[Auto-immune encephalitis in psychiatric practice]. / Auto-immune encefalitis in de psychiatrische praktijk.

BACKGROUND: Our knowledge about auto-immune limbic encephalitis is increasing rapidly and it is now evident that patients with this disease can present with psychiatric symptoms. AIM: To propose practical guidelines for the recognition and diagnosis of an underlying auto-immune limbic encephalitis in patients with acute psychiatric symptoms. METHOD: We studied recent reviews on the topic and had discussions with psychiatrists, a neurologist and a neuroimmunologist in order to reach consensus. RESULTS: Auto-immune limbic encephalitis is a rather rare but important diagnostic consideration in patients with acute psychiatric symptoms. We describe the different steps in the diagnostic work-up and mention features that can point to an underlying auto-immune encephalitis. These include atypical psychiatric symptoms, seizures, movement disorders and autonomic instability. CONCLUSION: Since patients with autoimmune limbic encephalitis often present with psychiatric symptoms, curative treatment is often available and the prognosis depends on the delay from presentation to treatment, psychiatrists should be aware of the signs of an underlying autoimmune encephalitis which have been described in this article.

[Auto-immune disorders as a possible cause of neuropsychiatric syndromes]. / Auto-immuunaandoeningen als mogelijke oorzaak van neuropsychiatrische syndromen.

BACKGROUND: Changes that occur in the behaviour of voltage-gated ion channels and ligand-gated receptor channels due to gene mutations or auto-immune attack are the cause of channelopathies in the central and peripheral nervous system. Although the relation between molecular channel defects and clinical symptoms has been explained in the case of many neuromuscular channelopathies, the pathophysiology of auto-immunity in neuropsychiatric syndromes is still unclear. AIM: To review recent findings regarding neuronal auto-immune reactions in severe neuropsychiatric syndromes. METHOD: Using PubMed, we consulted the literature published between 1990 and August 2014 relating to the occurrence of auto-immune antibodies in severe and persistent neuropsychiatric syndromes. RESULTS: Auto-antibodies have only limited access to the central nervous system, but if they do enter the system they can, in some cases, cause disease. We discuss recent findings regarding the occurrence of auto-antibodies against ligand-activated receptor channels and potassium channels in neuropsychiatric and neurological syndromes, including schizophrenia and limbic encephalitis. CONCLUSION: Although the occurrence of several auto-antibodies in schizophrenia has been confirmed, there is still no proof of a causal relationship in the syndrome. We still have no evidence of the prevalence of auto-immunity in neuropsychiatric syndromes. The discovery that an antibody against an ion channel is associated with some neuropsychiatric disorders may mean that in future it will be possible to treat patients by means of immunosuppression, which could lead to an improvement in a patient's cognitive abilities.

A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis.

Double-seronegative myasthenia gravis (dSN-MG, without detectable AChR and MuSK antibodies) presents a serious gap in MG diagnosis and understanding. Recently, autoantibodies against the low-density lipoprotein receptor-related protein 4 (LRP4) have been identified in several dSN-MG sera, but with dramatic frequency variation (∼2-50%). We have developed a cell based assay (CBA) based on human LRP4 expressing HEK293 cells, for the reliable and efficient detection of LRP4 antibodies. We have screened about 800 MG patient sera from 10 countries for LRP4 antibodies. The overall frequency of LRP4-MG in the dSN-MG group (635 patients) was 18.7% but with variations among different populations (range 7-32.7%). Interestingly, we also identified double positive sera: 8/107 anti-AChR positive and 10/67 anti-MuSK positive sera also had detectable LRP4 antibodies, predominantly originating from only two of the participating groups. No LRP4 antibodies were identified in sera from 56 healthy controls tested, while 4/110 from patients with other neuroimmune diseases were positive. The clinical data, when available, for the LRP4-MG patients were then studied. At disease onset symptoms were mild (81% had MGFA grade I or II), with some identified thymic changes (32% hyperplasia, none with thymoma). On the other hand, double positive patients (AChR/LRP4-MG and MuSK/LRP4-MG) had more severe symptoms at onset compared with any single positive MG subgroup. Contrary to MuSK-MG, 27% of ocular dSN-MG patients were LRP4 antibody positive. Similarly, contrary to MuSK antibodies, which are predominantly of the IgG4 subtype, LRP4 antibodies were predominantly of the IgG1 and IgG2 subtypes. The prevalence was higher in women than in men (female/male ratio 2.5/1), with an average disease onset at ages 33.4 for females and 41.9 for males. Overall, the response of LRP4-MG patients to treatment was similar to published responses of AChR-MG rather than to MuSK-MG patients.

A novel method for making human monoclonal antibodies.

We have developed a B cell immortalization method for low B cell numbers per well using simultaneous B cell stimulation by CpG2006 and B cell infection by Epstein-Barr virus (EBV), followed by an additional CpG2006 and interleukin-2 (IL-2) stimulus. Using this method, immunoglobulin G (IgG)-producing immortalized B cell lines were generated from peripheral blood IgG(+)CD22(+) B cells with an efficiency of up to 83%. Antibody can already be obtained from the culture supernatant after 3-4 weeks. Moreover, clonality analysis demonstrated monoclonality in 87% of the resulting immortalized B cell lines. Given the high immortalization efficiency and monoclonality rate, evidence is provided that no further subcloning is necessary. An important application of this B cell immortalization method is the characterization of (autoreactive) antibodies from patients with autoimmune disease. This could eventually lead to the identification of new autoantigens, disease markers or targets for therapy.

Epidemiological Characteristics of the Largest Kidney Transplant Program in Mexico: Western National Medical Center, Mexican Institute of Social Security.

BACKGROUND: According to the National Transplant Center (CENATRA), in 2013, a total of 2707 transplantations were performed in Mexico; of them, 10% (270 transplantations) were done in our Tertiary Care Hospital (Western National Medical Center). This means that one in 10 transplant recipients undergoes transplantation at our medical center. The aim of our study was to describe the characteristics of and to compare changes in the kidney transplantation program over time. MATERIALS AND METHODS: This was a cross-sectional study. Data were collected from the hospital transplant registry from January 1994 to December 2014. RESULTS: During the study period, 3643 kidney transplantations were conducted; most were living donor 3236 (89%), and only 407 patients (11%) received a graft from a deceased donor. Of living donors, 2786 (87%) were related, and 450 (13%) were genetically unrelated. The average recipient age was 28 years, and the average age of the donor was 34 years. It was observed that siblings donated more frequently (51%), followed by parents (34%). Among unrelated donors, spouses donated the most (66%). In 80% of cases, the cause of end-stage renal disease (ESRD) was unknown (80%). The most frequent renal replacement therapy was peritoneal dialysis (54%), followed by hemodialysis (18%); only 5% of patients received preemptive kidney transplant. The most frequent immunosuppression scheme was tacrolimus, mycophenolate mofetil, and prednisone in 70% of patients. CONCLUSION: The Western National Medical Center is the largest kidney transplantation program in Mexico. The main activity is living donor transplantation. Recipients are relatively young persons with unknown etiology of ESRD.

Titin antibodies in "seronegative" myasthenia gravis--A new role for an old antigen.

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction of skeletal muscles. Triple-seronegative MG (tSN-MG, without detectable AChR, MuSK and LRP4 antibodies), which accounts for ~10% of MG patients, presents a serious gap in MG diagnosis and complicates differential diagnosis of similar disorders. Several AChR antibody positive patients (AChR-MG) also have antibodies against titin, usually detected by ELISA. We have developed a very sensitive radioimmunoprecipitation assay (RIPA) for titin antibodies, by which many previously negative samples were found positive, including several from tSN-MG patients. The validity of the RIPA results was confirmed by western blots. Using this RIPA we screened 667 MG sera from 13 countries; as expected, AChR-MG patients had the highest frequency of titin antibodies (40.9%), while MuSK-MG and LRP4-MG patients were positive in 14.6% and 16.4% respectively. Most importantly, 13.4% (50/372) of the tSN-MG patients were also titin antibody positive. None of the 121 healthy controls or the 90 myopathy patients, and only 3.6% (7/193) of other neurological disease patients were positive. We thus propose that the present titin antibody RIPA is a useful tool for serological MG diagnosis of tSN patients.

[Infantile spinal atrophy: our experience in the last 25 years]. / Atrofia muscular espinal: revisión de nuestra casuística en los últimos 25 años.

OBJECTIVES: To determine the incidence of spinal muscular atrophy (SMA) in our study population and genetic distribution and epidemiological and clinical characteristics and to analyze the level of care and development. MATERIAL AND METHOD: Retrospective descriptive study of patients treated in our hospital in the past 25 years (from 1987 to early 2013), with a clinical and neurophysiological diagnosis of SMA. RESULTS: A total of 37 patients were found, representing an incidence for our reference population and year of 1 case per 10,000 live births. Males predominated (male/female ratio: 1.6/1). The type of SMA diagnosed more frequently was, type i (26 cases), followed by type ii (9 cases), one case with SMA type iii, and one case of spinal muscular atrophy with respiratory distress type 1 (SMARD1). The most frequent genetic alteration was homozygous deletion of exons 7 and 8 of SMN1 gene in 31 cases, while five patients had atypical genetics. The median survival for type i was 8.0 months and 15.8 years for type ii. CONCLUSIONS: The incidence in our population remains stable at around 1/10.000. Most cases presented with, predominantly male, typical genetics. In approximately 1/10 patients the genetic alteration was different from the classical one to the SMN gene. The prevalence of AME unrelated SMN gene was 1/37. The level of care has increased in line with social and welfare demands in recent years.

MuSK autoantibodies in myasthenia gravis detected by cell based assay--A multinational study.

Seronegative myasthenia gravis (MG) presents a serious gap in MG diagnosis and understanding. We applied a cell based assay (CBA) for the detection of muscle specific kinase (MuSK) antibodies undetectable by radioimmunoassay. We tested 633 triple-seronegative MG patients' sera from 13 countries, detecting 13% as positive. MuSK antibodies were found, at significantly lower frequencies, in 1.9% of healthy controls and 5.1% of other neuroimmune disease patients, including multiple sclerosis and neuromyelitis optica. The clinical data of the newly diagnosed MuSK-MG patients are presented. 27% of ocular seronegative patients were MuSK antibody positive. Moreover, 23% had thymic hyperplasia suggesting that thymic abnormalities are more common than believed.

Infection by human parvovirus B19: "gloves and socks" papular purpuric syndrome.

Human parvovirus B19 is the cause of erythema infectiosum a benign and self-limited infection, but sometimes the virus causes an acute and self-limiting dermatosis. It consists of a edema and erythema of the hands and feet in a gloves and sock distribution and is associated with oral lesions and fever. We report a case of a "gloves and socks" infection by human parvovirus B19.

Supraependymal cell clusters in the rat hypothalamus.

The fine structure of supraependymal cell clusters of the median eminence was studied with TEM. The cluster cells were identified on the basis of ultrastructure and histochemical determination of glial fibrillar acidic protein (GFA). The phagocytic properties were also studied by means of intraventricular injections of HRP. Neurons, neuroglia cells and degenerating ependyma- and glial cells were found. The extrusion of degenerating infundibular elements into the ventricle is a constant phenomenon but its precise localization and intensity are variable. The close proximity of the clusters to capillary loops is stressed. Because of the broken ependyma at the neck of the cluster, the permeability of the infundibular lining for HRP is increased. Clusters may be seen as sites lacking a brain--CSF barrier.

[Inflammation and infection in stable coronary disease and acute coronary syndrome]. / Inflamación e infección en la enfermedad coronaria estable y en el síndrome coronario agudo.

OBJECTIVE: To study whether inflammation and infection are related to coronary artery disease. DESIGN: Sixty patients (44 males, mean age 62 +/- 13 years) with acute coronary syndrome and 40 with stable coronary artery disease (31 males, age 64 +/- 10 years) and a control group of 40 individuals (34 males, 53 +/- 5 years) were analyzed. IgG against Chlamydia pneumoniae, Cytomegalovirus and Helicobacter pylori plus C-reactive protein were assessed in all serum samples. In addition, IgM against C. pneumoniae and Cytomegalovirus on admission and C-reactive protein one month later were measured in acute patients. RESULTS: No IgM seropositivity was observed. A high prevalence of IgG seropositivity with no significant differences among the groups was found: C. pneumoniae: acute group 44 (73%), stable group 29 (73%) and control group 25 (63%); Cytomegalovirus: 55 (92%), 37 (92%) and 38 (95%), respectively; and H. pylori, 43 (72%), 32 (80%) and 34 (85%) respectively. There was a high rate of positive C-reactive protein in the acute group: 48 (80%) vs 10 (25%) the stable group and 0% the control group (p < 0.001). C-reactive protein levels were higher in Q-wave infarction than in unstable angina/ non-Q-wave infarction (median 22.65 vs 7.69, p < 0.001). One month later, C-reactive protein levels decreased (median 22.65 vs 3.38, p < 0.001), but were still positive in 40%. CONCLUSIONS: These data suggest that inflammation is detected by the commonly used methods in clinic practice in acute coronary syndromes and to a lesser extent in stable coronary artery disease. It seems that different mechanisms other than infection account for this inflammatory response, at least this being so when infection is assessed by serology. Serology does not appear to be an adequate method to determine the possible relationship among coronary syndromes, infection and inflammation.

[Hemolytic anemia due to cold-reacting antibodies: association with human immunodeficiency virus infection and non-Hodgkin's lymphoma]. / Anemia hemolítica por anticuerpos fríos: asociación a infección por el virus de la inmunodeficiencia humana y linfoma no hodgkiniano.

Hemolytic disease by cold-reacting antibodies is a rare form of hemolytic anemia. In most cases a subjacent cause is found. This disease is generally related with reactive lymphoproliferative processes (infections by the Epstein-Barr virus and cytomegalovirus) or uncontrolled lymphoproliferative disorders (lymphomas, Waldenström disease, chronic lymphatic leukemia). The presence of high titers of cryoagglutinins have recently been described in patients infected by the human immunodeficiency virus (HIV); however, clinical manifestation as hemolytic anemia is very rare. A 37 year old male diagnosed with infection by HIV, non Hodgkin's lymphoma of Burkitt type non convoluted cells, chronic hepatopathy by the B and C virus, Brouet type III cryoglobulinemia and hemolytic anemia by cold-reacting antibodies is herewith described. This multiple association is exceptional as is the important clinical repercussion of the hemolytic anemia derived from the high titers and above all the wide thermic interval of the cryoagglutinin present. Finally, the relation of cryoagglutinin with each of these entities, the concomitant presence of cryoglobulins and the evolution of the titers of the same with the chemotherapy treatment administered for the lymphoma is analyzed.

Acute and chronic immunomodulatory changes in rat liver after fetal and perinatal asphyxia.

Hypoxic-ischemic encephalopathy (HIE) caused by fetal and perinatal asphyxia is an important cause of mortality in the neonatal period. Not only will asphyxia affect the brain but also other organs such as the liver and kidneys. Interestingly, it has been shown that liver damage is proportional to the severity of the asphyctic insult, implying an association between liver impairment and HIE. Accordingly, we investigated in an established rat model the acute and chronic hepatic response to both fetal (FA) and perinatal asphyxia (PA). In addition, we assessed whether fetal asphyctic preconditioning (PC) would have any beneficial effect on the liver. Inflammation, ceramide signaling and hepatocellular damage were analyzed in the livers of newborn and adult rats at several short- and long-term time points after both FA and PA. We found that although FA induced an acute inflammatory response, apoptotic mRNA levels and oxidative DNA damage were decreased at 96 h post FA. Whereas increased IL-6 and IL-10 mRNA levels were observed after PA, the combination of FA and PA (PC) attenuated the inflammatory response. Moreover, 6 h after PA anti-apoptotic genes were downregulated and associated with less lipid peroxidation, while preconditioned animals were comparable to controls. In summary, asphyctic PC seems to have an acute protective effect on the liver by modulating the inflammatory, apoptotic and anti-oxidative response. More insight into the hepatic response to asphyxia is necessary, as disturbed hepatic function is associated with metabolic diseases in later life.

A mouse model of the slow channel myasthenic syndrome: Neuromuscular physiology and effects of ephedrine treatment.

In the slow channel congenital myasthenic syndrome mutations in genes encoding the muscle acetylcholine receptor give rise to prolonged ion channel activations. The resulting cation overload in the postsynaptic region leads to damage of synaptic structures, impaired neuromuscular transmission and fatigable muscle weakness. Previously we identified and characterised in detail the properties of the slow channel syndrome mutation εL221F. Here, using this mutation, we generate a transgenic mouse model for the slow channel syndrome that expresses mutant human ε-subunits harbouring an EGFP tag within the M3-M4 cytoplasmic region, driven by a ~1500 bp region of the CHRNB promoter. Fluorescent mutant acetylcholine receptors are assembled, cluster at the motor endplates and give rise to a disease model that mirrors the human condition. Mice demonstrate mild fatigable muscle weakness, prolonged endplate and miniature endplate potentials, and variable degeneration of the postsynaptic membrane. We use our model to investigate ephedrine as a potential treatment. Mice were assessed before and after six weeks on oral ephedrine (serum ephedrine concentration 89 ± 3 ng/ml) using an inverted screen test and in vivo electromyography. Treated mice demonstrated modest benefit for screen hang time, and in measures of compound muscle action potentials and mean jitter that did not reach statistical significance. Ephedrine and salbutamol show clear benefit when used in the treatment of DOK7 or COLQ congenital myasthenic syndromes. Our results highlight only a modest potential benefit of these ß2-adrenergic receptor agonists for the treatment of the slow channel syndrome.

Gene-environment interaction research and transgenic mouse models of Alzheimer's disease.

The etiology of the sporadic form of Alzheimer's disease (AD) remains largely unknown. Recent evidence has suggested that gene-environment interactions (GxE) may play a crucial role in its development and progression. Whereas various susceptibility loci have been identified, like the apolipoprotein E4 allele, these cannot fully explain the increasing prevalence of AD observed with aging. In addition to such genetic risk factors, various environmental factors have been proposed to alter the risk of developing AD as well as to affect the rate of cognitive decline in AD patients. Nevertheless, aside from the independent effects of genetic and environmental risk factors, their synergistic participation in increasing the risk of developing AD has been sparsely investigated, even though evidence points towards such a direction. Advances in the genetic manipulation of mice, modeling various aspects of the AD pathology, have provided an excellent tool to dissect the effects of genes, environment, and their interactions. In this paper we present several environmental factors implicated in the etiology of AD that have been tested in transgenic animal models of the disease. The focus lies on the concept of GxE and its importance in a multifactorial disease like AD. Additionally, possible mediating mechanisms and future challenges are discussed.

B cell characterization and reactivity analysis in multiple sclerosis.

B cells are one of the key players in the pathogenesis of multiple sclerosis (MS). The peripheral B cell distributions are similar in healthy persons and MS patients. In healthy controls, B cells are rarely present in the cerebrospinal fluid (CSF) while in MS patients, a clonally expanded B cell population is detected. This consists of memory B cells, centroblasts and antibody-secreting plasma blasts and plasma cells that are responsible for intrathecal immunoglobulin G production and oligoclonal band formation in more than 90% of MS patients. Unfortunately, the targets of the autoreactive B cells and antibodies remain largely unknown. Various candidate antigens have been identified but often their involvement in the disease process is still unclear. Most studies characterizing these target antigens examined autoantibodies by analyzing sera or CSF of MS patients. An alternative approach is focusing on the clonally expanded B cells. In this way B cells directed against myelin, astroglia and axons have been denoted in MS patients. B cell immortalization, that is based on the antibody-producing potential of Epstein-Barr virus (EBV) transformed B cells, can be used to expand B cells from MS patients for the production of antibodies, that ultimately can be analysed for target identification.

New lineal immunoenzymatic assay for simultaneous detection of p24 antigen and HIV antibodies.

The aim of this study was to evaluate a new lineal immunoenzymatic assay for the simultaneous detection of HIV-1/HIV-2 antibodies and p24 antigen. A total of 320 serum samples were obtained from individuals infected by HIV (HIV 1, n = 183; HIV 2, n = 2), individuals with risk factors for HIV infection (n =49), recipients of multiple transfusions (n =40), and blood donors (n = 46). The Western blot for detection of HIV antibodies and an enzyme immunoassay for detection of p24 antigen, both established techniques, were used for direct comparison. In cases of recent infection, p24 antigen was generally detected at the same time by the lineal test and the established assay. The p24 antigen sensitivity was about 200 pg of HIV antigen per milliliter. The results seem to indicate that the new test could be used with sufficient reliability for screening biological samples (sensitivity, 99.5%; specificity, 94.8%). Use of the lineal immunoenzymatic assay may shorten the amount of time needed to diagnose acute infection with HIV to approximately 2 weeks.

[Diagnosis of dyslipidemia in primary care: a service to be improved. Results of a multicenter evaluation]. / El diagnóstico de las dislipemias en atención primaria: un servicio a mejorar. Resultados de una evaluación multicéntrica.

OBJECTIVE: The variability of the quality of care in the primary care procedures to diagnose lipaemia was evaluated. DESIGN: Observation, multi-centred and retrospective study. SETTING: Random sample of 10 primary care centres in the Murcia region. PATIENTS AND OTHER PARTICIPANTS: Patients over 19 with lipaemia detected over the previous twelve months in the general medical clinics at health centres. 500 cases in all were studied (50 per centre). MEASUREMENTS AND MAIN RESULTS: Compliance with criteria of good clinical practice was evaluated. These criteria were formulated by health centre doctors and included: adequate diagnosis, classification into primary or secondary, phenotype, recording of cardiovascular risk factors and assessment of cardiovascular (CV) risk. The differences between the centres studied and the effect of the centre's characteristics (teaching, location, existence of lipaemia programme) and of the patients' (age and gender) were also examined. We found that none of the cases evaluated satisfied the five quality criteria at the same time. Assessment of CV risk and the aetiopathogenic classification were the criteria least complied with (1.5% +/- 1.0). Centres varied considerably. Their characteristics affected the quality of the procedure evaluated, which in all centres had a lot of room for improvement. CONCLUSIONS: The quality of the procedures for diagnosing lipaemia can be considerably improved. It varies a lot from centre to centre.

[Social assessment of anxiety in primary health care]. / Valoración social de la ansiedad en atención primaria de salud.

OBJECTIVE: Identification of the social profile of our anxious patients, and analysis of the usefulness of Bell's questionnaire for our area of work. DESIGN: A retrospective observation study of a crossover type. SETTING: Primary Care. PARTICIPANTS: 55 patients who consulted their Family Doctor and were diagnosed as suffering from Anxiety. MEASUREMENTS AND MAIN RESULTS: We confirmed the diagnosis with the DSM-III-R and then analysed the level of Anxiety with the Hamilton Scale. The social evaluation was done by means of Bell's profile. As test statistics we used the lineal correlation Coefficient, the Student's t and Xi2 tests and Variance Analysis. 65% of diagnoses were Generalised Anxiety. The Hamilton mean was 20.9 points (S = 9.2). Overall social adaptation was unsatisfactory, with the worst results being for the emotional aspects. We observed a higher level of Anxiety as age increased (p = 0.021), related to a worse adaptation to Health (p = 0.014). Dissatisfaction with work and the working environment took the form of professional adaptation being poorer as their work situation deteriorated (p = 0.006). Anxiety levels were higher among the unemployed. Social adaptation was less among people with higher Anxiety levels (p = 0.04), above all as a consequence of worse adaptation to Health (p = 0.002) and worse emotional (p = 0.00001) adaptation. CONCLUSIONS: 1) We must introduce social aspects into analysis of patients with Anxiety. 2) Bell's profile enables us to identify those social aspects which can be tackled when caring for our patients. Its fundamental use is in individual application.