Plasma cytokines as potential biomarkers of kidney damage in patients with systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus is a heterogeneous chronic inflammatory autoimmune disorder characterized by an exacerbated expression of cytokines and chemokines in different tissues and organs. Renal involvement is a significant contributor to the morbidity and mortality of systemic lupus erythematosus, and its diagnosis is based on renal biopsy, an invasive procedure with a high risk of complications. Therefore, the development of alternative, non-invasive diagnostic tests for kidney disease in patients with systemic lupus erythematosus is a priority. AIM: To evaluate the plasma levels of a panel of cytokines and chemokines using multiplex xMAP technology in a cohort of Colombian patients with active and inactive systemic lupus erythematosus, and to evaluate their potential as biomarkers of renal involvement. RESULTS: Plasma from 40 systemic lupus erythematosus non-nephritis patients and 80 lupus nephritis patients with different levels of renal involvement were analyzed for 39 cytokines using Luminex xMAP technology. Lupus nephritis patients had significantly increased plasma eotaxin, TNF-α, interleukin-17-α, interleukin-10, and interleukin-15 as compared to the systemic lupus erythematosus non-nephritis group. Macrophage-derived chemokine, growth regulated oncogene alpha, and epidermal growth factor were significantly elevated in systemic lupus erythematosus non-nephritis patients when compared to lupus nephritis individuals. Plasma eotaxin levels allowed a discrimination between systemic lupus erythematosus non-nephritis and lupus nephritis patients, for which we performed a receiver operating characteristic curve to confirm. We observed a correlation of eotaxin levels with active nephritis (Systemic Lupus Erythematosus Disease Activity Index). Our data indicate that circulating cytokines and chemokines could be considered good predictors of renal involvement in individuals with systemic lupus erythematosus.

Evaluation of the burden of migraine on the partner's lifestyle.

BACKGROUND: Despite the number of research studies regarding the individual burden of migraine, few studies have examined its impact on the patients' partners. We aim to assess migraine effects on the patients' partners on sentimental relationship, children relationship, friendship, and work, as well as the caregiver burden, anxiety and/or depression. METHODS: A cross-sectional observational study was conducted through an online survey of partners of patients with migraine followed-up in 5 Headache Units. Questions about the 4 areas of interest and 2 scales (Hospital Anxiety and Depression Scale and Zarit scale) were included. Scores were compared against the population prevalence. RESULTS: One hundred and fifty-five answers were analysed. Among the patient's partners 135/155 (87.1%) were men, with a mean age of 45.6 ± 10.1 years. Migraine's main effects on partners were observed in the sentimental relationship and items concerning children and friendships, with a minor impact at work. Partners showed a moderate burden (12/155 = 7.7% [4.1%-13.1%]), and a higher moderate-severe anxiety rate (23/155 = 14.8% [9.6%-21.4%]), and similar depression rate (5/155 = 3.2% [1.1%-7.3%]) compared to the National Health Survey. CONCLUSIONS: The burden of migraine impacts the partners' personal relationship, childcare, friendship and work. Moreover, certain migraine partners showed a moderate burden according to Zarit scale and higher anxiety levels than the Spanish population.

Thanatophoric dysplasia type II with encephalocele and semilobar holoprosencephaly: Insights into its pathogenesis.

Thanatophoric dysplasia (TD) is a lethal form of short-limb skeletal dysplasia that is associated with macrocephaly, and variably cloverleaf skull. Two types of TD are clinically recognized, TD1 and TD2, mainly distinguished by their radiographic characteristics. The differences between the two are principally observed in the femur, which appears curved in TD1, while it remains straight but with a proximal medial spike in TD2, and are a less severe overall affectation in TD2. Both types of TD are caused by mutations in different functional domains of the FGFR3 gene. However, whereas several mutations in the different domains of FGFR3 cause TD1, the K650E mutation involving the change of a lysine to glutamic acid ("Lys650Glu") has been found in all TD2 cases to date. Here we describe a newborn infant with TD2 associated with brain defects that have either been infrequently observed (encephalocele) or not hitherto described (holoprosencephaly). Based on recent studies, we consider encephaloceles described in TD to be pseudoencephaloceles, since they are secondary to the intracranial pressure generated by severe hydrocephaly and to severe cranial structural anomalies. Finally, to analyze the mechanisms of holoprosencephaly observed in the case described here, we include a concise review on the current understanding of how FGFs and their receptors are expressed in the rostral signaling center (particularly Fgf8). In addition, we evaluated recent observations that FGF ligands and receptors (including FGFR3) act in concert to organize the whole telencephalon activity, rather than independently patterning different areas.

Application of matrix solid-phase dispersion to the determination of amitrole and urazole residues in apples by capillary electrophoresis with electrochemical detection.

A new method based on matrix solid-phase dispersion (MSPD) extraction was studied for the extraction of amitrole (3-amino-1,2,4-triazole), and its metabolite urazole (3,5-dihydroxy-1,2,4-triazole), in apple samples. The influence of experimental conditions on the yield of the extraction process and on the efficiency of the cleanup step was evaluated. Determination was carried out by capillary electrophoresis (CE) with electrochemical detection, demonstrating the compatibility between MSPD and CE techniques. The method has been successfully applied to different apple varieties. Recoveries in samples spiked at 1.6 and 1.7 microg g(-1) for amitrole and urazole were 88 and 82%, respectively. The limits of detection were 0.4 microg g(-1) for both compounds using electrochemical detection.

Obesity and the polycystic ovary syndrome.

The polycystic ovary syndrome (PCOS) is a mostly hyperandrogenic disorder and is possibly the most common endocrinopathy of premenopausal women. The primary defect in PCOS appears to be an exaggerated androgen synthesis and secretion by the ovaries and the adrenal glands. In a substantial proportion of PCOS patients, the primary defect in androgen secretion is triggered by factors such as the hyperinsulinism resulting from insulin resistance and/or the secretion of metabolically active substances by visceral adipose tissue, because these factors may facilitate androgen synthesis at the ovaries and the adrenals of predisposed women. The prevalence of obesity in PCOS patients is increased when compared to the general female population and, conversely, the prevalence of PCOS is increased in overweight and obese women when compared to their lean counterparts. Obesity exerts a major impact on the PCOS phenotype, particularly on the metabolic associations and complications of the syndrome. Among others, the presence obesity is clearly related to the infertility of PCOS, and increases the risk for the metabolic syndrome and its constellation of cardiovascular risk factors in these women. This review will summarize the pathophysiological mechanisms underlying the association of obesity and PCOS, the impact of obesity on the PCOS phenotype and on the association of PCOS with metabolic disorders and cardiovascular risk factors, and the new developments in the management of obese PCOS patients.

Determination of amitrole and urazole in water samples by capillary zone electrophoresis using simultaneous UV and amperometrical detection.

In this paper, capillary zone electrophoresis with amperometric detection (CZE-AD) was first applied to the simultaneous separation and determination of amitrole and urazole in water samples. A simple end-column electrochemical detector was used in combination with a commercially available capillary electrophoresis instrument with UV detection. The effects of several important factors were investigated to find optimum conditions. A carbon disk electrode was used as working electrode. Separation and determination of these compounds in water samples were performed in 0.030 mol l(-1) acetate buffers at pH 4.5, 25 kV as separation voltage and the samples were introduced by hydrodynamic mode for 1.5 s. Most of the studies realized showed that the direct electrochemical detection is more sensitive and selective than UV detection. Under the optimum conditions, excellent linearity was observed between peak amperometric signal and analyte concentrations in the range of 0.19-1.35 mg l(-1) for amitrole and 0.20-1.62 mg l(-1) for urazole. The detection limits were 63 and 68 microg l(-1) for amitrole and urazole, respectively. The utility of this method was demonstrated by monitoring water samples, and the assay results were satisfactory. The detection limits using a previous preconcentration step for amitrole and urazole in spiked mineral water samples were 0.6 and 1.0 microg l(-1) for amitrole and urazole, respectively.

Congenital eye malformations: clinical-epidemiological analysis of 1,124,654 consecutive births in Spain.

We analyzed Spanish Collaborative Study of Congenital Malformations (ECEMC) data on a series of 1,124,654 consecutive births to study congenital eye malformations from an epidemiological standpoint. We studied their frequencies as well as some causal and clinical aspects. Four hundred fourteen infants had eye malformations, for an overall prevalence of 3.68/10,000 newborns. Most frequent were: anophthalmia/microphthalmia (21.34/100,000), congenital cataract (6.31), coloboma (4.89), corneal opacity (3.11), and congenital glaucoma (2.85). In our data, the tendency of eye malformations to be associated with other congenital abnormalities is evident (only 21.01% of cases were isolated). Eye defects are heterogeneous, since we have observed them in clinical patterns with all modes of inheritance or caused by different environmental agents. Chromosomal syndromes represent 60% of total syndromes, followed by syndromes of autosomal-recessive inheritance (15%), environmental syndromes (10%), autosomal-dominant syndromes (5.83%), and other types which have a lower frequency. Regarding defects associated with eye malformations, most frequent are limb anomalies (affecting 59.3% of multiply malformed cases), auricular/facial (47.1%), central nervous system (42.5%), osteomuscular excluding limbs (42.2%), genital defects (30.6%), oral clefts (29.4%), and the rest of the body systems, which are less frequent. Using the method outlined by Prieto and Martínez-Frías [1996: Am J Med Genet 62:61-67], it was demonstrated that the association of coloboma and anophthalmia/microphthalmia was specific, as was the combination of cataract and anophthalmia/microphthalmia, and that of anophthalmia/microphthalmia with holoprosencephaly. From these statistical associations some pathogenetic relationships in human embryos can be inferred, supporting several previously proposed mechanisms.

Preaxial polydactyly of feet in infants of diabetic mothers: epidemiological test of a clinical hypothesis.

Using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), we tested the hypothesis of Carey et al. (Proc Greenwood Genet Cent 9:95, (1990) on maternal diabetes and preaxial polydactyly of feet in infants born to diabetic mothers. Our results seem to confirm their suggestion, although the hallucal type of preaxial polydactyly that they described seems to be much less frequent. Nevertheless, a high risk exists (OR = 24.60, P = 0.0004) for preaxial polydactyly of the feet in relation with other types of birth defects or postaxial polydactyly. This analysis shows the importance of clinical observations for epidemiologists, because such observations constitute hypotheses and provide actual issues for study, and clinicians will get epidemiological confirmation for their individual observations and hypotheses.

Anal atresia, vertebral, genital, and urinary tract anomalies: a primary polytopic developmental field defect identified through an epidemiological analysis of associations.

Anal atresia (AA) is observed per se or as part of different Mendelian or chromosomal syndromes, and as part of the VACTERL primary developmental field, CHARGE association, cloacal extrophy, in a mitochondrial cytopathy, and other multiple congenital anomaly patterns. There are only a few studies on the defects associated with AA, and in all of them it was observed that genitourinary defects are most frequent in infants with AA. Here we present the analysis of 28,410 malformed infants to study the frequency of 11 selected congenital defects in infants with AA in relation to their frequency in infants with multiple congenital anomaly patterns without AA. We conclude that the association of AA + spine defects + renal/urinary tract defects + genital defects constitutes a group of defects that tends to be present together in the same child because they are pathogenetically related, and since they are of blastogenetic origin they constitute a primary polytopic developmental field defect.

Clinical/epidemiological analysis of congenital anomalies associated with diaphragmatic hernia.

Several studies have been published on congenital diaphragmatic hernia (CDH), either as an isolated defect or as part of a multiple congenital anomaly (MCA) pattern. Here we present an epidemiological study designed to measure the association between CDH and a group of 17 selected congenital anomalies in an attempt to identify groups of specific defect patterns. This analysis was done using the data from the Spanish Collaborative Study of Congenital Malformations (ECEMC).

Pathogenetic classification of a series of 27,145 consecutive infants with congenital defects.

We studied a series of 27,145 consecutive infants with congenital defects and classified them into the currently recognized pathogenetic types of errors of morphogenesis, as defined by the International Working Group [Spranger et al., 1982: J Pediatrics 1:160-165]. Of all infants with congenital defects, 97.94% had malformations, 3.92% deformations, and 1.65% disruptions. Malformations associated with deformations were present in 3.12% of children with congenital anomalies, malformations with disruptions in 0.18%, deformations with disruptions in 0.07%, and malformations with deformations and disruptions in 0.14%. While deformations, including deformation sequences, were 2.38 times more common than disruptions and disruption sequences, isolated disruptions (1.27%) were more frequent than isolated deformations (0.59%). Knowledge of the frequencies of the different types of errors of morphogenesis (malformations, deformations, disruptions, developmental field defects, associations, complexes, unrecognized patterns of multiple congenital anomaly, and syndromes) may be of great value in the evaluation of patients with congenital anomalies.

Body stalk defects, body wall defects, amniotic bands with and without body wall defects, and gastroschisis: comparative epidemiology.

The presence of body wall defects with "evisceration" of thoracic and/or abdominal organs associated with other congenital anomalies, with or without limb deficiencies, is considered to be the body wall complex (BWC). The BWC is different from gastroschisis, which is usually a small body wall defect lateral to the umbilical cord that is not covered by any membrane and, in most of the cases, is an isolated defect. For the present analysis we separated the BWC group into three subgroups. One group was that of body stalk anomalies characterized by severe defects of the abdominal wall with absence of, or very small, umbilical cord, or this is continuing with the placenta. The second group was made up of those infants with body wall defects without amniotic bands, and the third group was of those children with body wall defects produced by amniotic bands. We considered two additional groups in the analysis, one was of infants with gastroschisis and the other those infants with amniotic bands without body wall affectation. We also included the control group (nonmalformed infants) for comparisons. From the results of our epidemiological study, we can conclude that amniotic bands with body wall affectation and amniotic bands without body wall defects are two different entities. The results also suggest that the characteristics of infants with amniotic bands with body wall defects are more similar to the group of infants with body stalk anomalies. This may indicate that the former group is produced during the very early gestation.

Epidemiological evidence that maternal diabetes does not appear to increase the risk for Down syndrome.

In 1997, Narchi and Kulaylat, studying the incidence of Down syndrome in infants of gestational diabetic mothers, concluded that maternal diabetes increases the risk for Down syndrome, but failed to control the maternal age in their analysis. Using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), we analyzed the relationship between Down syndrome and maternal diabetes mellitus, and maternal gestational diabetes, controlling the maternal age through the pair-matching analysis, stratifying by maternal age and logistic regression analysis. The analyses show that maternal age is related either to Down syndrome as well as to both types of maternal diabetes. Thus, the overall analysis could be confounded by maternal age. Once we controlled the maternal age, the risk of maternal diabetes mellitus for Down syndrome is: odds ratio (OR) = 0.92 (0.41-2.07); P = 0.83. Controlling maternal age in gestational diabetes, the risk is OR = 1.18 (0.61-2.35); P > 0.70. Based on our results, we conclude that Down syndrome is related to maternal age, but does not seem to be related to any type of maternal diabetes.

Analysis of deformations in 26,810 consecutive infants with congenital defects.

Here we present the analysis of deformations observed in a series of 26,810 consecutive infants with congenital defects. We observed that 3.88% of these infants had deformations, for a prevalence figure of 0.07% live-born infants. From the present study we can conclude that there are three different types of deformation sequences: one with polyhydramnios, thin skin without dermal ridges, hypotonia, and multiple deformations (hypokinesia sequence), which is most often due to intrinsic problems; another with oligohydramnios, redundant thick skin, and multiple deformations, which can be produced by intrinsic or extrinsic factors; and the third, with normal amniotic fluid volume, which is due to compression of different causes. Deformations of extrinsic cause are more frequently isolated defects and have a better prognosis, while deformations of intrinsic origin are more frequently associated with other congenital anomalies and, generally, have a poor prognosis.

Epidemiological aspects of Mendelian syndromes in a Spanish population sample: I. Autosomal dominant malformation syndromes.

Using a sample of 710,815 liveborn infants throughout Spain, monitored from April, 1976, to December, 1988, by the Spanish Collaborative Study of Congenital Malformations (ECEMC), we estimated the prevalence of each recognized autosomal dominant malformation syndrome for a total prevalence figure of 12.1 per 100,000 live births, including all detected autosomal dominant malformations syndromes. We estimated that the mutation rate for those syndromes was 48.5 per 1,000,000 gametes. The geographical distribution of these syndromes was homogeneous in the Spanish Regions.

Epidemiological aspects of Mendelian syndromes in a Spanish population sample: II. Autosomal recessive malformation syndromes.

From April, 1976, to December, 1988, the Spanish Collaborative Study of Congenital Malformations (ECEMC) monitored a total population of 710,815 liveborn infants in 16 of 17 Spanish Regions and identified 14,439 (2.0%) with congenital defects. Among the malformed children, we identified 73 with well recognized autosomal recessive syndromes, for an overall prevalence rate of 10.3 per 100,000 livebirths and a total carrier frequency of 1/49. Considering the Spanish Regions (Comunidades Autónomas), we analyzed the geographical distributions of these syndromes that were homogeneous. We studied the place of birth of the grandparents to determine the distribution of the gene as well as the gene flow.

Short rib-polydactyly syndrome (SRPS) with anencephaly and other central nervous system anomalies: a new type of SRPS or a more severe expression of a known SRPS entity?

We describe two patients with short rib-polydactyly syndrome (SRPS) from two unrelated Spanish families. These patients present clinical and radiological characteristics that overlap those of the different established types of SRPS. In addition, one patient had anencephaly and the other patient had severe brain abnormalities with a family history of an older sister with anencephaly, and a brother diagnosed with SRPS. This second family is interesting in that the two affected brothers present with different clinical and radiological findings; for example, one had ovoid tibiae and the other did not. This particular family shows that intrafamiliar variation is also observed within SRPS. It remains unsettled whether these cases might be considered a new type of SRPS or a variant of an established entity or whether the differences between the SRPS represent variability or heterogeneity. Molecular studies may answer this question in the near future.