A prospective, randomized, double-blinded single-site control study comparing blood loss prevention of tranexamic acid (TXA) to epsilon aminocaproic acid (EACA) for corrective spinal surgery

<p>Abstract</p> <p>Background</p> <p>Multilevel spinal fusion surgery has typically been associated with significant blood loss. To limit both the need for transfusions and co-morbidities associated with blood loss, the use of anti-fibrinolytic agents has been proposed. While there is some literature comparing the effectiveness of tranexamic acid (TXA) to epsilon aminocaproic acid (EACA) in cardiac procedures, there is currently no literature directly comparing TXA to EACA in orthopedic surgery.</p> <p>Methods/Design</p> <p>Here we propose a prospective, randomized, double-blinded control study evaluating the effects of TXA, EACA, and placebo for treatment of adolescent idiopathic scoliosis (AIS), neuromuscular scoliosis (NMS), and adult deformity (AD) via corrective spinal surgery. Efficacy will be determined by intraoperative and postoperative blood loss. Other clinical outcomes that will be compared include transfusion rates, preoperative and postoperative hemodynamic values, and length of hospital stay after the procedure.</p> <p>Discussion</p> <p>The primary goal of the study is to determine perioperative blood loss as a measure of the efficacy of TXA, EACA, and placebo. Based on current literature and the mechanism by which the medications act, we hypothesize that TXA will be more effective at reducing blood loss than EACA or placebo and result in improved patient outcomes.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov ID: NCT00958581</p

Molecular Mechanisms of Bortezomib Resistant Adenocarcinoma Cells

Bortezomib (Velcade™) is a reversible proteasome inhibitor that is approved for the treatment of multiple myeloma (MM). Despite its demonstrated clinical success, some patients are deprived of treatment due to primary refractoriness or development of resistance during therapy. To investigate the role of the duration of proteasome inhibition in the anti-tumor response of bortezomib, we established clonal isolates of HT-29 adenocarcinoma cells adapted to continuous exposure of bortezomib. These cells were ∼30-fold resistant to bortezomib. Two novel and distinct mutations in the β5 subunit, Cys63Phe, located distal to the binding site in a helix critical for drug binding, and Arg24Cys, found in the propeptide region were found in all resistant clones. The latter mutation is a natural variant found to be elevated in frequency in patients with MM. Proteasome activity and levels of both the constitutive and immunoproteasome were increased in resistant cells, which correlated to an increase in subunit gene expression. These changes correlated with a more rapid recovery of proteasome activity following brief exposure to bortezomib. Increased recovery rate was not due to increased proteasome turnover as similar findings were seen in cells co-treated with cycloheximide. When we exposed resistant cells to the irreversible proteasome inhibitor carfilzomib we noted a slower rate of recovery of proteasome activity as compared to bortezomib in both parental and resistant cells. Importantly, carfilzomib maintained its cytotoxic potential in the bortezomib resistant cell lines. Therefore, resistance to bortezomib, can be overcome with irreversible inhibitors, suggesting prolonged proteasome inhibition induces a more potent anti-tumor response

The Interplay Between GUT and Flavour Symmetries in a Pati-Salam x S4 Model

Both Grand Unified symmetries and discrete flavour symmetries are appealing ways to describe apparent structures in the gauge and flavour sectors of the Standard Model. Both symmetries put constraints on the high energy behaviour of the theory. This can give rise to unexpected interplay when building models that possess both symmetries. We investigate on the possibility to combine a Pati-Salam model with the discrete flavour symmetry $S_4$ that gives rise to quark-lepton complementarity. Under appropriate assumptions at the GUT scale, the model reproduces fermion masses and mixings both in the quark and in the lepton sectors. We show that in particular the Higgs sector and the running Yukawa couplings are strongly affected by the combined constraints of the Grand Unified and family symmetries. This in turn reduces the phenomenologically viable parameter space, with high energy mass scales confined to a small region and some parameters in the neutrino sector slightly unnatural. In the allowed regions, we can reproduce the quark masses and the CKM matrix. In the lepton sector, we reproduce the charged lepton masses, including bottom-tau unification and the Georgi-Jarlskog relation as well as the two known angles of the PMNS matrix. The neutrino mass spectrum can present a normal or an inverse hierarchy, and only allowing the neutrino parameters to spread into a range of values between $\lambda^{-2}$ and $\lambda^2$, with $\lambda\simeq0.2$. Finally, our model suggests that the reactor mixing angle is close to its current experimental bound.Comment: 62 pages, 4 figures; references added, version accepted for publication in JHE

3T3 Cell Lines Stably Expressing Pax6 or Pax6(5a) – A New Tool Used for Identification of Common and Isoform Specific Target Genes

Pax6 and Pax6(5a) are two isoforms of the evolutionary conserved Pax6 gene often co-expressed in specific stochiometric relationship in the brain and the eye during development. The Pax6(5a) protein differs from Pax6 by having a 14 amino acid insert in the paired domain, causing the two proteins to have different DNA binding specificities. Difference in functions during development is proven by the fact that mutations in the 14 amino acid insertion for Pax6(5a) give a slightly different eye phenotype than the one described for Pax6. Whereas quite many Pax6 target genes have been published during the last years, few Pax6(5a) specific target genes have been reported on. However, target genes identified by Pax6 knockout studies can probably be Pax6(5a) targets as well, since this isoform also will be affected by the knockout. In order to identify new Pax6 target genes, and to try to distinguish between genes regulated by Pax6 and Pax6(5a), we generated FlpIn-3T3 cell lines stably expressing Pax6 or Pax6(5a). RNA was harvested from these cell lines and used in gene expression microarrays where we identified a number of genes differentially regulated by Pax6 and Pax6(5a). A majority of these were associated with the extracellular region. By qPCR we verified that Ncam1, Ngef, Sphk1, Dkk3 and Crtap are Pax6(5a) specific target genes, while Tgfbi, Vegfa, EphB2, Klk8 and Edn1 were confirmed as Pax6 specific target genes. Nbl1, Ngfb and seven genes encoding different glycosyl transferases appeared to be regulated by both. Direct binding to the promoters of Crtap, Ctgf, Edn1, Dkk3, Pdgfb and Ngef was verified by ChIP. Furthermore, a change in morphology of the stably transfected Pax6 and Pax6(5a) cells was observed, and the Pax6 expressing cells were shown to have increased proliferation and migration capacities

Bryostatin Modulates Latent HIV-1 Infection via PKC and AMPK Signaling but Inhibits Acute Infection in a Receptor Independent Manner

HIV's ability to establish long-lived latent infection is mainly due to transcriptional silencing in resting memory T lymphocytes and other non dividing cells including monocytes. Despite an undetectable viral load in patients treated with potent antiretrovirals, current therapy is unable to purge the virus from these latent reservoirs. In order to broaden the inhibitory range and effectiveness of current antiretrovirals, the potential of bryostatin was investigated as an HIV inhibitor and latent activator. Bryostatin revealed antiviral activity against R5- and X4-tropic viruses in receptor independent and partly via transient decrease in CD4/CXCR4 expression. Further, bryostatin at low nanomolar concentrations robustly reactivated latent viral infection in monocytic and lymphocytic cells via activation of Protein Kinase C (PKC) -α and -δ, because PKC inhibitors rottlerin and GF109203X abrogated the bryostatin effect. Bryostatin specifically modulated novel PKC (nPKC) involving stress induced AMP Kinase (AMPK) inasmuch as an inhibitor of AMPK, compound C partially ablated the viral reactivation effect. Above all, bryostatin was non-toxic in vitro and was unable to provoke T-cell activation. The dual role of bryostatin on HIV life cycle may be a beneficial adjunct to the treatment of HIV especially by purging latent virus from different cellular reservoirs such as brain and lymphoid organs

Micropropagation and conservation of selected endangered anticancer medicinal plants from the Western Ghats of India

Globally, cancer is a constant battle which severely affects the human population. The major limitations of the anticancer drugs are the deleterious side effects on the quality of life. Plants play a vital role in curing many diseases with minimal or no side effects. Phytocompounds derived from various medicinal plants serve as the best source of drugs to treat cancer. The global demand for phytomedicines is mostly reached by the medicinal herbs from the tropical nations of the world even though many plant species are threatened with extinction. India is one of the mega diverse countries of the world due to its ecological habitats, latitudinal variation, and diverse climatic range. Western Ghats of India is one of the most important depositories of endemic herbs. It is found along the stretch of south western part of India and constitutes rain forest with more than 4000 diverse medicinal plant species. In recent times, many of these therapeutically valued herbs have become endangered and are being included under the red-listed plant category in this region. Due to a sharp rise in the demand for plant-based products, this rich collection is diminishing at an alarming rate that eventually triggered dangerous to biodiversity. Thus, conservation of the endangered medicinal plants has become a matter of importance. The conservation by using only in situ approaches may not be sufficient enough to safeguard such a huge bio-resource of endangered medicinal plants. Hence, the use of biotechnological methods would be vital to complement the ex vitro protection programs and help to reestablish endangered plant species. In this backdrop, the key tools of biotechnology that could assist plant conservation were developed in terms of in vitro regeneration, seed banking, DNA storage, pollen storage, germplasm storage, gene bank (field gene banking), tissue bank, and cryopreservation. In this chapter, an attempt has been made to critically review major endangered medicinal plants that possess anticancer compounds and their conservation aspects by integrating various biotechnological tool

Galectin-3C Inhibits Tumor Growth and Increases the Anticancer Activity of Bortezomib in a Murine Model of Human Multiple Myeloma

Galectin-3 is a human lectin involved in many cellular processes including differentiation, apoptosis, angiogenesis, neoplastic transformation, and metastasis. We evaluated galectin-3C, an N-terminally truncated form of galectin-3 that is thought to act as a dominant negative inhibitor, as a potential treatment for multiple myeloma (MM). Galectin-3 was expressed at varying levels by all 9 human MM cell lines tested. In vitro galectin-3C exhibited modest anti-proliferative effects on MM cells and inhibited chemotaxis and invasion of U266 MM cells induced by stromal cell-derived factor (SDF)-1α. Galectin-3C facilitated the anticancer activity of bortezomib, a proteasome inhibitor approved by the FDA for MM treatment. Galectin-3C and bortezomib also synergistically inhibited MM-induced angiogenesis activity in vitro. Delivery of galectin-3C intravenously via an osmotic pump in a subcutaneous U266 cell NOD/SCID mouse model of MM significantly inhibited tumor growth. The average tumor volume of bortezomib-treated animals was 19.6% and of galectin-3C treated animals was 13.5% of the average volume of the untreated controls at day 35. The maximal effect was obtained with the combination of galectin-3C with bortezomib that afforded a reduction of 94% in the mean tumor volume compared to the untreated controls at day 35. In conclusion, this is the first study to show that inhibition of galectin-3 is efficacious in a murine model of human MM. Our results demonstrated that galectin-3C alone was efficacious in a xenograft mouse model of human MM, and that it enhanced the anti-tumor activity of bortezomib in vitro and in vivo. These data provide the rationale for continued testing of galectin-3C towards initiation of clinical trials for treatment of MM

Pax6 Expression Is Sufficient to Induce a Neurogenic Fate in Glial Progenitors of the Neonatal Subventricular Zone

The forebrain subventricular zone (SVZ) of neonatal mammals contains a large, heterogeneous population of migratory and proliferating precursors of interneurons and glia. These cell types are produced in large numbers in the immediate postnatal period, the glioblasts populating the hemispheres with astrocytes and oligodendrocytes, the neuroblasts migrating to the olfactory bulb to become interneurons. How cell fate decisions are determined or stabilized in this mixed population is not clear, although previous studies indicate the importance of two transcription factors, Pax6 in neurons and Olig2 in glia, and suggest there may be reciprocal repression between these genes.In examining the SVZ of neonatal mouse and rat brain, we find that the very large majority of SVZ cells express either Pax6 or Olig2, but few express both. We have used in vivo retro- and lenti-virus injections into the neonatal SVZ and in vitro gene transfer to demonstrate that pax6 over-expression is sufficient to down-regulate olig2 and to promote a neuronal lineage development and migration pattern in olig2-expressing cells. Furthermore, we provide evidence that Pax6 binds to the olig2 promoter and that an HEB sequence in the promoter is required for the Pax6 repression of olig2 transcription. Lastly, we constructed a lentivirus to target olig2-expressing cells in the SVZ to trace their fates, and found that the very large majority developed into glia.We provide evidence for a direct repression of olig2 by Pax6. Since SVZ cells can display developmental plasticity in vitro, the cross-repression promotes a stabilization of cell fates. This repression may be critical in a germinal zone in which immature cells are highly migratory and are not organized into an epithelium

A new growth chart for preterm babies: Babson and Benda's chart updated with recent data and a new format

BACKGROUND: The Babson and Benda 1976 "fetal-infant growth graph" for preterm infants is commonly used in neonatal intensive care. Its limits include the small sample size which provides low confidence in the extremes of the data, the 26 weeks start and the 500 gram graph increments. The purpose of this study was to develop an updated growth chart beginning at 22 weeks based on a meta-analysis of published reference studies. METHODS: The literature was searched from 1980 to 2002 for more recent data to complete the pre and post term sections of the chart. Data were selected from population studies with large sample sizes. Comparisons were made between the new chart and the Babson and Benda graph. To validate the growth chart the growth results from the National Institute of Child Health and Human Development Neonatal Research Network (NICHD) were superimposed on the new chart. RESULTS: The new data produced curves that generally followed patterns similar to the old growth graph. Mean differences between the curves of the two charts reached statistical significance after term. Babson's 10(th )percentiles fell between the new data percentiles: the 5th to 17th for weight, the 5th and 15th for head circumference, and the 6th and 16th for length. The growth patterns of the NICHD infants deviated away from the curves of the chart in the first weeks after birth. When the infants reached an average weight of 2 kilograms, those with a birthweight in the range of 700 to 1000 grams had achieved greater than the 10(th )percentile on average for head growth, but remained below the 3(rd )percentile for weight and length. CONCLUSION: The updated growth chart allows a comparison of an infant's growth first with the fetus as early as 22 weeks and then with the term infant to 10 weeks. Comparison of the size of the NICHD infants at a weight of 2 kilograms provides evidence that on average preterm infants are growth retarded with respect to weight and length while their head size has caught up to birth percentiles. As with all meta-analyses, the validity of this growth chart is limited by the heterogeneity of the data sources. Further validation is needed to illustrate the growth patterns of preterm infants to older ages