytogenetic findings (15.8%). Digestive tract and hematologic toxicity was prolonged, compared to standard induction schedules. Median disease-free survival was approximately 8 months, with only 20% of patients staying in remission for more than 1 year. 5-Aza-2'-deoxycytidine is a good antileukemic agent with considerable toxicity. Current results merit further investigations in previously untreated leukemia.

The AML8A protocol of the European Organization for Research on Treatment of Cancer (EORTC) and GIMEMA Cooperative Groups studied the value of allogeneic (allo-BMT) and autologous bone marrow transplantation (autoBMT) in adult acute myelogenous leukemia (AML) when performed during first complete remission (CR). Following one or two courses of remission induction treatment, 66% of patients achieved a CR. Then 168 patients who had an HLA-identical sibling were assigned to alloBMT, while 254 were randomized for an autoBMT or for a second intensive consolidation course. Disease-free survival (DFS) of the intensive chemotherapy arm was 30% at 4 years, the DFS in the alloBMT and autoBMT arms were 55% and 48%, respectively. The two BMT arms gave significantly better results than the intensive chemotherapy arm (p = 0.03). The main reason for failure is relapse in both the autoBMT and the chemotherapy arms, while treatmentrelated mortality is higher in the alloBMT arm.

The Leukemia Cooperative Groups of the EORTC and the GIMEMA conducted a prospective randomized phase III trial, in order to assess the value of autologous BMT (ABMT) vs a second intensive consolidation course (IC2), following a common intensive consolidation course (IC1) for patients with AML. Patients with an HLA-identical sibling donor were not randomized, but were included in an allogeneic BMT (alloBMT) program. This is an analysis of prognostic factors which influence the outcome of treatment after alloBMT in first complete remission (CR). The study included 730 patients46 years of age in CR, 270 having a histocompatible sibling donor. In 169 of these patients alloBMT was performed in first CR. Early remitters (122 patients achieving CR with one course of treatment) had a DFS at 3 years of 67%, significantly longer than that of 44% for late remitters (47 patients achieving CR after more than one course of treatment) (P = 0.006). The relapse risk for early vs late remitters was 16 and 40% at 3 years (P = 0.001) and the treatment-related mortality (TRM) at 2 years was 21 vs 27%. Age appeared to be a prognostic factor for TRM, WBC for DFS, whereas the FAB classification was not of prognostic importance. Patients with poor risk cytogenetic abnormalities showed a trend towards a higher relapse risk. Patients transplanted shortly after achieving CR appeared to have a worse prognosis than those transplanted further into remission. Overall, the number of courses of induction therapy needed to achieve CR was the most important prognostic factor for outcome after allogeneic BMT.

In an attempt to reestablish normal hematopoiesis in symptomatic myelodysplasia (MDS) and to show the tolerability of a combination treatment of low-dose cytosine arabinoside (LD AraC) and interleukin-3 (IL-3), we treated 31 patients (pts., median age 65 years) who had more than 10% blasts in the bone marrow (BM) and hematopoietic failure with LD AraC (2 x 10 mg/m2 sc, day 1-14) plus IL-3 (once daily sc, day 8-21) at different dose steps (1.0, 2.5, 5.0, and 10.0 micrograms/kilogram body weight). The numbers of each 21-day cycle varied between 1 (3 pts.), 2 (6 pts.), 3 (8 pts.), 4 (1 pt.), 5 (5 pts.), and 6 (8 pts.), in total 116 cycles on an outpatient basis. Subjective tolerability was good in 20 cases (65%). Toxicities were fever (29 pts.), flu-like symptoms (17 pts.), infections (15 pts.), hepatic toxicity (10 pts.), and skin reactions (8 pts.). Overall response was seen in 13 cases (42%) and 5 complete responses (CR), while 10 pts. had stable disease (SD), 5 progressed (2 to acute leukemia), 2 were considered toxic deaths, and 1 died due to the disease. Median survival is 18 months, progression-free survival is 12.5 months (18.0 months in responding pts.), with an actuarial follow-up of 31 months. The data from this phase I/II study show that a combination of LD-AraC and IL-3 is well tolerated and that stable responses can be achieved in MDS by means of an easy outpatient therapy.

Cytokines, particularly interleukin 1 (IL-1) and tumor necrosis factor, are known to induce hypoglycemia in normal rodents or different experimental models of type II diabetes. We investigated, at the pre-diabetic stage, the effect of short-term administration of murine recombinant interleukin-1α (mrIL-1α) on the levels of glucose, insulin and corticosterone in the non-obese diabetic (NOD) mouse, a spontaneous model of type I diabetes. Two-month-old, pre-diabetic NOD mice of both sexes were insensitive to mrIL-1α (12·5 and 50 μg/kg) 2 h after administration, the time at which the maximal decrease (around 50%) was observed in the C57BL/6 mouse strain. Kinetic studies however showed that mrIL-1α lowered glycemia in both sexes of NOD mice, but the effect was limited and delayed. In the NOD and C57BL/6 strains, mrIL-1α had no influence on insulin levels in females, but significantly increased them in males (P Journal of Endocrinology (1996) 148, 139–148

The administration of a high iodide dose (HID; 10 μg/day) to goitrous mice is known to induce thyroid cell necrosis and inflammation, which, in most strains, is transient. In this study, we analyzed the effects of iodide in autoimmune prone non-obese diabetic (NOD) mice. Control NOD mice fed a standard diet (MID; 1 μg I/day) or HID did not spontaneously develop thyroiditis. In NOD mice previously made goitrous, HID provoked thyroid cell necrosis and diffuse inflammation within 4 days. Inflammatory cells consisted of MHC-class II+ antigen-presenting cells, CD4+ T helper cells and CD8+ T suppressor/cytotoxic cells. After 96 days of treatment with HID, thyroiditis similar to Hashimoto's disease was obtained in 100% of the animals, with destruction of thyroid follicles, large clusters of T and B cells, and antithyroid antibodies in the plasma. When treating goitrous mice with MID, no cell necrosis was observed and no autoimmune thyroiditis was obtained. The early iodide-induced cell necrosis and inflammation may thus be considered as an important factor in the induction and persistence of autoimmune thyroiditis in individuals carrying a genetic susceptibility to autoimmune disease. Journal of Endocrinology (1995) 147, 311–320

We conducted a prospective, multicenter pilot study of remission induction therapy in patients with poor prognosis MDS and AML evolving from a preceding phase of MDS. Fifty evaluable patients from 15 institutions were treated with one or two remission-induction courses consisting of i.v. idarubicin 12 mg/m2/day on days 1, 2, and 3 combined with a continuous i.v. infusion of cytarabine of 200 mg/m2/day on days 1 to 7. Of the 27 complete remitters (54%), 23 received a consolidation course which was identical to the remission-induction course except for the idarubicin 12 mg/m2 which was given on day 1 only. Fifteen patients received maintenance therapy consisting of six courses of cytarabine 10 mg/m2, s.c. twice daily, for 14 days. Two complete remitters were allografted and five patients received an ABMT. The median survival of all 50 treated patients was 14 months. The median duration of disease-free survival was 11 months with two patients in CR more than 2 years after entering CR. Twenty-four of the 27 remitters have relapsed. Four patients died during remission-induction therapy, but no patient died as a result of persisting hypoplasia. No fatal complications occurred during the consolidation and maintenance courses. Age and stage of disease had no significant impact on CR rate nor on remission duration. The CR rate was significantly (P = 0.03) higher in patients with only normal metaphases compared to patients with cytogenetic abnormalities. The DFS at 2 years was 33 vs 8%, respectively, for patients without or with cytogenetic abnormalities (P = 0.02). This study shows that patients below the age of 60 years with poor risk features are candidates for treatment with combination chemotherapy. A complete remission rate of more than 50% may be expected. Maintaining remission after remission-induction chemotherapy is a difficult issue. Patients not eligible for allogeneic BMT may be treated with intensive post-remission chemotherapy or autologous BMT.

Insulin-dependent diabetes mellitus (IDDM) is characterized by a progressive autoimmune destruction of pancreatic beta cells. Many data suggest that interleukin 1 (IL-1) plays a fundamental role in the pathogenesis of the disease. In the nonobese diabetic (NOD) mouse, a spontaneous model of IDDM, it was put forward that the disease is linked to a susceptibility locus, called idd5, which contains the IL-1 receptor (IL-1R) gene. The polymerase chain reaction (PCR) was used to characterize the IL-1R gene in our NOD mouse colony and in two mouse strains taken as controls. Using primers to amplify the IL-1R gene between bp-106 and +378, a 580 bp fragment was obtained from C57BL/6 DNA but not from DBA/2 and NOD DNA. However, amplification of the IL-1R gene region between bp +1 and +378 in the three strains yielded amplicons 480 bp long. The specificity of the amplification was confirmed by restriction analysis. Our results suggest, depending on the strain, the presence of one or two introns: one (480 bp) in the 5'-untranslated region and the other (100 bp) in the region coding for amino acids between 69 and 126, and an exon-intron organization of the mouse IL-1R gene different than that described in the human genome.

International audience; Numerous in vivo and in vitro studies have shown the effects of interleukin-1 (IL-1) on insulin and glucagon secretion. To understand the mechanism of these effects, we performed localization and characterization of IL-1 receptors (IL-1R) in pancreas using a quantitative autoradiography method and recombinant human (rh) [125I]IL-1 alpha as a ligand. Frozen sections of pancreas were studied in control (C3H/He) and nonobese diabetic (NOD) mice (a model of autoimmune type I diabetes). Compared to splenic IL-1R, a very high density of specific IL-1R (> 4-fold that in spleen) was found on the islets of Langerhans in both strains. In C3H/He mice, competition experiments demonstrated the presence of one high affinity binding site (Ki = 3.4 and 3.2 x 10(-10) M; binding capacity, 137 and 122 fmol/mg protein for rhIL-1 alpha and rhIL-1 beta, respectively), comparable to type I IL-1R described on T-lymphocytes. In prediabetic NOD mice, these IL-1R were expressed with the same density, affinity, and specificity as in the control strain. Before the onset of diabetes, the expression of IL-1R protein on the islet cells appears to be entirely normal. In contrast, in diabetic NOD mice, IL-1R are sharply decreased, correlating with the intensity of islet destruction. In conclusion, the localization and high density of IL-1R on the mouse islets of Langerhans complement previous studies showing the presence of messenger RNA for type I IL-1R on the islets of Langerhans. These results support a direct physiological effect of IL-1 on pancreatic hormones, such as insulin and glucagon, and a potential role of IL-1R in the pathogenesis of type I diabetes.

The existence of a physiological immunoneuroendocrine network clearly contributing to homeostasis has now been demonstrated. In this context, nervous, endocrine, and immune systems communicate with each other, using common mediators and respective receptors. An interesting aspect of this network involves the interactions between prolactin (PRL) and the immune system. Prolactin plays a significant role in regulation of the humoral and cellular immune responses in physiological as well as pathological situations, such as autoimmune diseases. This role is exerted via the existence of specific receptors on cells on the immune system. Recently, using monoclonal antibodies (mAbs) raised against the extracellular domain of the rat liver PRL-receptor (PRL-R), we demonstrated by immunochemistry and molecular biology the presence of functional PRL receptors on thymic epithelial cells, one of the major components of the thymic microenvironment, which significantly influences early events in T-cell differentiation. Furthermore, using analytical fluocytometry, we showed that human and murine lymphoid cells also expressed PRL receptors. In both of the primary lymphoid organs, namely the thymus and bone marrow, more than 80% of cells expressed this receptor. In the periphery, all B cells and macrophages and 70% of T cells, with similar percentages of CD4+ and CD8+ cells, were PRL-R+. The density of receptors was lower on T cells than on B cells and macrophages, but this density was significantly enhanced following stimulation by T cell mitogens. These data, together with the demonstration of PRL production by thymocytes led to the hypothesis that, in addition to the classical endocrine pathway, autocrine and paracrine PRL/PRL-R interactions may exist in both central and peripheral lymphoid organs, and involve lymphocytes and microenvironmental cells.

Sodium butyrate (NaBu) addition was found to increase the production of monoclonal antibodies (MAbs) by OKT3 hybridoma cells and of human Gamma-Glutamyltransferase (GGT) by recombinant CHO cells. The membrane-bound GGT enzymatic characteristics were not modified by NaBu induction. The GGT induction was tested in different culture modes with cells in aggregates or on microcarriers. Either for GGT or MAb production the cell growth state at the moment of induction appeared to be important.

Glutamate decarboxylase (GAD), especially the GAD 65 isoform, is a major autoantigen in autoimmune diabetes. To determine the role of GAD 65 in the pathogenesis of the disease, we developed a quantitative PCR method allowing to establish the absolute number of GAD 65 mRNA molecules expressed in pancreas of male and female non-obese diabetic (NOD) mice at 5 weeks of age, in comparison of the 2 non autoimmune mouse strains. It appeared that pancreatic expression of GAD was similar in the 3 strains (around 30,000 molecules/micrograms total RNA) in males. However, in the NOD mouse, sexual dimorphism was observed with low GAD 65 expression in the female known to show higher incidence of the disease than the male. This finding could contribute to the absence of GAD 65 tolerance in the female and suggests an hormonal control of GAD 65 gene expression.

(1994). EORTC-GIMEMA AML8 Protocol. A Phase III Study on Autologous Bone-Marrow Transplantation in Acute Myelogenous Leukemia (AML) Leukemia & Lymphoma: Vol. 13, No. sup1, pp. 101-101.

Acute promyelocytic leukemia (M3) is, as one of the FAB subtypes of AML, included in the EORTC/GIMEMA AML-8A and 8B randomized trials. In these trials 1519 patients were included, 477 of them in non-Italian EORTC-LCG centers and 1042 in GIMEMA centers. A total of 80 patients were classified as M3 including 18 patients with M3-variant. Thirty-nine were male and 41 female. Ages ranged from 15 to 59 years; 25 (31.3%) of them were younger than 30, 34 (42.5%) between 30 and 45, and 21 (26.3%) older than 45 years of age. 56.3% of the patients had leukocytes less than 5 x 10(9)/l at the time of diagnosis vs. 24.9% of the patients belonging to the other FAB subtypes. Remission induction consisted of a standard protocol with 3 days daunorubicin and 7 days of cytosine arabinoside. Forty-three patients (53.8%) achieved a complete remission compared to 64.6% of the remaining AML patients. After salvage treatment this percentage increased to 70%, which is the same as for the other AML subtypes. Thirteen (16.3%) patients died during remission induction, mainly due to hemorrhagic complications. This percentage is significantly higher than the death rate (9.1%) in the other FAB subtypes of AML. All patients received one course of consolidation treatment. Post consolidation treatment could be either standard maintenance, intensive consolidation courses, autologous or allogeneic transplantation, according to the guidelines of the treatment protocols. At present, relapses almost all in the bone marrow, are seen in only 34.9% of the M3 patients, compared to 48.4% in the remaining AML patients. Disease-free survival for patients less than 45 years of age with the M2 and M3 subtypes was approximately 50% at 3 years compared to 30-40% for the other FAB subtypes. Despite the higher death rate during induction, the long-term survival results were better for M3 patients in comparison with the remaining AML patients. The projected survival at 3 years was 50% for M3 patients vs. 38% for remaining patients.

With the objective to improve the cell behaviour understanding in fed-batch reactor, some detailed kinetic studies of hybridoma cultures have been realized with various feeding flow rates or medium compositions. Results indicate that if similar cell density as in the batch mode is obtained, higher Mab productivity can be reached. Moreover, an active cell metabolism is observed all over the culture with a better efficiency of medium utilization.

The evolution of the intracellular pH (pHi) is followed during hybridoma cultures in batch bioreactors, with or without control of the medium pH (pHe). The pH sensitive dye BCECF is used as a pH indicator and analysis of the cell populations is done by flow cytometry. The pHi is found to remain constant at its maximal value during the growth phase of both cultures, after an adaptation period. This value is slightly lower when the pHe is not controlled, however the pH barrier between the inside and outside of the cells is unchanged. The evolution of the pHi can be positively correlated to the evolution of the growth rate. The same relation has been observed in continuous culture. Concentrations of some ions in the medium are also followed.

Zinc is needed for growth and development, DNA synthesis, neurosensory functions, and cell-mediated immunity. Although zinc intake is reduced in elderly people, its deficiency and effects on cell-mediated immunity of the elderly have not been established. Subjects enrolled in "A Model Health Promotion and Intervention Program for Urban Middle Aged and Elderly Americans" were assessed for nutrition and zinc status. One hundred eighty healthy subjects were randomly selected for the study. Their mean dietary zinc intake was 9.06 mg/day, whereas the recommended dietary allowance is 15 mg/day. Plasma zinc was normal, but zinc in granulocytes and lymphocytes were decreased compared with younger control subjects. Of 118 elderly subjects in whom zinc levels in both granulocytes and lymphocytes were available, 36 had deficient levels. Plasma copper was increased, and interleukin 1 (IL-1) production was significantly decreased. Reduced response to the skin-test antigen panel and decreased taste acuity were observed. Thirteen elderly zinc-deficient subjects were supplemented with zinc, and various variables were assessed before and after zinc supplementation. Zinc supplementation corrected zinc deficiency and normalized plasma copper levels. Serum thymulin activity, IL-1 production, and lymphocyte ecto-5'-nucleotidase increased significantly after supplementation. Improvement in response to skin-test antigens and taste acuity was observed after zinc supplementation. A mild zinc deficiency appears to be a significant clinical problem in free-living elderly people.

The present study tested the hypothesis that inadequate Zn intake might be responsible for failure to thrive and impaired catch-up growth in young rural Gambian children, and that Zn supplements might be beneficial. Gambian children might be deprived of Zn because of its poor availability from their predominantly plant-based diet. Rural Gambian children (110; fifty boys, sixty girls) aged between 0.57 and 2.30 years were divided into two matched groups, one to receive 70 mg Zn twice weekly for 1.25 years, and the other a placebo. Growth and mid-upper-arm circumference were measured at weekly intervals throughout the study and illnesses were monitored. Capillary blood and urine samples were collected at 0, 2 and 8 weeks. Body weights and arm circumferences showed a linear increase, plus a seasonal effect (rainy season faltering). For body weight there was no significant overall effect of the supplement. For arm circumference, a very small (2 %) but significant (P < 0.01) difference favoured the supplemented group. Plasma thymulin was much lower at the first clinic than at the second and third clinics, and in vitro Zn stimulation was greater at the first clinic. There was, however, no effect of Zn in vivo. Likewise, Zn did not significantly benefit T-cell numbers or ratios, secretory IgA in urine, circulating hormone levels or biochemical indices of Zn status. One index of intestinal permeability, i.e. lactulose: creatinine, was improved (P < 0.02) by the supplement, but the lactulose: mannitol value was not; this requires further investigation. Dietary Zn deficiency is, thus, unlikely to be of major overall importance for rural Gambian children's ability to thrive, and blanket Zn supplementation is not justified. There may, however, be vulnerable sub-groups who would benefit from Zn supplements.

The potential use of thymulin levels as a sensitive and functional marker of energy deficiency was investigated in 13 obese women during a 3-week very-low-calorie diet. Mean weight loss was 8.92 +/- 0.52 kg after 21 days of treatment. The patients were free from infection as assessed by serum orosomucoid and C-reactive protein measurements. Serum albumin levels were not decreased throughout the experiment whereas transthyretin concentrations fell significantly during the first 2 weeks and remained fairly stable thereafter. Orosomucoid levels dropped only after 3 weeks of dieting. Serum zinc concentrations were within the normal range on admission and at the end of the experiment. Thymulin activity was not altered throughout the study, suggesting that this thymic hormone cannot be used as a functional marker of short-term energy restriction.

The nonobese diabetic (NOD) mouse develops an autoimmune type I diabetes, which is predominantly seen in females, is triggered by T cells, and whose frequency is enhanced following thymectomy at weaning. Attempting to characterize a thymic pathology in these animals, we analyzed the microenvironmental compartment of the organ with respect to structural and functional molecules expressed by thymic epithelial cells (TEC), as well as extracellular matrix components. We observed, in both males and females, a precocious decrease in the cell numbers of discrete medullary TEC subsets, namely, those respectively defined by the expression of cytokeratins 3/10 and cytokeratin 19. In addition, some cells bearing the TR.5 phenotype (normally restricted to the medulla) could be detected in the NOD mouse thymic cortex. There was also a significant early decrease in thymulin production in females, as compared to males. As regards the extracellular matrix compartment, the most striking alteration was the presence of abnormally enlarged perivascular spaces, increasing in size with age. In these structures large amounts of T cells and, to a lesser extent, B cells were consistently encountered. In addition to B cells, the NOD mouse thymus showed on both TEC and extracellular matrix the presence of deposits of immunoglobulins, revealed with fluorescence-labeled goat anti-mouse Ig sera. Finally, the NOD mouse sera labeled both TEC and extracellular matrix proteins on normal mouse thymus frozen sections. Together, these data clearly demonstrate that the NOD mouse thymus undergoes a variety of microenvironmental changes, whose particular role in the pathophysiology of the disease is yet to be demonstrated.

To determine the influence of the inoculum age on the kinetics of hybridoma growth and metabolism, spinner flasks have been inoculated with cells previously propagated in T flasks for 43, 52, 62 and 71 hr respectively. Increasing the age of the inoculum is found to result in a longer lag phase, in a lower maximum specific growth rate and in a reduced maximal cell density. During the growth phase specific rates of glucose and glutamine uptake and of ammonia and lactate production are similar. However, with the older inoculum, much higher metabolic activities are observed during the lag phase. The production of antibodies is delayed with increasing inoculum age, but the final antibody concentrations are similar, which indicates a higher specific antibody production rate when inoculating with older cells.

Extended Kalman Filter (EKF) is used for the on-line estimation of viable cell and monoclonal antibody (MAb) concentrations during batch and fed batch cultures of the OKT3 hybridoma cell line. A kinetic model and an experimental system are presented. The practicability of EKF is demonstrated under both cultivation modes using glucose and ammonia as observation variables. For the same process duration, the concentration of viable cells and antibodies are twice as high in the fed batch as in the batch culture.

Es werden verschiedene neue Techniken der Augenchirurgie unter Anwendung eines Picosekundenlasers gezeigt. Die Prinzipien dieser Techniken werden durch Computer-Animation dargestellt, an die sich praktische Beispiele aus der Chirurgie zu folgenden Themen anschliesen: Es wird eine mit Originalbeispielen aus der Chirurgie erganzte Computer-Animation intrastromaler Myopie- und Hyperopie-Korrekturen gezeigt. In der gleichen Weise stellt der Film die Technik der Linsenverflussigung und -aspiration ebenso wie einige posteriore Kapsulotomien dar. Eine weitere, interessante Indikation zur Anwendung dieses Lasers ist die Trabekulotomie durch partielles Entfernen des Trabekelwerks. Am Ende werden mit demselben Laser durchgefuhrte, prazise Koagulationen der Retina gezeigt.

The production of thymulin by the thymic epithelium is under complex control involving the endocrine system. Experimental models have suggested that prolactin (PRL) and growth hormone (GH) participate in this regulation but this has not been documented in humans. Using a bioassay we measured circulating thymulin levels in patients with hyperprolactinemia (n = 21), acromegaly (n = 15), or both (n = 6). Thymulin was elevated in these three groups of patients compared with normal subjects or with patients with pituitary disease but no excess in PRL or GH. Contrasting with observations in control groups, thymulin did not decrease as a function of age in patients. No correlation between thymulin and PRL or GH levels was observed while thymulin and insulin-like growth factor 1 levels were correlated. A new radioimmunoassay used in some patients for thymulin determination yielded similar results. Overall these data demonstrate that PRL and GH are involved in the hormonal control of thymulin production by the thymic epithelium in the human.