Predicting the onset of major depression in primary care: international validation of a risk prediction algorithm from Spain.

BACKGROUND: The different incidence rates of, and risk factors for, depression in different countries argue for the need to have a specific risk algorithm for each country or a supranational risk algorithm. We aimed to develop and validate a predictD-Spain risk algorithm (PSRA) for the onset of major depression and to compare the performance of the PSRA with the predictD-Europe risk algorithm (PERA) in Spanish primary care. METHOD: A prospective cohort study with evaluations at baseline, 6 and 12 months. We measured 39 known risk factors and used multi-level logistic regression and inverse probability weighting to build the PSRA. In Spain (4574), Chile (2133) and another five European countries (5184), 11 891 non-depressed adult primary care attendees formed our at-risk population. The main outcome was DSM-IV major depression (CIDI). RESULTS: Six variables were patient characteristics or past events (sex, age, sex×age interaction, education, physical child abuse, and lifetime depression) and six were current status [Short Form 12 (SF-12) physical score, SF-12 mental score, dissatisfaction with unpaid work, number of serious problems in very close persons, dissatisfaction with living together at home, and taking medication for stress, anxiety or depression]. The C-index of the PSRA was 0.82 [95% confidence interval (CI) 0.79-0.84]. The Integrated Discrimination Improvement (IDI) was 0.0558 [standard error (s.e.)=0.0071, Zexp=7.88, p<0.0001] mainly due to the increase in sensitivity. Both the IDI and calibration plots showed that the PSRA functioned better than the PERA in Spain. CONCLUSIONS: The PSRA included new variables and afforded an improved performance over the PERA for predicting the onset of major depression in Spain. However, the PERA is still the best option in other European countries.

Effect of IL-2 and IL-6 on parameters related to metastatic activity in a murine melanoma.

Previous results have shown that the metastatic colonization with B16F10 melanoma in vivo increased after in vitro treatment of the cells with IL-2 or IL-6. To further investigate the mechanisms underlying this effect, we have studied adhesion, invasion, and proliferation properties of B16 melanoma, using two sublines with different metastatic ability. Adhesion of tumor cells to Matrigel coats increased using IL-6, which also induced upregulation of VLA-4 expression in both sublines. Unexpectedly, invasion through Matrigel filters was almost completely inhibited by IL-6 and decreased in the presence of IL-2. Cell growth was not affected by these interleukins; however, IL-6 could partially overcome the proliferation blockade induced by stress conditions. Taken together, these results suggest that upregulation of adhesion properties and/or the protective effect induced by IL-6 could account for the enhancement of metastasis exerted by this interleukin.

Interleukin-2 enhances the growth of human melanoma cells derived form primary but not from metastatic tumours.

Previously, we demonstrated that in vitro treatment of B16F10 murine melanoma cells with interleukin-2 (IL-2) enhances proliferation and metastasis. To further investigate the role played by IL-2 in human melanomas, we studied the expression of IL-2/IL-2 receptor and the effect of IL-2 on the proliferation of melanoma cell lines derived from primary (A375 and RMS cell lines) and metastatic (Hs294T cell line) tumours. We found a constitutive expression of cytoplasmic IL-2 and alpha, beta and gamma-subunits of the IL-2R on the surface of the three melanoma cell lines. The presence of IL-2 in the culture increased the proliferation rate in A375 and RMS cell lines, but no effect was observed in Hs294T metastatic cells. Biologically active IL-2 could be found in the supernatant of the three melanoma cell lines, particularly in A375 and RMS cells, in which an inhibition of the proliferation rate was observed when IL-2 was blocked. Moreover, the combination of anti-IL-2R beta and anti-IL-2R gamma blocking antibodies induced a significant down-regulation of cell proliferation in the three melanoma cell lines, and the combination of anti-IL-2R alpha, anti-IL-2R beta and anti-IL-2R gamma blocking antibodies inhibited IL-2-mediated growth stimulation in A375 and Hs294T cell lines. In RMS cells, a more significant effect was observed when only IL-2R gamma was blocked. Finally, exogenous IL-2 modulated the IL-2 endogenously produced by melanoma cells. These data show that IL-2 may modulate the growth of melanoma cells through autocrine or/and paracrine mechanisms.

Soluble interleukin-2 receptor, intercellular adhesion molecule-1 and interleukin-10 serum levels in patients with melanoma.

Serum soluble interleukin-2 receptor (sIL-2R), intercellular adhesion molecule-1 (sICAM-1) and interleukin-10 (IL-10) have each been reported as useful markers for melanoma progression. To evaluate the clinical relevance of these three markers, we simultaneously analysed their serum levels in patients with melanoma. A longitudinal study with a 3-year follow-up was performed and different stages of the disease were considered. Mean values of sIL-2R were significantly higher than in normal controls in all stages and correlated with the disease progression. The prognosis of patients with levels > 529 U/ml of sIL-2R was significantly poorer than in patients with sIL-2R levels < 529 U/ml. Levels of sICAM-1 were also elevated in melanoma patients, specially at the time of the metastatic disease. Serum IL-10 levels were more frequently detectable in the patients that developed metastasis during follow-up, and the prognosis of patients with detectable IL-10 levels was significantly poorer than in those patients with IL-10 undetected levels. Statistical analysis based on Logistic and Cox regression models showed that only sex, stage and sIL-2R value are factors significantly associated with metastatic progression. Moreover, high levels of sIL-2R could be a risk factor for malignant progression in melanoma.

[Acute myeloid leukemia in those over 70 years of age. Experience using low-dose ara-C treatment]. / Leucemia mieloide aguda en mayores de 70 años. Experiencia utilizando tratamiento con Ara-C a bajas dosis.

PURPOSE: The treatment of elderly patients with acute myeloid leukaemia (AML) remains controversial. We present the results of the treatment of a group of patients aged above 70 years with AML diagnosed in our Hospital since 1990. PATIENTS AND METHODS: We have studied retrospectively the cases of AML in patients older than 70 years diagnosed in our Service since January 1990 to June 1996. Induction treatment was performed, in all cases but one, with two cycles of Ara-C 10 mg/m2/12 h s.c. for 21 days and after haematological recuperation, if complete remission had been achieved, monthly maintenance treatment with Ara-C (25 mg/m2/12 h oral x 5 days), prednisone (40 mg/m2/day x 5 days) y vincristine (1 mg/m2 i.v. x 1 day) was begun. RESULTS: During the period of study 48 patients with AML have been diagnosed in our Service, among them 22 (45.8%) were older than 70 years. One of them could not be considered for the study as not all data from him could be compiled. Among the other 21 patients 5 presented previous haematological processes (4 myelodysplastic syndrome and 1 Waldenström's macroglobulinemia). Initial diagnosis according to FAB classification for AML was as follows: 7 M1, 6 M2, 4 M4, 2 M5 and 2 M6. From these 21 patients 2 received no treatment due to rapid progression and death, among the other 19, one was directly treated with a modification of the maintenance treatment with vincristine and prednisone without response (survival 2 months). The other 18 patients were treated with low-dose Ara-C (described above), among them 3 (16.7%) were not evaluable as they did not finish the first cycle of induction treatment; 8 (44.4%) showed no response; 2 (11.1%) achieved partial remission and 5 (27.8%) complete remission. One patient did not show any response after two cycles of low-dose Ara-C but she obtained complete remission when treated with Ara-C and idaurubicin. Overall mean survival was 5.7 months (median 2; 95% confidence interval 1.6-9.8 months). In the group of patients treated with low-dose Ara-C mean survival was 6.6 months (median 3.5; 95% confidence interval 1.9-11.2 months). CONCLUSION: We consider that the treatment with low-dose Ara-C is a valid option in the treatment of elderly patients (aged 70 or above) with AML because 28% complete remissions can be achieved, specially in those ones in which other more aggressive treatments are not possible.

Cyclosporin A upmodulates the alpha-subunit of the interleukin-2 receptor and the metastatic ability of murine B16F10 melanoma cells.

In the present study, the effect of in vitro cyclosporin A (CsA) treatment on IL-2R expression and the metastatic behavior of B16F10 melanoma cells has been reported. CsA treatment was found to increase the percentage of B16F10 cells expressing the alpha-subunit of IL-2R on the cell surface and also at the mRNA level. Moreover, CsA treated B16F10 cells also express the beta-subunit of IL-2. In vivo experiments showed that CsA increases the affinity of B16F10 metastazing cells for the liver and decreases that for the lung. CsA modulated the expression of MHC class I and class II antigens, but no significant differences in the resistance of CsA-treated B16F10 cells to NK lysis were observed. Finally, proliferation of B16F10 cells in the presence of several doses of CsA did not vary and CsA increased the amount of IL-1beta mRNA expression. These results suggest that CsA, through the modulation of cytokines and MHC antigen expression on B16F10 cells, could have an effect upon the metastatic progression of the B16F10 melanoma.

Serum-soluble IL-2 receptor and IL-6 levels in patients with melanoma.

Elevated soluble IL-2 receptor (sIL-2R) and IL-6 serum concentrations have been reported as adverse prognostic factors in several types of cancer. In order to determine whether these factors are predictive of metastatic progression in melanoma, sIL-2R and IL-6 levels were measured in sera from 172 patients with melanoma and 60 in healthy controls. Mean sIL-2R values were significantly higher in the patients than in normal controls and the highest values were observed in those that developed metastasis during follow-up. However, no correlation was found with the stage of the disease. Serum IL-6 levels were found to be correlated with age and sex, but not correlated with sIL-2R levels. Statistical analysis was based on logistic and Cox regression models. The factors considered were age, sex, stage, disease-free interval and serum sIL-2R and IL-6 levels. The analysis showed that only the sIL-2R value is significantly linked to metastatic progression. This finding suggests that high serum levels of sIL-2R could be a predictive factor of metastatic progression in malignant melanoma.

IL-2 treatment of B16F10 melanoma cells stimulates metastatic colonization in the liver.

We had previously shown that murine B16F10 melanoma cells express the receptor for IL-2, transcribe the gene for IL-2 and respond to its factor by increasing their proliferation. In the present work we have investigated the effect of in vitro IL-2 treatment on the metastatic ability of B16F10 cells. In vivo experiments showed that the metastatic colonization of the liver was notably higher after intrasplenic inoculation of IL-2-treated cells. However, no change was observed when cells were intravenously inoculated. In vitro, cells became more resistant to NK lysis although the cytometric analysis of class 1 MHC molecules revealed a decrease in H-2Kb expression. In contrast IL-2 induced a two fold increment in the expression of la antigen. On the other hand slot-blot analysis showed that IL-2 gene expression could be upregulated, however no free IL-2 was released into the culture medium of B16F10 cells. We conclude that IL-2 increases the ability of B16F10 cells to metastase to the liver. The increase in the resistance to NK activity and in la antigen expression could be involved in the mechanisms underlying this effect.

[Comparative study of the stability of oral anticoagulant treatments (warfarin vs acenocoumarol)]. / Estudio comparativo de la estabilidad del tratamiento anticoagulante oral (warfarina versus acenocumarol).

PURPOSE: To compare the stability of the effect of two oral anticoagulants, one of them (acenocoumarol) with a short half life and the other one with a long half life (warfarin) in patients in the stable phase of treatment (at least 2 months with treatment before entering the study). PATIENTS AND METHODS: During a year period (January-December 1993) a comparative study of two groups of 53 patients each was performed: group 1 patients were treated with warfarin and group 2 with acenocoumarol. Both groups were paired with respect to age, sex, diagnosis for anticoagulant therapy and desired therapeutic range (INR 3-4.5). The mean value of controls per patient, the dosage changes, the evolutive controls and the incidence of haemorrhagic and thromboembolic episodes were studied. RESULTS: The controls performed in group 1 were 728 in total with a mean value of 13.74 per patient and 800 in group 2 with a mean value of 15.09 per patient. A change in the dosage was performed in 214 controls in patients of group 1 and in 269 of group 2. Seventeen patients had 38 haemorrhagic episodes (2 major and 36 minor) in group 1, and 6 of group 2 had 20 episodes (2 major and 18 minor). Significant differences were observed in the mean value of controls (p = 0.04), the evolutive controls (p < 0.001), the global incidence of haemorrhages (p = 0.008) and incidence of minor ones (p = 0.006). No significant differences in dosage were observed. In both groups no thromboembolic episodes during the period of study were reported. CONCLUSIONS: Anticoagulant treatment with warfarin is more stable than with acenocoumarol. The total controls and the mean value of controls per patient are decreased. Nevertheless with warfarin we have observed a greater incidence of haemorrhagic episodes.

B16F10 murine melanoma cells express interleukin-2 and a functional interleukin-2 receptor.

In this study, we analyzed interleukin-2 (IL-2) and IL-2 receptor (IL-2R) expression in murine B16F10 melanoma and studied the effect of recombinant IL-2 (rIL-2) on the proliferation of these cells. Flow cytometry analysis revealed the presence of the IL-2R alpha subunit in B16F10 melanoma, with a mean positivity rate of 30%. Using confocal microscopy, the expression of this chain could be visualized on the surface of B16F10 cells and in intracellular compartments when the cells were permeabilized with ethanol. In addition to the alpha subunit, the IL-2R beta subunit was also expressed in B16F10 cells as shown by reverse transcription and polymerase chain reaction analysis. The functionality of the IL-2R on B16F10 cells was shown by the fact that cell proliferation increased dose-dependently with the addition of rIL-2 to the culture medium. We also detected expression of the IL-2 gene in B16F10 cells. In Northern blot assays, a typical band of 0.9 kb corresponding to IL-2 mRNA was observed, although supernatants from B16F10 cultures had no detectable IL-2 activity. Furthermore, the addition of neutralizing antibody (anti-IL-2) to cell cultures had no effect on cell proliferation. From these results, we concluded that an IL-2 signalling system is present in murine B16F10 melanoma cells and that IL-2 favors B16F10 cell proliferation, suggesting a role for this cytokine in the tumoral activity of these cells.

[Treatment with oral anticoagulants (acenocoumarol): influence of the initial doses in the incidence of hemorrhagic and thromboembolic episodes]. / Tratamiento con anticoagulantes orales (acenocumarol): influencia de la dosis inicial en la incidencia de episodios hemorrágicos y tromboembólicos.

PURPOSE: To compare two initial doses of oral anticoagulant (acenocoumarin) studying the haemorrhagic and thromboembolic episodes occurred during the first month of treatment, the mean time and necessary controls until achievement of the desired level of anticoagulation. PATIENTS AND METHODS: From january 1992 to december 1993; a comparative study of two groups of patients was performed: group 1, compiling 129 patients chosen at random and retrospectively, who begun oral anticoagulant treatment with 4 daily mg of acenocoumarin; and group 2, compiling 129 patients chosen prospectively, who begun with 2 mg daily. In both groups the mean time and the number of controls performed until achieving the desired level of anticoagulation were analyzed, as well as the haemorrhagic episodes occurred during the first month of treatment, their severity (classified into major and minor ones), the level of anticoagulation when they occurred and their possible causes. In the same way the thromboembolic processes occurred during that period in both groups were studied. RESULTS: The mean time necessary to achieve the desired level of anticoagulation was 3.8 days in group 1 and 6.3 in group 2; the mean number of controls performed in group 1 was 1.2 and in group 2 it was 1.8. We have observed 19 haemorrhagic episodes, 15 in group 1 (4 minor and 11 major); and 4 in group 2 (2 minor and 2 major). We have found significant differences with respect to the mean time (p < 0.01), number of controls (p < 0.01) and incidence of hemorrhages (p = 0.017) between groups 1 and 2. One thromboembolic episode was registered in each group: in group 1 a deep venous thrombosis and in group 2 a stroke. CONCLUSION: The initial daily doses of acenocoumarin of 2 mg is as effective as the 4 mg one in the prevention of thromboembolic episodes, with a significant reduction in the number of haemorrhages observed during the first month of treatment. However this produces a prolongation in the necessary mean time and more number of controls performed until the achievement of the desired level of anticoagulation.

[Human recombinant erythropoietin in the treatment of myelodysplastic syndromes anemia. Meta-analytic study]. / Eritropoyetina recombinante humana en el tratamiento de la anemia de los síndromes mielodisplásicos. Estudio metaanalítico.

PURPOSE: To study the usefulness of different published epidemiological and analytic parameters to decide the treatment with human recombinant erythropoietin (rHuEPO) of anaemic patients with myelodysplastic syndromes (MDS). PATIENTS AND METHODS: We have revised 10 published series compiling 115 patients, studying age, sex, initial diagnosis, route of administration and posology, criteria of response, duration of the study, dosis with the response was obtained, response according to initial diagnosis, duration of responses, and effect of the treatment on other hematopoietic series. We have made a comparison between responders and non-responders based on epidemiological and analytical parameters. RESULTS: We have compiled 115 patients with a rate of global response of 23.5%. We have not found significative differences between the route (s.c. or i.v.) or frequency of administration, however the number of responses was higher when rHuEPO was administered three times weekly. A great variability in the criteria of response was observed among the different studies. Most of studies have a duration of three months but we have observed significative differences in the number of responses when the study is longer. We have not found significative differences between responders and non-responders with respect to age, sex, used dosis, transfusional dependency and degree of transfusional dependency, basal serum erythropoietin, time since diagnosis, transfusional period, haemoglobin level among non-transfusion dependent patients and haemoglobin level among transfusion dependent patients. We have found significative differences with respect to initial diagnosis, a higher rate of responses was observed in the refractory anaemia with excess of blasts (RAEB) group. We have not found a higher rate of transformations into acute myeloid leukaemia (AML) among these patients. The effects of the treatment on other haematopoietic series can be considered as anecdotical. CONCLUSION: The different epidemiological and analytic parameters published up to now are not useful in the decision of including an anaemic patient with MDS in the treatment with rHuEPO. Those patients with RAEB can be benefited with the treatment with rHuEPO. The concomitant use of other cytokines could improve these results.

A laboratory model of canine leishmaniasis: the inoculation of dogs with Leishmania infantum promastigotes from midguts of experimentally infected phlebotomine sandflies.

Twenty-five dogs (beagles) were infected with Leishmania infantum by the intradermal inoculation of an estimated 5-8,000 metacyclic promastigotes harvested from the midguts of 320 experimentally infected P. perniciosus. Details are given of the methods of infecting the flies and harvesting the parasites. All dogs developed small, self-healing chancres at the sites of inoculation. Parasites were isolated from lymph nodes, bone marrow or spleen of 21 dogs, 12 of which developed signs of disease and raised IFAT litres to Leishmania. Nine of the 21 remained healthy over a five-year observation period. Six of the nine were shown to have a cell mediated immune response to Leishmania. No parasites were isolated from four of the 25 dogs, two of which had a demonstrable cell mediated immunity and another had low transitory IFAT titres. The fourth had chancres at the sites of inoculation. The results show that dogs can be readily infected with promastigotes from the midguts of sandflies. However, a high proportion develop a cell mediated immunity and show on signs of disease. It is suggested that serological surveys of dogs for canine leishmaniasis reveal neither the true prevalence of infection nor the intensity of transmission. The efficacy of controlling human visceral leishmaniasis caused by L. infantum by destroying seropositive dogs is questioned.

[Lymphoma of the ocular adnexa]. / Linfomas de los anexos oculares.

Ocular adnexa are rarely involved in lymphomas. Four cases are reported of lymphoma involving the ocular adnexa. In two cases a previous systemic involvement existed or simultaneous to the ocular involvement; another patient had systemically a different histological pattern to that observed in the ocular region, and the fourth patient only had ocular region, and the fourth patient only had ocular symptoms; we therefore recorded two cases of primary ocular lymphoma. The lymphoma was located at the orbit in two cases and at the conjunctiva in the other two cases; the condition was bilateral in three cases. The most common symptom was exophtalmus; other major symptoms were diplopia and disturbances in ocular motility. The histological examination revealed three low grade lymphomas and one case of intermediate grade. Management of patients included radiotherapy and different chemotherapeutic regimens with a good response in all cases. A higher ocular relapse rate was observed in those patients with systemic involvement; in one primary case the condition resolved spontaneously. A review of the literature on clinical, diagnostic and therapeutic issues is made.

Enhancement of Ia antigen expression and nonproliferating cells correlates with metastatic capacity.

Maintaining B16F10 tumor cells in stirring culture for 48 h leads to an increase in lung and liver colonizing capacity in comparison with cells in adherent culture. Parallel to the increased metastatic capacity, we have observed a decrease in the proliferative rate of tumor cells (as the percentage of proliferating cell nuclear antigen-positive cells) and an increase in the population of tumor cells expressing Ia antigen. These results are not exclusive to B16F10 cells, since the same results were obtained when we analyzed 3LL cells maintained in identical culture conditions. In all the tumor lines tested, we found an association between the nonproliferating and the Ia-positive cell populations. We induced Ia expression by treating B16F10 cells in adherent culture with the lectin concanavalin A and again, coincident with an increase in metastatic capacity, we found the same association between the two parameters analyzed--nonproliferating state and Ia antigen expression. In addition, it was found that B16F10 cells induce lymphocytic proliferation, and a direct relationship was established between the number of Ia+ cells and lymphocytic proliferation.

[Hemorrhagic complications in patients treated with oral anticoagulants]. / Complicaciones hemorrágicas en pacientes en tratamiento anticoagulante oral.

PURPOSE: We have studied the haemorrhagic episodes occurred in patients treated with oral anticoagulants, with special reference to their type, frequency and severity and analyzing the risk factors that could influence in their production. PATIENTS AND METHODS: We carried out a retrospective study in 435 patients of the haemorrhagic episodes occurred since January 1989 to December 1991, determining in each one the prothrombin time expressed as INR, the time from the beginning of treatment, the patient's age and the known or underlying pathologies that could predispose to haemorrhage; depending on their severity these episodes were classified as moderate and major. RESULTS: We observed 50 haemorrhagic episodes in 50 patients (11.5%) which represents 7 x 100 patient/years, 30 (6.8% of the total patients or 4.2 x 100 patient-years) were moderate and 20 (4.5% of the total patients or 2.8 x 100 patient/years) were major. The mean age in patients with haemorrhage was 50.5 years. The incidence of hemorrhages in the first month of treatment was 60.8 x 100 patient/years; 9.4 x 100 patient/years in the period from the first month to the first year of treatment; and 3.6 x 100 patient/years in the period from the first year of treatment. The most frequent type of haemorrhage among the moderate ones was haematuria (46%) and among major ones digestive haemorrhages (26%). Depending on the coagulation level, 37 patients (66%) were within therapeutical range. Depending on patients' sex, the incidence was 23 (46%) males and 27 (54%) females. We observed at risk predisposing factors hypertension (18%), stroke (12%), hepatic disease (8%) and myocardial infarction (8%). CONCLUSION: We have found no relationship between haemorrhagic episodes and patients' age or sex. The risk of haemorrhage is higher at the beginning of the treatment and increases with the level of anticoagulation, which makes the beginning of treatment with lower doses more desirable, increasing them progressively until the desired level is achieved. Previous hypertension, stroke, hepatic disease and myocardial infarction are factors predisposing to haemorrhage.

[Chronic neutrophilic leukemia associated with myeloma. Simultaneous presentation]. / Leucemia neutrofílica crónica asociada a mieloma. Presentación simultánea.

A case of chronic neutrophilic leukaemia associated with multiple myeloma is reported. The patient had a 6 months history of bruising and weight loss, and showed mature neutrophilic leukocytosis, hepatosplenomegaly, high neutrophil alkaline phosphatase score, hyperuricaemia, neutrophils with pseudotoxic granulation and scarce Döhle bodies; moreover, a monoclonal IgG lambda was detected amounting 57.3 g/L. The bone marrow was grossly hypercellular with marked myeloid hyperplasia and aggregates of immature plasma cells. After treatment during 1 year with melphalan and prednisone she is well, although persisting with neutrophilic leukocytosis, slight splenomegaly, and the monoclonal IgG decreased to 25.8 g/L.