Serial determinations of asymmetric dimethylarginine and homocysteine during pregnancy to predict pre-eclampsia: a longitudinal study.

OBJECTIVE: To evaluate the usefulness of serial determinations of asymmetric dimethylarginine (ADMA) and homocysteine (Hcy) concentrations during pregnancy to predict pre-eclampsia, taking into account maternal obesity and B vitamin status. DESIGN: Longitudinal study. SETTING: Two obstetric referral hospitals. SAMPLE: Two hundred and fifty-two of 411 women invited to participate in the study. METHODS: The women made monthly visits from ≤20 weeks of gestation until delivery for measurements of plasma ADMA, Hcy, and vitamins B6 , B12, and folic acid, and for the recording of clinical information. MAIN OUTCOME MEASURE: Early elevations in plasma ADMA and Hcy related to the development of pre-eclampsia. RESULTS: Of the 252 women who completed the study, 179 had no complications, 49 developed pre-eclampsia, and 24 presented with complications other than pre-eclampsia. ADMA and Hcy increased gradually throughout pregnancy in the pre-eclampsia group, independent of maternal B-vitamin status and obesity, but remained constant in women with no complications. Relative to the preceding month, ADMA and Hcy levels increased 1 month prior to the onset of pre-eclampsia: 124 ± 27 nmol (P < 0.001) and 1177 ± 278 nmol (P = 0.001), respectively, in the pre-eclampsia group. The group of women with no complications did not show any significant changes. Increases of 80 nmol ADMA and 1000 nmol Hcy at 1 month prior to the onset of pre-eclampsia demonstrated the best potential for prediction. CONCLUSIONS: Increased ADMA and Hcy levels precede clinical manifestations of pre-eclampsia. Therefore, serial determinations of their concentrations may be helpful in identifying women at risk. TWEETABLE ABSTRACT: Increased ADMA and Hcy precede clinical pre-eclampsia and may identify women at risk.

Identification of genetic risk factors associated with ischaemic stroke in young Mexican patients.

BACKGROUND: Numerous polymorphisms in candidate genes coding for haemostatic system proteins have been proposed as risk factors for thrombosis. METHODS: We performed a case-control study of consecutive ischaemic stroke survivors aged ≤45 years, treated at our neurology department from 2006 to 2014. Polymerase chain reaction-restriction fragment length polymorphism identified the following polymorphisms: Thr325Ile and Ala147Thr in TAFI, 4G/5G in PAI-1, PLA1/A2 in platelet glycoprotein IIb/IIIa, Glu298Asp in eNOS, and C677T in 5,10-MTHFR. A multivariate logistic regression analysis was performed to evaluate the independent risk of stroke. RESULTS: 204 cases and 204 age- and sex-matched controls were included in the study. Clinical and genetic variables associated with ischaemic stroke were hypertension (P=.03), tobacco use (P=.02), and the polymorphisms Glu298Asp (genotype: P=.001, allele frequency: P=.001) and C677T (genotype: P=.01); the Ala147Thr, Thr325IIe, 4G/5G, and PLA1/A2 mutations were not associated with ischaemic stroke. The 298Asp (P=.03) and T (P=.01) alleles, hypertension (P=.03), tobacco use (P=.01) and family history of stroke (P=.04) were identified as independent risk factors. CONCLUSION: The polymorphisms Glu298Asp and C677T, affecting the eNOS and 5,10-MTHFR enzymes, respectively, and smoking, hypertension, and family history of stroke were associated with ischaemic stroke in young Mexican patients; this was not the case for the Thr325Ile, Ala147Thr, 4G/5G, and PLA1/A2 polymorphisms of the genes coding for fibrinolytic proteins and platelet receptors.

Identificación de factores de riesgo genéticos asociados a la enfermedad vascular cerebral de tipo isquémico en jóvenes mexicanos / Identification of genetic risk factors associated with ischaemic stroke in young Mexican patients

Introducción: Diversos polimorfismos en genes candidatos que codifican proteínas del sistema hemostático se han propuesto como factores de riesgo para el desarrollo de trombosis.MétodosCasos y controles, sobrevivientes de enfermedad vascular cerebral (EVC) isquémica idiopática ≤ 45 años de edad del servicio de neurología incluidos de manera consecutiva de 2006 a 2014. Por PCR-RFLP se identificaron los polimorfismos: Thr325Ile y Ala147Thr del gen de TAFI, 4G/5G del gen de PAI-1, PLA1/A2 del gen de la glucoproteína plaquetaria IIb/IIIa, Glu298Asp del gen de eNOS, y C677T del gen de la 5,10 MTHFR. Se realizó un análisis multivariado de regresión logística para calcular el riesgo independiente de EVC.ResultadosDoscientos cuatro casos y 204 controles pareados por edad y sexo. Se asoció al polimorfismo Glu298Asp (genotipo p = 0,001 y frecuencia alélica p = 0,001), C677T (genotipo p = 0,01), hipertensión (p = 0,03) y tabaquismo (p = 0,02) con la presencia de EVC isquémico, no así para los polimorfismos Ala147Thr, Thr325IIe, 4G/5G y PLA1/A2. Se identificó como factor de riesgo independiente al alelo 298Asp (p = 0,03), T (p = 0,01), hipertensión (p = 0,03), tabaquismo (p = 0,01) y AHFEAT (p = 0,04).ConclusionesLos polimorfismos Glu298Asp y C677T de los genes que codifican a la enzima eNOS y 5,10 MTHFR, tabaquismo, hipertensión y AHFEAT se asociaron a la presencia de EVC isquémico en jóvenes mexicanos, no así el Thr325Ile, Ala147Thr, 4G/5G, PLA1/A2 en genes que codifican proteínas del sistema de fibrinólisis y receptores plaquetarios. (AU)

Introduction: Numerous polymorphisms in candidate genes coding for haemostatic system proteins have been proposed as risk factors for thrombosis.MethodsWe performed a case-control study of consecutive ischaemic stroke survivors aged ≤ 45 years, treated at our neurology department from 2006 to 2014. Polymerase chain reaction–restriction fragment length polymorphism identified the following polymorphisms: Thr325Ile and Ala147Thr in TAFI, 4G/5G in PAI-1, PLA1/A2 in platelet glycoprotein IIb/IIIa, Glu298Asp in eNOS, and C677T in 5,10-MTHFR. A multivariate logistic regression analysis was performed to evaluate the independent risk of stroke.Results204 cases and 204 age- and sex-matched controls were included in the study. Clinical and genetic variables associated with ischaemic stroke were hypertension (P = .03), tobacco use (P = .02), and the polymorphisms Glu298Asp (genotype: P = .001, allele frequency: P = .001) and C677T (genotype: P = .01); the Ala147Thr, Thr325IIe, 4G/5G, and PLA1/A2 mutations were not associated with ischaemic stroke. The 298Asp (P = .03) and T (P = .01) alleles, hypertension (P = .03), tobacco use (P = .01) and family history of stroke (P = .04) were identified as independent risk factors.ConclusionsThe polymorphisms Glu298Asp and C677T, affecting the eNOS and 5,10-MTHFR enzymes, respectively, and smoking, hypertension, and family history of stroke were associated with ischaemic stroke in young Mexican patients; this was not the case for the Thr325Ile, Ala147Thr, 4G/5G, and PLA1/A2 polymorphisms of the genes coding for fibrinolytic proteins and platelet receptors. (AU)

Persistence of macroprolactinemia due to antiprolactin autoantibody before, during, and after pregnancy in a woman with systemic lupus erythematosus.

A woman with systemic lupus erythematosus (SLE) with marked increases in circulating 150-kDa PRL was studied from before conception, throughout pregnancy, and after pregnancy. The clinical features of the patient included idiopathic hyperprolactinemia without clinical symptoms such as amenorrhea and galactorrhea before pregnancy. No clinical lupus activity was present during follow-up. Serum PRL increase during pregnancy in this patient was considerably higher at weeks 27 and 33 than in normal pregnant women. In contrast, serum-free PRL levels were considerably lower at weeks 20, 27, and 33 than in normal pregnant women. A 150-kDa PRL (big big PRL) species persisted as the predominant circulating form of PRL throughout each measurement in this woman with SLE. In contrast, the predominant form of PRL in serum from healthy pregnant women was little PRL (or monomeric PRL). The nature of big big PRL was due to the presence of anti-PRL autoantibodies forming an IgG-23 kDa PRL complex, in accordance with the studies by affinity chromatography for IgG and Western blot analysis. The IgG-PRL complex was fully bioactive in vitro (Nb2 rat lymphoma cell assay). Injection of the serum into the rats demonstrated that the IgG-PRL complex was cleared more slowly than serum containing predominantly monomeric PRL. The data suggest that the IgG-PRL complex has biological activity; the absence of symptoms in this woman may be attributed to the fact that due to its large molecular weight, big big PRL does not easily cross the capillary walls. Delayed clearance may account for increased serum PRL levels in this SLE patient with anti-PRL autoantibodies.

Frequency of macroprolactinemia due to autoantibodies against prolactin in pregnant women.

The frequency of macroprolactinemia related to the presence of anti-PRL autoantibodies in the serum of 209 healthy women at different stages of pregnancy was studied. Measurements were taken of serum PRL concentrations before and after chromatographic separation (gel filtration and affinity with proteins A and G) and extraction of free PRL with polyethylene glycol (PEG). Sera from 8 of the 209 women (3.8%) were found to have a significantly high proportion of precipitated PRL by PEG (macroprolactinemia); in these patients, gel filtration showed that a substantial amount of big big PRL (molecular mass >100 kDa) was present (19.0--78.2% vs. 3.8-4.9%, P = 0.009 in normal pregnant women with a normal proportion of precipitated PRL by PEG). The presence of macroprolactinemia was attributable to anti-PRL autoantibodies in 5 of the 8 women. Comparison of serum levels of direct and free PRL between women with macroprolactinemia related to anti-PRL autoantibodies and women without macroprolactinemia showed significant differences (direct PRL: 270.2 +/- 86.9 vs. 203.4 +/- 69.0 microg/L, P = 0.04; and free PRL: 107.0 +/- 75.9 vs. 173.3 +/- 67.6 microg/L, P = 0.002). On the other hand, there was no difference between women with macroprolactinemia not related to anti-PRL autoantibodies and women with macroprolactinemia caused by anti-PRL autoantibodies, nor was there a difference between women with macroprolactinemia not related to anti-PRL autoantibodies and women without macroprolactinemia. There was a positive correlation between titers of the anti-PRL autoantibody and serum PRL levels (r = 0.82, P = 0.09). The presence of the anti-PRL autoantibody had no relation to the patient's age, stage of gestation, or number of previous pregnancies. We concluded that the frequency of macroprolactinemia was 3.8% among healthy, pregnant women, which was caused by a anti-PRL autoantibodies in 62.5% of the cases. The autoantibodies were found in the bloodstream, forming a PRL-IgG complex, in accordance with the following observations: 1) immunoreactive PRL on gel filtration was eluted in the fractions corresponding to the molecular mass of IgG (150 kDa); 2) a significantly high proportion of immunoreactive PRL was retained on an affinity gel for IgG (proteins A and G); and 3) a significantly high proportion of serum PRL bound to IgG was precipitated by protein A. There was a positive correlation between titers of anti-PRL autoantibodies and serum PRL levels. Serum levels of total PRL were higher, and serum levels of free PRL were lower, in pregnant women with anti-PRL autoantibodies than in pregnant women without macroprolactinemia.

Development of a diagnostic test for Entamoeba histolytica using idiotype expression in human.

The protozoan parasite Entamoeba histolytica is the etiological agent of human amebiasis. The pathology of the disease starts with the cytolysis of the host target cells by amoebae. It is initiated by the adhesion of trophozoites to the host cells, through surface lectin via specific receptors. These adherence lectins have been demonstrated to be highly conserved, and can be recognised by serum antibodies from patients with invasive amebiasis. Some of these molecules have been used as antigens in serologic studies, which has been very helpful in the diagnosis of invasive intestinal amebiasis. However, false-positive serologic reactivity can occur using E. histolytica extracts and purified antigens. Additional problems are because the extracts display a great enzymatic activity. Several diagnostic methods, using different molecules and techniques, have been described. However, the problem still remains since these tests are not capable of differentiating between amoebic liver abscess (ALA) and intestinal amebiasis.Here, the research has been addressed to the 66-kDa antigen, which is a part of the outer membrane proteins from the E. histolytica strain HM1-IMSS trophozoites. First of all, we characterized the 66-kDa antigen in order to prove the relevance. We found that the 66-kDa antigen is a part of the plasma membranes and is distributed rather homogeneously on the cell surface of trophozoites. Apparently, the 66-kDa antigen is a glycoprotein. Using a monoclonal antibody (MAb), we found 25% of inhibition in the erythrophagocytosis by the trophozoites. Starting form one monoclonal antibody, we prepared an anti-idiotype (anti-Id) antibody reagent, with the purpose of searching for the different expressions of the idiotype between the sera from ALA and the intestinal amebiasis patients. Moreover, we produced the antibody Ab3 that is capable of recognising the 66-kDa antigen; it means that the Ab2 displays the internal image of the antigen. We found that 91.6% of the serum from ALA patients displayed the expression of the Id. In contrast, 15.7% of the E. histolytica asymtomatic cyst carriers displayed the Id expression, 6.6% of the patients with another parasite infection, and 11% of the negative controls (serum from umbilical cords of newborn babies). Our results showed that the expression of the Id could be differentiated among the AHA patients from the other groups with a 91.6% sensibility and 88.3% specificity.

[Factors predicting survival in patients on peritoneal dialysis]. / Factores predictivos de sobrevida de pacientes en diálisis peritoneal.

OBJECTIVE: To determine the factors associated with survival in a cohort of 74 patients with end-stage renal disease (ESRD) undergoing chronic peritoneal dialysis (CPD). SETTING: The study was carried out at a general hospital of the Instituto Mexicano del Seguro Social. DESIGN: Analysis of a retrolective cohort under a nested case control design. PATIENTS AND METHODS: The variables studied included age, gender, cause of ESRD (diabetic or non-diabetic), socioeconomic status, modality of CPD (intermittent vs continuous ambulatory peritoneal dialysis), catheters per patient, rate of peritonitis, levels of serum creatinine and albumin at the beginning of the CPD. RESULTS: During a 75.1 years-patient follow up, there were 41 deaths (cases). The main cause of death was peritonitis. The cumulated survival of the 74 patients was 64%, 29% and 13% at 12, 24 and 33 months, respectively. Intermittent peritoneal dialysis, the rate of peritonitis and the level of basal serum albumin were associated with a decreased survival in a univariate analysis. Only a high rate of peritonitis was associated with an increase in mortality rate independent from other variables (p = 0.002). CONCLUSIONS: The probability of survival in ESRD in our hospital was low in relation to other nephrology departments of Mexico and other countries. A high rate of peritonitis proved to be an important independent predictor of a lesser survival rate in patients under CPD in our institution.

[Factors associated with peritoneal dialysis catheter failure in chronic renal insufficiency]. / Factores asociados a falla del catéter de diálisis peritoneal en insuficiencia renal crónica.

AIM: To determine the frequency, time of occurrence and factors associated with the failure of the permanent peritoneal catheter during dialysis in cases of chronic renal failure (CRF). MATERIAL AND METHODS: A retrospective cohort under a nested case control design was studied at a second level health care unit of the Instituto Mexicano del Seguro Social. A total of 149 catheters, double cushion straight Tenckhoff type, were evaluated in 74 patients with CRF due to diabetic nephropathy in 36/74 patients (49%). Information concerning functionality time and causes of catheter failure as well as the clinical and technical factors concerning insertion were obtained from the clinical chart. RESULTS: The cumulated time of dialysis was 814 months. Catheter failure occurred in 101 cases (68%): 67 due to obstruction, 24 due to infection, to leakage in 6 and to other causes in 4. Those of non-infectious origin were more frequent (p < 0.01). In the first month post-insertion there was a higher number of failures than after one month, (p < 0.0005). The global functionality of the catheter at one month, one and two years was 55%, 31% and 16%, respectively. There was a greater permanence of the catheters in continuous ambulatory peritoneal dialysis than in intermittent peritoneal dialysis (p = 0.02). CONCLUSIONS: It is concluded that the frequency of the peritoneal catheter failure was high; that the most frequent cause was due to non-infectious complications during the first month of insertion; and the factor associated to catheter failure was intermittent peritoneal dialysis as compared to continuous ambulatory dialysis.

[Diagnostic yield of various urine tests in urinary tract infections]. / Rendimiento diagnóstico de algunas pruebas en orina en las infecciones de vías urinarias.

OBJECTIVES: 1. To determine the value of pyuria and bacteriuria by high-power field (hpf) in centrifuged urine and of tests with reactive strips for determining leukocyte estearase activity and nitrites in the diagnosis of urinary tract infection (UTI). 2. To establish the ideal cut-off point for these tests. DESIGN: Comparative survey. SETTING: Second level health care unit of the Instituto Mexicano del Seguro Social. PATIENTS AND METHODS: A total of 105 patients were prospectively studied, with or without urinary symptoms, seen in the emergency ward. MEASUREMENTS: A clinical history and physical exploration was done in each patient. A urine sample was used for microscopic analysis for determining leukocytes and bacteria using hpf microscopy; the urine leukocytes count was assayed as well as leukocyte estearase and nitrites using reactive strips. All samples were subjected to urine culture. Urine samples were obtained using a Nelaton probe in 65% of the patients and the rest using the midstream urination technique. RESULTS: Forty patients (38%) were identified as UTI cases based on clinical and laboratory criteria (urine culture and leukocyte count). The best cut-off point for number of leukocytes was 8 per hpf and for bacteriuria it was 2+ per hpf and for leukocyte estearase it was 1+. The sensitivity, specificity and predictive values of the pyuria hpf, bacteriuria by hpf and leukocyte estearase by reactive strip were comparable. The nitrites had a lower sensitivity than the other tests (p < 0.05). The negative predictive value of the nitrites was less than the microscopic bacteriuria (74% vs 85%, p = 0.005). The combination of positive tests in leukocytes and bacteriuria increased the specificity and the positive predictive value (99% and 96% respectively) when compared to the individual tests. CONCLUSIONS: The diagnostic performance of leukocyte estearase by reactive strips was similar to the microscopy of leukocytes and bacteria but the nitrite test had a lower performance. The combination of the leukocytes and bacteriuria measured by hpf appears to be very useful in the diagnosis of UTI.

Diferencia entre la concentración de factores angiogénicos en preeclampsia e hipertensión gestacional y su relación con el resultado materno y perinatal / Differences between concentrations of angiogenic factors in preeclampsia and gestational hypertension and their relationship with adverse maternal and perinatal outcome

Resumen OBJETIVO: determinar la relación entre las concentraciones séricas de factores angiogénicos con la severidad de la preeclampsia e hipertensión gestacional y con el resultado materno y perinatal adverso. MATERIALES Y MÉTODOS: estudio transversal y comparativo efectuado en pacientes atendidas entre los meses de septiembre de 2013 y agosto de 2015 en la Unidad Médica de Alta Especialidad. La población de estudio se dividió en cinco grupos: 1) hipertensión gestacional leve, 2) preeclampsia leve, 3) hipertensión gestacional severa, 4) preeclampsia severa y 5) preeclampsia severa complicada. Además, el total de pacientes se analizó según el resultado materno o perinatal adverso. Las concentraciones séricas de sFlt-1, PlGF y su relación sFlt1/PlGF se midieron con electroquimioluminiscencia. RESULTADOS: se estudiaron 196 mujeres con embarazo único ≥ 20 semanas de gestación, con hipertensión gestacional y preeclampsia. Las concentraciones de sFlt-1, PlGF y la relación sFlt1/PlGF fueron significativamente diferentes entre los cinco grupos de estudio (p < 0.001). La diferencia en la concentración de los factores angiogénicos fue más marcada conforme mayor fue la severidad de la enfermedad hipertensiva en el embarazo (p < 0.001). La relación sFlt-1/PIGF fue significativamente mayor en las pacientes con resultado materno o perinatal adverso en comparación con quienes no lo tuvieron (222.5 vs 112.8 y 158.3 vs 53.1, respectivamente) p < 0.001. CONCLUSIÓN: conforme mayor fue la severidad de la enfermedad hipertensiva en el embarazo se observó mayor alteración en la concentración de factores angiogénicos (p < 0.001). Así mismo, la relación sFlt-1/PIG fue mayor en pacientes con resultado materno y perinatal adverso (p < 0.001).

Abstract BACKGROUND: Preeclampsia is a major cause of maternal and fetal morbidity and mortality. The loss of the balance between pro-angiogenic and antiangiogenic factors precedes the clinical presentation of preeclampsia. This alteration is greater in early and severe forms of the disease and shows association to adverse perinatal outcome. OBJECTIVE: To determine the relationship between serum concentrations of angiogenic factors and the severity of preeclampsia and gestational hypertension with the maternal and perinatal outcome. MATERIALS AND METHODS: A cross-sectional comparative study from September 2013 to August 2015 was performed in the Hospital of Gynecology and Obstetrics No. 4 IMSS Luis Castelazo Ayala. A total of 196 patients were analyzed including singleton pregnancies ≥ 20 weeks' gestation diagnosed with preeclampsia and gestational hypertension. The patients were divided in five groups: mild gestational hypertension (n = 46), mild preeclampsia (n = 20), severe gestational hypertension (n = 19), severe preeclampsia (n = 89), and severe complicated preeclampsia (n = 22). Additionally the total patients were divided in two groups: with and without adverse maternal outcome and the second group with and without adverse perinatal outcome. The serum concentration of sFlt-1, PlGF and the respective sFlt1/PLGF ratio were determinate with electrochemiluminescence. The management and timing of the termination of pregnancy was performed based on established guidelines for clinical practice. RESULTS: The serum concentration of sFlt-1, PlGF and the respective sFlt1/PLGF ratio were significant different between the 5 groups analyzed (p < 0.001). Moreover, the difference of the concentrations of angiogenic factors are closely associated with the severity of hypertensive disease of pregnancy (p < 0.001). The sFlt1/PLGF ratio was higher in those with adverse maternal and fetal outcomes compared to those who did not had (222.5 vs 112.8 and 158.3 vs 53.1 respectively) p < 0.001. CONCLUSION: Major alteration was observed in the concentration of angiogenic factors as the greater the severity of hypertensive disease in pregnancy. Likewise, the sFlt-1/PlGF ratio was higher in those with adverse maternal and perinatal outcomes compared to those who did not have. Therefore this relationship has potential use as a biochemical marker of severity and risk stratification.

Anti-prolactin autoantibodies in pregnant women with systemic lupus erythematosus: maternal and fetal outcome.

The aim of this study was to determine in pregnant women with systemic lupus erythematosus (SLE) the frequency of anti-prolactin autoantibodies and to compare the outcome of pregnancy in SLE women with and without anti-prolactin autoantibodies. Ninety-nine consecutive SLE pregnant women and 151 healthy pregnant women were studied prospectively. Patients with or without anti-prolactin autoantibodies were identified by gel filtration chromatography and affinity chromatography for IgG. Serum total and free prolactin (PRL) levels and molecular heterogeneity of PRL at each trimester of pregnancy were determined. The frequency of anti-PRL autoantibodies in SLE pregnant women was 13.1%. Serum total PRL levels were significantly higher in women with anti-PRL autoantibodies compared with SLE women without anti-PRL autoantibodies and in healthy pregnant women; and serum free PRL levels were lower in the third trimester in women with anti-PRL autoantibodies than in healthy pregnant women. In contrast, serum total and free PRL levels were significantly lower in the second and third trimester in SLE pregnant women without anti-PRL autoantibodies compared with healthy pregnant women. All adverse outcomes of pregnancy studied were more frequent in SLE women without anti-PRL autoantibodies than anti-PRL autoantibody-positive SLE women. Moreover, both maternal and fetal main complications were significantly higher in SLE women without anti-PRL autoantibodies than anti-PRL autoantibody-positive SLE women (P

Serum free prolactin concentrations in patients with systemic lupus erythematosus are associated with lupus activity.

OBJECTIVE: To determine in patients with systemic lupus erythematosus (SLE) the relationships among serum total and free prolactin (PRL) levels, isoforms of PRL and lupus activity. METHODS: In a cross-sectional study, 259 patients with SLE were tested for serum total PRL, serum free PRL, and PRL in fractions obtained after gel filtration chromatography (in 70 sera taken at random) by immunoradiometric assay based on disease activity. RESULTS: A significant correlation between direct PRL and free PRL levels was found in patients with and without lupus activity (r = 0.475, P<0.001); however, this was less so for non-active patients than for active patients (r=0.433, P<0.001 and r=0.909, P<0.001, respectively). SLE Disease Activity Index (SLEDAI) scores correlated positively with serum free PRL levels (r=0.314, P<0.001) and percentage of little PRL (r=0.33, P=0.005) and negatively with percentage of big big PRL (r=-0.3, P=0.012). Patients with active disease had higher serum free PRL levels (median 12.6 vs 9.3 ng/ml, P<0.001), higher percentages of little PRL (83.1 +/- 21.2 vs 63.6 +/- 24.8%, P=0.011) and lower percentages of big big PRL (9.4 +/- 18.0 vs 25.2 +/- 24.3%, P=0.031). Different clinical manifestations and serological parameters of lupus disease activity were more frequent in patients with free hyperprolactinaemia than in patients with normal serum free PRL levels (such as neurological manifestations, renal involvement, serositis, haematological manifestations, anti-double-stranded DNA and hypocomplementaemia; P<0.021). CONCLUSION: An increase in serum free PRL levels, higher percentages of little PRL and lower percentages of big big PRL proved to be factors related to lupus activity in a subset of patients with SLE. These novel data must be taken into account in future studies aiming to establish a relationship between PRL and disease activity in SLE.

Association between prolactin and disease activity in systemic lupus erythematosus. Influence of statistical power.

OBJECTIVE: To analyze the statistical power of studies in the medical literature on the relationship between prolactin (PRL) and systemic lupus erythematosus (SLE) activity. METHODS: Published studies that were identified through MEDLINE search, as well as references from these articles, were reviewed. RESULTS: We identified 5 articles that sought to establish a relationship between PRL and SLE activity. In 4 of them, the frequency of hyperprolactinemia in SLE (>20 ng/ml) was 2.2-47.2%, and in one article, there was a relationship between PRL and SLE activity. A power analysis of individual studies could be carried out in only 2 of the 5; there were no significant effects; the 2 articles cited differences in the frequency of hyperprolactinemia in patients with and without lupus activity (1.6 and 12.3%, respectively), but because of a low power of the studies (> or =30.8%), it could not be determined whether the differences in the frequency of hyperprolactinemia were significant. On the other hand, joint analysis of 3 articles showed a significant association between hyperprolactinemia and lupus activity. CONCLUSION: Published clinical results concerning the relationship between PRL and Jupus activity are contradictory, due in part to the statistical power of the studies. Our analysis of these studies showed that PRL is related to lupus activity, without establishing a formal causal relationship.

Analysis of anti-prolactin autoantibodies in systemic lupus erythematosus.

Evidence has shown that prolactin is an essential component of an effective immune response. In systemic lupus erythematosus, clinical trials have produced controversial information about the role of PRL. Some results find association between serum PRL levels and disease activity. In contrast, other authors did not find this. Recently, autoantibodies against prolactin in SLE patients have been described. One hundred percent of SLE patients with anti-PRL autoantibodies had hyperprolactinemia (hPRL) and 31.7% of the SLE patients classified with idiopathic hPRL had anti-prolactin antibodies. A similar result was found in 103 pediatric SLE patients. The patients with idiopathic hyperprolactinemia and anti-PRL autoantibodies had less clinical and serological lupus activity than the SLE patients with idiopathic hyperprolactinemia, but without anti-PRL autoantibodies. This evidence suggests that anti-PRL autoantibodies or the complex with any other molecule, like macroprolactinemia (big-big PRL) could have attenuated biological activity and this could explain why some clinical studies did not find any association between serum PRL levels and disease activity in SLE patients. However, studies in vitro have shown normal or elevated biological activity in Nb2 cell lines using PRL from serum with anti-PRL autoantibodies from patients with or without autoimmune diseases. Several conclusions could be drawn. One is that while a set of hyperprolactinemic SLE patients display autoantibodies against PRL, it is not clear what role these autoantibodies play in the whole system. However, until now, we knew that the patients with antibodies to PRL lacked the clinical symptoms of hyperprolactinemia such as menstrual disturbances and/or galactorrhea and show less clinical and serological lupus activity.

Biologic activity and plasma clearance of prolactin-IgG complex in patients with systemic lupus erythematosus.

OBJECTIVE: To characterize the clinical findings in hyperprolactinemic systemic lupus erythematosus (SLE) patients with or without macroprolactinemia (big, big prolactin [PRL]) due to anti-PRL autoantibodies (PRL-IgG complex), and to assess the bioactivity and structure of big, big PRL. METHODS: Twenty-seven SLE patients with hyperprolactinemia (HPRL) were studied. Patients with (n = 8) or without (n = 19) big, big PRL were identified by gel filtration chromatography and affinity chromatography for IgG. PRL concentrations in serum and fractions by gel filtration chromatography and affinity chromatography were characterized by immunoradiometric assay (IRMA), Nb2 bioassay, sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting, and clearance studies. RESULTS: SLE patients without big, big PRL had significantly higher levels of disease activity, cause-proven HPRL, and menstrual disturbances compared with patients with big, big PRL (P < or = 0.05). The big, big PRL fractions by Western blotting revealed a single 23-kd nonglycosylated PRL. The Nb2:IRMA ratio of the samples with big, big PRL was significantly higher than that of the samples without big, big PRL (P < or = 0.02). However, bioactivity of big, big PRL in the Nb2 cells was very similar to that of 23-kd nonglycosylated PRL. Clearance studies in rats demonstrated that the PRL-IgG complex was eliminated more slowly than monomeric PRL (little PRL). CONCLUSION: We demonstrated that the PRL-IgG complex was formed by 23-kd nonglycosylated PRL that was noncovalently bound to IgG and showed that the complex was fully active in vitro. This result suggests that the absence of symptoms of HPRL or lower levels of lupus activity in these patients is not explained by lower bioactivity of the complex. Instead, because of the large molecular size of the complex, the PRL does not easily cross the capillary walls. Delayed clearance of the PRL-IgG complex may account for increased serum levels of PRL in SLE patients with anti-PRL autoantibodies.

Detection of macroprolactinemia with the polyethylene glycol precipitation test in systemic lupus erythematosus patients with hyperprolactinemia.

The objective of this study was to determine the diagnostic performance of the percentage of serum prolactin (PRL) precipitated with polyethylene glycol (PEG) for the detection of macroprolactinemia in systemic lupus erythematosus (SLE) patients with hyperprolactinemia. Serum samples from SLE patients were examined. Serum PRL was measured by immunoradiometric assay (IRMA) and samples with hyperprolactinemia (> 20 ng/ml) were submitted to PEG precipitation, gel filtration chromatography and affinity chromatography with protein-G sepharose. A comparative survey was used. Among 259 consecutive serum samples from SLE patients, PRL was > 20.1 ng/ml in 43 samples (16.6%). Gel filtration showed a predominant pattern of macroprolactinemia (> 100 kDa) in 14 (32.6%), a predominant pattern of monomeric PRL (23 kDa) in 27 (62.7%), and a variable pattern in two (4.7%). All sera with a predominant pattern of macroprolactinemia displayed anti-PRL autoantibodies by affinity chromatography for IgG. The best cut-off point for percentage of serum PRL precipitated with PEG for detection of macroprolactinemia was > or = 58.4%. Sensitivity and specificity were 100 and 96.6%, respectively. We can conclude that PEG precipitation is a convenient and simple procedure to screen for the presence of macroprolactinemia in sera from SLE patients. Precipitations > or = 58.4% are indicative of the presence of, and those < 50% the absence of, macroprolactinemia. However, samples with precipitations between 50 and 58.3% require gel filtration chromatography to characterize the predominant molecular form of PRL. Therefore, it is important to take these findings into account in future studies that aim to establish a relationship between PRL and disease activity in SLE.

Antiprolactin autoantibodies in systemic lupus erythematosus: frequency and correlation with prolactinemia and disease activity.

OBJECTIVE: To determine in patients with systemic lupus erythematosus (SLE) (1) the frequency of antiprolactin (anti-PRL) autoantibodies, and (2) the relationships among anti-PRL autoantibodies, serum prolactin (PRL) levels, and lupus activity. METHODS: In a cross sectional study 259 consecutive patients with SLE were tested for serum PRL levels and anti-PRL autoantibodies based on disease activity. RESULTS: The frequency of anti-PRL was 5% (13/259), and all SLE patients with anti-PRL had hyperprolactinemia. There was lupus activity in 110 patients (42.5%) and there was no significant difference in frequency of anti-PRL autoantibodies between patients with or without lupus activity (5.5 vs 4.7%; p = 0.99). Only a high level of serum PRL was associated with lupus activity independent from other studied variables (p = 0.024). There was a negative but nonsignificant correlation between the titers of anti-PRL autoantibody and SLEDAI (r(s) = -0.16, p = 0.59). Anti-PRL positive patients had higher levels of serum PRL than anti-PRL negative patients (33.2+/-13.8 vs 11.6+/-13.2 ng/ml; p = 0.0001) and a significantly different frequency of hyperprolactinemia (100 vs 11.4%; p = 0.00001). CONCLUSION: The presence of anti-PRL autoantibodies was associated with hyperprolactinemic status and high serum PRL levels; these data suggest that anti-PRL autoantibodies could be the cause of hyperprolactinemia in a subset of patients with SLE. An increase in serum PRL levels proved to be an important independent factor related to lupus activity, but there was no relationship between anti-PRL autoantibodies and lupus activity.

Anti-prolactin autoantibodies in paediatric systemic lupus erythematosus patients.

The aim of this study was to determine the frequency of anti-prolactin autoantibodies and the relationship among anti-prolactin autoantibodies, serum prolactin (PRL) levels and lupus activity in paediatric patients with systemic lupus erythematosus (SLE) using a transversal study. One-hundred and three consecutive paediatric SLE patients were tested for serum anti-PRL autoantibodies and PRL levels. Clinical disease activity was scored using the SLEDAI index. Anti-PRL autoantibodies were measured by means of gel filtration. The frequency of anti-PRL autoantibodies was 6.7% (7/103), on the basis of the amount of immunoreactive PRL eluted in molecular weight fraction corresponding to IgG (150 kDa). No anti-PRL autoantibodies were found in normoprolactinaemic patients. By contrast, 21.8% (7/32) hyperprolactinaemic patients (hPRL) had anti-PRL autoantibodies. There was a correlation between anti-PRL autoantibody and serum levels of PRL (r(s) = 0.98, P = 0.0001). Lupus activity was present in 64/103 (62.1%) patients, without a significant difference in the frequency of anti-PRL autoantibodies when compared to inactive lupus (7.8 vs 5.1%, P > 0.05). Higher levels of serum PRL were associated with lupus activity regardless of other variables (39.6% vs 17.9%, P = 0.05). Patients with anti-PRL autoantibodies had higher levels of serum PRL than those without anti-PRL autoantibody (41.85 vs 17.77 ng/ml, P = 0.01) and significantly different frequency of hPRL (100 vs 26%, r = 0.4531, P < 0.001). We have identified a subset of paediatric SLE patients with hPRL and anti-PRL autoantibodies. Anti-PRL autoantibodies were associated with hPRL state and antibody titres correlated positively with serum PRL levels. These data suggest that anti-PRL autoantibodies could be responsible for hPRL in a subset of SLE patients. An increase in serum PRL levels proved to be related to lupus activity, but there was no statistical relationship between anti-PRL autoantibodies and lupus activity.

[Prolactin as an immunomodulator]. / Prolactina como inmunomodulador.

The aim of this revision is to explore the possible role of the prolactin in the immune response. The prolactin is a hormone secreted by the pituitary. However, it has a trophic function in the proliferation of the lymphocytes. The cell of the immune system show outer membrane receptor for the prolactin. Moreover, the lymphocytes are capable to produce and secret prolactin. In cell culture, different levels of prolactin show different immune responses- low levels of prolactin awake a weak immune response. In contrast, high levels of prolactin show a strong immune response. Alteration in the sera levels of prolactin has been describes in severe autoimmune disease like systemic lupus erythematosus. Reiter syndrome, adjuvant arthritis, uveitis etc. Until now many evidences has been reported about the roles of the prolactin in the immune response acting like an immunomodulator, but the relevance of this phenomena in the clinical practice is still unclear.