Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22-q23.

Manic depressive illness, or bipolar disorder (BP), is characterized by episodes of elevated mood (mania) and depression. We designed a multistage study in the genetically isolated population of the Central Valley of Costa Rica to identify genes that promote susceptibility to severe BP (termed BPI), and screened the genome ot two Costa Rican BPI pedigrees (McInnes et al., submitted). We considered only individuals who fulfilled very stringent diagnostic criteria for BPI to be affected. The strongest evidence for a BPI locus was observed in 18q22-q23. We tested 16 additional markers in this region and seven yielded peak lod scores over 1.0. These suggestive lod scores were obtained over a far greater chromosomal length (about 40 cM) than in any other genome region. This localization is supported by marker haplotypes shared by 23 of 26 BPI affected individuals studied. Additionally, marker allele frequencies over portions of this region are significantly different in the patient sample from those of the general Costa Rican population. Finally, we performed an analysis which made use of both the evidence for linkage and for association in 18q23, and we observed significant lod scores for two markers in this region.

Recovery of vision after treatment of hemodialysis related bilateral optic nerve ischemia.

PURPOSE: We present the case of a patient who lost light perception in both eyes after hemodialysis and subsequently recovered vision after treatment with erythropoietin and intravenous steroids. OBSERVATIONS: Our patient reported loss of light perception in both eyes (NLP) 2 hours after hemodialysis. Examination confirmed NLP vision, chronic retinal vascular changes, and no acute changes in optic nerve appearance. A presumptive diagnosis of posterior optic neuropathy was made. The patient was treated with erythropoietin and intravenous steroids according to the protocol of Nikkah. Over a period of 14 hours, he recovered vision to his baseline. CONCLUSIONS AND IMPORTANCE: Bilateral loss of light perception is a rare complication of hemodialysis. The presumed mechanism is posterior ischemic optic neuropathy. Prompt treatment with erythropoietin and intravenous steroids should be considered in similar situations that result in Posterior ischemic optic neuropathy (PION) related to procedure-based hypotension.

Meta-analysis of 32 genome-wide linkage studies of schizophrenia.

A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P(SR)) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.

Analyses of Programmed Cell Death Protein 1 in High Immunologic-Risk Transplant Patients.

Kidney transplant (KT) is the first therapeutic option for most patients with chronic renal failure that requires renal function replacement. The main complication associated with renal graft loss is immune rejection. The T regulatory pathways play a key role in this process, and abnormalities in some of these molecules could participate in the graft rejection. In this paper, our group performed an exploratory analysis of the behavior of the coinducible molecules (CD28, CTLA-4, ICOS, PD-1) in patients with KT rejection and control KT patients without rejection. The Mann-Whitney U test, used for 2 groups, showed significant differences (P = .0005), indicating that PD-1 is underexpressed in patients with allograft rejection. No differences were found in CD28+, regulatory T cells (T reg), CTLA-4, and ICOS, so we are proposing that PD-1 is a key player in the immunotolerance phenomenon and its underexpression participates in the rejection process. More research needs to be performed on this topic.

Antibody-Mediated Rejection Treatment With Bortezomib in Renal Transplant Recipients: A Single-Center 24-Month Follow-up Case Report.

INTRODUCTION: Antibody-mediated rejection (AMR) is related to a poor prognosis in graft survival, with 27% to 40% of patients experiencing graft loss within the first year. The mechanism of damage in AMR is mediated by donor-specific antibodies (DSA). No standard treatment for AMR exists, and conventional management includes high doses of steroids, plasmapheresis, intravenous immunoglobulin, and either rituximab or bortezomib. Because of the high cost of these medications and the lack of prospective studies to evaluate their efficacy and safety, their routine use is limited. In the following study, we describe the use of bortezomib for the treatment of AMR in 5 renal transplant recipients with a 24-month follow-up and compare this case with the reviewed literature. MATERIAL AND METHODS: Five cases of AMR diagnosed by biopsy are reported, and these patients received bortezomib at a rate of 1.3 mg/m2 on days 1, 4, 8, and 11; plasmapheresis; and 1 patient received 30 g of intravenous immunoglobulin. RESULTS: All patients received his or her first transplant; 4 were from a cadaveric donor, and 1 patient received thymoglobulin at a standard dose. All patients had maintenance therapy based on cyclosporine, mycophenolate mofetil, and prednisone, with an average baseline creatinine level of 1.3 mg/dL. The average days until rejection event were 952 days. DISCUSSION AND CONCLUSION: AMR treatment with bortezomib was effective, showing stable renal function at 24 months. Patients had adequate tolerance for administration. So far, these results contrast with the literature reviewed, so additional studies and follow-up are required for a new evaluation.

Metabolic Syndrome, a Real Barrier for Living Kidney Donor Transplant.

INTRODUCTION: Renal transplantation is the optimal renal replacement therapy. In Mexico, most of the kidney transplants are from living donors. It is essential to identify conditions that increase the risk of developing chronic kidney disease (CKD) in donors, such as metabolic syndrome (MS). MATERIALS AND METHODS: In retrospect from January 2008 to December 2018, the donation protocols for renal transplantation of the Hospital Central Sur Alta Especialidad "Picacho" were reviewed, classifying all the cases of donors by nephrectomy or no nephrectomy and describing the demographic characteristics, prevalence of metabolic diseases, and cause of rejection of the protocol. RESULTS: A total of 178 donors were studied: 82 women (46%), 96 men (54%), mean age of 42 years, average body mass index (BMI) 27.9 kg/m2, glomerular filtration rate (GFR) by Chronic Kidney Disease Epidemiology Collaboration 99 mL/min, 59 patients with grade I and II obesity (BMI ≥ 30 kg/m2), and 1 patient with morbid obesity (BMI ≥ 40 kg/m2). A total of 39 patients (22%) underwent nephrectomy and 139 (78%) did not. The following characteristics and alterations were found: Of the 139 patients who did not undergo nephrectomy, 91 had metabolic disorders, 20 had low GFR, 21 had albuminuria, and 4 recipients received cadaveric transplants, 3 due to critical conditions of the recipient. The metabolic alterations in the rejected donors were as follows: MS 54 (59%), prediabetes 55 (39%), newly diagnosed hypertension 70 (76%), diabetes mellitus 20 (14%), obesity 47 (51.6%), dyslipidemia 76 (83%), hyperuricemia 17 (12%). DISCUSSION: The prevalence of MS in apparently healthy donors is similar to that of other studies in Mexico. Both MS and its components are independently associated with an increased risk of cardiovascular disease and CKD. It has been shown that these donors have a greater degree of glomerular and interstitial fibrosis; therefore, diagnosis, prevention, and timely treatment in this group are important.

The serotonin transporter 5-HTTPR polymorphism is associated with current and lifetime depression in persons with chronic psychotic disorders.

OBJECTIVE: Variation in the serotonin transporter gene (SLC6A4) promoter region has been shown to influence depression in persons who have been exposed to a number of stressful life events. METHOD: We evaluated whether genetic variation in 5-HTTLPR, influences current depression, lifetime history of depression and quantitative measures of depression in persons with chronic psychotic disorders. This is an association study of a genetic variant with quantitative and categorical definitions of depression conducted in the southwest US, Mexico and Costa Rica. We analyzed 260 subjects with a history of psychosis, from a sample of 129 families. RESULTS: We found that persons carrying at least one short allele had a statistically significant increased lifetime risk for depressive syndromes (P < 0.02, odds ratio 2.18, 95% CI 1.10-4.20). CONCLUSION: The 'ss' or 'sl' genotype at the 5-HTTLPR promoter polymorphic locus increases the risk of psychotic individuals to develop major depression during the course of their illness.

Complete atrioventricular block as initial manifestation of systemic lupus erythematosus.

Only a few cases of complete atrioventricular block (AVB) in adult lupus patients have been previously described, but only one as the initial manifestation. A 19-year-old woman who presented with seizures and loss of consciousness, was diagnosed with complete ABV and underwent pacemaker placement. Over the next weeks she developed serositis, joint, cutaneous, and renal involvement; positive antinuclear antibodies and high anti-SSA/Ro titers. This is the second case with AVB as a feature of SLE at onset. A review of previous complete AVB cases of adult SLE patients is presented.

Biological degradation of a mixture of municipal wastewater and organic garbage leachate in expanded bed anaerobic reactors and a zeolite filter.

Municipal wastewater was amended with organic garbage leachates at a concentration around 700 mgCOD(soluble)/L and fed to three different anaerobic systems to compare their performance: a down flow fluidized bed (DFFB), an expanded granular sludge bed (EGSB) and a zeolite-packed anaerobic filter reactor (ZPF). The DFFB and EGSB reactors were operated at HRT of 6 and 4 h and the ZPF reactor at 12 and 36 h. Organic loads rate for the DFFB reactor were 2.3+/-0.9 and 4.8+/-1.8 gCOD/L.d, with removal efficiencies around 40% and a methane productivity of 0.2+/-0.03 L/L(reactor).d. For the EGSB reactor, organic loads tested were 2.1+/-0.9 and 4.3+/-1.3 gCOD/L.d, removal efficiencies attained were of 77.6+/-12.7% and 84.4+/-4.9%, respectively at both conditions and total suspended solids were removed in 54.6+/-19.3%, while methane productivity at 4 h HRT was of 1.29+/-0.4 L/L(reactor).d. The ZPF reactor was operated at lower organic loading rates, 1.4+/-0.27 and 0.42+/-0.13 gCOD/L.d and attained removal efficiencies of 48+/-18% and 83+/-8%, respectively, reaching a methane productivity of 0.21+/-0.09 and 0.12+/-0.04 L/L(reactor).d, 83+/-8.0% of total suspended solids were retained in the reactor and as HRT was increased ammonium concentrations increased in 39%. Specific methanogenic activity in all systems was around 0.2 gCOD-CH(4)/gVSS d.

Hybrid position/force output feedback second-order sliding mode control for a prototype of an active orthosis used in back-assisted mobilization.

This article shows the design of a robust second-order sliding mode controller to solve the trajectory tracking problem of an active orthosis for assisting back physiotherapies. The orthosis was designed in agreement with morphological dimensions and its articulations distribution followed the same designing rules. The orthosis has six articulated arms attached to an articulated column. The orthosis was fully instrumented with actuators and position sensors at each articulation. The controller implemented a class of hybrid/position controller depending on the relative force exerted by the patient and the orthosis movement. The position information provided by each articulation was supplied to a distributed super-twisting differentiator to recover the corresponding angular velocity. A set of twisting controllers was implemented to regulate the position of the robot in agreement to predefined reference trajectories. Reference trajectories were obtained from a biomechanical-based analysis. The hybrid tracking control problem solved the automation of the assisted therapy to the patient, including the force feedback. The performance of the orthosis was tested with different dummy bodies with different resistance. The robust output feedback controller successfully tracked the reference trajectories despite the material of the dummy used during the testing. The orthosis was evaluated with two volunteers using a simple reference trajectory. Graphical Abstract General structure of the active back assisted orthosis.

[Analysis of polymorphism rs1051730 of CHRNA3 in patients with dual pathology in a Mexican population]. / Analisis del polimorfismo rs1051730 de CHRNA3 en pacientes con patologia dual en poblacion mexicana.

INTRODUCTION: Epidemiological studies have described a high comorbidity of substance use disorders with another psychiatric disorder, which has been called dual pathology. However, the aetiological mechanisms underlying this association are still not fully understood. AIM: To carry out a preliminary study of the effect of polymorphism rs1051730 of the gene group CHRNA5-CHRNA3-CHRNB4 through a case-control study. SUBJECTS AND METHODS: A total of 225 subjects were selected and divided into three groups: those diagnosed with bipolar disorder, those with nicotine dependence, and subjects without nicotine dependence or any other psychiatric disorder. Genotyping was performed by real-time polymerase chain reaction. Genetic association analysis was performed using chi-square tests and multivariate logistic regressions. RESULTS: On comparing allelic frequencies with the control group, we found that polymorphism rs1051730 was associated with nicotine dependence (p = 0.03), but not with bipolar disorder (p = 0.94). CONCLUSION: Variant rs1051730 was associated with nicotine dependence in the Mexican population and showed the same effect in dual pathology. However, further studies are recommended to obtain conclusive results.

TITLE: Analisis del polimorfismo rs1051730 de CHRNA3 en pacientes con patologia dual en poblacion mexicana.Introduccion. Estudios epidemiologicos han descrito una alta comorbilidad de los trastornos de uso de sustancias con otro trastorno psiquiatrico, al cual se le ha llamado patologia dual. Sin embargo, los mecanismos etiologicos de esta asociacion continuan siendo dificiles de entender. Objetivo. Realizar un estudio preliminar del efecto del polimorfismo rs1051730 del grupo de genes CHRNA5-CHRNA3-CHRNB4 a traves de un estudio de casos y controles. Sujetos y metodos. Se selecciono a un total de 225 sujetos, divididos en tres grupos: con diagnostico de trastorno bipolar, con dependencia a la nicotina y sujetos sin dependencia a la nicotina o cualquier otro trastorno psiquiatrico. La genotipificacion se realizo mediante reaccion en cadena de la polimerasa en tiempo real. El analisis de asociacion genetica se realizo mediante pruebas de chi cuadrado y regresiones logisticas multivariables. Resultados. Al comparar las frecuencias alelicas con el grupo control, encontramos que el polimorfismo rs1051730 se asocio con el grupo de dependencia a la nicotina (p = 0,03), pero no con el de trastorno bipolar (p = 0,94). Conclusion. La variante rs1051730 se asocio con dependencia a la nicotina en la poblacion mexicana y mostro el mismo efecto en la patologia dual. Sin embargo, se recomiendan estudios adicionales para tener resultados concluyentes.

Peripheral Blood Regulatory T Cells Are Diminished in Kidney Transplant Patients With Chronic Allograft Nephropathy.

BACKGROUND: Our aim in this study was to assess peripheral blood CD4+CD25+FOXP3+ regulatory T cell (Treg) levels in patients with chronic allograft nephropathy (CAN) 1 year after kidney transplantation. METHODS: Twelve renal transplant patients with an initial onset of CAN, 12 patients with chronic kidney disease (CKD) stage G5 on dialysis, and 13 healthy control individuals were evaluated regarding the proportion of Tregs in their peripheral blood via flow cytometry. RESULTS: The renal transplant patients with CAN had a significantly lower proportion of Tregs than the hemodialysis CKD patients and healthy controls (P < .0001). In contrast, the hemodialysis CKD patients showed higher levels of Tregs than the renal transplant patients with CAN and the healthy controls (P < .0001). CONCLUSION: The high level of peripheral blood Tregs in the hemodialysis CKD patients suggests a chronic inflammatory state. However, the low frequency of Tregs in the peripheral blood from the renal transplant patients with CAN suggests an unfavorable prognosis for allograft immune tolerance.

Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder.

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP-h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

Use of linkage disequilibrium approaches to map genes for bipolar disorder in the Costa Rican population.

Linkage disequilibrium (LD) analysis provides a powerful means for screening the genome to map the location of disease genes, such as those for bipolar disorder (BP). As described in this paper, the population of the Central Valley of Costa Rica, which is descended from a small number of founders, should be suitable for LD mapping; this assertion is supported by reconstruction of extended haplotypes shared by distantly related individuals in this population suffering low-frequency hearing loss (LFHL1), which has previously been mapped by linkage analysis. A sampling strategy is described for applying LD methods to map genes for BP, and clinical and demographic characteristics of an initially collected sample are discussed. This sample will provide a complement to a previously collected set of Costa Rican BP families which is under investigation using standard linkage analysis.

An approach to investigating linkage for bipolar disorder using large Costa Rican pedigrees.

Despite the evidence that major gene effects exist for bipolar disorder (BP), efforts to map BP loci have so far been unsuccessful. A strategy for mapping BP loci is described, focused on investigation of large pedigrees from a genetically homogenous population, that of Costa Rica. This approach is based on the use of a conservative definition of the BP phenotype in preparation for whole genome screening with polymorphic markers. Linkage simulation analyses are utilized to indicate the probability of detecting evidence suggestive of linkage, using these pedigrees. These analyses are performed under a series of single locus models, ranging from recessive to nearly dominant, utilizing both lod score and affected pedigree member analyses. Additional calculations demonstrate that with any of the models employed, most of the information for linkage derives from affected rather than unaffected individuals.

Genome screening for linkage disequilibrium in a Costa Rican sample of patients with bipolar-I disorder: a follow-up study on chromosome 18.

Linkage disequilibrium (LD) methods offer great promise for mapping complex traits, but have thus far been applied sparingly. In this paper we describe an LD mapping study of severe bipolar disorder (BP-I) in the genetically isolated population of the Central Valley of Costa Rica. This study provides the first complete screen of a chromosome for a complex trait using LD mapping and presents the first application of a new LD mapping statistic (ancestral haplotype reconstruction (AHR)) that evaluates haplotype sharing among affected individuals. The results of this chromosome-wide analysis are instructive for genome-wide LD mapping in isolated populations. Furthermore, the analysis continues to support a possible BP-I locus on 18pter, suggested by previous analyses in this population. Evidence for a possible BP-I locus on 18q12.2 is also described.

Diagnosis and treatment of mood disorders that co-occur with schizophrenia.

Affective syndromes, particularly mania and depression, often occur during the course of illness in patients who have a diagnosis of schizophrenia. Our current diagnostic system allows clear classification of the overlap of affective symptoms and psychotic symptoms. However, this diagnostic system will eventually require major revisions so that it will more accurately reflect the biologic mechanisms that underlie different symptoms. This article reviews the historical underpinnings of the diagnostic classification of affective and psychotic symptoms, including a discussion of current diagnostic practices and a review of the few studies on treatment of affective symptoms and syndromes in patients with schizophrenia. There is a great need for additional research on treatment of mood disorders that arise during the course of schizophrenia, especially with regard to newer mood stabilizers and antidepressants.

Water participation for poverty alleviation--the case of Meseta Purépecha, Mexico.

The construction of small water reservoirs has been used in an effort to alleviate poverty in Messeta Purépecha region in Mexico. The programme's rationale can be characterised as incentive-based participation, using both local employment and shared risks concepts. The programme so far has been a relative success. However, in the light of poverty alleviation questions have to be raised about the isolated nature of the programme as well as the role of the incentives used.

[Evaluation of ultrasonographic variables of the endometrium in relation with histopathologic findings in patients with postmenopausal uterine bleeding]. / Evaluación de las variables ultrasonográficas del endometrio en relación con los hallazgos histopatológicos en pacientes con sangrado uterino posmenopáusico.

The purpose of this study was to determine the sensitivity, specificity, positive and negative predictive value of analyzed variables in the ultrasonographic endometrial study in patients with postmenopausal uterine bleeding. Nineteen women with postmenopausal uterine bleeding were studied, in all of them and in the same day a transvaginal ultrasound and endometrial biopsy were performed. It was observed that endometrial thickness median was 4 mm; most of the endometria were proliferative (n = 12), and a greater trend to obesity and upper segment fat distribution was found. Endometrial thickness, refringence and liquid on uterine cavity had a sensitivity and a negative predictive value NPV) of 100%, specificity and positive predictive value were lower. When endometrial thickness and refringence were associated also a sensitivity and NPV of a 100% was found. It can be concluded that transvaginal ultrasound is useful to define in which patient with postmenopausal uterine bleeding the endometrial biopsy is indicated.

[Correlation of histopathologic findings with ultrasonography variables of the endometrium according to body weight and adipose tissue distribution in postmenopause]. / Correlación de los hallozgos histopatológicos con las variables ultrasonográficas del endometrio conforme al peso corporal y distribucióndel tejido adiposo en la posmenopausia.

The purpose of this work was to correlate the histologic findings and ultrasonographic variables of the endometrium in relation to corporal weight and body fat distribution, in two groups of women: one with posmenopausal uterine bleeding and other under hormonal replacement therapy (HRT). Thirty one posmenopausal women were studied and divided into two groups: I. women with posmenopausal uterine bleeding (n = 19) and II women with HRT (conjugated estrogens and chlormadinone) (n = 12). In both groups transvaginal ultrasound was accomplished the same day previous to the endometrial biopsy (EB). The EB was taken in the group I the day they attended the hospital referring transvaginal bleeding and in group I a statistical significant correlation was found among the corporal weight and histologic findings and among the endometrial refringence and the histologic findings. In group II there was a statistical significant correlation among the body fat distribution and endometrial refringence and among the endometrial thickness and histologic findings. It can be concluded that in women with posmenopausal bleeding the corporal weight influences the histologic findings and the refringence is related with histologic findings, while those under HRT is more important the body fat distribution over endometrial refringence and the endometrial thickness is related with histologic findings.