A genome-wide association study of attempted suicide

The heritable component to attempted and completed suicide is partly related to psychiatric disorders and also partly independent of them. Although attempted suicide linkage regions have been identified on 2p11-12 and 6q25-26, there are likely many more such loci, the discovery of which will require a much higher resolution approach, such as the genome-wide association study (GWAS). With this in mind, we conducted an attempted suicide GWAS that compared the single-nucleotide polymorphism (SNP) genotypes of 1201 bipolar (BP) subjects with a history of suicide attempts to the genotypes of 1497 BP subjects without a history of suicide attempts. In all, 2507 SNPs with evidence for association at P<0.001 were identified. These associated SNPs were subsequently tested for association in a large and independent BP sample set. None of these SNPs were significantly associated in the replication sample after correcting for multiple testing, but the combined analysis of the two sample sets produced an association signal on 2p25 (rs300774) at the threshold of genome-wide significance (P=5.07 × 10(-8)). The associated SNPs on 2p25 fall in a large linkage disequilibrium block containing the ACP1 (acid phosphatase 1) gene, a gene whose expression is significantly elevated in BP subjects who have completed suicide. Furthermore, the ACP1 protein is a tyrosine phosphatase that influences Wnt signaling, a pathway regulated by lithium, making ACP1 a functional candidate for involvement in the phenotype. Larger GWAS sample sets will be required to confirm the signal on 2p25 and to identify additional genetic risk factors increasing susceptibility for attempted suicide.     

The effect of topography on differentiation fates of matrigel-coated mouse embryonic stem cells cultured on PLGA nanofibrous scaffolds

Due to pluripotency of embryonic stem (ES) cells, these cells are an invaluable in vitro model that investigates the influence of different physical and chemical cues on differentiation/development pathway of specialized cells. We sought the effect of roughness and alignment, as topomorpholocial properties of scaffolds on differentiation of green fluorescent protein-expressing ES (GFP-ES) cells into three germ layers derivates simultaneously. Furthermore, the effect of Matrigel as a natural extracellular matrix in combination with poly(lactic-co-glycolic acid) (PLGA) nanofibrous scaffolds on differentiation of mouse ES cells has been investigated. The PLGA nanofibrous scaffolds with different height and distribution of roughness and alignments were fabricated. Then, the different cell differentiation fats of GFP-ES cells plated on PLGA and PLGA/Matrigel scaffolds were analyzed by gene expression profiling. The findings demonstrated that distinct ranges of roughness, height, and distribution can support/promote a specific cell differentiation fate on scaffolds. Coating of scaffolds with Matrigel has a synergistic effect in differentiation of mesoderm-derived cells and germ cells from ES cells, whereas it inhibits the derivation of endodermal cell lineages. It was concluded that the topomorpholocial cues such as roughness and alignment should be considered in addition to other scaffolds properties to design an efficient electrospun scaffold for specific tissue engineering.     

Direct Technetium radiopharmaceuticals production using a 30MeV Cyclotron

Background and the purpose of the study

Technetium-99m is the major radionuclide used in the world and mainly is provided by fission product. However extensive research has been conducted on the use of accelerators for production of ^99mTc. This investigation reports the production of ^99mTc radioisotope using cyclotrons and the preparation, quality control and biodistribution studies of four major Tc-radiopharmaceuticals.

Methods

The high purity molybdenum natural target (130 mg/cm²) was irradiated in a Cyclone 30 accelerator using 160 µA of 25 MeV proton beam energy for 1000 µA-h. After dissolution, the technetium radionuclides were extracted using methyl ethyl ketone (MEK) followed by preparation of Tc-MIBI, Tc-DTPA, Tc-DMSA and Tc-phytate as radiopharmaceutical samples.

Results

The results of quality controls and animal biodistribution studies showed successful production of Tc radionuclides (including ^99mTc) in the bombarded target and subsequent labelling of the kit with Tc.

Conclusion

The developed high power Mo target if constructed using enriched ¹⁰⁰Mo, could be a practical method for large-scale production of ^99mTc and promising as an alternative to fission product ⁹⁹Mo-^99mTc generators for local applications near cyclotron facilities.     

Family-based association of FKBP5 in bipolar disorder

The FKBP5 gene product forms part of a complex with the glucocorticoid receptor and can modulate cortisol-binding affinity. Variations in the gene have been associated with increased recurrence of depression and with rapid response to antidepressant treatment. We sought to determine whether common FKBP5 variants confer risk for bipolar disorder. We genotyped seven tag single-nucleotide polymorphisms (SNPs) in FKBP5, plus two SNPs previously associated with illness, in 317 families with 554 bipolar offspring, derived primarily from two studies. Single marker and haplotypic analyses were carried out with FBAT and EATDT employing the standard bipolar phenotype. Association analyses were also conducted using 11 disease-related variables as covariates. Under an additive genetic model, rs4713902 showed significant overtransmission of the major allele (P=0.0001), which was consistent across the two sample sets (P=0.004 and 0.006). rs7757037 showed evidence of association that was strongest under the dominant model (P=0.001). This result was consistent across the two datasets (P=0.017 and 0.019). The dominant model yielded modest evidence for association (P<0.05) for three additional markers. Covariate-based analyses suggested that genetic variation within FKBP5 may influence attempted suicide and number of depressive episodes in bipolar subjects. Our results are consistent with the well-established relationship between the hypothalamic-pituitary-adrenal (HPA) axis, which mediates the stress response through regulation of cortisol, and mood disorders. Ongoing whole-genome association studies in bipolar disorder and major depression should further clarify the role of FKBP5 and other HPA genes in these illnesses.     

Premenstrual mood symptoms: study of familiality and personality correlates in mood disorder pedigrees

We sought to determine whether premenstrual mood symptoms exhibit familial aggregation in bipolar disorder or major depression pedigrees. Two thousand eight hundred seventy-six women were interviewed with the Diagnostic Interview for Genetic Studies as part of either the NIMH Genetics Initiative Bipolar Disorder Collaborative study or the Genetics of Early Onset Major Depression (GenRED) study and asked whether they had experienced severe mood symptoms premenstrually. In families with two or more female siblings with bipolar disorder (BP) or major depressive disorder (MDD), we examined the odds of having premenstrual mood symptoms given one or more siblings with these symptoms. For the GenRED MDD sample we also assessed the impact of personality as measured by the NEO-FFI. Premenstrual mood symptoms did not exhibit familial aggregation in families with BP or MDD. We unexpectedly found an association between high NEO openness scores and premenstrual mood symptoms, but neither this factor, nor NEO neuroticism influenced evidence for familial aggregation of symptoms. Limitations include the retrospective interview, the lack of data on premenstrual dysphoric disorder, and the inability to control for factors such as medication use.     

Confronting infertility in Iranian clients: a grounded theory

The present study examined how infertile Iranian clients confront infertility. Research on infertility has confirmed the significance of a socio-cultural context in the formation of responses to infertility. This study used the grounded theory approach to explore the experiences of infertile individuals presenting at the Royan Institute in Iran from October 2013 to September 2014. Clients with infertility of at least two years in duration were recruited using purposive sampling followed by theoretical sampling. A total of 41 interviews were conducted with 36 people. Data were collected through in-depth unstructured interviews and field notes. Data analysis was performed using MAXQDA 2007. A sense of ‘insecurity about personal and family identity’ shaped in the context of ‘facing the cultural-economic dilemmas’ was identified as the main concern of infertile clients. The clients dealt with this concern through a series of strategies that included gradual acceptance of infertility, seeking information and consultation, pursuing treatment, focusing on saving the marriage, self-control and resilience and fighting inner turmoil. All these approaches suggest ‘protecting personal and family identity’ as the core concept. The findings highlight the need for the health care system to treat infertility as a broad concept than mere individual and biological dysfunction.     

Characterization of azurocidin as a permeability factor in the retina: involvement in VEGF-induced and early diabetic blood-retinal barrier breakdown

PURPOSE: Azurocidin, released by neutrophils during leukocyte-endothelial interaction, is a main cause of neutrophil-evoked vascular leakage. Its role in the retina, however, is unknown. METHODS: Brown Norway rats received intravitreal injections of azurocidin and vehicle control. Blood-retinal barrier (BRB) breakdown was quantified using the Evans blue (EB) dye technique 1, 3, and 24 hours after intravitreal injection. To block azurocidin, aprotinin was injected intravenously before the intravitreal injections. To investigate whether azurocidin plays a role in vascular endothelial growth factor (VEGF)-induced BRB breakdown, rats were treated intravenously with aprotinin, followed by intravitreal injection of VEGF(164). BRB breakdown was quantified 24 hours later. To investigate whether azurocidin may mediate BRB breakdown in early diabetes, aprotinin or vehicle was injected intravenously each day for 2 weeks to streptozotocin-induced diabetic rats, and BRB breakdown was quantified. RESULTS: Intravitreal injection of azurocidin (20 microg) induced a 6.8-fold increase in vascular permeability compared with control at 1-3 hours (P < 0.05), a 2.7-fold increase at 3 to 5 hours (P < 0.01), and a 1.7-fold increase at 24 hours (P < 0.05). Aprotinin inhibited azurocidin-induced BRB breakdown by more than 95% (P < 0.05). Furthermore, treatment with aprotinin significantly suppressed VEGF-induced BRB breakdown by 93% (P < 0.05) and BRB breakdown in early experimental diabetes by 40.6% (P < 0.05). CONCLUSIONS: Azurocidin increases retinal vascular permeability and is effectively blocked by aprotinin. The inhibition of VEGF-induced and early diabetic BRB breakdown with aprotinin indicates that azurocidin may be an important mediator of leukocyte-dependent BRB breakdown secondary to VEGF. Azurocidin may become a new therapeutic target in the treatment of retinal vascular leakage, such as during diabetic retinopathy.     

Hematologic risk factors of vascular disease and their relation to dementia

Multiple studies have implicated vascular-related conditions as risk factors for dementia. Clarification of these factors in dementia is important because most are modifiable, and may serve as the basis for preventive strategies. Several hematologic factors are associated with vascular diseases, but their relation to dementia is unclear. This review examines biological and epidemiological evidence concerning the role of these hematologic factors in dementia, and dementia subtypes. Reviewed factors include homocysteine, cholesterol, fatty acids, antioxidants, and C-reactive protein. The vast majority of studies reviewed are cross-sectional. Longitudinal studies with serial hematologic measures are needed to clarify the relationship between these factors and dementia over the lifespan. A necessary step is to examine multiple hematologic factors simultaneously, rather than in isolation, to determine how these factors are interrelated.