Comparison of (18)F SPECT with PET in myocardial imaging: A realistic thorax-cardiac phantom study

BACKGROUND: Positron emission tomography (PET) imaging with fluorine-18 ((18)F) Fluorodeoxyglucose (FDG) and flow tracer such as Rubidium-82 ((82)Rb) is an established method for evaluating an ischemic but viable myocardium. However, the high cost of PET imaging restricts its wider clinical use. Therefore, less expensive (18)F FDG single photon emission computed tomography (SPECT) imaging has been considered as an alternative to (18)F FDG PET imaging. The purpose of the work is to compare SPECT with PET in myocardial perfusion/viability imaging. METHODS: A nonuniform RH-2 thorax-heart phantom was used in the SPECT and PET acquisitions. Three inserts, 3 cm, 2 cm and 1 cm in diameter, were placed in the left ventricular (LV) wall to simulate infarcts. The phantom acquisition was performed sequentially with 7.4 MBq of (18)F and 22.2 MBq of Technetium-99m ((99m)Tc) in the SPECT study and with 7.4 MBq of (18)F and 370 MBq of (82)Rb in the PET study. SPECT and PET data were processed using standard reconstruction software provided by vendors. Circumferential profiles of the short-axis slices, the contrast and viability of the inserts were used to evaluate the SPECT and PET images. RESULTS: The contrast for 3 cm, 2 cm and 1 cm inserts were for (18)F PET data, 1.0 ± 0.01, 0.67 ± 0.02 and 0.25 ± 0.01, respectively. For (82)Rb PET data, the corresponding contrast values were 0.61 ± 0.02, 0.37 ± 0.02 and 0.19 ± 0.01, respectively. For (18)F SPECT the contrast values were, 0.31 ± 0.03 and 0.20 ± 0.05 for 3 cm and 2 cm inserts, respectively. For (99m)Tc SPECT the contrast values were, 0.63 ± 0.04 and 0.24 ± 0.05 for 3 cm and 2 cm inserts respectively. In SPECT, the 1 cm insert was not detectable. In the SPECT study, all three inserts were falsely diagnosed as "viable", while in the PET study, only the 1 cm insert was diagnosed falsely "viable". CONCLUSION: For smaller defects the (99m)Tc/(18)F SPECT imaging cannot entirely replace the more expensive (82)Rb/(18)F PET for myocardial perfusion/viability imaging, due to poorer image spatial resolution and poorer defect contrast

Site-specific prolapse surgery. I. Reliability and durability of native tissue paravaginal repair

Introduction and hypothesis: This study aims to compare native tissue abdominal and vaginal paravaginal repair, and to investigate whether surgical outcome was independent of operative route. Methods: Retrospective comparison of 111 displacement cysto-urethrocoeles, repaired between 1997 and 2007. Treatment was by surgeon assignment, 52 women having abdominal (APVR) and 59 vaginal paravaginal repairs. Main outcome measures were same-site prolapse recurrence, time to failure and surgical complications. Initial reliability was evaluated by chi-square test, 10-year durability by Kaplan-Meier survival analysis and Cox proportional hazards model. Results: When examined in the Cox proportional hazards model, anatomic results of APVR were more durable than a mechanically analogous transvaginal operation done [95% CI=1.029-2.708 (p value=0.038)]. Kaplan-Meier curves plateaued within 38 months. Symptom resolution was broadly equivalent. Surgical complication rate was 3.6%. Conclusions: Site-specific re-suture of torn native tissue has genuine curative potential. Most of the long-term success was attributable to site-specific repair, rather than nonspecific scar formation.9 page(s

Endometriosis and Headache

Headache and endometriosis show some similarities in their clinical and epidemiological features that are probably due to the influence of female sexual hormones on both disorders. Epidemiological studies indicate that they are comorbid disorders. However, the nature of the comorbidity is not known with certainty, but a likely explanation may be common susceptibility genes. Another possibility is that, because they both are related to pain, increased pain sensitivity induced by one of the disorders may lead to a higher likelihood of developing the other, possibly mediated by nitrogen oxide or prostaglandins. A common link to the widespread use of estroprogestins may seem less probable. For physicians dealing with women with either of these disorders, awareness of the comorbidity may be helpful in the treatment of the patient

Next-gen sequencing identifies non-coding variation disrupting miRNA-binding sites in neurological disorders

Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large-scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome is likely to play an important role in these phenotypes. Herein we show the importance of 3 prime untranslated region (3'UTR) non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from next generation sequencing (NGS) data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant and the affected gene (ARHGEF39) represent new putative risk factors for SLI. Furthermore, we identified 3'UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease

The GABA transporter 1 (SLC6A1): a novel candidate gene for anxiety disorders

Recent evidence suggests that the GABA transporter 1 (GAT-1; SLC6A1) plays a role in the pathophysiology and treatment of anxiety disorders. In order to understand the impact of genetic variation within SLC6A1 on pathological anxiety, we performed a case–control association study with anxiety disorder patients with and without syndromal panic attacks. Using the method of sequential addition of cases, we found that polymorphisms in the 5′ flanking region of SLC6A1 are highly associated with anxiety disorders when considering the severity of syndromal panic attacks as phenotype covariate. Analysing the effect size of the association, we observed a constant increase in the odds ratio for disease susceptibility with an increase in panic severity (OR ~ 2.5 in severely affected patients). Nominally significant association effects were observed considering the entire patient sample. These data indicate a high load of genetic variance within SLC6A1 on pathological anxiety and highlight GAT-1 as a promising target for treatment of anxiety disorders with panic symptoms

Preferential Entry of Botulinum Neurotoxin A Hc Domain through Intestinal Crypt Cells and Targeting to Cholinergic Neurons of the Mouse Intestine

Botulism, characterized by flaccid paralysis, commonly results from botulinum neurotoxin (BoNT) absorption across the epithelial barrier from the digestive tract and then dissemination through the blood circulation to target autonomic and motor nerve terminals. The trafficking pathway of BoNT/A passage through the intestinal barrier is not yet fully understood. We report that intralumenal administration of purified BoNT/A into mouse ileum segment impaired spontaneous muscle contractions and abolished the smooth muscle contractions evoked by electric field stimulation. Entry of BoNT/A into the mouse upper small intestine was monitored with fluorescent HcA (half C-terminal domain of heavy chain) which interacts with cell surface receptor(s). We show that HcA preferentially recognizes a subset of neuroendocrine intestinal crypt cells, which probably represent the entry site of the toxin through the intestinal barrier, then targets specific neurons in the submucosa and later (90–120 min) in the musculosa. HcA mainly binds to certain cholinergic neurons of both submucosal and myenteric plexuses, but also recognizes, although to a lower extent, other neuronal cells including glutamatergic and serotoninergic neurons in the submucosa. Intestinal cholinergic neuron targeting by HcA could account for the inhibition of intestinal peristaltism and secretion observed in botulism, but the consequences of the targeting to non-cholinergic neurons remains to be determined

Comparative genetic architectures of schizophrenia in East Asian and European populations

Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations