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1.  Genetic analysis of candidate SNPs for metabolic syndrome in obstructive sleep apnea (OSA) 
Gene  2013;521(1):150-154.
Obstructive sleep apnea (OSA) is a common disorder characterized by the reduction or complete cessation in airflow resulting from an obstruction of the upper airway. Several studies have observed an increased risk for cardiovascular morbidity and mortality among OSA patients. Metabolic syndrome (MetS), a cluster of cardiovascular risk factors characterized by the presence of insulin resistance, is often found in patients with OSA, but the complex interplay between these two syndromes is not well understood. In this study, we present the results of a genetic association analysis of 373 candidate SNPs for MetS selected in a previous genome wide association analysis (GWAS). The 384 selected SNPs were genotyped using the Illumina VeraCode Technology in 387 subjects retrospectively assessed at the Internal Medicine Unit of the “Virgen de Valme” University Hospital (Seville, Spain). In order to increase the power of this study and to validate our findings in an independent population, we used data from the Framingham Sleep study which comprises 368 individuals. Only the rs11211631 polymorphism was associated with OSA in both populations, with an estimated OR=0.57 (0.42-0.79) in the joint analysis (p=7.21 × 10-4). This SNP was selected in the previous GWAS for MetS components using a digenic approach, but was not significant in the monogenic study. We have also identified two SNPs (rs2687855 and rs4299396) with a protective effect from OSA only in the abdominal obese subpopulation. As a whole, our study does not support that OSA and MetS share major genetic determinants, although both syndromes share common epidemiological and clinical features.
doi:10.1016/j.gene.2013.03.024
PMCID: PMC4039742  PMID: 23524009
Obstructive sleep apnea; Metabolic syndrome; Polymorphisms; Genome wide association analysis
2.  Network Efficient Power Control for Wireless Communication Systems 
The Scientific World Journal  2014;2014:650653.
We introduce a two-loop power control that allows an efficient use of the overall power resources for commercial wireless networks based on cross-layer optimization. This approach maximizes the network's utility in the outer-loop as a function of the averaged signal to interference-plus-noise ratio (SINR) by considering adaptively the changes in the network characteristics. For this purpose, the concavity property of the utility function was verified with respect to the SINR, and an iterative search was proposed with guaranteed convergence. In addition, the outer-loop is in charge of selecting the detector that minimizes the overall power consumption (transmission and detection). Next the inner-loop implements a feedback power control in order to achieve the optimal SINR in the transmissions despite channel variations and roundtrip delays. In our proposal, the utility maximization process and detector selection and feedback power control are decoupled problems, and as a result, these strategies are implemented at two different time scales in the two-loop framework. Simulation results show that substantial utility gains may be achieved by improving the power management in the wireless network.
doi:10.1155/2014/650653
PMCID: PMC3934094  PMID: 24683350
3.  Electrochemistry at Edge of Single Graphene Layer in a Nanopore 
ACS nano  2012;7(1):834-843.
We study the electrochemistry of single layer graphene edges using a nanopore-based structure consisting of stacked graphene and Al2O3 dielectric layers. Nanopores, with diameters ranging from 5 to 20 nm, are formed by an electron beam sculpting process on the stacked layers. This leads to unique edge structure which, along with the atomically thin nature of the embedded graphene electrode, demonstrates electrochemical current densities as high as 1.2 × 104 A/cm2. The graphene edge embedded structure offers a unique capability to study the electrochemical exchange at an individual graphene edge, isolated from the basal plane electrochemical activity. We also report ionic current modulation in the nanopore by biasing the embedded graphene terminal with respect to the electrodes in the fluid. The high electrochemical specific current density for a graphene nanopore-based device can have many applications in sensitive chemical and biological sensing, and energy storage devices.
doi:10.1021/nn305400n
PMCID: PMC3551991  PMID: 23249127
Nanopores; graphene; graphene electrochemistry; nano-bio sensors; stacked graphene
4.  Multiple Mutations in Hepatitis C Virus NS5A Domain II Are Required To Confer a Significant Level of Resistance to Alisporivir 
Antimicrobial Agents and Chemotherapy  2012;56(10):5113-5121.
Alisporivir is the most advanced host-targeting antiviral cyclophilin (Cyp) inhibitor in phase III studies and has demonstrated a great deal of promise in decreasing hepatitis C virus (HCV) viremia in infected patients. In an attempt to further elucidate the mechanism of action of alisporivir, HCV replicons resistant to the drug were selected. Interestingly, mutations constantly arose in domain II of NS5A. To demonstrate that these mutations are responsible for drug resistance, they were reintroduced into the parental HCV genome, and the resulting mutant viruses were tested for replication in the presence of alisporivir or in the absence of the alisporivir target, CypA. We also examined the effect of the mutations on NS5A binding to itself (oligomerization), CypA, RNA, and NS5B. Importantly, the mutations did not affect any of these interactions. Moreover, the mutations did not preserve NS5A-CypA interactions from alisporivir rupture. NS5A mutations alone render HCV only slightly resistant to alisporivir. In sharp contrast, when multiple NS5A mutations are combined, significant resistance was observed. The introduction of multiple mutations in NS5A significantly restored viral replication in CypA knockdown cells. Interestingly, the combination of NS5A mutations renders HCV resistant to all classes of Cyp inhibitors. This study suggests that a combination of multiple mutations in domain II of NS5A rather than a single mutation is required to render HCV significantly and universally resistant to Cyp inhibitors. This in accordance with in vivo data that suggest that alisporivir is associated with a low potential for development of viral resistance.
doi:10.1128/AAC.00919-12
PMCID: PMC3457393  PMID: 22802259
5.  The Cyclophilin Inhibitor SCY-635 Disrupts Hepatitis C Virus NS5A-Cyclophilin A Complexes 
The nonimmunosuppressive cyclophilin (Cyp) inhibitor SCY-635 blocks hepatitis C virus (HCV) replication both in vitro and in vivo and represents a novel potent anti-HCV agent. However, its mechanism of action remains to be fully elucidated. A growing body of evidence suggests that cyclophilin A (CypA) is absolutely necessary for HCV replication and that the HCV nonstructural 5A (NS5A) protein serves as a main viral ligand for CypA. In this study, we examined the effect of SCY-635 on HCV replication. Specifically, we asked whether SCY-635 blocks HCV replication by targeting CypA-NS5A interactions. We also investigated the possibility that HCV can escape SCY-635 selection pressure and whether this resistance influences either CypA-NS5A interactions or the dependence of HCV on CypA. We found not only that SCY-635 efficiently inhibits HCV replication, but it is sufficient alone to clear HCV replicon-containing cells. We found that SCY-635 prevents CypA-NS5A interactions in a dose-dependent manner. SCY-635 prevents the contact between CypA and NS5A derived from genotypes 1 to 3. Together, these data suggest that NS5A-CypA interactions control HCV replication and that SCY-635 blocks viral replication by preventing the formation of these complexes. We also found that NS5A mutant proteins found in SCY-635-resistant HCV replicons behave similarly to wild-type NS5A in terms of both CypA binding and SCY-635-mediated dissociation and inhibition of CypA binding. However, the NS5A mutations found in SCY-635-resistant HCV replicons rescued viral replication in CypA-knockdown cells, suggesting that the NS5A mutations, which arose in vitro under SCY-635 selection, do not alter the binding affinity of CypA for NS5A. These specific mutations in NS5A eliminate the dependence of HCV RNA replication on the expression of host CypA
doi:10.1128/AAC.00693-12
PMCID: PMC3393457  PMID: 22585215
6.  Complete Genome Sequence of the First Canine Circovirus 
Journal of Virology  2012;86(12):7018.
We found a highly divergent circovirus in serum samples from several dogs. Phylogenetic analysis indicates that canine circovirus genotype 1 (CaCV-1) represents the first circovirus reported in dogs and is genetically most closely related to the only known mammalian circovirus, porcine circovirus. Here we report the complete genome sequence of the CaCV-1 strain NY214, which will help toward understanding the evolutionary and pathogenic characteristics of mammalian circoviruses.
doi:10.1128/JVI.00791-12
PMCID: PMC3393582  PMID: 22628401
7.  Superior Human Leukocyte Reconstitution and Susceptibility to Vaginal HIV Transmission in Humanized NOD-scid IL-2R −/− (NSG) BLT Mice 
Virology  2011;417(1):154-160.
Humanized Bone marrow/Liver/Thymus (BLT) mice recapitulate the mucosal transmission of HIV, permitting study of early events in HIV pathogenesis and evaluation of preexposure prophylaxis methods to inhibit HIV transmission. Human hematopoiesis is reconstituted in NOD-scid mice by implantation of human fetal liver and thymus tissue to generate human T cells plus intravenous injection of autologous liver-derived CD34+ hematopoietic stem cells to engraft the mouse bone marrow. In side-by-side comparisons, we show that NOD-scid mice homozygous for a deletion of the IL-2Rγ-chain (NOD-scid IL-2Rγ−/−) are far superior to NOD-scid mice in both their peripheral blood reconstitution with multiple classes of human leukocytes (e.g., a mean of 182 versus 14 CD4+ T cells per μl 12 weeks after CD34+ injection) and their susceptibility to intravaginal HIV exposure (84% versus 11% viremic mice at 4 weeks). These results should speed efforts to obtain preclinical animal efficacy data for new HIV drugs and microbicides.
doi:10.1016/j.virol.2011.05.013
PMCID: PMC3152643  PMID: 21684569
HIV/AIDS pathogenesis; HIV vaginal transmission; Humanized mice; HIV animal models; Hematopoietic stem cells; BLT mice; NOD-scid mice; NOD-scid IL-2Rγ−/− mice
8.  Quality of Life in Patients with Neurocysticercosis in Mexico 
The objective of this study was to compare quality of life measures in patients with neurocysticercosis (NCC) to those of a matched control group. The NCC outpatients and their controls were recruited from two neurology referral hospitals in Mexico City, Mexico during 2007–2008. The quality of life of 224 NCC patients was compared with 224 age-sex-hospital-day matched controls using the short form 12 v2 (SF-12 v2) quality of life survey. Medical chart reviews were also conducted for the NCC outpatients to evaluate presenting clinical manifestations. Compared with the controls, NCC patients had a significantly lower score for each of the eight domains of health evaluated and significantly lower Physical and Mental Component Summary scores. Chart reviews indicated that hydrocephalus (48%), severe headaches (47%), and epilepsy (31%) were the most common clinical manifestations in these NCC outpatients.
doi:10.4269/ajtmh.2011.10-0646
PMCID: PMC3083747  PMID: 21540389
9.  Estimating the Non-Monetary Burden of Neurocysticercosis in Mexico 
Background
Neurocysticercosis (NCC) is a major public health problem in many developing countries where health education, sanitation, and meat inspection infrastructure are insufficient. The condition occurs when humans ingest eggs of the pork tapeworm Taenia solium, which then develop into larvae in the central nervous system. Although NCC is endemic in many areas of the world and is associated with considerable socio-economic losses, the burden of NCC remains largely unknown. This study provides the first estimate of disability adjusted life years (DALYs) associated with NCC in Mexico.
Methods
DALYs lost for symptomatic cases of NCC in Mexico were estimated by incorporating morbidity and mortality due to NCC-associated epilepsy, and morbidity due to NCC-associated severe chronic headaches. Latin hypercube sampling methods were employed to sample the distributions of uncertain parameters and to estimate 95% credible regions (95% CRs).
Findings
In Mexico, 144,433 and 98,520 individuals are estimated to suffer from NCC-associated epilepsy and NCC-associated severe chronic headaches, respectively. A total of 25,341 (95% CR: 12,569–46,640) DALYs were estimated to be lost due to these clinical manifestations, with 0.25 (95% CR: 0.12–0.46) DALY lost per 1,000 person-years of which 90% was due to NCC-associated epilepsy.
Conclusion
This is the first estimate of DALYs associated with NCC in Mexico. However, this value is likely to be underestimated since only the clinical manifestations of epilepsy and severe chronic headaches were included. In addition, due to limited country specific data, some parameters used in the analysis were based on systematic reviews of the literature or primary research from other geographic locations. Even with these limitations, our estimates suggest that healthy years of life are being lost due to NCC in Mexico.
Author Summary
Neurocysticercosis (NCC) is a major public health problem caused by the larvae of the parasite Taenia solium. The condition occurs when humans ingest eggs of the pork tapeworm Taenia solium, which then develop into larvae in the central nervous system. The disease is predominantly found and considered important in Latin American, Asian, and African countries and is associated with a large social and economic burden. Very few studies have been conducted to evaluate the burden of NCC and there are no estimates from Mexico. We estimated the disability adjusted life years (DALYs) lost due to NCC in Mexico incorporating morbidity and mortality due to NCC-associated epilepsy, and morbidity due to NCC-associated severe chronic headaches. NCC-associated epilepsy and severe chronic headaches were estimated to cause a loss of approximately 0.25 healthy year of life per 1,000 persons annually in Mexico. This is the first estimate of DALYs associated with NCC in Mexico. However, this value is likely to be underestimated since only the clinical manifestations of epilepsy and severe chronic headaches were included.
doi:10.1371/journal.pntd.0001521
PMCID: PMC3283554  PMID: 22363827
10.  Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans 
Science (New York, N.y.)  2010;330(6011):1695-1699.
Although the mammalian immune system is generally thought to develop in a linear fashion, findings in avian and murine species argue instead for the developmentally ordered appearance (or “layering”) of unique hematopoietic stem cells (HSC) that give rise to distinct lymphocyte lineages at different stages of development. Here, we provide evidence of an analogous “layered” immune system in humans. Our results suggest that fetal and adult T cells are distinct populations that arise from different populations of HSC present at different stages of development. We also provide evidence that the fetal T cell lineage is biased towards immune tolerance. These observations offer a mechanistic explanation for the tolerogenic properties of the developing fetus and for variable degrees of immune responsiveness at birth.
doi:10.1126/science.1196509
PMCID: PMC3276679  PMID: 21164017
11.  Development of a Flow Cytometry Live Cell Assay for the Screening of Inhibitors of Hepatitis C Virus (HCV) Replication 
The Open Virology Journal  2012;6:97-102.
In this study, we established a flow cytometry live cell-based assay that permits the screening of hepatitis C virus (HCV) inhibitors. Specifically, we created a stable cell line, which harbors a subgenomic replicon encoding an NS5A-YFP fusion protein. This system allows direct measurement of YFP fluorescence in live hepatoma cells in which the HCV replicon replicates. We demonstrated that this stable fluorescent system permits the rapid and sensitive quantification of HCV replication inhibition by direct-acting antiviral agents (DAA) including protease and NS5A inhibitors and host-targeting antiviral agents (HTA) including cyclophilin inhibitors. This flow cytometry-based live cell assay is well suited for multiple applications such as the evaluation of HCV replication as well as antiviral drug screening.
doi:10.2174/1874357901206010097
PMCID: PMC3514710  PMID: 23230455
Direct-acting antiviral; FACS assay; HCV; hepatoma cells; host-targeting antiviral; inhibitors.
12.  Intraocular and systemic levels of vascular endothelial growth factor in advanced cases of retinopathy of prematurity 
Purpose:
To measure vitreous, aqueous, subretinal fluid and plasma levels of vascular endothelial growth factor in late stages of retinopathy of prematurity.
Methods:
Interventional study. We enrolled patients with clinical diagnoses of bilateral stage V retinopathy of prematurity, confirmed by b-scan ultrasound and programmed for vitrectomy. During surgery we took samples from blood, aqueous, vitreous, and subretinal fluids. The vascular endothelial growth factor concentration in each sample was measured by ELISA reaction. A control sample of aqueous, vitreous and blood was taken from patients with congenital cataract programmed for phacoemulsification. For statistical analysis, a Mann–Whitney and a Wilcoxon W test was done with a significant P value of 0.05.
Results:
We took samples of 16 consecutive patients who met the inclusion criteria. The vascular endothelial growth factor levels in the study group were: aqueous, 76.81 ± 61.89 pg/mL; vitreous, 118.53 ± 65.87 pg/mL; subretinal fluid, 1636.58 ± 356.47 pg/mL; and plasma, 74.64 ± 43.94 pg/mL. There was a statistical difference between the study and the control group (P < 0.001) in the aqueous and vitreous samples.
Conclusion:
Stage 5 retinopathy of prematurity has elevated intraocular levels of vascular endothelial growth factor, which remains high despite severe retinal lesion. There was no statistical difference in plasma levels of the molecule between the control and study group.
PMCID: PMC2938272  PMID: 20856587
VEGF; late stages; ROP
13.  Implication of Serine Residues 271, 273, and 275 in the Human Immunodeficiency Virus Type 1 Cofactor Activity of Lens Epithelium-Derived Growth Factor/p75▿  
Journal of Virology  2009;84(2):740-752.
Lens epithelium-derived growth factor (LEDGF)/p75 is a cellular cofactor for HIV-1 DNA integration. It is well established that the simultaneous binding of LEDGF/p75 to chromatin and to HIV-1 integrase is required for its cofactor activity. However, the exact molecular mechanism of LEDGF/p75 in HIV-1 integration is not yet completely understood. Our hypothesis is that evolutionarily conserved regions in LEDGF/p75 exposed to solvent and harboring posttranslational modifications may be involved in its HIV-1 cofactor activity. Therefore, a panel of LEDGF/p75 deletion mutants targeting these protein regions were evaluated for their HIV-1 cofactor activity, chromatin binding, integrase interaction, and integrase-to-chromatin-tethering activity by using different cellular and biochemical approaches. The deletion of amino acids 267 to 281 reduced the cofactor activity of LEDGF/p75 to levels observed for chromatin-binding-defective mutants. This region contains a serine cluster (residues 271, 273, and 275) recurrently found to be phosphorylated in both human and mouse cells. Importantly, the conversion of these Ser residues to Ala was sufficient to impair the ability of LEDGF/p75 to mediate HIV-1 DNA integration, although these mutations did not alter chromatin binding, integrase binding, or the integrase-to-chromatin-tethering capability of LEDGF/p75. These results clearly indicated that serine residues 271, 273, and 275 influence the HIV-1 cofactor activity of integrase-to-chromatin-tethering-competent LEDGF/p75.
doi:10.1128/JVI.01043-09
PMCID: PMC2798348  PMID: 19889764
14.  LEDGF/p75 Proteins with Alternative Chromatin Tethers Are Functional HIV-1 Cofactors 
PLoS Pathogens  2009;5(7):e1000522.
LEDGF/p75 can tether over-expressed lentiviral integrase proteins to chromatin but how this underlies its integration cofactor role for these retroviruses is unclear. While a single integrase binding domain (IBD) binds integrase, a complex N-terminal domain ensemble (NDE) interacts with unknown chromatin ligands. Whether integration requires chromatin tethering per se, specific NDE-chromatin ligand interactions or other emergent properties of LEDGF/p75 has been elusive. Here we replaced the NDE with strongly divergent chromatin-binding modules. The chimeras rescued integrase tethering and HIV-1 integration in LEDGF/p75-deficient cells. Furthermore, chromatin ligands could reside inside or outside the nucleosome core, and could be protein or DNA. Remarkably, a short Kaposi's sarcoma virus peptide that binds the histone 2A/B dimer converted GFP-IBD from an integration blocker to an integration cofactor that rescues over two logs of infectivity. NDE mutants were corroborative. Chromatin tethering per se is a basic HIV-1 requirement and this rather than engagement of particular chromatin ligands is important for the LEDGF/p75 cofactor mechanism.
Author Summary
Like other retroviruses, HIV-1 integrates a DNA copy of its genome into a host cell chromosome in each replication cycle. The resulting integrated proviruses are the basis for two important clinical problems: the inability to eradicate HIV-1 from the body and the permanent archiving of drug-resistant viruses. The DNA recombining steps catalyzed by the viral integrase are known, but the process as it occurs between the incoming virus and chromatin in cells is incompletely understood. LEDGF/p75 has been identified as an HIV-1 integration cofactor. If integrase is over-expressed in the absence of other viral components, it becomes linked to chromatin via LEDGF/p75. Whether this chromatin attachment function is the necessary and sufficient basis for its cofactor role in the viral life cycle has been unclear. The current work shows that HIV-1 cofactor function is preserved if the chromatin binding modules of LEDGF/p75 are replaced with widely disparate chromatin linkages. These results are evidence that chromatin tethering per se rather than connections to specific chromatin ligands is central to the LEDGF/p75 mechanism. They also have implications for targeting of lentiviral vectors within the human genome.
doi:10.1371/journal.ppat.1000522
PMCID: PMC2706977  PMID: 19609362
15.  A Structural Model of the Staphylococcus aureus ClfA–Fibrinogen Interaction Opens New Avenues for the Design of Anti-Staphylococcal Therapeutics 
PLoS Pathogens  2008;4(11):e1000226.
The fibrinogen (Fg) binding MSCRAMM Clumping factor A (ClfA) from Staphylococcus aureus interacts with the C-terminal region of the fibrinogen (Fg) γ-chain. ClfA is the major virulence factor responsible for the observed clumping of S. aureus in blood plasma and has been implicated as a virulence factor in a mouse model of septic arthritis and in rabbit and rat models of infective endocarditis. We report here a high-resolution crystal structure of the ClfA ligand binding segment in complex with a synthetic peptide mimicking the binding site in Fg. The residues in Fg required for binding to ClfA are identified from this structure and from complementing biochemical studies. Furthermore, the platelet integrin αIIbβ3 and ClfA bind to the same segment in the Fg γ-chain but the two cellular binding proteins recognize different residues in the common targeted Fg segment. Based on these differences, we have identified peptides that selectively antagonize the ClfA-Fg interaction. The ClfA-Fg binding mechanism is a variant of the “Dock, Lock and Latch” mechanism previously described for the Staphylococcus epidermidis SdrG–Fg interaction. The structural insights gained from analyzing the ClfANFg peptide complex and identifications of peptides that selectively recognize ClfA but not αIIbβ3 may allow the design of novel anti-staphylococcal agents. Our results also suggest that different MSCRAMMs with similar structural organization may have originated from a common ancestor but have evolved to accommodate specific ligand structures.
Author Summary
Staphylococcus aureus (S. aureus) is a common pathogen that can cause a range of diseases from mild skin infections to life-threatening sepsis in humans. Some surface proteins on S. aureus play important roles in the S. aureus disease process. One of these bacterial surface proteins is clumping factor A (ClfA) that binds to the C-terminal region of one of the three chains of fibrinogen (Fg), a blood protein that plays a key role in coagulation. We carried out biochemical and structural studies to understand the binding mechanism of ClfA to Fg and to define the residues in Fg that interact with ClfA. Interestingly, the platelet integrin, which is important for platelet aggregation and thrombi formation, also binds to the same region of Fg as ClfA. Despite the fact that the two proteins bind at the same region, the mode of recognition is significantly different. Exploiting this difference in recognition, we have demonstrated that agents could be designed that inhibit the ClfA–Fg interaction but do not interfere with the interaction of Fg with the platelet integrin. This opens the field for the design of a novel class of anti-staph therapeutics.
doi:10.1371/journal.ppat.1000226
PMCID: PMC2582960  PMID: 19043557
16.  Cytotrophoblast induction of arterial apoptosis and lymphangiogenesis in an in vivo model of human placentation 
Journal of Clinical Investigation  2006;116(10):2643-2652.
We studied the vascular effects of invasive human cytotrophoblasts in vivo by transplanting placental villi to the fifth mammary fat pads or beneath the kidney capsules of Scid mice. Over 3 weeks, robust cytotrophoblast invasion was observed in both locations. The architecture of the mammary fat pad allowed for detailed analysis of the cells’ interactions with resident murine blood vessels, which revealed specific induction of apoptosis in the endothelial cells and smooth muscle walls of the arterioles. This finding, and confirmation of the results in an in vitro coculture model, suggests that a parallel process is important for enabling cytotrophoblast endovascular invasion during human pregnancy. Cytotrophoblast invasion of the kidney parenchyma was accompanied by a robust lymphangiogenic response, while in vitro, the cells stimulated lymphatic endothelial cell migration via the actions of VEGF family members, FGF, and TNF-α. Immunolocalization analyses revealed that human pregnancy is associated with lymphangiogenesis in the decidua since lymphatic vessels were not a prominent feature of the nonpregnant endometrium. Thus, the placenta triggers the development of a decidual lymphatic circulation, which we theorize plays an important role in maintaining fluid balance during pregnancy, with possible implications for maternal-fetal immune cell trafficking.
doi:10.1172/JCI27306
PMCID: PMC1570373  PMID: 16998586
17.  A randomized, controlled trial of spinal endoscopic adhesiolysis in chronic refractory low back and lower extremity pain [ISRCTN 16558617] 
BMC Anesthesiology  2005;5:10.
Background
Postoperative epidural fibrosis may contribute to between 5% to 60% of the poor surgical outcomes following decompressive surgery. Correlations have been reported between epidural scarring and radicular pain, poor surgical outcomes, and a lack of any form of surgical treatment. The use of spinal endoscopic adhesiolysis in recent years in the management of chronic refractory low back and lower extremity pain has been described.
Methods
A prospective, randomized, double-blind trial was conducted to determine the outcome of spinal endoscopic adhesiolysis to reduce pain and improve function and psychological status in patients with chronic refractory low back and lower extremity pain. A total of 83 patients were evaluated, with 33 patients in Group I and 50 patients in Group II. Group I served as the control, with endoscopy into the sacral level without adhesiolysis, followed by injection of local anesthetic and steroid. Group II received spinal endoscopic adhesiolysis, followed by injection of local anesthetic and steroid.
Results
Among the 50 patients in the treatment group receiving spinal endoscopic adhesiolysis, significant improvement without adverse effects was shown in 80% at 3 months, 56% at 6 months, and 48% at 12 months. The control group showed improvement in 33% of the patients at one month and none thereafter. Based on the definition that less than 6 months of relief is considered short-term and longer than 6 months of relief is considered long-term, a significant number of patients obtained long-term relief with improvement in pain, functional status, and psychological status.
Conclusion
Spinal endoscopic adhesiolysis with targeted delivery of local anesthetic and steroid is an effective treatment in a significant number of patients with chronic low back and lower extremity pain without major adverse effects.
doi:10.1186/1471-2253-5-10
PMCID: PMC1187869  PMID: 16000173
18.  Genetic Variability of Immunomodulatory Genes in Ectromelia Virus Isolates Detected by Denaturing High-Performance Liquid Chromatography 
Journal of Virology  2003;77(18):10139-10146.
The genetic variability of nine genes in 12 isolates and strains of ectromelia virus, which causes a smallpox-like disease (mousepox) in mice, was determined and allows for classification of ectromelia viruses. The low genetic variability suggests that evolutionary pressure maintains the activity of immunomodulatory genes in natural poxvirus infections.
doi:10.1128/JVI.77.18.10139-10146.2003
PMCID: PMC224613  PMID: 12941926
19.  Risk of whole body radiation exposure and protective measures in fluoroscopically guided interventional techniques: a prospective evaluation 
BMC Anesthesiology  2003;3:2.
Background
Fluoroscopic guidance is frequently utilized in interventional pain management. The major purpose of fluoroscopy is correct needle placement to ensure target specificity and accurate delivery of the injectate. Radiation exposure may be associated with risks to physician, patient and personnel. While there have been many studies evaluating the risk of radiation exposure and techniques to reduce this risk in the upper part of the body, the literature is scant in evaluating the risk of radiation exposure in the lower part of the body.
Methods
Radiation exposure risk to the physician was evaluated in 1156 patients undergoing interventional procedures under fluoroscopy by 3 physicians. Monitoring of scattered radiation exposure in the upper and lower body, inside and outside the lead apron was carried out.
Results
The average exposure per procedure was 12.0 ± 9.8 seconds, 9.0 ± 0.37 seconds, and 7.5 ± 1.27 seconds in Groups I, II, and III respectively. Scatter radiation exposure ranged from a low of 3.7 ± 0.29 seconds for caudal/interlaminar epidurals to 61.0 ± 9.0 seconds for discography. Inside the apron, over the thyroid collar on the neck, the scatter radiation exposure was 68 mREM in Group I consisting of 201 patients who had a total of 330 procedures with an average of 0.2060 mREM per procedure and 25 mREM in Group II consisting of 446 patients who had a total of 662 procedures with average of 0.0378 mREM per procedure. The scatter radiation exposure was 0 mREM in Group III consisting of 509 patients who had a total 827 procedures. Increased levels of exposures were observed in Groups I and II compared to Group III, and Group I compared to Group II.
Groin exposure showed 0 mREM exposure in Groups I and II and 15 mREM in Group III. Scatter radiation exposure for groin outside the apron in Group I was 1260 mREM and per procedure was 3.8182 mREM. In Group II the scatter radiation exposure was 400 mREM and with 0.6042 mREM per procedure. In Group III the scatter radiation exposure was 1152 mREM with 1.3930 mREM per procedure.
Conclusion
Results of this study showed that scatter radiation exposure to both the upper and lower parts of the physician's body is present. Protection was offered by traditional measures to the upper body only.
doi:10.1186/1471-2253-3-2
PMCID: PMC194671  PMID: 12904269
20.  Benefits of Using a Computerized Documentation Aide in Specifying and Documenting DoD Automated Health Care Systems 
Effective systems development requires careful analysis of functional requirements before design activities begin. In addition, system documentation can easily become so massive that it is nearly impossible to maintain. Hospital information systems are, because of funding realities, often implemented in building-block fashion, which carries with it the risk that individual automated ancillary systems will not be able to communicate with one another to form a comprehensive management information system. The use of an automated documentation tool during the systems analysis phase provides the capability to specify individual ancillary services' automated systems such that interdependencies are identified early on in the analysis process. Additionally, automated documentation tools provide significant benefits when it comes to maintaining the documentation of implemented systems. This paper reports on the use of one automated documentation/specification tool, the Problem Statement Language/Problem Statement Analyzer, in specifying and documenting requirements for multiple hospital ancillary, or work center, systems in preparation for integration.
PMCID: PMC2580245
21.  Year-round high physical activity levels in agropastoralists of Bolivian Andes: Results from repeated measurements of DLW method in peak and slack seasons of agricultural activities 
American Journal of Human Biology  2009;21(3):337-345.
By the repeated use of the doubly labeled water method (DLW), this study aimed to investigate (1) the extent of changes in energy expenditure and physical activity level (PAL) in response to increased agricultural work demands, and (2) whether the seasonal work demands induce the changes in the fairly equitable division of work and similarity of energy needs between men and women observed in our previous study (Phase 1 study; Kashiwazaki et al., 1995: Am J Clin Nutr 62: 901–910). In a rural small agropastoral community of the Bolivian Andes, we made the follow-up study (Phase 2, 14 adults; a time of high agricultural activity) of the Phase 1 study (12 adults; a time of low agricultural activity). In the Phase 2 study, both men and women showed very high PAL (mean±SD), but there was no significant difference by sex (men; 2.18 ± 0.23 (age; 64 ± 11 years, n = 7), women; 2.26 ± 0.25 (63 ± 10 years, n = 7)). The increase of PAL by 11% (P = 0.023) in the Phase 2 was equally occurred in both men and women. The factorial approach underestimated PAL significantly by ≈15% (P < 0.05). High PAL throughout the year ranging on average 2.0 and 2.2 was attributable to everyday tasks for subsistence and domestic works undertaking over 9–11 h (men spent 2.7 h on agricultural work and 4.7 h on animal herding, whereas women spent 7.3 h almost exclusively on animal herding). The seasonal increase in PAL was statistically significant, but it was smaller than those anticipated from published reports. A flexible division of labor played an important role in the equitable energetic increase in both men and women. Am. J. Hum. Biol., 2009. © 2009 Wiley-Liss, Inc.
doi:10.1002/ajhb.20864
PMCID: PMC2842569  PMID: 19127525

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