Subcortical shape alterations in major depressive disorder: Findings from the ENIGMA major depressive disorder working group

Alterations in regional subcortical brain volumes have been investigated as part of the efforts of an international consortium, ENIGMA, to identify reliable neural correlates of major depressive disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work by precisely mapping localized MDD-related differences in subcortical regions using shape analysis. In this meta-analysis of subcortical shape from the ENIGMA-MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta-analysis. Relative to CTL, patients with adolescent-onset MDD (≤ 21 years) had lower thickness and surface area of the subiculum, cornu ammonis (CA) 1 of the hippocampus and basolateral amygdala (Cohen's d = ?0.164 to ?0.180). Relative to first-episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala (Cohen's d = ?0.173 to ?0.184). Our results suggest that previously reported MDD-associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features.     

Characterization of Hantavirus N Protein Intracellular Dynamics and Localization

Hantaviruses are enveloped viruses that possess a tri-segmented, negative-sense RNA genome. The viral S-segment encodes the multifunctional nucleocapsid protein (N), which is involved in genome packaging, intracellular protein transport, immunoregulation, and several other crucial processes during hantavirus infection. In this study, we generated fluorescently tagged N protein constructs derived from Puumalavirus (PUUV), the dominant hantavirus species in Central, Northern, and Eastern Europe. We comprehensively characterized this protein in the rodent cell line CHO-K1, monitoring the dynamics of N protein complex formation and investigating co-localization with host proteins as well as the viral glycoproteins Gc and Gn. We observed formation of large, fibrillar PUUV N protein aggregates, rapidly coalescing from early punctate and spike-like assemblies. Moreover, we found significant spatial correlation of N with vimentin, actin, and P-bodies but not with microtubules. N constructs also co-localized with Gn and Gc albeit not as strongly as the glycoproteins associated with each other. Finally, we assessed oligomerization of N constructs, observing efficient and concentration-dependent multimerization, with complexes comprising more than 10 individual proteins.     

Intrapericardial Mature Cystic Teratoma in an Adult: Case Presentation

Cardiac Teratoma is a tumor of very rare occurrence in adult population. Here we report a case in a Caucasian male with history of Human immunodeficiency virus infection where the symptom as presentation was recurrent episodes of tachycardia. The chest radiograph showed a lesion in the right heart border and subsequent investigation revealed an intrapericardial lesion, which was demonstrated to be a pericardial teratoma diagnosed by histopathology. In this case the initial differential diagnosis included lymphoma or an infectious organism as possible causes in a immunocompromised patient. Cardiac teratomas are among the less common types of cardiac tumors being more frequent in child population and around 1% of all the cardiac tumors in adults. Imaging studies are very helpful. CT and MRI are the best due to their resolution and ability to assess the relationship of the mass with the surrounding structures. Echocardiogram in also helpful determining the presence of pericardial effusion because cardiac teratomas are most of the time present in the pericardium. The final diagnosis is mostly made after surgical excision and this is the most effective treatment because they are relatively resistant to chemotherapy and radiotherapy. The authors have no funding, financial relationships, or conflicts of interest to disclose.     

Use of yeast-secreted in vivo biotinylated recombinant antibodies (Biobodies) in bead-based ELISA.

PURPOSE: To measure circulating antigens, sandwich ELISA assays require two complementary affinity reagents. Mouse monoclonal antibodies (mAb) and polyclonal antibodies (pAb) are commonly used, but because their production is lengthy and costly, recombinant antibodies are emerging as an attractive alternative. EXPERIMENTAL DESIGN: We developed a new class of recombinant antibodies called biobodies (Bb) and compared them to mAb for use in serodiagnosis. Bbs were secreted biotinylated in vivo by diploid yeast and used as affinity reagents after Ni purification. Bead-based assays for HE4 and mesothelin were developed using Bbs in combination with pAbs (Bb/pAb assays). To assess precision, reproducibility studies were done using four runs of 16 replicates at six analyte levels for each marker. Pearson correlations and receiver-operator characteristic analyses were done in 214 patient serum samples to directly compare the Bb/pAb assays to mAb assays. Diagnostic performance of the Bb/pAb assay was further assessed in an expanded set of 336 ovarian cancer cases and controls. RESULTS: On average across analyte levels, Bb/pAb assays yielded within-run and between-run coefficients of variations of 11.7 and 23.8, respectively, for HE4 and 14.0 and 14.5, respectively, for mesothelin. In the subset (n = 214), Pearson correlations of 0.95 for HE4 and 0.92 for mesothelin were observed between mAb and Bb/pAb assays. The area under the curves for the mAb and Bb/pAb assays were not significantly different for HE4 (0.88 and 0.84, respectively; P = 0.20) or mesothelin (0.74 and 0.72, respectively; P = 0.38). CONCLUSION: Yeast-secreted Bbs can be used reliably in cost-effective yet highly sensitive bead-based assays for use in large validation studies.     

Methyl tertiary butyl ether lacks tumor-promoting activity in N-nitrosodiethylamine-initiated B6C3F1 female mouse liver

Methyl tertiary butyl ether (MTBE) is an additive in some formulationsof unleaded gasoline (UG) that enhances octane and reduces carbonmonoxide emissions from motor vehicles. MTBE in CD-I mice andUG in B6C3F1 mice increased the incidence of liver tumors selectivelyin female mice in their chronic bioassays. Both agents werenegative in in vitro tests of genotoxicity, and exhibit similarhepatic microsomal cytochrome P450 activity and hepatocyte proliferationafter short-term exposure. We previously demonstrated that UGhas hepatic tumor-promoting activity in DEN-initiated femaleB6C3F1 mice. Thus, we hypothesized that MTBE would have hepatictumor-promoting activity in the same initiation-promotion modelsystem in which UG was a hepatic tumor promoter. Twelve-day-oldfemale B6C3F1 mice were initiated with a single i.p. injectionof the mutagen N-nitrosodiethylamine (DEN) (5 mg DEN/kg, 7.1ml/kg body weight) or saline. Beginning at 8 weeks of age, micewere exposed to 0 ppm or the hepatocarcinogenic dose of approximately8000 ppm MTBE. After subchronic exposure, MTBE significantlyincreased liver weight and hepatic microsomal cytochrome P450activity without hepa-totoxicity or an increase in non-focalhepatocyte DNA synthesis. These are subchronic effects similarto those produced by UG. However, MTBE did not significantlyincrease the mean size of hepatic foci and volume fraction ofthe liver occupied by foci as compared to DEN-initiated controlsat either 16 or 32 weeks. The lack of tumor-promoting abilityof MTBE in DEN-initiated female mouse liver was unexpected andsuggests that MTBE does not produce liver tumors through a tumor-promotingmechanism similar to that of UG.     

Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome

Membrane cofactor protein (MCP; CD46) is a widely expressed transmembrane complement regulator. Like factor H it inhibits complement activation by regulating C3b deposition on targets. Factor H mutations occur in 10-20% of patients with hemolytic uremic syndrome (HUS). We hypothesized that MCP mutations could predispose to HUS, and we sequenced MCP coding exons in affected individuals from 30 families. MCP mutations were detected in affected individuals of three families: a deletion of two amino acids (D237/S238) in family 1 (heterozygous) and a substitution, S206P, in families 2 (heterozygous) and 3 (homozygous). We evaluated protein expression and function in peripheral blood mononuclear cells from these individuals. An individual with the D237/S238 deletion had reduced MCP levels and approximately 50% C3b binding compared with normal controls. Individuals with the S206P change expressed normal quantities of protein, but demonstrated approximately 50% reduction in C3b binding in heterozygotes and complete lack of C3b binding in homozygotes. MCP expression and function was evaluated in transfectants reproducing these mutations. The deletion mutant was retained intracellularly. S206P protein was expressed on the cell surface but had a reduced ability to prevent complement activation, consistent with its reduced C3b binding and cofactor activity. This study presents further evidence that complement dysregulation predisposes to development of thrombotic microangiopathy and that screening patients for such defects could provide informed treatment strategies.