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Biomedical subjects

D Ho

Publications and source records attributed to D Ho.

At least 19 recordsLinked to original sources
PubMed1997

Dendrite cell-T cell mixtures, isolated from the skin and mucosae of macaques, support the replication of SIV.

Previous studies have shown that HIV-1 exploits dendritic cells (DCs) to replicate and spread among CD4+ T cells. The DCs within mucosal surfaces may be especially important, but these are more difficult to access. To study more extensively the properties of DCs and other leukocytes from skin and different mucosae, DCs were isolated from uninfected macaques and their sensitivity assessed to infection with SIV in vitro. Dendritic cells and T cells readily emigrated from organ cultures of macaque skin, as described previously for humans. In addition, characteristic cells emigrated from explants of mucosae, both nasopharyngeal (adenoid and tonsil) and genital (vagina and cervix). The macaque DCs reacted with the monoclonals that are used to study human DCs, such as MAbs to CD40, CD86, CD83, and the p55 protein. When SIV was added to the DC-T cell mixtures from these different organs, extensive replication was observed in all but the cervical leukocytes. SIV replication occurred without the use mitogens, and with virus that had been grown in a cell line in the absence of mitogens and IL-2. Most of the newly synthesized viral protein is observed in syncytia. Therefore, mixtures of DCs and T cells isolated from mucosal surfaces served as a naturally permissive environment for SIV replication.

Animals↗
PubMed1997

Cutaneous dendritic cells promote replication of immunodeficiency viruses.

The cutaneous or mucosal DC-T cell environments seem extremely supportive of immunodeficiency virus replication. Apart from very early after SIV infection, similar virus producing cells have been difficult to detect in the lymphoid tissues where DCs and T cells are also known to interact. Large amounts of virus can be visualized in the germinal centers of the lymph nodes, much of which represents immune complexed virus that is trapped on the follicular dendritic cell surface. However, whether these virus-carrying cells actually make virus or even virus proteins requires further investigation. We believe that once an individual is systemically infected, free virus and/or virus-infected cells will seed peripheral tissues and when encountering similar DC-T cell environments as described in the oral mucosae, can set up sites of chronic virus replication. For instance, a virus-carrying T cell that migrates to the periphery would, on entering this milieu, interact with the mature DCs and activate virus production. This likely occurs at similar sites around the body, such as the mucosal associated lymphoid tissue of the gut, and is probably independent of the route of infection.

Animals↗
PubMed1997

Ocular abnormalities in Down syndrome: an analysis of 140 Chinese children.

One hundred forty Chinese children with Down syndrome (DS) treated in the Child Assessment Centre of the Duchess of Kent Children's Hospital in Hong Kong between 1985 and 1996 underwent a detailed ophthalmologic evaluation, including test of visual acuity by behavioral testing or retinoscopy, determination of ocular motility, visual field examination, binocular examination for strabismus, determination of near point convergence and pupillary reflex, and/or slit lamp bimicroscopy and ophthalmoscopy to assess ocular health. Only 43 children (31%) had no ocular abnormalities. The overall incidence of ocular abnormalities was 69%, and included refractive error (58%), strabismus (20%), nystagmus (11%), blepharitis/conjunctivitis (7%), lens opacities (4%), and glaucoma (0.7%). No child had Brushfield spots or keratoconus. The incidence of refractive errors increased with increasing age and nearly doubled at school age. As compared with white children with DS, the Chinese children with DS exhibited a higher incidence of refractive error and a similar incidence of lens opacities but a lower incidence of strabismus, nystagmus, blepharitis, Brushfield spots, and keratoconus. Regular visual surveillance, especially of visual acuity, in children with DS as they mature is important in preventing amblyopia.

Adolescent↗
PubMed1996

A new approach to fecal occult blood testing based on the detection of haptoglobin.

BACKGROUND: Colorectal carcinoma is a common disease, occurring in 1 in 20 adults in Western society, and there is a compelling need for an effective early diagnostic test. Several serum tests, including carcinoembryonic antigen have been used, but none are sufficiently sensitive for the early diagnosis of the disease. METHODS: In a novel approach using fecal extracts from patients with colorectal cancer as the antigen for immunization, several MoAbs were produced. One (FE14.1) was found to react with the feces from patients with colon cancer, but not with those from normal subjects. A sandwich enzyme-linked immunoadsorbent assay was developed, and its ability to diagnose colorectal carcinoma evaluated. RESULTS: Of the patients with colorectal carcinoma, 91.5% (43/46) were positive compared with 1.9% of normal individuals (4/211). Analysis of the N-terminal amino acid sequence of a subunit of the molecule detected by FE14.1 shows it to be the beta chain of haptoglobin. CONCLUSIONS: The assay developed in this study has several advantages compared with current fecal occult blood tests, including no requirement for dietary restriction and the ability to distinguish between upper and lower gastrointestinal bleeding, while retaining the sensitivity and specificity of the current tests. Furthermore, the sensitivity of the tests increases to 100% if the FE14.1 and HemeSelect are combined. In addition, the study shows the potential to produce anticancer agents by immunizing with fecal material.

Adult↗
PubMed1996

A herpes simplex virus vector overexpressing the glucose transporter gene protects the rat dentate gyrus from an antimetabolite toxin.

The use of herpes simplex virus vectors offers an attractive means for the in vitro and in vivo transfer of novel genes into postmitotic neurons. Such an approach allows for the introduction of genes with the potential to protect neurons from necrotic insults. Toward that end, we have previously constructed a bicistronic herpes viral vector expressing the gene for the Glut-1 rat brain glucose transporter (GT), along with the Escherichia coli lacZ reporter gene. We observed that this vector enhances glucose uptake both in primary hippocampal cultures and in the hippocampus itself. Moreover, we have found that this vector will protect a variety of types of cultured neurons from necrotic insults and protect hippocampal neurons in vivo from seizure-induced damage. In the present report, we further demonstrate the neuroprotective potential of this GT-expressing vector. 3-Acetylpyridine, an electron transport uncoupler which is preferentially toxic to the dentate gyrus, was microinfused into the dorsal hippocampus of rats. Infection of dentate neurons with GT vectors at the time of exposure to the toxin significantly decreased damage, whereas infection with a physiologically neutral control vector did not. Moreover, there was a window of opportunity for this intervention, as microinfusion of the GT-expressing vector up to 1 h, but not 4 h, after the insult was still neuroprotective.

Animals↗
PubMed1996

Antiviral and resistance studies of AG1343, an orally bioavailable inhibitor of human immunodeficiency virus protease.

AG1343 ([3S-(3R*,4aR*,8aR*,2'S*,3'S*)]-2-[2' hydroxy-3'-phenylthiomethyl-4'-aza-5'-oxo-5'-(2''-methyl-3''-hydro xy-phenyl) pentyl]-decahydroiso-quinoline-3-N-t-butylcarboxamide methanesulfonic acid) is a selective, nonpeptidic inhibitor of human immunodeficiency virus (HIV) protease (Ki = 2 nM) that was discovered by protein structure-based drug design methodologies. AG1343 was effective against the replication of several laboratory and clinical HIV type 1 (HIV-1) or HIV-2 isolates including pyridinone- and zidovudine-resistant strains, with 50% effective concentrations ranging from 9 to 60 nM. In reversibility studies, inhibition of gag (p55) proteolytic processing in HIV-1 particles from cells treated with AG1343 was maintained for up to 36 h after drug removal. The ability of virus to develop resistance to AG1343 was studied by serial passage of HIV-1 NL4.3 in the presence of increasing concentrations of drug. After 28 passages, a variant with a 30-fold reduction in susceptibility to AG1343 was isolated. Molecular analysis of the protease from this variant indicated a double change from a Met to Ile at residue 46 and an Ile to Val or Ala at residue 84 (M46I+I84V, A). Consistent with these findings, reductions in susceptibility were observed for recombinant viruses constructed to contain the single I84V change or the double M46I+I84V substitutions. Resistance, however, was not detected for recombinant viruses containing other key mutations in HIV-1 protease, including a Val to Ile change at residue 32 or a Val to Ala or Phe at residue 82. The potent anti-HIV activity of AG1343 against several isolates suggests that AG1343 should perform well during ongoing human phase II clinical trials.

Amino Acid Sequence↗
PubMed1995

Assessment of abdominal aortic aneurysm with magnetic resonance imaging.

Pre-operative imaging of abdominal aortic aneurysms (AAA) is important in determining suitability for operation and operative approach. Ultrasound imaging is an excellent screening modality but is relatively poor at identifying renal arteries and the extent of iliac involvement. Computed tomography scanning with intravenous contrast and arteriography are invasive modalities that are associated with a small risk. Magnetic resonance imaging (MRI) offers the potential of accurate anatomical definition without use of contrast agents and passage of an intra-arterial catheter. Eight patients who had their AAA evaluated with MRI are reported. All had renal arteries accurately defined, intra-aneurysmal thrombosis was well delineated, and iliac extension was correctly identified in four cases. The initial experience has been most encouraging and the authors consider that MRI may become the investigation of choice for pre-operative AAA assessment.

Aged↗
PubMed1995

Low copy number and limited variability of proviral DNA in alveolar macrophages from HIV-1-infected patients: evidence for genetic differences in HIV-1 between lung and blood macrophage populations.

BACKGROUND: We investigated the human immunodeficiency virus (HIV) proviral DNA sequence and copy number in alveolar macrophages (AM) and peripheral blood monocytes (PBM) from 10 HIV-positive patients without any active concurrent pulmonary disease to understand the nature of HIV-1 infection in vivo in the lung microenvironment. MATERIALS AND METHODS: The 10 seropositive patients without active pulmonary disease were selected based on chest roentegenography and pathological/cytological test of bronchoalveolar (BAL) fluid. In order to determine accurate proviral copy numbers, AM and PBM were isolated to 99 and 94% purity, respectively, and quantitative polymerase chain reaction (PCR), with a sensitivity to detect three copies of HIV proviral DNA per 10(5) cells, was applied. For analysis of genetic variation in HIV-1, PCR-amplified HIV-1 DNA from AM and PBM of five patients were subcloned and 2-12 clones from each sample underwent DNA sequence analysis of HIV-1 gp120 V3-V5. Heteroduplex mobility assays were performed to confirm the results of the sequence analysis. RESULTS: The proviral copy number in AM or PBM were less than 20 copies/10(5) cells in all patients, and five patients had less than the detection limit. There was no significant difference in HIV copy number between AM and PBM. No correlation was found between PBM/AM HIV copy number and CD4+ lymphocyte count in the peripheral blood. Sequence analysis revealed that the mean intrapatient genetic similarity in AM was 97.5 +/- 0.18% (n = 107), which was significantly higher than that in PBM (96.2 +/- 0.26% (n = 94), p < 0.001), suggesting that variability of HIV-1 DNA in AM was relatively limited. Divergence occurred when AM derived HIV-1 sequence was compared with PBM derived sequence from the same patient (95.8 +/- 0.17% (n = 223) p < 0.001). Phylogenetic analysis of DNA sequence demonstrated complete separation of HIV lineages from lung and blood in four of five patients. CONCLUSIONS: The results suggest the HIV-1 infection in AM is restricted in vivo with low viral burden and homogenous genotype. We propose that the pulmonary microenvironment may limit the extent of HIV-1 infection.

Adult↗
PubMed1994

Correlation of perinatal transmission of human immunodeficiency virus type 1 with maternal viremia and lymphocyte phenotypes.

OBJECTIVE: To determine whether maternal transmission of human immunodeficiency virus (HIV) is correlated with increased quantities of HIV, decreased frequencies of CD4+ T cells, or increased levels of CD8+ T cells in the transmitting mother. METHODS: Peripheral blood obtained from HIV-infected women at different times during pregnancy was used to measure quantitative cell-associated HIV-1 and CD3+CD4+ and CD3+CD8+ proportions; the plasma was used to perform measurements of quantitative viremia by culture and subsequently to measure quantitative HIV-1 ribonucleic acid levels. These measurements were analyzed with respect to their association with HIV transmission to the baby, which occurred in one fourth of the cases. The children were also studied to determine whether HIV-1 was detected near birth or not until 1 to 8 weeks of life. RESULTS: Increased clonal frequencies of HIV-1-infected peripheral blood mononuclear cells were found in mothers of infected children; fivefold fewer cells were required for a positive culture result (median cell numbers of 10(4.5) vs 10(5.2); p = 0.008). Higher frequencies of infected cells were seen in mothers of babies with evidence of infection at birth than in mothers of infected babies without evidence of infection at birth (p < 0.05). Plasma viremia was measured in 10% of cultures without regard to whether the mothers transmitted virus to their babies. Increased levels of ribonucleic acid as detected by the branched-chain DNA method were measurable more often (45% vs 17%) in the mothers of infected children than in mothers of uninfected children. Proportions of CD4+ and CD8+ T cells were indistinguishable in these two groups of women. CONCLUSIONS: Increased viremia was present in mothers who transmitted HIV to their offspring. This variable could be used to select women at highest risk of transmitting HIV to their offspring for treatment to decrease the HIV burden five-fold.

CD4-CD8 Ratio↗
PubMed1994

Oxygen tension regulates osteoblast function.

Abrupt changes in oxygen availability within the periodontium have been suggested to have a regulatory role in alveolar bone remodeling during tooth movement; arguably, similar to that seen in bone growth or fracture healing. The purpose of this investigation was therefore to study the effects of ambient hypoxia and hyperoxia on osteoblast function in vitro. Osteoblast-enriched cultures from fetal rat calvariae were exposed to atmospheres of hyperoxia (90% O2) and hypoxia (10% O2) and assayed for media pH, pO2, pCO2, cellular proliferation, alkaline phosphatase (AP) activity, and collagen synthesis. Results of this study show that in low ambient oxygen tension cellular proliferation increases, whereas the AP activity, collagen synthesis, media pO2, PCO2 decreases. In contrast, in hyperoxic conditions cellular proliferation is suppressed with concomitant increases in: AP activity, collagen synthesis, and partial pressures for oxygen and carbon dioxide. Media pH remained unaffected. In crossover experiments, where cells were initially grown in hypoxic conditions and were switched to hyperoxic conditions, their metabolic activities were abruptly reversed. These findings in conjunction with earlier reports, suggest a triggering role for oxygen tension (an environmental factor) in bone remodeling.

Alkaline Phosphatase↗
PubMed1994

Bioequivalence of 20-mg once-daily tamoxifen relative to 10-mg twice-daily tamoxifen regimens for breast cancer.

PURPOSE: We studied the bioequivalence of a new once-daily regimen of tamoxifen citrate relative to the standard twice-daily regimen of tamoxifen citrate, an established antiestrogenic treatment for breast cancer. PATIENTS AND METHODS: Of 30 women with breast cancer, 27 completed this open, two-period, crossover randomized trial. During one 3-month period, patients took one standard 10-mg tamoxifen tablet twice daily; during the preceding or following 3-month period, patients took one of the new 20-mg tablets once daily. Pharmacokinetic profiles and safety parameters were assessed at the end of each 3-month treatment period. RESULTS: Overall, measured concentrations of tamoxifen and its principal active metabolite, N-desmethyltamoxifen, remained relatively constant over the 24-hour sampling periods at the end of each treatment sequence. For both compounds, the percentage differences of the geometric means for all pharmacokinetic parameters indicated bioequivalence of the once-daily regimen of tamoxifen relative to the standard twice-daily regimen. Both treatment sequences were well tolerated; reported adverse events occurred at similar frequencies with the two treatment regimens. CONCLUSION: The 20-mg tamoxifen tablet taken once daily was bioequivalent to the 10-mg tamoxifen tablet taken twice daily, with no difference in relative risk. The once-daily treatment is a simpler regimen and may facilitate compliance, which may enhance therapeutic outcomes during long-term treatment of breast cancer.

Administration, Oral↗
PubMed1993

HIV tropism.

Explore the source record for details and available documents.

CD4 Antigens↗
PubMed1993

Acute intracerebral haematomas: assessment for possible underlying cause with MRI scanning.

Forty-seven patients presenting with acute intracerebral haematomas between 1989 and 1992 were retrospectively examined to assess the role of Magnetic Resonance Imaging (MRI) in identifying any underlying lesion. None had any prior known intracerebral pathology. Magnetic resonance imaging scans were done on a 0.5 T unit. Ten patients with an average age of 35 years had angiographically occult vascular malformations (AOVM) found by MRI (one with biopsy confirmation). One of three cases of glioma, three of three cases with secondary tumour, one case of superior sagittal sinus thrombosis with haemorrhagic infarction, one of two cases of venous angioma and one case of arteriovenous malformation were detected by MRI. Progress computed tomography scans discovered two cases of glioma and angiography found a venous angioma and an arterial aneurysm, all undetected by MRI. It is concluded that MRI scanning is helpful in detecting underlying AOVM as a cause of intracerebral haemorrhage but its role in imaging haemorrhagic tumours remains unclear.

Acute Disease↗
PubMed1993

Functional and immunologic characterization of human immunodeficiency virus type 1 envelope glycoproteins containing deletions of the major variable regions.

Deletions of the major variable regions (V1/V2, V3, and V4) of the human immunodeficiency virus type 1 (HIV-1) gp120 exterior envelope glycoprotein were created to study the role of these regions in function and antigenicity. Deletion of the V4 region disrupted processing of the envelope glycoprotein precursor. In contrast, the deletion of the V1/V2 and/or V3 regions yielded processed exterior envelope glycoproteins that retained the ability to interact with the gp41 transmembrane glycoprotein and the CD4 receptor. Shedding of the gp120 exterior glycoprotein by soluble CD4 was observed for the mutant with the V3 deletion but did not occur for the V1/V2-deleted mutant. None of the deletion mutants formed syncytia or supported virus entry. Importantly, the affinity of neutralizing antibodies directed against the CD4-binding region for the multimeric envelope glycoprotein complex was increased dramatically by the removal of both the V1/V2 and V3 structures. These results indicate that, in addition to playing essential roles in the induction of membrane fusion, the major variable regions mask conserved neutralization epitopes of the HIV-1 gp120 glycoprotein from antibodies. These results explain the temporal pattern associated with generation of HIV-1-neutralizing antibodies following infection and suggest stratagems for eliciting improved immune responses to conserved gp120 epitopes.

Animals↗
PubMed1992

Phase I trial of a 72-h continuous-infusion schedule of fazarabine.

Fazarabine (Ara-AC), a structural analog derived from the antitumor nucleoside cytosine arabanoside (Ara-C) and 5-azacytidine (5-AC), was studied in a phase I clinical trial. Doses ranging from 0.2 to 2.0 mg m-2 h-1 were given intravenously over 72 h every 28 days. The maximum tolerated dose (MDT) was 2.00 mg m-2 h-1. The dose-limiting toxicity was myelosuppression, with granulocytopenia being quantitatively more important than thrombocytopenia or anemia. Nonhematologic toxicity was minimal. Associated with the solvent dimethylsulfoxide (DMSO) was a bitter taste and a garlic-like odor.

Adult↗
PubMed1992

Relationship of the human immunodeficiency virus type 1 gp120 third variable loop to a component of the CD4 binding site in the fourth conserved region.

Neutralizing antibodies that recognize the human immunodeficiency virus gp120 exterior envelope glycoprotein and are directed against either the third variable (V3) loop or conserved, discontinuous epitopes overlapping the CD4 binding region have been described. Here we report several observations that suggest a structural relationship between the V3 loop and amino acids in the fourth conserved (C4) gp120 region that constitute part of the CD4 binding site and the conserved neutralization epitopes. Treatment of the gp120 glycoprotein with ionic detergents resulted in a V3 loop-dependent masking of both linear C4 epitopes and discontinuous neutralization epitopes overlapping the CD4 binding site. Increased recognition of the native gp120 glycoprotein by an anti-V3 loop monoclonal antibody, 9284, resulted from from single amino acid changes either in the base of the V3 loop or in the gp120 C4 region. These amino acid changes also resulted in increased exposure of conserved epitopes overlapping the CD4 binding region. The replication-competent subset of these mutants exhibited increased sensitivity to neutralization by antibody 9284 and anti-CD4 binding site antibodies. The implied relationship of the V3 loop, which mediates post-receptor binding steps in virus entry, and components of the CD4 binding region may be important for the interaction of these functional gp120 domains and for the observed cooperativity of neutralizing antibodies directed against these regions.

Animals↗
PubMed1991

Isolation of mitotic p34cdc2 apoenzyme from human cells.

A simple procedure was devised for isolating from homogenates of mitotic cells the human homolog to the fission yeast cdc2 gene product. The identity of the purified protein was established with anti-p34cdc2 antibodies and p13suc 1, both specific ligands for p34cdc2. Active-site labeling with oxidized [alpha 32P]ATP showed the purified molecule to be an ATP-binding protein. Its ability to phosphorylate casein but not histone, and its phosphorylation on tyrosine, detected by anti-phosphotyrosine antibodies, indicates the form of p34cdc2 purified is the inactive or apoenzyme form. Purified quantities of human p34cdc2 should be of considerable value in establishing the mechanism of its activation at mitosis by phosphatases.

Apoenzymes↗