Olanzapine and fluoxetine combination therapy for treatment-resistant depression: review of efficacy, safety, and study design issues

Treatment-resistant depression (TRD) is a common occurrence in clinical practice. Up to 30% of patients with major depression do not respond to conventional antidepressant treatment, while a significantly greater number of patients experience only partial symptom reduction. Numerous strategies may be applied by the practicing clinician to overcome limitations in the effectiveness of antidepressant monotherapy, including combining drug treatment with evidence-supported psychotherapies, combining antidepressants (combination pharmacotherapy), and combining antidepressants with other non-antidepressant psychotropic medications (augmentation treatment). One such augmentation strategy, the combination of the selective serotonin reuptake inhibitor, fluoxetine (FLX), with the atypical antipsychotic drug, olanzapine (OLZ), is supported by the results of four randomized, double-blind, acute phase studies of patients who had responded inadequately to antidepressant monotherapy. In each study, the FLX/OLZ combination caused rapid reduction in Montgomery-Asberg Depression Rating scale scores, with two of the four studies showing significantly greater improvement than antidepressant monotherapy at study endpoint. Effects of the FLX/OLZ combination were strongest in cases where failure to respond to two antidepressants prior to randomization was established during the current depressive episode. The FLX/OLZ combination was well-tolerated; however, body weight gain and increases in prolactin were greater than that of the antidepressant monotherapy groups, and were comparable to that of OLZ monotherapy. While effective during acute-phase treatment, questions remain regarding the long-term efficacy and safety of FLX/OLZ relative to antidepressant monotherapy and other combination strategies. Efforts aimed at determining the placement of FLX/OLZ among the available options for addressing TRD are limited by lack of comparison and sequential treatment studies. Important aspects of study design and directions for future research are discussed

Greenhouse and Field Evaluations of Entomopathogenic Nematodes (Nematode: Heterorhabditidae and Steinernematidae) for Control of Cabbage Maggot (Diopters: Anthomyiidae) on Cabbage

Entomb pathogenic nematodes-Heterorhabditis bacteriophora Poinar (Oswego strain), Steinenema carpocapsae (Weiser) (NY001 strain), Steinemema carpocapsae (25 strain), Steinemema feltiae Filipjev (=Neoaplectana carpocapsae Weiser) (369 strain), Steinernema feltiae (27 strain), and Steinernema riobravus Cabanillas and Poinar (355 strain)-were examined for pathogenicity against cabbage maggot, Delia radicum (L.), larvae in the greenhouse and field. Applications (per plant) of 3,000 and 4,000 infective juveniles of S. feltiae (369 strain), 30,000 infective juveniles of H. bacteriophora (Oswego strain), and 300 and 30,000 infective juveniles of S. feltiae (27 strain) reduced the number of D. radicum that developed to pupae on potted cabbage plants. H. bacteriophora (Oswego) at applications of 3,000 and 30,000 infective juveniles per plant and S. feltiae (27 strain) at applications of 30,000 (but not 3,000) infective juveniles per plant significantly reduced root damage caused by larvae of D. radicum. Logarithmically increased dosages between 100 and 100,000 infective juveniles per plant of S. feltiae (27 strain) linearly reduced the number of D. radicum pupae that developed on potted cabbage plants and the damage caused to the roots by D. radicullarvae. Root and stem dry weights of cabbage plants infested with D. radicum were significantly greater for plants inoculated with 100,000 infective juveniles of S. feltiae (27 strain) than for plants not inoculated with nematodes. Nematode inoculation did not prevent significant losses in root or stem dry weights at dosages less than 100,000 infective juveniles per plant. Soil surface applications of 100,000 and 200,000 infective juveniles per plant of S. feltiae (27 strain) were more effective than subsurface applications in preventing damage by natural or augmented populations of D. radicum larvae on cabbage in the field. However, mortality rates of wax moth larvae exposed to soil samples treated with S. feltiae (27 strain) suggested that this nematode showed greater persistence when applied beneath rather than on the soil surfac

Interactions between Two Cytoskeleton-associated Tyrosine Kinases: Calcium-dependent Tyrosine Kinase and Focal Adhesion Tyrosine Kinase

The calcium-dependent tyrosine kinase (CADTK), also known as Pyk2/RAFTK/CAKbeta/FAK2, is a cytoskeleton-associated tyrosine kinase. We compared CADTK regulation with that of the highly homologous focal adhesion tyrosine kinase (FAK). First, we generated site-specific CADTK mutants. Mutation of Tyr402 eliminated autophosphorylation and significantly decreased kinase activity. Mutation of Tyr881, a putative Src kinase phosphorylation site predicted to bind Grb2, had little effect on CADTK regulation. Src family tyrosine kinases resulted in CADTK tyrosine phosphorylation even when co-expressed with the Tyr402/Tyr881 double mutant, suggesting that Src/Fyn etc. phosphorylate additional tyrosine residues. Interestingly, CADTK tyrosine-phosphorylated FAK when both were transiently expressed, but FAK did not phosphorylate CADTK. Biochemical experiments confirmed direct CADTK phosphorylation of FAK. This phosphorylation utilized tyrosine residues other than Tyr397, Tyr925, or Tyr576/Tyr577, suggesting that new SH2-binding sites might be created by CADTK-dependent FAK phosphorylation. Last, expression of the CADTK carboxyl terminus (CRNK) abolished CADTK but not FAK autophosphorylation. In contrast, FAK carboxyl terminus overexpression inhibited both FAK and CADTK autophosphorylation, suggesting that a FAK-dependent cytoskeletal function may be necessary for CADTK activation. Thus, CADTK and FAK, which both bind to some, but not necessarily the same, cytoskeletal elements, may be involved in coordinate regulation of cytoskeletal structure and signaling

MADNESS: A Multiresolution, Adaptive Numerical Environment for Scientific Simulation

MADNESS (multiresolution adaptive numerical environment for scientific simulation) is a high-level software environment for solving integral and differential equations in many dimensions that uses adaptive and fast harmonic analysis methods with guaranteed precision based on multiresolution analysis and separated representations. Underpinning the numerical capabilities is a powerful petascale parallel programming environment that aims to increase both programmer productivity and code scalability. This paper describes the features and capabilities of MADNESS and briefly discusses some current applications in chemistry and several areas of physics

Effect of Composting on the Fate of Steroids in Beef Cattle Manure

In this study, the fate of steroid hormones in beef cattle manure composting is evaluated. The fate of 16 steroids and metabolites was evaluated in composted manure from beef cattle administered growth promotants and from beef cattle with no steroid hormone implants. The fate of estrogens (primary detected as estrone), androgens, progesterone, and the fusarium metabolite and implant a-zearalanol was monitored in manure compost piles. First-order decay rates were calculated for steroid half-lives in compost and ranged from 8 d for androsterone to 69 d for 4-androstenedione. Other steroid concentration data could not be fit to first-order decay models, which may indicate that microbial processes may result in steroid production or synthesis in composting systems. We demonstrate that composting is an effective strategy to remove steroid hormones from manure. Total steroid hormone removal in composted beef cattle manure ranged from 79 to 87%

Effect of rainfall timing and tillage on the transport of steroidhormones in runoff from manure amended row crop fields

Runoff generated from livestock manure amended row crop fields is one of the major pathways of hormone transport to the aquatic environment. The study determined the effects of manure handling, tillage methods, and rainfall timing on the occurrence and transport of steroid hormones in runoff from the row crop field. Stockpiled and composted manure from hormone treated and untreated animals were applied to test plots and subjected to two rainfall simulation events 30 days apart. During the two rainfall simulation events, detection of any steroid hormone or metabolites was identified in 8–86% of runoff samples from any tillage and manure treatment. The most commonly detected hormones were 17 _estradiol, estrone, estriol, testosterone, and _zearalenol at concentrations ranging up to 100–200 ng L−1. Considering the maximum detected concentrations in runoff, no more than 10% of the applied hormone can be transported through the dissolved phase of runoff. Results from the study indicate that hormones can persist in soils receiving livestock manure over an extended period of time and the dissolved phase of hormone in runoff is not the preferred pathway of transport from the manure applied fields irrespective of tillage treatments and timing of rainfall

Divergent patterns of incorporation of bromodeoxyuridine and iododeoxyuridine in human colorectal tumor cell lines

Using a panel of four human colorectal tumor (HCT) cell lines, we have quantitatively characterized the incorporation of bromodeoxyuridine (BrdUrd) and iododeoxyuridine (IdUrd) into DNA, both as individual agents and in combination with fluoropyrimidines. The intrinsic ability of these cell lines to incorporate BrdUrd, as reflected by the concentration required to achieve half- maximal incorporation, varied almost 4-fold across this panel, from 1.6 [mu]M for HuTu80 cells to 6.1 [mu]M for HT29 cells. Three of the four cell lines (HT29, SW480, SW620) responded to fluoropyrimidines as expected, displaying 100-150% increases in BrdUrd incorporation when combined with growth inhibitory concentrations of fluorouracil (FUra). In contrast, neither FUra nor fluorodeoxyuridine (FdUrd) was able to increase BrdUrd incorporation in HuTu80 cells by more than 25%, even in the presence of 100 [mu]M leucovorin. IdUrd incorporation was modulated to a substantially higher degree in both HT29 and HuTu80 cell lines. Finally we demonstrate the feasibility of a technique for evaluating the net effect of fluoropyrimidine treatments on de novo thymidine nucleotide production in a single specimen, using a combination of normotopic and stable-isotope labeled BrdUrd. We propose that this approach may be useful in evaluating the response of an individual tumor to fluoropyrimidines in vivo.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29276/1/0000335.pd

The State of Research on Racial and Ethnic Discrimination in the Receipt of Health Care

https://ajph.aphapublications.org/doi/pdf/10.2105/AJPH.2012.30077

HER4 D-Box Sequences Regulate Mitotic Progression and Degradation of the Nuclear HER4 Cleavage Product s80HER4

Heregulin-mediated activation of HER4 initiates receptor cleavage (releasing an 80-kDa HER4 intracellular domain, s80HER4, containing nuclear localization sequences) and results in G2/M delay by unknown signaling mechanisms. We report herein that s80HER4 contains a functional cyclin B-like sequence known as a D-box, which targets proteins for degradation by APC/C, a multisubunit ubiquitin ligase. s80HER4 ubiquitination and ptoteosomal degradation occurred during mitosis but not during S-phase. Inhibition of an APC subunit (APC2) using siRNA knock-down impaired s80HER4 degradation. Mutation of the s80HER4 D-box sequence stabilized s80HER4 during mitosis, and s80HER4-dependent growth inhibition via G2/M delay was significantly greater with the D-box mutant. Polyomvirus middle-T antigen-transformed HC11 cells expressing s80HER4 resulted in smaller, less proliferative, more differentiated tumors in vivo than those expressing kinase-dead s80HER4 or the empty vector. Cells expressing s80HER4 with a disrupted D-box did not form tumors, instead forming differentiated ductal structures. These results suggest that cell cycle-dependent degradation of s80HER4 limits its growth inhibitory action, and stabilization of s80HER4 enhances tumor suppression, thus providing a link between HER4-mediated growth inhibition and cell cycle control