Escitalopram—translating molecular properties into clinical benefit: reviewing the evidence in major depression

The majority of currently marketed drugs contain a mixture of enantiomers; however, recent evidence suggests that individual enantiomers can have pharmacological properties that differ importantly from enantiomer mixtures. Escitalopram, the S-enantiomer of citalopram, displays markedly different pharmacological activity to the R-enantiomer. This review aims to evaluate whether these differences confer any significant clinical advantage for escitalopram over either citalopram or other frequently used antidepressants. Searches were conducted using PubMed and EMBASE (up to January 2009). Abstracts of the retrieved studies were reviewed independently by both authors for inclusion. Only those studies relating to depression or major depressive disorder were included. The search identified over 250 citations, of which 21 studies and 18 pooled or meta-analyses studies were deemed suitable for inclusion. These studies reveal that escitalopram has some efficacy advantage over citalopram and paroxetine, but no consistent advantage over other selective serotonin reuptake inhibitors. Escitalopram has at least comparable efficacy to available serotonin-norepinephrine reuptake inhibitors, venlafaxine XR and duloxetine, and may offer some tolerability advantages over these agents. This review suggests that the mechanistic advantages of escitalopram over citalopram translate into clinical efficacy advantages. Escitalopram may have a favourable benefit-risk ratio compared with citalopram and possibly with several other antidepressant agents

Key Role of Polyphosphoinositides in Dynamics of Fusogenic Nuclear Membrane Vesicles

The role of phosphoinositides has been thoroughly described in many signalling and membrane trafficking events but their function as modulators of membrane structure and dynamics in membrane fusion has not been investigated. We have reconstructed models that mimic the composition of nuclear envelope precursor membranes with naturally elevated amounts of phosphoinositides. These fusogenic membranes (membrane vesicle 1(MV1) and nuclear envelope remnants (NER) are critical for the assembly of the nuclear envelope. Phospholipids, cholesterol, and polyphosphoinositides, with polyunsaturated fatty acid chains that were identified in the natural nuclear membranes by lipid mass spectrometry, have been used to reconstruct complex model membranes mimicking nuclear envelope precursor membranes. Structural and dynamic events occurring in the membrane core and at the membrane surface were monitored by solid-state deuterium and phosphorus NMR. “MV1-like” (PC∶PI∶PIP∶PIP2, 30∶20∶18∶12, mol%) membranes that exhibited high levels of PtdIns, PtdInsP and PtdInsP2 had an unusually fluid membrane core (up to 20% increase, compared to membranes with low amounts of phosphoinositides to mimic the endoplasmic reticulum). “NER-like” (PC∶CH∶PI∶PIP∶PIP2, 28∶42∶16∶7∶7, mol%) membranes containing high amounts of both cholesterol and phosphoinositides exhibited liquid-ordered phase properties, but with markedly lower rigidity (10–15% decrease). Phosphoinositides are the first lipids reported to counterbalance the ordering effect of cholesterol. At the membrane surface, phosphoinositides control the orientation dynamics of other lipids in the model membranes, while remaining unchanged themselves. This is an important finding as it provides unprecedented mechanistic insight into the role of phosphoinositides in membrane dynamics. Biological implications of our findings and a model describing the roles of fusogenic membrane vesicles are proposed

Use of Tissue-Specific MicroRNA to Control Pathology of Wild-Type Adenovirus without Attenuation of Its Ability to Kill Cancer Cells

Replicating viruses have broad applications in biomedicine, notably in cancer virotherapy and in the design of attenuated vaccines; however, uncontrolled virus replication in vulnerable tissues can give pathology and often restricts the use of potent strains. Increased knowledge of tissue-selective microRNA expression now affords the possibility of engineering replicating viruses that are attenuated at the RNA level in sites of potential pathology, but retain wild-type replication activity at sites not expressing the relevant microRNA. To assess the usefulness of this approach for the DNA virus adenovirus, we have engineered a hepatocyte-safe wild-type adenovirus 5 (Ad5), which normally mediates significant toxicity and is potentially lethal in mice. To do this, we have included binding sites for hepatocyte-selective microRNA mir-122 within the 39 UTR of the E1A transcription cassette. Imaging versions of these viruses, produced by fusing E1A with luciferase, showed that inclusion of mir-122 binding sites caused up to 80-fold decreased hepatic expression of E1A following intravenous delivery to mice. Animals administered a ten-times lethal dose of wild-type Ad5 (5610 10 viral particles/mouse) showed substantial hepatic genome replication and extensive liver pathology, while inclusion of 4 microRNA binding sites decreased replication 50-fold and virtually abrogated liver toxicity. This modified wild-type virus retained full activity within cancer cells and provided a potent, liver-safe oncolytic virus. In addition to providing many potent new viruses for cancer virotherapy, microRNA control of virus replication should provide a new strategy for designing safe attenuated vaccines applied across a broad range of viral disease

MicroRNA Controlled Adenovirus Mediates Anti-Cancer Efficacy without Affecting Endogenous MicroRNA Activity

MicroRNAs are small non-coding RNA molecules that regulate mRNA translation and stability by binding to complementary sequences usually within the 3′ un-translated region (UTR). We have previously shown that the hepatic toxicity caused by wild-type Adenovirus 5 (Ad5WT) in mice can be prevented by incorporating 4 binding sites for the liver-specific microRNA, mir122, into the 3′ UTR of E1A mRNA. This virus, termed Ad5mir122, is a promising virotherapy candidate and causes no obvious liver pathology. Herein we show that Ad5mir122 maintains wild-type lytic activity in cancer cells not expressing mir122 and assess any effects of possible mir122 depletion in host cells. Repeat administration of 2×1010 viral particles of Admir122 to HepG2 tumour bearing mice showed significant anti-cancer efficacy. RT-QPCR showed that E1A mRNA was down-regulated 29-fold in liver when compared to Ad5WT. Western blot for E1A confirmed that all protein variants were knocked down. RT-QPCR for mature mir122 in infected livers showed that quantity of mir122 remained unaffected. Genome wide mRNA microarray profiling of infected livers showed that although the transcript level of >3900 different mRNAs changed more than 2-fold following Ad5WT infection, less than 600 were changed by Ad5mir122. These were then filtered to select mRNAs that were only altered by Ad5mir122 and the remaining 21 mRNAs were compared to predicted mir122 targets. No mir122 target mRNAs were affected by Ad5 mir122. These results demonstrate that the exploitation of microRNA regulation to control virus replication does not necessarily affect the level of the microRNA or the endogenous mRNA targets

Autism and Intellectual Disability Are Differentially Related to Sociodemographic Background at Birth

Background: Research findings investigating the sociodemographics of autism spectrum disorder (ASD) have been inconsistent and rarely considered the presence of intellectual disability (ID). Methods: We used population data on Western Australian singletons born from 1984 to 1999 (n = 398,353) to examine the sociodemographic characteristics of children diagnosed with ASD with or without ID, or ID without ASD compared with non-affected children. Results: The profiles for the four categories examined, mild-moderate ID, severe ID, ASD without ID and ASD with ID varied considerably and we often identified a gradient effect where the risk factors for mild-moderate ID and ASD without ID were at opposite extremes while those for ASD with ID were intermediary. This was demonstrated clearly with increased odds of ASD without ID amongst older mothers aged 35 years and over (odds ratio (OR) = 1.69 [CI: 1.18, 2.43]), first born infants (OR = 2.78; [CI: 1.67, 4.54]), male infants (OR = 6.57 [CI: 4.87, 8.87]) and increasing socioeconomic advantage. In contrast, mild-moderate ID was associated with younger mothers aged less than 20 years (OR = 1.88 [CI: 1.57, 2.25]), paternal age greater than 40 years (OR = 1.59 [CI: 1.36, 1.86]), Australian-born and Aboriginal mothers (OR = 1.60 [CI: 1.41, 1.82]), increasing birth order and increasing social disadvantage (OR = 2.56 [CI: 2.27, 2.97]). Mothers of infants residing in regional or remote areas had consistently lower risk of ASD or ID and may be linked to reduced access to services or underascertainment rather than a protective effect of location. Conclusions: The different risk profiles observed between groups may be related to aetiological differences or ascertainment factors or both. Untangling these pathways is challenging but an urgent public health priority in view of the supposed autism epidemic

Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1

Aberrant transforming growth factor–β (TGF-β) signaling is a hallmark of the stromal microenvironment in cancer. Dickkopf-3 (Dkk-3), shown to inhibit TGF-β signaling, is downregulated in prostate cancer and upregulated in the stroma in benign prostatic hyperplasia, but the function of stromal Dkk-3 is unclear. Here we show that DKK3 silencing in WPMY-1 prostate stromal cells increases TGF-β signaling activity and that stromal cellconditioned media inhibit prostate cancer cell invasion in a Dkk-3-dependent manner. DKK3 silencing increased the level of the cell-adhesion regulator TGF-β–induced protein (TGFBI) in stromal and epithelial cell-conditioned media, and recombinant TGFBI increased prostate cancer cell invasion. Reduced expression of Dkk-3 in patient tumors was associated with increased expression of TGFBI. DKK3 silencing reduced the level of extracellular matrix protein-1 (ECM-1) in prostate stromal cell-conditioned media but increased it in epithelial cell-conditioned media, and recombinant ECM-1 inhibited TGFBI-induced prostate cancer cell invasion. Increased ECM1 and DKK3 mRNA expression in prostate tumors was associated with increased relapse-free survival. These observations are consistent with a model in which the loss of Dkk-3 in prostate cancer leads to increased secretion of TGFBI and ECM-1, which have tumor-promoting and tumor-protective roles, respectively. Determining how the balance between the opposing roles of extracellular factors influences prostate carcinogenesis will be key to developing therapies that target the tumor microenvironment

Is Canada ready for patient accessible electronic health records? A national scan

<p>Abstract</p> <p>Background</p> <p>Access to personal health information through the electronic health record (EHR) is an innovative means to enable people to be active participants in their own health care. Currently this is not an available option for consumers of health. The absence of a key technology, the EHR, is a significant obstacle to providing patient accessible electronic records. To assess the readiness for the implementation and adoption of EHRs in Canada, a national scan was conducted to determine organizational readiness and willingness for patient accessible electronic records.</p> <p>Methods</p> <p>A survey was conducted of Chief Executive Officers (CEOs) of Canadian public and acute care hospitals.</p> <p>Results</p> <p>Two hundred thirteen emails were sent to CEOs of Canadian general and acute care hospitals, with a 39% response rate. Over half (54.2%) of hospitals had some sort of EHR, but few had a record that was predominately electronic. Financial resources were identified as the most important barrier to providing patients access to their EHR and there was a divergence in perceptions from healthcare providers and what they thought patients would want in terms of access to the EHR, with providers being less willing to provide access and patients desire for greater access to the full record.</p> <p>Conclusion</p> <p>As the use of EHRs becomes more commonplace, organizations should explore the possibility of responding to patient needs for clinical information by providing access to their EHR. The best way to achieve this is still being debated.</p

The Ubiquitin-Proteasome Reporter GFPu Does Not Accumulate in Neurons of the R6/2 Transgenic Mouse Model of Huntington's Disease

Impairment of the ubiquitin-proteasome system (UPS) has long been considered an attractive hypothesis to explain the selective dysfunction and death of neurons in polyglutamine disorders such as Huntington's disease (HD). The fact that inclusion bodies in HD mouse models and patient brains are rich in ubiquitin and proteasome components suggests that the UPS may be hindered directly or indirectly by inclusion bodies or their misfolded monomeric or oligomeric precursors. However, studies into UPS function in various polyglutamine disease models have yielded conflicting results, suggesting mutant polyglutamine tracts may exert different effects on the UPS depending on protein context, expression level, subcellular localisation and cell-type. To investigate UPS function in a well-characterised mouse model of HD, we have crossed R6/2 HD mice with transgenic UPS reporter mice expressing the GFPu construct. The GFPu construct comprises GFP fused to a constitutive degradation signal (CL-1) that promotes its rapid degradation under conditions of a healthy UPS. Using a combination of immunoblot analysis, fluorescence and immunofluorescence microscopy studies, we found that steady-state GFPu levels were not detectably different between R6/2 and non-R6/2 brain. We observed no correlation between inclusion body formation and GFPu accumulation, suggesting no direct relationship between protein aggregation and global UPS inhibition in R6/2 mice. These findings suggest that while certain branches of the UPS can be impaired by mutant polyglutamine proteins, such proteins do not necessarily cause total blockade of UPS-dependent degradation. It is therefore likely that the relationship between mutant polyglutamine proteins and the UPS is more complex than originally anticipated