312 research outputs found
Subsequent abdominal surgery after laparoscopic ventral and incisional hernia repair with an expanded polytetrafluoroethylene mesh: a single institution experience with 72 reoperations
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Risk Factors for Symptomatic Hyperlactatemia and Lactic Acidosis Among Combination Antiretroviral Therapy-Treated Adults in Botswana: Results from a Clinical Trial
Nucleoside analogue reverse transcriptase inhibitors are an integral component of combination antiretroviral treatment regimens. However, their ability to inhibit polymerase-γ has been associated with several mitochondrial toxicities, including potentially life-threatening lactic acidosis. A total of 650 antiretroviral-naive adults (69% female) initiated combination antiretroviral therapy (cART) and were intensively screened for toxicities including lactic acidosis as part of a 3-year clinical trial in Botswana. Patients were categorized as no lactic acidosis symptoms, minor symptoms but lactate <4.4 mmol/liter, and symptoms with lactate ≥ 4.4 mmol/liter [moderate to severe symptomatic hyperlactatemia (SH) or lactic acidosis (LA)]. Of 650 participants 111 (17.1%) developed symptoms and/or laboratory results suggestive of lactic acidosis and had a serum lactate drawn; 97 (87.4%) of these were female. There were 20 events, 13 having SH and 7 with LA; all 20 (100%) were female (p<0.001). Cox proportional hazard analysis limited to the 451 females revealed that having a higher baseline BMI was predictive for the development of SH/LA [aHR=1.17 per one-unit increase (1.08-1.25), p<0.0001]. Ordered logistic regression performed among all 650 patients revealed that having a lower baseline hemoglobin [aOR=1.28 per one-unit decrease (1.1-1.49), p=0.002] and being randomized to d4T/3TC-based cART [aOR=1.76 relative to ZDV/3TC (1.03-3.01), p=0.04] were predictive of the symptoms and/or the development of SH/LA. cART-treated women in sub-Saharan Africa, especially those having higher body mass indices, should receive additional monitoring for SH/LA. Women presently receiving d4T/3TC-based cART in such settings also warrant more intensive monitoring
Proteorhodopsin Phototrophy Promotes Survival of Marine Bacteria during Starvation
Mutational analysis provides direct evidence for the link between proteorhodopsin light-harvesting and enhanced survival of marine bacteria
A Bayesian Approach to Analyse Genetic Variation within RNA Viral Populations
The development of modern and affordable sequencing technologies has allowed the
study of viral populations to an unprecedented depth. This is of particular
interest for the study of within-host RNA viral populations, where variation due
to error-prone polymerases can lead to immune escape, antiviral resistance and
adaptation to new host species. Methods to sequence RNA virus genomes include
reverse transcription (RT) and polymerase chain reaction (PCR). RT-PCR is a
molecular biology technique widely used to amplify DNA from an RNA template. The
method itself relies on the in vitro synthesis of copy DNA from
RNA followed by multiple cycles of DNA amplification. However, this method
introduces artefactual errors that can act as confounding factors when the
sequence data are analysed. Although there are a growing number of published
studies exploring the intra- and inter-host evolutionary dynamics of RNA
viruses, the complexity of the methods used to generate sequences makes it
difficult to produce probabilistic statements about the likely sources of
observed sequence variants. This complexity is further compounded as both the
depth of sequencing and the length of the genome segment of interest increase.
Here we develop a Bayesian method to characterise and differentiate between
likely structures for the background viral population. This approach can then be
used to identify nucleotide sites that show evidence of change in the
within-host viral population structure, either over time or relative to a
reference sequence (e.g. an inoculum or another source of infection), or both,
without having to build complex evolutionary models. Identification of these
sites can help to inform the design of more focussed experiments using molecular
biology tools, such as site-directed mutagenesis, to assess the function of
specific amino acids. We illustrate the method by applying to datasets from
experimental transmission of equine influenza, and a pre-clinical vaccine trial
for HIV-1
Internal flows and energy circulation in light beams
We review optical phenomena associated with the internal energy
redistribution which accompany propagation and transformations of monochromatic
light fields in homogeneous media. The total energy flow (linear-momentum
density, Poynting vector) can be divided into spin part associated with the
polarization and orbital part associated with the spatial inhomogeneity. We
give general description of the internal flows in the coordinate and momentum
(angular spectrum) representations for both nonparaxial and paraxial fields.
This enables one to determine local densities and integral values of the spin
and orbital angular momenta of the field. We analyse patterns of the internal
flows in standard beam models (Gaussian, Laguerre-Gaussian, flat-top beam,
etc.), which provide an insightful picture of the energy transport. The
emphasize is made to the singular points of the flow fields. We describe the
spin-orbit and orbit-orbit interactions in the processes of beam focusing and
symmetry breakdown. Finally, we consider how the energy flows manifest
themselves in the mechanical action on probing particles and in the
transformations of a propagating beam subjected to a transverse perturbation.Comment: 50 pages, 21 figures, 173 references. This is the final version of
the manuscript (v1) modified in accord to the referee's remarks and with
allowance for the recent development. The main changes are: additional
discussion of the energy flows in Bessel beams (section 4.1), a lot of new
references are added and the Conclusion is shortened and made more accurat
HLA Alleles Associated with Slow Progression to AIDS Truly Prefer to Present HIV-1 p24
Background: The mechanism behind the association between human leukocyte antigen (HLA) molecules and the rate of HIV-1
disease progression is still poorly understood. Recent data suggest that ‘‘protective’’ HLA molecules, i.e. those associated with
a low HIV-1 viral load and relatively slow disease progression, tend to present epitopes from the Gag capsid protein. Although
this suggests that preferential targeting of Gag delays disease progression, the apparent preference for Gag could also be
a side-effect of the relatively high immunogenicity of the protein. Methods and Findings: To separate cause and effect, we
predicted HIV-1 epitopes from the whole genome of HIV-1, and found that protective HLA alleles have a true preference for the
p24 Gag protein, while non-protective HLA alleles preferentially target HIV-1 Nef. In line with this, we found a significant
negative correlation between the predicted affinity of the best-binding p24 epitopes and the relative hazard of HIV-1 disease
progression for a large number of HLA molecules. When the epitopes targeted by protective HLA alleles were mapped to the
known p24 structure, we found that mutations in these epitopes are likely to disturb the p24 dimer structure, which is
expected to severely reduce the fitness of the virus. Conclusions: Our results suggest that the intrinsic preference of different
HLA molecules to present p24 peptides explains why some HLA molecules are more protective than others
Biology of moderately halophilic aerobic bacteria
The moderately halophilic heterotrophic aerobic bacteria form a diverse group of microorganisms. The property of halophilism is widespread within the bacterial domain. Bacterial halophiles are abundant in environments such as salt lakes, saline soils, and salted food products. Most species keep their intracellular ionic concentrations at low levels while synthesizing or accumulating organic solutes to provide osmotic equilibrium of the cytoplasm with the surrounding medium. Complex mechanisms of adjustment of the intracellular environments and the properties of the cytoplasmic membrane enable rapid adaptation to changes in the salt concentration of the environment. Approaches to the study of genetic processes have recently been developed for several moderate halophiles, opening the way toward an understanding of haloadaptation at the molecular level. The new information obtained is also expected to contribute to the development of novel biotechnological uses for these organisms
Unique CRF01_AE Gag CTL Epitopes Associated with Lower HIV-Viral Load and Delayed Disease Progression in a Cohort of HIV-Infected Thais
Cytotoxic T Lymphocytes (CTLs) play a central role in controlling HIV-replication. Although numerous CTL epitopes have been described, most are in subtype B or C infection. Little is known about CTL responses in CRF01_AE infection. Gag CTL responses were investigated in a cohort of 137 treatment-naïve HIV-1 infected Thai patients with high CD4+ T cell counts, using gIFN Enzyme-Linked Immunospot (ELISpot) assays with 15-mer overlapping peptides (OLPs) derived from locally dominant CRF01_AE Gag sequences. 44 OLPs were recognized in 112 (81.8%) individuals. Both the breadth and magnitude of the CTL response, particularly against the p24 region, positively correlated with CD4+ T cell count and inversely correlated with HIV viral load. The breadth of OLP response was also associated with slower progression to antiretroviral therapy initiation. Statistical analysis and single peptide ELISpot assay identified at least 17 significant associations between reactive OLP and HLA in 12 OLP regions; 6 OLP-HLA associations (35.3%) were not compatible with previously reported CTL epitopes, suggesting that these contained new CTL Gag epitopes. A substantial proportion of CTL epitopes in CRF01_AE infection differ from subtype B or C. However, the pattern of protective CTL responses is similar; Gag CTL responses, particularly against p24, control viral replication and slow clinical progression
Transabdominal Preperitoneal Repair for Obturator Hernia
信州大学博士(医学)・学位論文・平成23年3月31日授与(甲第889号)・横山隆秀Background A laparoscopic surgical approach for obturator hernia (OH) repair is uncommon. The aim of the present study was to assess the effectiveness of laparoscopic transabdominal preperitoneal (TAPP) repair for OH. Methods From 2001 to May 2010, 659 patients with inguinal hernia underwent TAPP repair at in our institutes. Among these, the eight patients with OH were the subjects of this study. Results Three of the eight patients were diagnosed as having occult OH, and the other five were diagnosed preoperatively, by ultrasonography and/or computed tomography, as having strangulated OH. Bilateral OH was found in five patients (63%), and combined groin hernias, either unilaterally or bilaterally, were observed in seven patients (88%), all of whom had femoral hernia. Of the five patients with bowel obstruction at presentation, four were determined not to require resection after assessment of the intestinal viability by laparoscopy. There was one case of conversion to a two-stage hernia repair performed to avoid mesh contamination: addition of mini-laparotomy, followed by extraction of the gangrenous intestine for resection and anastomosis with simple peritoneal closure of the hernia defect in the first stage, and a Kugel hernia repair in the second stage. There was no incidence of postoperative morbidity, mortality, or recurrence. Conclusions Because TAPP allows assessment of not only the entire groin area bilaterally but also simultaneous assessment of the viability of the incarcerated intestine with a minimum abdominal wall defect, we believe that it is an adequate approach to the treatment of both occult and acutely incarcerated OH. Two-stage hernia repair is technically feasible in patients requiring resection of the incarcerated intestine.ArticleWORLD JOURNAL OF SURGERY. 35(10):2323-2327 (2011)journal articl
Molecular Epidemiology of HIV-1 Subtypes in India: Origin and Evolutionary History of the Predominant Subtype C
This thesis describes the translational genomics of HIV-1subtype C in India from its origin to therapeutic response with the aim to improve our knowledge for better therapeutic and preventive strategies to combat HIV/AIDS. In a systemic approach, we identified the molecular phylogeny of HIV-1 subtypes circulating in India and the time to most recent common ancestors (tMRCA) of predominant HIV-1 subtype C strains. Additionally, this thesis also studied drug resistance mutations in children, adolescents and adults, the role of host factors in evolution of drug resistance, and population dynamics of viremia and viral co-receptor tropism in perinatal transmission. Finally, the long term therapeutic responses on Indian national first-line antiretroviral therapy were also studied.
In Paper I, we reported an increase in the HIV-1 recombinant forms in the HIV-1 epidemiology using a robust subtyping methodology. While the study confirmed HIV- 1 subtype C as a dominant subtype, its origin was dated back to the early 1970s from a single or few genetically related strains from South Africa, whereafter, it has evolved independently. In Paper II, the lethal hypermutations due to the activity of human apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (hA3G) was significantly associated with antiretroviral therapy (ART) failure in Indian HIV-1 subtype C patients. The presence of M184I and M230I mutations were observed due to the editing of hA3G in the proviral compartment but stop codons were also found in the open reading frames and the same drug resistance mutations were absent in plasma virus. Therefore, it is unlikely that the viral variants which exhibit hypermutated sequences and M184I and/or M230I will mature and expand in vivo and hence are unlikely to have any clinical significance. The high concordance of drug resistance genotyping in the plasma and proviral compartments in therapy-naïve patients, gives weight to the idea of using whole blood for surveillance of drug resistance mutations which precludes logistic challenges of cold chain transport.
In Papers III and IV, we identified a substantial proportion of HIV-1 subtype C perinatally-infected older children who had a high burden of plasma viremia but also had high CD4+ T-cell counts. In addition, older children with HIV-1 subtype C infection presented a high prevalence of predicted X4 and R5/X4 tropic strains which indicates that HIV-1 subtype C strains required longer duration of infection and greater disease progression to co-receptor transition from R5- to X4-tropic strains (IV). Our studies also indicate that transmitted drug resistance is low among Indian HIV-1 infected children, adolescents (III) and adults (II).
In Paper V, in a longitudinal cohort study, a good long-term response to the Indian national first-line therapy for a median of nearly four years with 2.8% viral failure, indicating the overall success of the Indian ART program. Our study also showed that three immunologically well patients with virological rebound and major viral drug resistance mutations (M184V, K103N and Y181C) during one study visit had undetectable viral load at their next visit. These findings suggest that use of multiple parameters like patients’ immunological (CD4+ T-cell count), virological (viral load) and drug resistance data should all be used to optimize the treatment switch to second line therapy.
In conclusion, this translational genomics study enhances our knowledge about the HIV-1 subtype C strains circulating in India which are genetically distinct from prototype African subtype C strains. Considerably more research using appropriate models need to be performed to understand the phenotypic and biological characteristics of these strains to guide efficient disease intervention and management strategies
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