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1.
J Antimicrob Chemother ; 78(11): 2653-2659, 2023 11 06.
Article in English | MEDLINE | ID: mdl-37681452

ABSTRACT

BACKGROUND: Feminizing hormone therapy (FHT) is essential to many trans women. Concern about negative drug interactions between FHT and ART can be an ART adherence barrier among trans women with HIV. OBJECTIVES: In this single-centre, parallel group, cross-sectional pilot study, we measured serum oestradiol concentrations in trans women with HIV taking FHT and unboosted integrase strand transfer inhibitor (INSTI)-based ART versus trans women without HIV taking FHT. METHODS: We included trans women with and without HIV, aged ≥18 years, taking ≥2 mg/day of oral oestradiol for at least 3 months plus an anti-androgen. Trans women with HIV were on suppressive ART ≥3 months. Serum oestradiol concentrations were measured prior to medication dosing and 2, 4, 6 and 8 h post-dose. Median oestradiol concentrations were compared between groups using Wilcoxon rank-sum tests. RESULTS: Participants (n = 8 with HIV, n = 7 without) had a median age of 32 (IQR: 28, 39) years. Among participants, the median oral oestradiol dose was 4 mg (range 2-6 mg). Participants had been taking FHT for a median of 4 years (IQR: 2, 8). Six trans women with HIV were taking bictegravir/emtricitabine/tenofovir alafenamide and two were taking dolutegravir/abacavir/lamivudine. All oestradiol concentrations were not significantly different between groups. Eleven (73%) participants had target oestradiol concentrations in the range 200-735 pmol/L at C4h (75% among women with HIV, 71% among those without HIV). CONCLUSIONS: Oestradiol concentrations were not statistically different in trans women with HIV compared with those without HIV, suggesting a low probability of clinically relevant drug-drug interactions between FHT and unboosted INSTI-based ART.


Subject(s)
HIV Infections , HIV Integrase Inhibitors , HIV-1 , Humans , Female , Adolescent , Adult , HIV Infections/drug therapy , Pilot Projects , Emtricitabine/therapeutic use , Cross-Sectional Studies , HIV Integrase Inhibitors/therapeutic use
3.
HIV Med ; 23(4): 324-330, 2022 04.
Article in English | MEDLINE | ID: mdl-35193172

ABSTRACT

INTRODUCTION: This study aimed to characterize and identify factors associated with HIV care among transgender (trans) women living with HIV (TWLWH) in two urban centres in Canada. METHODS: Retrospective data were collected from clinic charts of TWLWH aged 16 years and older across seven family medicine, endocrinology and/or HIV clinics in Montreal and Toronto, Canada, from 2018 to 2019 (n = 86). We assessed the proportion of individuals being ever engaged in HIV care [defined as having any recorded antiretroviral therapy (ART) regimen and/or viral load], current ART use, and most recent viral load (suppressed [<200 copies/ml] vs. unsuppressed) overall and compared across subgroups using χ2 tests. RESULTS: All TWLWH in our sample [100.0%, 95% confidence interval (CI): 95.8-100.0%] were engaged in HIV care; most (93.0%, 95% CI: 85.4-97.4%) were currently using ART and most (93.4%, 95% CI: 85.3-97.8%) with complete data (n = 71/76) were virally suppressed. A higher proportion of trans women of colour (100.0%) reported current ART use compared with white trans women (76.9%, p = 0.017). A higher proportion of those with no documented history of injection drug use (IDU; 96.6%) were virally suppressed compared with those with a history of IDU (66.7%, p = 0.022). Although not statistically significant, 96.2% of those currently reporting feminizing hormone use were virally suppressed, compared with 85.0% of those not reporting use (p = 0.202). CONCLUSIONS: Once engaged in HIV care, TWLWH in Canada appear to have excellent ART use and viral suppression. Findings can be leveraged to identify target populations to enhance HIV care and to further explore the relationship between gender-affirming medical care and HIV care.


Subject(s)
HIV Infections , Transgender Persons , Adolescent , Canada/epidemiology , Female , Humans , Retrospective Studies , Viral Load
4.
Oxid Med Cell Longev ; 2019: 1486232, 2019.
Article in English | MEDLINE | ID: mdl-31467629

ABSTRACT

Ionizing radiation-induced cardiovascular diseases (CVDs) have been well documented. However, the mechanisms of CVD genesis are still not fully understood. In this study, human umbilical vein endothelial cells (HUVECs) were exposed to gamma irradiation at different doses ranging from 0.2 Gy to 5 Gy. Cell viability, migration ability, permeability, oxidative and nitrosative stresses, inflammation, and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway activation were evaluated postirradiation. It was found that gamma irradiation at doses ranging from 0.5 Gy to 5 Gy inhibited the migration ability of HUVECs without any significant effects on cell viability at 6 h and 24 h postirradiation. The decreased transendothelial electrical resistance (TEER), increased permeability, and disruption of cellular junctions were observed in HUVECs after gamma irradiation accompanied by the lower levels of junction-related proteins such as ZO-1, occludin, vascular endothelial- (VE-) cadherin, and connexin 40. The enhanced oxidative and nitrosative stresses, e.g., ROS and NO2 - levels and inflammatory cytokines IL-6 and TNF-α were demonstrated in HUVECs after gamma irradiation. Western blot results showed that protein levels of mitogen-activated protein kinase (MAPK) pathway molecules p38, p53, p21, and p27 increased after gamma irradiation, which further induced the activation of the NF-κB pathway. BAY 11-7085, an inhibitor of NF-κB activation, was demonstrated to partially block the effects of gamma radiation in HUVECs examined by TEER and FITC-dextran permeability assay. We therefore concluded that the gamma irradiation-induced disruption of cellular junctions in HUVECs was through the inflammatory MAPK/NF-κB signaling pathway.


Subject(s)
Gamma Rays/adverse effects , Human Umbilical Vein Endothelial Cells/radiation effects , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Humans
5.
Nat Commun ; 9(1): 2411, 2018 06 20.
Article in English | MEDLINE | ID: mdl-29925835

ABSTRACT

Asparaginyl endopeptidases (AEPs) are proteases that have crucial roles in plant defense and seed storage protein maturation. Select plant AEPs, however, do not function as proteases but as transpeptidases (ligases) catalyzing the intra-molecular ligation of peptide termini, which leads to peptide cyclization. These ligase-type AEPs have potential biotechnological applications ranging from in vitro peptide engineering to plant molecular farming, but the structural features enabling these enzymes to catalyze peptide ligation/cyclization rather than proteolysis are currently unknown. Here, we compare the sequences, structures, and functions of diverse plant AEPs by combining molecular modeling, sequence space analysis, and functional testing in planta. We find that changes within the substrate-binding pocket and an adjacent loop, here named the "marker of ligase activity", together play a key role for AEP ligase efficiency. Identification of these structural determinants may facilitate the discovery of more ligase-type AEPs and the engineering of AEPs with tailored catalytic properties.


Subject(s)
Cysteine Endopeptidases/metabolism , Peptides, Cyclic/biosynthesis , Plant Proteins/metabolism , Plants/metabolism , Cysteine Endopeptidases/genetics , Models, Molecular , Plant Proteins/genetics , Plants/genetics , Plants, Genetically Modified , RNA, Plant/genetics , Sequence Analysis, RNA
6.
Cell Death Dis ; 7: e2155, 2016 Mar 24.
Article in English | MEDLINE | ID: mdl-27010856

ABSTRACT

Studies on the role of Wnt/ß-catenin signaling in different forms of kidney disease have yielded discrepant results. Here, we report the biphasic change of renal ß-catenin expression in mice with overload proteinuria in which ß-catenin was upregulated at the early stage (4 weeks after disease induction) but abrogated at the late phase (8 weeks). Acute albuminuria was observed at 1 week after bovine serum albumin injection, followed by partial remission at 4 weeks that coincided with overexpression of renal tubular ß-catenin. Interestingly, a rebound in albuminuria at 8 weeks was accompanied by downregulated tubular ß-catenin expression and heightened tubular apoptosis. In addition, there was an inverse relationship between Dickkopf-3 (Dkk-3) and renal tubular ß-catenin expression at these time points. In vitro, a similar trend in ß-catenin expression was observed in human kidney-2 (HK-2) cells with acute (upregulation) and prolonged (downregulation) exposure to albumin. Induction of a proapoptotic phenotype by albumin was significantly enhanced by silencing ß-catenin in HK-2 cells. Finally, Dkk-3 expression and secretion was increased after prolonged exposure to albumin, leading to the suppression of intracellular ß-catenin signaling pathway. The effect of Dkk-3 on ß-catenin signaling was confirmed by incubation with exogenous Dkk-3 in HK-2 cells. Taken together, these data suggest that downregulation of tubular ß-catenin signaling induced by Dkk-3 has a detrimental role in chronic proteinuria, partially through the increase in apoptosis.


Subject(s)
Apoptosis , Intercellular Signaling Peptides and Proteins/metabolism , Kidney Diseases/metabolism , Kidney Tubules/metabolism , Proteinuria/metabolism , Wnt Signaling Pathway , beta Catenin/metabolism , Adaptor Proteins, Signal Transducing , Animals , Cell Line , Chemokines , Gene Expression Regulation , Humans , Intercellular Signaling Peptides and Proteins/genetics , Kidney Diseases/genetics , Kidney Diseases/pathology , Kidney Tubules/pathology , Mice , Proteinuria/genetics , Proteinuria/pathology , beta Catenin/genetics
7.
Rev Sci Instrum ; 86(8): 083501, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26329186

ABSTRACT

A grid image refractometer (GIR) has been implemented at the Nike krypton fluoride laser facility of the Naval Research Laboratory. This instrument simultaneously measures propagation angles and transmissions of UV probe rays (λ = 263 nm, Δt = 10 ps) refracted through plasma. We report results of the first Nike-GIR measurement on a CH plasma produced by the Nike laser pulse (∼1 ns FWHM) with the intensity of 1.1 × 10(15) W/cm(2). The measured angles and transmissions were processed to construct spatial profiles of electron density (ne) and temperature (Te) in the underdense coronal region of the plasma. Using an inversion algorithm developed for the strongly refracted rays, the deployed GIR system probed electron densities up to 4 × 10(21) cm(-3) with the density scale length of 120 µm along the plasma symmetry axis. The resulting n(e) and T(e) profiles are verified to be self-consistent with the measured quantities of the refracted probe light.

8.
Antimicrob Agents Chemother ; 59(4): 2113-21, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25624332

ABSTRACT

Staphylococcus aureus is a virulent pathogen that is responsible for a wide range of superficial and invasive infections. Its resistance to existing antimicrobial drugs is a global problem, and the development of novel antimicrobial agents is crucial. Antimicrobial peptides from natural resources offer potential as new treatments against staphylococcal infections. In the current study, we have examined the antimicrobial properties of peptides isolated from anuran skin secretions and cyclized synthetic analogues of these peptides. The structures of the peptides were elucidated by nuclear magnetic resonance (NMR) spectroscopy, revealing high structural and sequence similarity with each other and with sunflower trypsin inhibitor 1 (SFTI-1). SFTI-1 is an ultrastable cyclic peptide isolated from sunflower seeds that has subnanomolar trypsin inhibitory activity, and this scaffold offers pharmaceutically relevant characteristics. The five anuran peptides were nonhemolytic and noncytotoxic and had trypsin inhibitory activities similar to that of SFTI-1. They demonstrated weak in vitro inhibitory activities against S. aureus, but several had strong antibacterial activities against S. aureus in an in vivo murine wound infection model. pYR, an immunomodulatory peptide from Rana sevosa, was the most potent, with complete bacterial clearance at 3 mg · kg(-1). Cyclization of the peptides improved their stability but was associated with a concomitant decrease in antimicrobial activity. In summary, these anuran peptides are promising as novel therapeutic agents for treating infections from a clinically resistant pathogen.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Anura/metabolism , Peptides/therapeutic use , Skin Diseases, Bacterial/drug therapy , Staphylococcal Infections/drug therapy , Trypsin Inhibitors/therapeutic use , Animals , Anti-Bacterial Agents/chemical synthesis , Cell Survival/drug effects , Cyclization , Female , Humans , In Vitro Techniques , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Models, Molecular , Peptides/chemical synthesis , Peptides/chemistry , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Skin Diseases, Bacterial/microbiology , Staphylococcal Infections/microbiology , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/chemistry
9.
Med J Malaysia ; 66(5): 497-8, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22390110

ABSTRACT

We present a rare case of Tay-Sachs disease with retinal 'cherry-red spots' in a 19-month-old Malay child. Molecular genetic studies confirmed the diagnosis. The case highlights that 'cherry-red spot' is a useful clinical clue in Tay-Sachs disease and several other lysosomal storage disorders. It serves as an ideal illustration of the eye as a window to inborn error of metabolism.


Subject(s)
Retinal Diseases/pathology , Tay-Sachs Disease/pathology , Hexosaminidase A/genetics , Humans , Infant , Malaysia , Male , Retinal Diseases/genetics , Tay-Sachs Disease/genetics
10.
Br J Surg ; 96(11): 1323-35, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19847872

ABSTRACT

BACKGROUND: Postoperative intra-abdominal adhesion is associated with high morbidity and mortality. Smad7, a protein that occupies a strategic position in fibrogenesis, inhibits the transforming growth factor (TGF) beta/Smad signalling pathway. In this study the therapeutic potential of exogenous Smad7 in preventing fibrogenesis in postoperative intra-abdominal adhesion was investigated. METHODS: Intra-abdominal adhesion was induced in a rodent model by peritoneal abrasion. Smad7 was delivered into the peritoneal cavity by a non-viral ultrasound-microbubble-mediated naked gene transfection system. The effect of Smad7 transgene on adhesion formation was studied by measuring changes in TGF-beta, fibrogenic factors, alpha-SMA and Smad2/3 activation in the anterior abdominal wall. RESULTS: Four weeks after surgical abrasion, all rats developed significant peritoneal adhesion with enhanced TGF-beta expression, increased levels of extracellular matrix components and activated myofibroblasts, accompanied by decreased Smad7 expression and increased Smad2/3 activation. In rats treated with the Smad7 transgene, the incidence and severity of peritoneal adhesion were significantly reduced, with biochemical downregulation of fibrogenic factors and inhibition of Smad2/3 activation. Serial quantitation using magnetic resonance imaging revealed a significant reduction in adhesion areas from day 14 onwards. CONCLUSION: Ultrasound-microbubble-mediated gene transfection provides timely targeted gene delivery for the treatment of postoperative peritoneal adhesions.


Subject(s)
Gene Transfer Techniques , Genetic Vectors/physiology , Peritoneal Diseases/prevention & control , Smad7 Protein/administration & dosage , Tissue Adhesions/prevention & control , Transgenes/physiology , Abdominal Wall , Animals , Extracellular Matrix/pathology , Immunohistochemistry , Male , Microbubbles , Peritoneal Diseases/metabolism , Peritoneal Diseases/pathology , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Smad2 Protein/metabolism , Smad3 Protein/metabolism , Smad7 Protein/genetics , Tissue Adhesions/metabolism , Tissue Adhesions/pathology , Transforming Growth Factor beta/biosynthesis , Up-Regulation
11.
Anaesth Intensive Care ; 37(5): 773-83, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19775042

ABSTRACT

Mortality and cost outcomes of elderly intensive care unit (ICU) trauma patients were characterised in a retrospective cohort study from an Australian tertiary ICU Trauma patients admitted between January 2000 and December 2005 were grouped into three major age categories: aged > or =65 years admitted into ICU (n = 272); aged -65 years admitted into general ward (n = 610) and aged < 65 years admitted into ICU (n = 1617). Hospital mortality predictors were characterised as odds ratios (OR) using logistic regression. The impact of predictor variables on (log) total hospital-stay costs was determined using least squares regression. An alternate treatment-effects regression model estimated the mortality cost-effect as an endogenous variable. Mortality predictors (P < or = 0.0001, comparator: ICU > or = 65 years, ventilated) were: ICU < 65 not-ventilated (OR 0.014); ICU < 65 ventilated (OR 0.090); ICU age > or = 65 not-ventilated (OR 0.061) and ward > or = 65 (OR 0.086); increasing injury severity score and increased Charlson comorbidity index of 1 and 2, compared with zero (OR 2.21 [1.40 to 3.48] and OR 2.57 [1.45 to 4.55]). The raw mean daily ICU and hospital costs in A$ 2005 (US$) for age < 65 and > or = 65 to ICU, and > or = 65 to the ward were; for year 2000: ICU, $2717 (1462) and $2777 (1494); hospital, $1837 (988) and $1590 (855); ward $933 (502); for year 2005: ICU, $3202 (2393) and $3086 (2307); hospital, $1938 (1449) and $1914 (1431); ward $1180 (882). Cost increments were predicted by age < or = 65 and ICU admission, increasing injury severity score, mechanical ventilation, Charlson comorbidity index increments and hospital survival. Mortality cost-effect was estimated at -63% by least squares regression and -82% by treatment-effects regression model. Patient demographic factors, injury severity and its consequences predict both cost and survival in trauma. The cost mortality effect was biased upwards by conventional least squares regression estimation.


Subject(s)
Critical Care/economics , Hospital Mortality , Patients' Rooms/economics , Wounds and Injuries , Adult , Aged , Australia/epidemiology , Cohort Studies , Hospital Costs , Hospitals, Community , Humans , Length of Stay , Middle Aged , Regression Analysis , Respiration, Artificial/statistics & numerical data , Retrospective Studies , Wounds and Injuries/economics , Wounds and Injuries/mortality
12.
Kidney Int ; 73(3): 288-99, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18033243

ABSTRACT

Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins have renoprotective effects. We studied the cellular mechanisms for this effect in adriamycin-treated mice receiving captopril, losartan, simvastatin, or their combinations. The mice developed albuminuria, renal insufficiency, and parenchymal inflammation/fibrosis accompanied by overexpression of intrarenal converting enzyme and angiotensin II. Only captopril consistently improved these abnormalities and reduced the cortical expression of several proinflammatory and profibrotic factors including transforming growth factor-beta (TGF-beta). These effects were independent of blood pressure, accompanied by increased urine N-acetylseryl-aspartyl-lysyl-proline (Ac-SDKP) levels, and the restoration of renal angiotensin-converting enzyme and angiotensin II to baseline levels. Losartan or simvastatin alone or together had no effect, and their addition to captopril did not enhance protection. In vitro, angiotensin II stimulated TGF-beta in renal tubular cells via mitogen-activated protein kinase (MAPK) signaling. Captopril or Ac-SDKP suppressed angiotensin II-induced MAPK activation and TGF-beta secretion. Angiotensin-converting enzyme inhibition confers renoprotection in adriamycin nephropathy by reducing intrarenal angiotensin II and augmenting Ac-SDKP expression that together attenuate MAPK signaling and its downstream proinflammatory and fibrogenic properties. The addition of receptor blocker and/or statin failed to potentiate such effects.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Glomerulosclerosis, Focal Segmental/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Kidney/drug effects , Angiotensin II/metabolism , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Cell Proliferation/drug effects , Cells, Cultured , Chemokine CCL2/metabolism , Collagen Type I/metabolism , Doxorubicin/adverse effects , Drug Therapy, Combination , Epithelial Cells/drug effects , Glomerulosclerosis, Focal Segmental/metabolism , Glomerulosclerosis, Focal Segmental/pathology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Kidney/immunology , Kidney/metabolism , Kidney/pathology , Macrophages/drug effects , Mice , Mice, Inbred BALB C , Peptidyl-Dipeptidase A/metabolism , Phenotype , Placenta Growth Factor , Pregnancy Proteins/metabolism , Signal Transduction/drug effects , Transforming Growth Factor beta/metabolism
13.
Gene Ther ; 14(24): 1712-20, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17960163

ABSTRACT

Gene transfer into the peritoneal cavity by nonviral methods may provide an effective therapeutic approach for peritoneal diseases. Herein, we investigated the feasibility and the effectiveness of ultrasound-microbubble-mediated delivery of naked plasmid DNA into the peritoneal cavity in rats. Following the intraperitoneal or the intravenous administration of a mixture of plasmid DNA (100 microg) and ultrasound contrast agent microbubbles, an ultrasound transducer was applied on the abdominal wall. The reporter pTRE plasmid encoding Smad7 was used to evaluate transfection efficiency. Smad7 expression was induced by doxycycline in drinking water. We detected less than 10% apoptotic cells and no inflammatory reaction in peritoneal tissues following the ultrasound-microbubble-mediated transfection. More importantly, the insonation significantly improved the transfection efficiency in peritoneal tissues. The transfection efficiency by intraperitoneal delivery route was higher than the intravenous route. The reporter gene, pTRE-Smad7, was readily detected in the parietal peritoneum, mesentery, greater omentum and adipose tissue. The peak of transgene expression occurred 2 days after transfection and the transgene expression diminished in a time-dependent manner thereafter. Overall, the effectiveness and simplicity of the ultrasound-microbubble-mediated system may provide a promising nonviral means for improving gene delivery for treating peritoneal diseases in vivo.


Subject(s)
DNA/administration & dosage , Genetic Therapy/methods , Genetic Vectors/administration & dosage , Transfection/methods , Albumins , Animals , Apoptosis , Contrast Media , Fluorocarbons , Gene Expression , Injections, Intraperitoneal , Injections, Intravenous , Microbubbles , Peritoneum/pathology , Rats , Rats, Sprague-Dawley , Smad7 Protein/analysis , Smad7 Protein/genetics , Time Factors , Transgenes , Ultrasonics
14.
Leukemia ; 21(7): 1423-30, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17476279

ABSTRACT

Aldehyde dehydrogenase (ALDH) activity is used to define normal hematopoietic stem cell (HSC), but its link to leukemic stem cells (LSC) in acute myeloid leukemia (AML) is currently unknown. We hypothesize that ALDH activity in AML might be correlated with the presence of LSC. Fifty-eight bone marrow (BM) samples were collected from AML (n=43), acute lymphoblastic leukemia (ALL) (n=8) and normal cases (n=7). In 14 AML cases, a high SSC(lo)ALDH(br) cell population was identified (ALDH(+)AML) (median: 14.89%, range: 5.65-48.01%), with the majority of the SSC(lo)ALDH(br) cells coexpressing CD34(+). In another 29 cases, there was undetectable (n=23) or rare (< or =5%) (n=6) SSC(lo)ALDH(br) population (ALDH(-)AML). Among other clinicopathologic variables, ALDH(+)AML was significantly associated with adverse cytogenetic abnormalities. CD34(+) BM cells from ALDH(+)AML engrafted significantly better in NOD/SCID mice (ALDH(+)AML: injected bone 21.11+/-9.07%; uninjected bone 1.52+/-0.75% vs ALDH(-)AML: injected bone 1.77+/-1.66% (P=0.05); uninjected bone 0.23+/-0.23% (P=0.03)) with the engrafting cells showing molecular and cytogenetic aberrations identical to the original clones. Normal BM contained a small SSC(lo)ALDH(br) population (median: 2.92%, range: 0.92-5.79%), but none of the ALL cases showed this fraction. In conclusion, SSC(lo)ALDH(br) cells in ALDH(+)AML might denote primitive LSC and confer an inferior prognosis in patients.


Subject(s)
Aldehyde Dehydrogenase/analysis , Leukemia, Myeloid/pathology , Neoplasm Transplantation , Neoplastic Stem Cells/pathology , Acute Disease , Adult , Aged , Animals , Antigens, CD34/analysis , Bone Marrow Examination , Case-Control Studies , Female , Humans , Leukemia, Myeloid/diagnosis , Male , Mice , Mice, SCID , Middle Aged , Neoplasm Proteins/analysis , Prognosis
15.
Kidney Int ; 71(6): 526-38, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17245394

ABSTRACT

We hypothesize an interaction between T cells/monocytes and the tubules in the development of tubulointerstitial injury in chronic proteinuric nephropathy. We established in vitro co-culture systems of proximal tubular epithelial cells (PTEC) and T cells/monocytes to study the contribution of soluble factors and cell-to-cell contact in the development of tubulointerstitial injury. The release of monocyte chemoattractant protein-1 (MCP1 or CCL2), Regulated upon Activation, normal T cell Expressed and Secreted (RANTES or CCL5), soluble intracellular adhesion molecules-1 (sICAM-1), or interleukin-6 (IL-6) was increased in PTEC following apical exposure to human serum albumin (HSA). The release of CCL2, CCL5, or sICAM-1 from PTEC was enhanced by contact of monocytes/T cells on the basolateral surface. Tumor necrosis factor-alpha (TNF-alpha) and IL-1beta are important soluble factors as suggested by the blocking effect of antibodies (Abs) against TNF-alpha or IL-1beta but not against other cytokines. The percentage of CD4+ T cells expressing both chemokine receptors, CCR2 and CCR5, was increased after culturing with supernatant from the apical or basolateral surface of PTEC following apical exposure to HSA. However, only CCR2 was upregulated in CD8+ T cells, whereas CCR5 expression was increased in monocytes. The chemotaxis of CD4+ or CD8+ T cells to supernatant from PTEC upon apical exposure to HSA was reduced with neutralizing Abs against CCL5 and/or CCL2, whereas the chemotaxis of monocytes was only reduced by anti-CCL5 but not by anti-CCL2. In summary, chemokines released by HSA-activated PTEC are amplified by monocytes/T cells. Mediators released by HSA-activated PTEC can differentially modulate the expression of chemokine receptors in monocytes/T cells and hence, alter their chemotaxis towards activated PTEC. These interactions are pivotal in the development of tubulointerstitial injury.


Subject(s)
Cell Communication/physiology , Epithelial Cells/pathology , Kidney Tubules, Proximal/pathology , Monocytes/pathology , Proteinuria/pathology , T-Lymphocytes/pathology , Cells, Cultured , Chemokine CCL2/genetics , Chemokine CCL2/metabolism , Chemokine CCL5 , Chemokines, CC/genetics , Chemokines, CC/metabolism , Chemotaxis/drug effects , Chemotaxis/physiology , Coculture Techniques , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Humans , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/metabolism , Interleukin-2 Receptor alpha Subunit/genetics , Interleukin-2 Receptor alpha Subunit/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Kidney Tubules, Proximal/drug effects , Kidney Tubules, Proximal/metabolism , Monocytes/physiology , Proteinuria/physiopathology , Receptors, Chemokine/genetics , Receptors, Chemokine/metabolism , Serum Albumin/pharmacology , T-Lymphocytes/physiology
16.
Ultrasound Obstet Gynecol ; 28(6): 789-93, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17063457

ABSTRACT

OBJECTIVE: Tissue Doppler imaging (TDI) is an echocardiographic technique for assessing the diastolic function that is relatively independent of preload. Since loading conditions change significantly during pregnancy, a load-independent technique will give a more accurate assessment of diastolic function in pregnant women. The aim of this study was to evaluate maternal diastolic function using tissue Doppler imaging. METHODS: This was a prospective observational study on 35 healthy pregnant women. M-mode, transmitral inflow (peak transmitral flow velocities during early diastole (E wave) and atrial contraction (A wave)) and TDI studies (peak myocardial velocities during early diastole (Em wave), during atrial contraction (Am wave) and peak systole in ejection phase (Sm)) were performed in each trimester and postpartum. The differences in variables between trimesters were analyzed. RESULTS: The peak transmitral inflow velocity during early diastole (E wave) was significantly decreased during the third trimester and postpartum. The peak flow velocity during atrial contraction (A wave) was increased in the second trimester, but decreased again in the third trimester and postpartum period. As a result, the E/A ratio progressively reduced as pregnancy advanced. TDI showed that peak myocardial velocities during early diastole (Em) tended to increase during the second trimester, and then decreased significantly in the third trimester or postpartum period. The peak myocardial velocities during atrial contraction (Am) increased significantly with advancing gestational age. As a consequence, both Em/Am and E/Em ratios decreased significantly throughout pregnancy. CONCLUSIONS: This study demonstrates the changes in myocardial relaxation velocity throughout pregnancy. Because of its advantage of being relatively load-independent, TDI may be a useful non-invasive technique for monitoring maternal cardiac function in high-risk pregnancies to detect the early signs of cardiac failure and to prevent further deterioration with prompt interventions.


Subject(s)
Echocardiography, Doppler, Pulsed/methods , Pregnancy/physiology , Ultrasonography, Prenatal/methods , Ventricular Function, Left/physiology , Diastole , Echocardiography, Doppler, Pulsed/instrumentation , Evaluation Studies as Topic , Female , Humans , Pregnancy Trimesters , Prospective Studies , Ultrasonography, Prenatal/instrumentation
17.
BJOG ; 113(11): 1259-63, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16978226

ABSTRACT

OBJECTIVE: To evaluate the operative outcomes when trainees first perform caesarean sections independently. DESIGN: A retrospective study in a tertiary obstetric unit. POPULATION: Five hundred caesarean sections, which represented the first 50 caesarean sections performed independently by each of ten trainees, were studied. METHODS: The effect of learning curve on outcome was analysed. MAIN OUTCOME MEASURES: Total operative time, incision-to-delivery interval, operative blood loss, Apgar score, cord arterial pH, incidence of neonatal intensive care unit admission, postoperative complication rates and duration of hospitalisation. RESULTS: The mean operative time for the first five cases by trainees was 52.2 +/- 11.4 minutes. It progressively decreased and reached 39.6 +/- 8.4 minutes for the 46th to 50th cases. The operative time was significantly longer in the first 15 caesarean sections (P < 0.05). Moreover, the incision-to-delivery interval was also longer during the first five cases (P= 0.02). Besides the time of the operation, the trend for operative blood loss stabilised after the first ten caesarean sections (P < 0.05). Otherwise, there were no significant differences among other outcome variables. CONCLUSION: This study shows that trainees need to perform 10-15 caesarean sections before their skills become more proficient. Senior obstetricians may need to provide guidance to the trainees during their first independent 15 caesarean sections.


Subject(s)
Cesarean Section/standards , Medical Staff, Hospital/education , Obstetric Labor Complications/surgery , Apgar Score , Blood Loss, Surgical , Clinical Competence/statistics & numerical data , Female , Hong Kong , Humans , Intensive Care, Neonatal , Length of Stay , Medical Staff, Hospital/statistics & numerical data , Practice, Psychological , Pregnancy , Pregnancy Outcome , Retrospective Studies
18.
Ultrasound Obstet Gynecol ; 28(2): 162-5, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16708416

ABSTRACT

OBJECTIVE: To evaluate the effect of fetal position on measurement of amniotic fluid index (AFI) and of the single deepest pocket (SDP). METHODS: This was a prospective observational study, in a university obstetric unit, of women with an uncomplicated singleton pregnancy with longitudinal lie and cephalic presentation at or beyond 28 weeks of gestation. AFI was calculated and SDP measured and the fetal position was characterized in terms of three parameters. These were: the side of the maternal abdomen on which the fetus lay; a numerical representation (laterality score) of the distance that the fetus was from the sagittal midline plane of the maternal abdomen; the orientation of the fetal trunk (ventral anterior, lateral or posterior). RESULTS: Eighty-one women were recruited into the study. There was a significant relationship between the laterality score and the AFI (P = 0.005) but not the SDP (P = 0.23): AFI was on average 4.35 cm higher in fetuses lying centrally compared with those lying laterally inside the uterus. There was no significant difference for either SDP (P = 0.8) or AFI (P = 0.3) between fetuses lying on the right or the left side of the maternal abdomen. Similarly, there was no significant difference in SDP (P = 0.9) or AFI (P = 1.0) for the different orientations of the fetal trunk. CONCLUSION: Fetal position affects the measurement of AFI but not that of SDP. Therefore, SDP may be a more consistent parameter for the estimation of amniotic fluid volume.


Subject(s)
Amniotic Fluid/diagnostic imaging , Fetus/embryology , Ultrasonography, Prenatal , Abdomen/diagnostic imaging , Adult , Female , Gestational Age , Humans , Labor Presentation , Pregnancy , Prospective Studies
19.
Int J Mol Med ; 17(6): 1151-5, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16685429

ABSTRACT

Musculoskeletal allotransplantion is the most common form of human tissue transplantation. Unlike solid organ transplants, bone allotransplants undergo rigorous processing and are considered non-viable tissue. In this study, we propose that donor genetic material may exist in circulation after bone allotransplantation. Fifty-one female patients who received bone allotransplants from male donors were assessed. Blood plasma samples were analyzed using real-time quantitative polymerase chain reaction (PCR) with dual labeled fluorogenic probes for the presence of the SRY gene on the Y chromosome. Of the total 51 patients, the SRY sequence was detected in 6 patients. Five were positive at day 1 postoperatively and negative thereafter, with the remaining patient positive at 3 months post-transplantation. Our results document, for the first time, the presence of donor DNA in the circulation of recipients after bone allotransplantation. Our findings suggest a potential new investigative tool to assess the postoperative status of bone allotransplants.


Subject(s)
Bone Remodeling/genetics , Bone Transplantation , DNA/blood , Tissue Donors , Chromosomes, Human, Y/genetics , Female , Genes, sry/genetics , Humans , Male , Middle Aged , Polymerase Chain Reaction , Prognosis , Transplantation, Homologous
20.
Kidney Int ; 69(11): 2078-86, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16641931

ABSTRACT

Marked increase in leptin concentration in spent peritoneal dialysate has been reported following continuous ambulatory peritoneal dialysis treatment. The present study was designed to determine whether functional leptin receptor is expressed by human peritoneal mesothelial cells and if so, the possible implication in dialysis. Expression of leptin receptors in cultured mesothelial cells and omental tissue was examined. The effect of leptin on the production of transforming growth factor-beta (TGF-beta) by mesothelial cells in the presence or absence of high glucose was determined using in vitro culture model of human peritoneal mesothelial cells and adipocytes. The signaling mechanism involved in leptin-induced TGF-beta synthesis by mesothelial cells was studied. Both mRNA and protein of the full-length leptin receptor are constitutively expressed in mesothelial cells. The leptin receptor expression in mesothelial cells was upregulated by glucose but not leptin. In adipocytes, glucose increased the mRNA expression and synthesis of leptin. The Janus kinase-signal transducers and activation (JAK-STAT) signal transduction pathway in mesothelial cells was activated by either exogenous or adipocytes-derived leptin. Exogenous leptin induced the release of TGF-beta by mesothelial cells. The TGF-beta synthesis induced by leptin was amplified by glucose through increased leptin receptor expression. Our novel findings reveal that functional leptin receptor is present on human peritoneal mesothelial cells. The leptin-induced TGF-beta synthesis in mesothelial cells is associated with the expression of leptin receptor and the activation of the JAK-STAT signal transduction pathway.


Subject(s)
Epithelial Cells/physiology , Leptin/physiology , Peritoneum/cytology , Receptors, Cell Surface/biosynthesis , Transforming Growth Factor beta/biosynthesis , Cells, Cultured , Humans , Receptors, Leptin
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