Computational analysis of variation in C. elegans ugts.

Caenorhabditis elegans are free-living nematodes with a relatively short life cycle and a wealth of genomic information across multiple databases. Uridine diphosphate-glycosyltransferases (UGTs) are a family of enzymes involved in Phase II modification of xenobiotics in C. elegans , which is the addition of a sizeable water-soluble molecule to a xenobiotic to allow for its excretion out of a cell. Little is known about the variation in UGTs across wild isolates and how that might affect their innate immune response. We analyzed the diversity in ugt genes across C. elegans isolates from different geographical locations from the Caenorhabditis elegans Natural Diversity Resource (CaeNDR) database. This was accomplished using whole genome data and data identifying genome regions as hyper-divergent for each isotype. We implemented three steps to identify ugt genes and make inferences based on their variation. First, we created a catalog of UGTs in the N2 reference strain and used them to create a phylogenetic tree that depicts the relationships between the UGT protein sequences. We then quantified ugt variation using the strains from the CaeNDR database and used their data to remove hyper-divergent ugt genes. The third step was to catalog the occurrence of minor allele frequency (MAF) > 0.05 for all the ugts to compare how that aligned with genes classified as hyper-divergent by CaeNDR. Of the 67 ugt genes analyzed, 18 were hyper-divergent. This research will help improve our understanding of ugt variation in C. elegans .

Atovaquone is active against AML by upregulating the integrated stress pathway and suppressing oxidative phosphorylation.

Atovaquone, a US Food and Drug Administration-approved antiparasitic drug previously shown to reduce interleukin-6/STAT3 signaling in myeloma cells, is well tolerated, and plasma concentrations of 40 to 80 µM have been achieved with pediatric and adult dosing. We conducted preclinical testing of atovaquone with acute myeloid leukemia (AML) cell lines and pediatric patient samples. Atovaquone induced apoptosis with an EC50 <30 µM for most AML lines and primary pediatric AML specimens. In NSG mice xenografted with luciferase-expressing THP-1 cells and in those receiving a patient-derived xenograft, atovaquone-treated mice demonstrated decreased disease burden and prolonged survival. To gain a better understanding of the mechanism of atovaquone, we performed an integrated analysis of gene expression changes occurring in cancer cell lines after atovaquone exposure. Atovaquone promoted phosphorylation of eIF2α, a key component of the integrated stress response and master regulator of protein translation. Increased levels of phosphorylated eIF2α led to greater abundance of the transcription factor ATF4 and its target genes, including proapoptotic CHOP and CHAC1. Furthermore, atovaquone upregulated REDD1, an ATF4 target gene and negative regulator of the mechanistic target of rapamycin (mTOR), and caused REDD1-mediated inhibition of mTOR activity with similar efficacy as rapamycin. Additionally, atovaquone suppressed the oxygen consumption rate of AML cells, which has specific implications for chemotherapy-resistant AML blasts that rely on oxidative phosphorylation for survival. Our results provide insight into the complex biological effects of atovaquone, highlighting its potential as an anticancer therapy with novel and diverse mechanisms of action, and support further clinical evaluation of atovaquone for pediatric and adult AML.

Determinants of psychiatric inpatient admission to general hospital psychiatric wards: an epidemiological study in a region of central Italy.

OBJECTIVE: To determine which factors contribute to the decision to admit individuals to psychiatric wards in general hospitals. METHOD: Data on 1,379 individuals undergoing psychiatric evaluation in eight emergency rooms in a region of central Italy were collected. A logistic regression analysis was used to evaluate the likelihood of psychiatric admission considering the independent effects of demographic, social, and clinical factors and of the history of psychiatric treatment. RESULTS: The adjusted odds ratio for psychiatric admission significantly increased with the following variables: severity of symptoms; presence of paranoid states and schizophrenic psychoses, affective psychoses and acute psychotic conditions (with neurotic disorders used as reference); a history of outpatient treatment; the presence of a staff member of a community mental health facility upon presentation at the emergency room; and the availability of beds in the psychiatric ward. CONCLUSION: The independent effect played by the presence of a staff member of a community mental health facility is of particular interest, suggesting the existence of a collaborative relationship between inpatient and outpatient services.

Integrated history in a psychiatric ward.

The present study begins from the hypothesis that the psychiatric admission can be considered to be, in many cases, a symptomatical act in which the patient, his family, the relational context that sends him and the institution as a whole take part. Such hypothesis has become necessary at the moment of the request for hospitalization, together with news from the patient and from his context about: the sender, the motivations, the type of request, the type of the insufficiency-urgency it is responding, the phenomenon of the "presenting disturbance", a greater definition of the problem by everyone... This work will have the object to look for a correlation between the course of the illness and the life cycle, to attempt to give a historicity of the crisis and the request of the hospitalization, too often presented, lived, received and cured as historically closed.

Couple relationship in hysterical patients staying in a psychiatric ward.

The study starts from the observation about the high frequency of hysteric patient that spontaneously ask the psychiatric admission often with a consent of the husband. The hospitalization has revealed important clinical information, gained by the use of integrated story. In fact extending the observation about the familiar context of the hysteric patient, and in particular to the interaction with the partner, have showed some redundance: 1) patient were especially household; 2) with a lower education level; 3) were married with sons in the age of independency; 4) live important life events; 5) the husbands were often involved with the families of origin; 6) the symptomatology presented; 7) the beginning of the symptomatology often happen after the marriage and the birth of the first son; 8) the husbands of these patients present mostly an obsessive personality with hypochondriac manner; 9) the patient often manifest several dissatisfied request.

High tibial osteotomy in osteoarthrosis of the knee (a long term clinical study of 187 knees).

This is a clinical research study of 415 cases of high tibial osteotomy in arthrosis of the knee, supported by radiographic and aetiopathogenetic data. It is the largest series with complete documentation so far reported in the literature. It is a critical study based on the clinical findings which marks the beginning of a work intended to evaluate the quality of the results during a period of 5-15 years following surgery (187 knees). The results so far confirm the value of the procedure and emphasize the importance of the fixed flexion factor in the probable pathogenesis of pain. It also shows that perfect axial reconstruction in the frontal plane is of lesser comparative importance.