Treatment of hepatic epithelioid hemangioendothelioma with liver transplantation

Ten patients received liver transplants for unresectable epithelioid hemangioendothelioma (EHE). At the time of transplantation, four patients had microscopic metastases to the hilar lymph nodes, and one of the four also had metastases to a rib. The fifth patient had metastases to the lung, pleura, and diaphragm. The remaining five patients were believed to be free of metastatic disease. Two of these five patients died of metastatic disease at 3 and 16 months, respectively, after transplantation. Interestingly, all five patients with metastatic involvement are currently alive 40.6 ± 22 months (mean ± standard error of mean [SEM]) after transplantation, although one of these patients currently has metastatic disease to the lungs and mediastinum. Thus, the projected 5‐year actuarial survival rate is 76%, with two patients at risk after the third year. In conclusion, liver transplantation is a reasonable procedure for bulky, otherwise unresectable, EHE even in the presence of metastatic disease. Copyright © 1988 American Cancer Societ

Are genetic risk factors for psychosis also associated with dimension-specific psychotic experiences in adolescence?

Psychosis has been hypothesised to be a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder represent its extreme manifestations. Evidence suggests that common genetic variants play an important role in liability to both schizophrenia and bipolar disorder. Here we tested the hypothesis that these common variants would also influence psychotic experiences measured dimensionally in adolescents in the general population. Our aim was to test whether schizophrenia and bipolar disorder polygenic risk scores (PRS), as well as specific single nucleotide polymorphisms (SNPs) previously identified as risk variants for schizophrenia, were associated with adolescent dimension-specific psychotic experiences. Self-reported Paranoia, Hallucinations, Cognitive Disorganisation, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms, as measured by the Specific Psychotic Experiences Questionnaire (SPEQ), were assessed in a community sample of 2,152 16-year-olds. Polygenic risk scores were calculated using estimates of the log of odds ratios from the Psychiatric Genomics Consortium GWAS stage-1 mega-analysis of schizophrenia and bipolar disorder. The polygenic risk analyses yielded no significant associations between schizophrenia and bipolar disorder PRS and the SPEQ measures. The analyses on the 28 individual SNPs previously associated with schizophrenia found that two SNPs in TCF4 returned a significant association with the SPEQ Paranoia dimension, rs17512836 (p-value=2.57x10-4) and rs9960767 (p-value=6.23x10-4). Replication in an independent sample of 16-year-olds (N=3,427) assessed using the Psychotic-Like Symptoms Questionnaire (PLIKS-Q), a composite measure of multiple positive psychotic experiences, failed to yield significant results. Future research with PRS derived from larger samples, as well as larger adolescent validation samples, would improve the predictive power to test these hypotheses further. The challenges of relating adult clinical diagnostic constructs such as schizophrenia to adolescent psychotic experiences at a genetic level are discussed

Extreme genetic fragility of the HIV-1 capsid

Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency >3%, and were also present in the mutant library, had fitness levels that were >40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies

Impact of episiotomy on pelvic floor disorders and their influence on women's wellness after the sixth month postpartum: a retrospective study

<p>Abstract</p> <p>Background</p> <p>The role of episiotomy as a protective factor against pelvic floor disorders postpartum has been debated for many years, but its routine use has been hitherto discouraged in the literature. Comparisons between restrictive and routine use of episiotomy in existent literature, however, fail to include any consideration relating to quality of life. The aim of this study, therefore, is to state the role of episiotomy in preserving the perineum from damage, in order to prevent the influence of pelvic floor disorders on women's psycho-physical wellness after the sixth month postpartum.</p> <p>Methods</p> <p>A follow-up telephone interview was performed among 377 primiparous and secondiparous Caucasian women who had a child by spontaneous or operative vaginal delivery in 2006 using a self-created questionnaire and King's Health Questionnaire (KHQ).</p> <p>Results</p> <p>The mean age at delivery was 35.26 (±4.68) years and episiotomy was performed in 59.2% of women. Multivariate linear regression shows episiotomy associated to higher quality of life after the sixth month postpartum by correlating with inferior values of King's Health Questionnaire (p < 0.05).</p> <p>Conclusions</p> <p>Episiotomy appears to be a protective factor for women's wellness. Women who had episiotomy and who experienced perineal symptoms have a better psycho-physical health status in the 12.79 months (±3.3) follow-up.</p

An accurate and efficient identification of children with psychosocial problems by means of computerized adaptive testing

Background: Questionnaires used by health services to identify children with psychosocial problems are often rather short. The psychometric properties of such short questionnaires are mostly less than needed for an accurate distinction between children with and without problems. We aimed to assess whether a short Computerized Adaptive Test (CAT) can overcome the weaknesses of short written questionnaires when identifying children with psychosocial problems. Method: We used a Dutch national data set obtained from parents of children invited for a routine health examination by Preventive Child Healthcare with 205 items on behavioral and emotional problems (n = 2,041, response 84%). In a random subsample we determined which items met the requirements of an Item Response Theory (IRT) model to a sufficient degree. Using those items, item parameters necessary for a CAT were calculated and a cut-off point was defined. In the remaining subsample we determined the validity and efficiency of a Computerized Adaptive Test using simulation techniques, with current treatment status and a clinical score on the Total Problem Scale (TPS) of the Child Behavior Checklist as criteria. Results: Out of 205 items available 190 sufficiently met the criteria of the underlying IRT model. For 90% of the children a score above or below cut-off point could be determined with 95% accuracy. The mean number of items needed to achieve this was 12. Sensitivity and specificity with the TPS as a criterion were 0.89 and 0.91, respectively. Conclusion: An IRT-based CAT is a very promising option for the identification of psychosocial problems in children, as it can lead to an efficient, yet high-quality identification. The results of our simulation study need to be replicated in a real-life administration of this CAT

Loss of Pluripotency in Human Embryonic Stem Cells Directly Correlates with an Increase in Nuclear Zinc

The pluripotency of human embryonic stem cells (hESCs) is important to investigations of early development and to cell replacement therapy, but the mechanism behind pluripotency is incompletely understood. Zinc has been shown to play a key role in differentiation of non-pluripotent cell types, but here its role in hESCs is directly examined. By mapping the distribution of metals in hESCs at high resolution by x-ray fluorescence microprobe (XFM) and by analyzing subcellular metal content, we have found evidence that loss of pluripotency is directly correlated with an increase in nuclear zinc. Zinc elevation not only redefines our understanding of the mechanisms that support pluripotency, but also may act as a biomarker and an intervention point for stem cell differentiation

The Effect of Rural-to-Urban Migration on Obesity and Diabetes in India: A Cross-Sectional Study

Shah Ebrahim and colleagues examine the distribution of obesity, diabetes, and other cardiovascular risk factors among urban migrant factory workers in India, together with their rural siblings. The investigators identify patterns of change of cardiovascular risk factors associated with urban migration

Post-Training Dephosphorylation of eEF-2 Promotes Protein Synthesis for Memory Consolidation

Memory consolidation, which converts acquired information into long-term storage, is new protein synthesis-dependent. As protein synthesis is a dynamic process that is under the control of multiple translational mechanisms, however, it is still elusive how these mechanisms are recruited in response to learning for memory consolidation. Here we found that eukaryotic elongation factor-2 (eEF-2) was dramatically dephosphorylated within 0.5–2 hr in the hippocampus and amygdala of mice following training in a fear-conditioning test, whereas genome-wide microarrays did not reveal any significant change in the expression level of the mRNAs for translational machineries or their related molecules. Moreover, blockade of NMDA receptors with MK-801 immediately following the training significantly impeded both the post-training eEF-2 dephosphorylation and memory retention. Notably, with an elegant sophisticated transgenic strategy, we demonstrated that hippocampus-specific overexpression of eEF-2 kinase, a kinase that specifically phosphorylates and hence inactivates eEF-2, significantly inhibited protein synthesis in the hippocampus, and this effects was more robust during an “ongoing” protein synthesis process. As a result, late phase long-term potentiation (L-LTP) in the hippocampus and long-term hippocampus-dependent memory in the mice were significantly impaired, whereas short-term memory and long-term hippocampus-independent memory remained intact. These results reveal a novel translational underpinning for protein synthesis pertinent to memory consolidation in the mammalian brain

Protective Efficacy of Serially Up-Ranked Subdominant CD8+ T Cell Epitopes against Virus Challenges

Immunodominance in T cell responses to complex antigens like viruses is still incompletely understood. Some data indicate that the dominant responses to viruses are not necessarily the most protective, while other data imply that dominant responses are the most important. The issue is of considerable importance to the rational design of vaccines, particularly against variable escaping viruses like human immunodeficiency virus type 1 and hepatitis C virus. Here, we showed that sequential inactivation of dominant epitopes up-ranks the remaining subdominant determinants. Importantly, we demonstrated that subdominant epitopes can induce robust responses and protect against whole viruses if they are allowed at least once in the vaccination regimen to locally or temporally dominate T cell induction. Therefore, refocusing T cell immune responses away from highly variable determinants recognized during natural virus infection towards subdominant, but conserved regions is possible and merits evaluation in humans