Angiotensin II receptor agonist antibodies are associated with microvascular damage in lupus nephritis.

Angiotensin II type 1 receptor agonist antibodies (AT1R-AAs) have been associated with hypertension, atherosclerosis and vascular inflammation in human diseases. The aim of the study was to evaluate the prevalence of AT1R-AAs in active lupus nephritis (LN) patients and their association with vascular damage. One hundred and seven active LN patients underwent a complete clinical examination, measurement of AT1R-AAs, ambulatory blood pressure monitoring, carotid intima-media thickness measurement and morphometric analysis of subintimal fibrosis and medial hyperplasia of the vessels in the kidney tissue. Plasma AT1R-AAs were positive in 58 (54.2%) patients. The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, complement C3 and C4 levels and titers of anti-dsDNA antibodies were higher in the group with positive AT1R-AAs compared with those with negative AT1R-AAs. The AT1R-AA titers correlated with anti-dsDNA antibody titers and with complement C3 and C4 serum levels. In the kidney biopsy, the percentage of subintimal fibrosis and the area of medial hyperplasia were greater in the AT1R-AA-positive patients. No differences in arterial pressure, carotid intima-media thickness and response to therapy were detected. In conclusion, AT1R-AAs are prevalent in active LN patients and are associated with histologic features of microvascular damage.

The PHF21B gene is associated with major depression and modulates the stress response.

Major depressive disorder (MDD) affects around 350 million people worldwide; however, the underlying genetic basis remains largely unknown. In this study, we took into account that MDD is a gene-environment disorder, in which stress is a critical component, and used whole-genome screening of functional variants to investigate the 'missing heritability' in MDD. Genome-wide association studies (GWAS) using single- and multi-locus linear mixed-effect models were performed in a Los Angeles Mexican-American cohort (196 controls, 203 MDD) and in a replication European-ancestry cohort (499 controls, 473 MDD). Our analyses took into consideration the stress levels in the control populations. The Mexican-American controls, comprised primarily of recent immigrants, had high levels of stress due to acculturation issues and the European-ancestry controls with high stress levels were given higher weights in our analysis. We identified 44 common and rare functional variants associated with mild to moderate MDD in the Mexican-American cohort (genome-wide false discovery rate, FDR, <0.05), and their pathway analysis revealed that the three top overrepresented Gene Ontology (GO) processes were innate immune response, glutamate receptor signaling and detection of chemical stimulus in smell sensory perception. Rare variant analysis replicated the association of the PHF21B gene in the ethnically unrelated European-ancestry cohort. The TRPM2 gene, previously implicated in mood disorders, may also be considered replicated by our analyses. Whole-genome sequencing analyses of a subset of the cohorts revealed that European-ancestry individuals have a significantly reduced (50%) number of single nucleotide variants compared with Mexican-American individuals, and for this reason the role of rare variants may vary across populations. PHF21b variants contribute significantly to differences in the levels of expression of this gene in several brain areas, including the hippocampus. Furthermore, using an animal model of stress, we found that Phf21b hippocampal gene expression is significantly decreased in animals resilient to chronic restraint stress when compared with non-chronically stressed animals. Together, our results reveal that including stress level data enables the identification of novel rare functional variants associated with MDD.

Linkage and association analysis of ADHD endophenotypes in extended and multigenerational pedigrees from a genetic isolate.

Attention-deficit/hyperactivity disorder (ADHD) is a heritable, chronic, neurodevelopmental disorder with serious long-term repercussions. Despite being one of the most common cognitive disorders, the clinical diagnosis of ADHD is based on subjective assessments of perceived behaviors. Endophenotypes (neurobiological markers that cosegregate and are associated with an illness) are thought to provide a more powerful and objective framework for revealing the underlying neurobiology than syndromic psychiatric classification. Here, we present the results of applying genetic linkage and association analyses to neuropsychological endophenotypes using microsatellite and single nucleotide polymorphisms. We found several new genetic regions linked and/or associated with these endophenotypes, and others previously associated to ADHD, for example, loci harbored in the LPHN3, FGF1, POLR2A, CHRNA4 and ANKFY1 genes. These findings, when compared with those linked and/or associated to ADHD, suggest that these endophenotypes lie on shared pathways. The genetic information provided by this study offers a novel and complementary method of assessing the genetic causes underpinning the susceptibility to behavioral conditions and may offer new insights on the neurobiology of the disorder.

APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease.

Alzheimer's disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed ~50 000 common and rare functional genomic variants from 71 individuals of the 'Paisa' pedigree, the world's largest pedigree segregating a severe form of early-onset AD, who were affected carriers of the fully penetrant E280A mutation in the presenilin-1 (PSEN1) gene. Affected carriers with ages at the extremes of the ADAOO distribution (30s-70s age range), and linear mixed-effects models were used to build single-locus regression models outlining the ADAOO. We identified the rs7412 (APOE*E2 allele) as a whole exome-wide ADAOO modifier that delays ADAOO by ~12 years (ß=11.74, 95% confidence interval (CI): 8.07-15.41, P=6.31 × 10(-8), PFDR=2.48 × 10(-3)). Subsequently, to evaluate comprehensively the APOE (apolipoprotein E) haplotype variants (E1/E2/E3/E4), the markers rs7412 and rs429358 were genotyped in 93 AD affected carriers of the E280A mutation. We found that the APOE*E2 allele, and not APOE*E4, modifies ADAOO in carriers of the E280A mutation (ß=8.24, 95% CI: 4.45-12.01, P=3.84 × 10(-5)). Exploratory linear mixed-effects multilocus analysis suggested that other functional variants harbored in genes involved in cell proliferation, protein degradation, apoptotic and immune dysregulation processes (i.e., GPR20, TRIM22, FCRL5, AOAH, PINLYP, IFI16, RC3H1 and DFNA5) might interact with the APOE*E2 allele. Interestingly, suggestive evidence as an ADAOO modifier was found for one of these variants (GPR20) in a set of patients with sporadic AD from the Paisa genetic isolate. This is the first study demonstrating that the APOE*E2 allele modifies the natural history of AD typified by the age of onset in E280A mutation carriers. To the best of our knowledge, this is the largest analyzed sample of patients with a unique mutation sharing uniform environment. Formal replication of our results in other populations and in other forms of AD will be crucial for prediction, follow-up and presumably developing new therapeutic strategies for patients either at risk or affected by AD.

Pooling/bootstrap-based GWAS (pbGWAS) identifies new loci modifying the age of onset in PSEN1 p.Glu280Ala Alzheimer's disease.

The literature on GWAS (genome-wide association studies) data suggests that very large sample sizes (for example, 50,000 cases and 50,000 controls) may be required to detect significant associations of genomic regions for complex disorders such as Alzheimer's disease (AD). Because of the challenges of obtaining such large cohorts, we describe here a novel sequential strategy that combines pooling of DNA and bootstrapping (pbGWAS) in order to significantly increase the statistical power and exponentially reduce expenses. We applied this method to a very homogeneous sample of patients belonging to a unique and clinically well-characterized multigenerational pedigree with one of the most severe forms of early onset AD, carrying the PSEN1 p.Glu280Ala mutation (often referred to as E280A mutation), which originated as a consequence of a founder effect. In this cohort, we identified novel loci genome-wide significantly associated as modifiers of the age of onset of AD (CD44, rs187116, P=1.29 × 10⁻¹²; NPHP1, rs10173717, P=1.74 × 10⁻¹²; CADPS2, rs3757536, P=1.54 × 10⁻¹°; GREM2, rs12129547, P=1.69 × 10⁻¹³, among others) as well as other loci known to be associated with AD. Regions identified by pbGWAS were confirmed by subsequent individual genotyping. The pbGWAS methodology and the genes it targeted could provide important insights in determining the genetic causes of AD and other complex conditions.

A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD.

In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10(-8)) and 11q and 17p (P<1 × 10(-6)). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.

A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication.

Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.

Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function.

BACKGROUND: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. OBJECTIVE: To characterise genetic and clinical findings in patients with SIX3 mutations. METHODS: Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish. RESULTS: In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of non-chromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%. CONCLUSIONS: Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype-phenotype correlation, as shown by functional studies using animal models.

ADHD Endophenotypes in Caribbean Families.

Objective: The aim of this study is to contrast the genetics of neuropsychological tasks in individuals from nuclear families clustering ADHD in a Caribbean community. Method: We recruited and clinically characterized 408 individuals using an extensive battery of neuropsychological tasks. The genetic variance underpinning these tasks was estimated by heritability. A predictive framework for ADHD diagnosis was derived using these tasks. Results: We found that individuals with ADHD differed from controls in tasks of mental control, visuospatial ability, visuoverbal memory, phonological and verbal fluency, verbal and semantic fluency, cognitive flexibility, and cognitive ability. Among them, tasks of mental control, visuoverbal memory, phonological fluency, semantic verbal fluency, and intelligence had a significant heritability. A predictive model of ADHD diagnosis using these endophenotypes yields remarkable classification rate, sensitivity, specificity, and precision values (above 80%). Conclusion: We have dissected new cognitive endophenotypes in ADHD that can be suitable to assess the neurobiological and genetic basis of ADHD.

[Prostatic carcinoma: healthy population screening or a better diagnosis?]. / Carcinoma de próstata: screening de población sana o mejor diagnóstico?

In the light of present knowledge with regard to prostate carcinoma, the concerns and objections that arise due to an eventual recommendation to the healthy population for systematic screening of prostate cancer are presented together with the possible identification of certain population groups which could benefit from it. It is concluded that in opposition to the concept of mass screening there is more logic today in the selective screening of risk groups and also that in future studies on the incidence on mortality figures these should be done on the country's own population. Up to the present time, the association of rectal examination and PSA is the best method available to establish a suspected diagnosis of prostate cancer.

[Ectopic thoracic kidney]. / Ectopia renal torácica.

We present a case of kidney ecthopy in a 62 years old male patient, discovered by chance during complementary explorations realized in the diagnostic process of an acute respiratory pathology. We review the literature related to this anomaly: 200 cases have been published to the date. The thoracic kidney is a rare kind of kidney ecthopy, tipically without synomathology & it requires no treatment.

[Cancer of the prostate: current diagnostic aspects]. / Cáncer de próstata: aspectos actuales del diagnóstico.

Presentation of the initial results from a program for early diagnosis of prostate cancer, implemented a year ago at the Urology Unit of the Miguel Servet Hospital with the collaboration of the Region's specialists. All patients attending the Urology services, regardless the pathology, are evaluated when rectal examination is suspicious or the plasma PSA levels are higher than 4 ng/ml. Assessment is made through transrectal ultrasound scanning, with random or ultrasound-directed prostatic biopsy depending on the findings. A total of 83 prostatic biopsies have been analyzed n patients thus selected, presence of prostatic carcinoma becoming apparent in 52 (62.6%), 19 of which have undergone radical prostatectomy. The association suspected rectal examination/increased PSA has produced the higher percentages of diagnostic precision (80%) clearly improving those of rectal examination and PSA alone. The methods for local and nodular staging are analyzed, considering the systematic use of laparoscopic lymphadenectomy and biopsy of seminal vesicles highly useful for higher diagnostic precision in these patients. The diagnostic relevance of prognostic factors in advanced cancer is analyzed, this analysis being mandatory to evaluate the different therapeutic.

[Inverted papilloma of the ureter. Apropos of a case]. / Papiloma invertido de uréter. A propósito de un caso.

Presentation of one case of inverted papilloma of the renal pelvis, an uncommon entity with very few cases described in the international literature. The pathoanatomic presentation is that of a benign tumour, which would provide an option for conservative therapy through segmentary resection and termino-terminal anastomosis. Due to its low frequency, pre-operative diagnosis of this tumour is difficult, although the number of diagnosis could be increased with the use of endourologic techniques. In spite of the benign nature, it can be multifocal and relapsing. A close follow-up monitoring is recommended.

[Primary signet cell adenocarcinoma of the bladder]. / Adenocarcinoma de células en anillo de sello primario de vejiga.

The primary signet-ring cell adenocarcinoma of the bladder is a rare tumor, with great biological aggressivity and bad prognosis. We report a clinical case of a 65 years old patient, starting with bladder irritative symptoms and suffering from advanced disease at the initial diagnosis. We review clinical and etiopathogenic aspects about this entity.

[Renal oncocytoma: infrequent presentation form]. / Oncocitoma renal: una forma infrecuente de presentación.

Case report describing a solid renal mass as an incidental finding while evaluating a different condition. This is an oncocytoma infiltrating perirenal fat. The various aspects of the process are described.

[Melanoma of female distal urethra: apropos of a case]. / Melanoma de uretra distal femenina: a propósito de un caso.

A case is presented of melanoma located at the distal urethra in a 74-year-old patient who underwent local surgery. At present the survival rate is 5 years and local relapse and metastases of one inguinal ganglion has been observed. The different clinical, diagnostic and therapeutic aspects of this neoplasia are discussed.

[Laparoscopic ureterolithectomy. A new option]. / Ureterolitectomía laparoscópica. Un nuevo recurso.

An integral conception of patients with various diseases can benefit from the contemporary technological developments which allow to differentiated non-invasive approaches as diagnostic and therapeutical resources. This kind of patient has allowed further development of laparoscopic surgery in urology derived from the addition of reported conditions: obstructive prostate carcinoma, juxta-vesical gross lithiasis imbedded for 2 years, complexity of ureteroscopic access, large volume for extracorporeal lithotripsy and the need to know the extend of nodular affectation.

[Urinary continence after radial prostatectomy. Prognostic factors and recovery time]. / Continencia urinaria tras prostatectomía radical. Factores pronósticos y tiempo de recuperación.

OBJECTIVES: To assess the urinary continence after radical prostatectomy and its evolution over time. To analyse possible prognosis factors. MATERIAL AND METHODS: We have reviewed 101 patients that have undergone radical prostatectomy. We define "continent patient" as that one who doesn't require any type of urinary protection. By means of Kaplan-Meier method, we evaluate the recovery of continence along time. We analyze potential conditional factors (age, stage, surgery technique, surgery experience,...). The statistical tools used are: chi-square, Fisher, Cox regression, T-test and Kaplan-Meier. RESULTS: Median monitoring time: 27.33 months. 80% are continent patients, 48.7% of which reach maximum continence before the 3rd, month is due and 17.5% after the 6 months (2.5% between 9-12 months). Their probability of becoming "continents" during the first 4 months es 0.4692. patients under 70 years old recover continence before those who are over 70 years old (medians: 3.51 months and 5.67 months respectively, p = 0.0211). CONCLUSIONS: The recovery of continence takes place progressively and a 17.5% of patients reach plain recovery in the 6-12 months period after surgery. The evaluation of the surgery treatment to correct incontinence should consider the possibility of "spontaneous" recovery in a 2.5% of patients in the 9-12 months period after surgery. Age affects negatively the recovery time; it is significantly less for patients under 70.

[Infrequent retroperitoneal tumor: benign schwannoma]. / Tumor retroperitoneal infrecuente: Schwannoma benigno.

Case report of a retroperitoneal benign Schwannoma diagnosed accidentally during ultrasound scanning for a different pathology and treated by surgical exeresis. The diagnostic and therapeutic features of this rare neoplasia are reviewed.

[PSA in the staging and monitoring of cancer of the prostate]. / PSA en el estadiaje y monitorización del cáncer de próstata.

The prostatic surface antigen (PSA), exclusively secreted by the prostatic epithelial cells, can be raised in the sera of patients with various prostatic pathologies. Serum levels of this marker depend on many factors (prostatic manipulation, associated inflammation, volume of benign node hyperplasia, volume and grading of tumour differentiation), all of which will have to be taken into account when interpreting any specific level. The usefulness of this antigen has a distinctive role in the suspected diagnosis, staging and monitoring following treatment of prostate cancer. PSA has shown to be more effective than other markers in the diagnosis of prostate cancer. Following the review of 106 patients with prostate cancer in various clinical stages, PSA was higher in 76.5% and PAP only in 49%. There is also a correlation between PSA and the extension of the disease. Of 43 patients surgically (stages B, C, D1) or radiologically (stages D2) staged, increases PSA has been found in 25% B stages, 77.7% C stages and 88.4% D stages. With regard to post-treatment monitoring, PSA is highly useful to determine its effectiveness, detect any residual illness and predict a recurrence or progression.