Comparison of Side Effects with Extended Release Epidural Morphine and Other Analgesic Modalities

Opioids are the mainstay of post-operative pain management and may produce side effects that impact patient recovery. Use of Extended Release Epidural Morphine (EREM) has been shown to result in significantly less average morphine usage and to have superior analgesic efficacy than other modes of postoperative pain management. The purpose of this retrospective review was to compare the incidence and onset of side effects of ERE and other post-operative Analgesic regiments

Spinal anesthesia: should everyone receive a urinary catheter?: a randomized, prospective study of patients undergoing total hip arthroplasty.

BACKGROUND: The objective of this randomized prospective study was to determine whether a urinary catheter is necessary for all patients undergoing total hip arthroplasty under spinal anesthesia. METHODS: Consecutive patients undergoing total hip arthroplasty under spinal anesthesia were randomized to treatment with or without insertion of an indwelling urinary catheter. All patients received spinal anesthesia with 15 to 30 mg of 0.5% bupivacaine. The catheter group was subjected to a standard postoperative protocol, with removal of the indwelling catheter within forty-eight hours postoperatively. The experimental group was monitored for urinary retention and, if necessary, had straight catheterization up to two times prior to the placement of an indwelling catheter. RESULTS: Two hundred patients were included in the study. There was no significant difference between the two groups in terms of the prevalence of urinary retention, the prevalence of urinary tract infection, or the length of stay. Nine patients in the no-catheter group and three patients in the catheter group (following removal of the catheter) required straight catheterization because of urinary retention. Three patients in the catheter group and no patient in the no-catheter group had development of urinary tract infection. CONCLUSIONS: Patients undergoing total hip arthroplasty under spinal anesthesia appear to be at low risk for urinary retention. Thus, a routine indwelling catheter is not required for such patients

Collaborative Enhancement of Antibody Binding to Distinct PECAM-1 Epitopes Modulates Endothelial Targeting

Antibodies to platelet endothelial cell adhesion molecule-1 (PECAM-1) facilitate targeted drug delivery to endothelial cells by “vascular immunotargeting.” To define the targeting quantitatively, we investigated the endothelial binding of monoclonal antibodies (mAbs) to extracellular epitopes of PECAM-1. Surprisingly, we have found in human and mouse cell culture models that the endothelial binding of PECAM-directed mAbs and scFv therapeutic fusion protein is increased by co-administration of a paired mAb directed to an adjacent, yet distinct PECAM-1 epitope. This results in significant enhancement of functional activity of a PECAM-1-targeted scFv-thrombomodulin fusion protein generating therapeutic activated Protein C. The “collaborative enhancement” of mAb binding is affirmed in vivo, as manifested by enhanced pulmonary accumulation of intravenously administered radiolabeled PECAM-1 mAb when co-injected with an unlabeled paired mAb in mice. This is the first demonstration of a positive modulatory effect of endothelial binding and vascular immunotargeting provided by the simultaneous binding a paired mAb to adjacent distinct epitopes. The “collaborative enhancement” phenomenon provides a novel paradigm for optimizing the endothelial-targeted delivery of therapeutic agents

Molecular Modeling-Based Evaluation of hTLR10 and Identification of Potential Ligands in Toll-Like Receptor Signaling

Toll-like receptors (TLRs) are pattern recognition receptors that recognize pathogens based on distinct molecular signatures. The human (h)TLR1, 2, 6 and 10 belong to the hTLR1 subfamilies, which are localized in the extracellular regions and activated in response to diverse ligand molecules. Due to the unavailability of the hTLR10 crystal structure, the understanding of its homo and heterodimerization with hTLR2 and hTLR1 and the ligand responsible for its activation is limited. To improve our understanding of the TLR10 receptor-ligand interaction, we used homology modeling to construct a three dimensional (3D) structure of hTLR10 and refined the model through molecular dynamics (MD) simulations. We utilized the optimized structures for the molecular docking in order to identify the potential site of interactions between the homo and heterodimer (hTLR10/2 and hTLR10/1). The docked complexes were then used for interaction with ligands (Pam3CSK4 and PamCysPamSK4) using MOE-Dock and ASEDock. Our docking studies have shown the binding orientations of hTLR10 heterodimer to be similar with other TLR2 family members. However, the binding orientation of hTLR10 homodimer is different from the heterodimer due to the presence of negative charged surfaces at the LRR11-14, thereby providing a specific cavity for ligand binding. Moreover, the multiple protein-ligand docking approach revealed that Pam3CSK4 might be the ligand for the hTLR10/2 complex and PamCysPamSK4, a di-acylated peptide, might activate hTLR10/1 hetero and hTLR10 homodimer. Therefore, the current modeled complexes can be a useful tool for further experimental studies on TLR biology

Characterisation of heart failure with normal ejection fraction in a tertiary hospital in Nigeria

<p>Abstract</p> <p>Background</p> <p>The study aimed to determine the frequency and characteristics of heart failure with normal EF in a native African population with heart failure.</p> <p>Methods</p> <p>It was a hospital cohort study. Subjects were 177 consecutive individuals with heart failure and ninety apparently normal control subjects. All the subjects underwent transthoracic echocardiography. The group with heart failure was further subdivided into heart failure with normal EF (EF ≥ 50) (HFNEF) and heart failure with low EF(EF <50)(HFLEF).</p> <p>Results</p> <p>The subjects with heart failure have a mean age of 52.3 ± 16.64 years vs 52.1 ± 11.84 years in the control subjects; p = 0.914. Other baseline characteristics except blood pressure parameters and height were comparable between the group with heart failure and the control subjects. The frequency of HFNEF was 39.5%. Compared with the HFLEF group, the HFNEF group have a smaller left ventricular diameter (in diastole and systole): (5.2 ± 1.22 cm vs 6.2 ± 1.39 cm; p < 0.0001 and 3.6 ± 1.24 cm vs 5.4 ± 1.35 cm;p < 0.0001) respectively, a higher relative wall thickness and deceleration time of the early mitral inflow velocity: (0.4 ± 0.12 vs 0.3 ± 0.14 p < 0.0001 and 149.6 ± 72.35 vs 110.9 ± 63.40 p = 0.001) respectively.</p> <p>The two groups with heart failure differed significantly from the control subjects in virtually all echocardiographic measurements except aortic root diameter, LV posterior wall thickness(HFLEF), and late mitral inflow velocity(HFNEF). HFNEF accounted for 70(39.5%) of cases of heart failure in this study.</p> <p>Hypertension is the underlying cardiovascular disease in 134(75.7%) of the combined heart failure population, 58 (82.9%) of the subjects with HFNEF group and 76(71%) of the HFLEF group. Females accounted for 44 (62.9%) of the subjects with HFNEF against 42(39.3%) in the HFLEF group (p = 0.002).</p> <p>Conclusion</p> <p>The frequency of heart failure with normal EF in this native African cohort with heart failure is comparable with the frequency in other populations. These groups of patients are more likely female, hypertensive with concentric pattern of left ventricular hypertrophy.</p

Cloning, Functional Characterization and Nutritional Regulation of Delta 6 Fatty Acyl Desaturase in the Herbivorous Euryhaline Teleost Scatophagus Argus

Marine fish are generally unable or have low ability for the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFA) from C18 PUFA precursors, with some notable exceptions including the herbivorous marine teleost Siganus canaliculatus in which such a capability was recently demonstrated. To determine whether this is a unique feature of S. canaliculatus or whether it is common to the herbivorous marine teleosts, LC-PUFA biosynthetic pathways were investigated in the herbivorous euryhaline Scatophagus argus. A putative desaturase gene was cloned and functionally characterized, and tissue expression and nutritional regulation were investigated. The full-length cDNA was 1972 bp, containing a 1338 bp open-reading frame encoding a polypeptide of 445 amino acids, which possessed all the characteristic features of fatty acyl desaturase (Fad). Functional characterization by heterologous expression in yeast showed the protein product of the cDNA efficiently converted 18:3n-3 and 18:2n-6 to 18:4n-3 and 18:3n-6, respectively, indicating D6 desaturation activity. Quantitative real-time PCR showed that highest D6 fad mRNA expression was detected in liver followed by brain, with lower expression in other tissues including intestine, eye, muscle, adipose, heart kidney and gill, and lowest expression in stomach and spleen. The expression of D6 fad was significantly affected by dietary lipid and, especially, fatty acid composition, with highest expression of mRNA in liver of fish fed a diet with a ratio of 18:3n-3/18:2n-6 of 1.72:1. The results indicated that S. argus may have a different LC-PUFA biosynthetic system from S. canaliculatus despite possessing similar habitats and feeding habits suggesting that LC-PUFA biosynthesis may not be common to all marine herbivorous teleosts

Identifying Consensus Disease Pathways in Parkinson's Disease Using an Integrative Systems Biology Approach

Parkinson's disease (PD) has had six genome-wide association studies (GWAS) conducted as well as several gene expression studies. However, only variants in MAPT and SNCA have been consistently replicated. To improve the utility of these approaches, we applied pathway analyses integrating both GWAS and gene expression. The top 5000 SNPs (p<0.01) from a joint analysis of three existing PD GWAS were identified and each assigned to a gene. For gene expression, rather than the traditional comparison of one anatomical region between sets of patients and controls, we identified differentially expressed genes between adjacent Braak regions in each individual and adjusted using average control expression profiles. Over-represented pathways were calculated using a hyper-geometric statistical comparison. An integrated, systems meta-analysis of the over-represented pathways combined the expression and GWAS results using a Fisher's combined probability test. Four of the top seven pathways from each approach were identical. The top three pathways in the meta-analysis, with their corrected p-values, were axonal guidance (p = 2.8E-07), focal adhesion (p = 7.7E-06) and calcium signaling (p = 2.9E-05). These results support that a systems biology (pathway) approach will provide additional insight into the genetic etiology of PD and that these pathways have both biological and statistical support to be important in PD

Maturation of GABAergic Inhibition Promotes Strengthening of Temporally Coherent Inputs among Convergent Pathways

Spike-timing-dependent plasticity (STDP), a form of Hebbian plasticity, is inherently stabilizing. Whether and how GABAergic inhibition influences STDP is not well understood. Using a model neuron driven by converging inputs modifiable by STDP, we determined that a sufficient level of inhibition was critical to ensure that temporal coherence (correlation among presynaptic spike times) of synaptic inputs, rather than initial strength or number of inputs within a pathway, controlled postsynaptic spike timing. Inhibition exerted this effect by preferentially reducing synaptic efficacy, the ability of inputs to evoke postsynaptic action potentials, of the less coherent inputs. In visual cortical slices, inhibition potently reduced synaptic efficacy at ages during but not before the critical period of ocular dominance (OD) plasticity. Whole-cell recordings revealed that the amplitude of unitary IPSCs from parvalbumin positive (Pv+) interneurons to pyramidal neurons increased during the critical period, while the synaptic decay time-constant decreased. In addition, intrinsic properties of Pv+ interneurons matured, resulting in an increase in instantaneous firing rate. Our results suggest that maturation of inhibition in visual cortex ensures that the temporally coherent inputs (e.g. those from the open eye during monocular deprivation) control postsynaptic spike times of binocular neurons, a prerequisite for Hebbian mechanisms to induce OD plasticity