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Biomedical subjects

S Ho

Publications and source records attributed to S Ho.

At least 73 records · Page 4Linked to original sources
PubMed1998

Topiramate increases cerebral GABA in healthy humans.

Topiramate (TOP) is a novel anticonvulsant drug with multiple mechanisms of action used in the treatment of epilepsy. Measurements of cerebral GABA were obtained in six controls using 1H MRS at baseline and at 3 and 6 hours following the administration of 3 mg/kg of TOP. Brain GABA concentrations rose by 72% at 3 hours and by 64% at 6 hours compared with baseline (p < 0.004). This study demonstrates that TOP significantly increases human cerebral GABA concentrations in healthy individuals.

Adult↗
PubMed1997

Role for IL-15/IL-15 receptor beta-chain in natural killer 1.1+ T cell receptor-alpha beta+ cell development.

Mouse TCR alphabeta+ cells expressing NKR-P1 (NK1+ T cells in the C57BL/6 strain) are classified as a unique subset that require beta2m-associated, MHC class I-like molecules for development and preferentially express particular V beta and V alphaJ domains of the TCR. We show here that NK1+ T cells express the IL-2R beta/IL-15R beta that is normally present on conventional NK cells, but not T cells. In mice lacking IL-2R beta/IL-15R beta chain, the number of NK1+ T cells is dramatically reduced. However, in IL-2-deficient mice, NK1+ T cells develop normally. Moreover, NK1+ T cells proliferate upon stimulation by IL-15, and the proliferation is blocked by the addition of anti-IL-2R beta/IL-15R beta Abs. Collectively, our data indicate that NK1+ T cells require IL-2R beta/IL-15R beta chain in an IL-2-independent manner and demonstrate that IL-15 plays a crucial role during development.

Animals↗
PubMed1997

Identification and analysis of a novel member of the ubiquitin family expressed in dendritic cells and mature B cells.

Using a cDNA subtraction technique, a novel member of the ubiquitin family was isolated from human dendritic cells. This gene encodes a diubiquitin protein containing tandem head to tail ubiquitin-like domains, with the conservation of key functional residues. Expression of this 777-bp mRNA was restricted to dendritic cells and B cells, with strong expression in mature B cells. Southern blot analysis indicated that a single copy of this gene is present. In situ hybridization on tonsillar tissue showed expression in epithelial cells and isolated cells within the germinal center. With respect to an expressed-sequence tag (EST) this cDNA could be localized to the major histocompatibility complex class I region of chromosome 6. Comparative analysis and the expression pattern of this gene suggests a function in antigen processing and presentation.

Amino Acid Sequence↗
PubMed1997

Polymerase chain reaction-based identification of a novel serpin from human dendritic cells.

A subtraction library of CD40-stimulated human tonsil dendritic cells has been constructed using a polymerase chain reaction approach adapted for low numbers of cells. From this library we identified a cDNA for a serine protease inhibitor, a serpin, which is absent from monocytes, B cells and T cells but expressed in CD40-activated monocyte- and progenitor cell-generated dendritic cells. In addition, the serpin is expressed in a lung fibroblast cell line and keratinocytes. Its mRNA is detected only in tonsil and thymus. The serpin described here reportedly functions as a megakaryocyte maturation factor in the presence of interleukin (IL)-3 and IL-11. This suggests that dendritic cells may promote the immune response by protecting IL-3 and IL-11 or other essential proteins from degradation.

Amino Acid Sequence↗
PubMed1997

Clinical evaluation of the partition model for estimating radiation doses from yttrium-90 microspheres in the treatment of hepatic cancer.

Radiation doses to the tumour and non-tumorous liver compartments from yttrium-90 microspheres in the treatment of hepatic cancer, as estimated by a partition model, have been verified by correlation with the actual doses measured with a beta probe at open surgery. The validity of the doses to the lungs, the tumour and non-tumorous liver compartment as estimated by the partition model was further evaluated in clinical settings. On the basis of the observation that one of three patients who received more than 30 Gy from a single treatment and one of two patients who received more than 50 Gy from multiple treatments developed radiation pneumonitis, it was deduced that an estimated lung dose < 30 Gy from a single treatment and a cumulative lung dose < 50 Gy from multiple treatments were probably the tolerance limits of the lungs. Three of five patients who received lung doses > 30 Gy as estimated by the partition model and were predicted to develop radiation pneumonitis, did so despite the use of partial hepatic embolization to reduce the degree of lung shunting. Furthermore, a higher radiological response rate and prolonged survival were found in the group of patients who received higher tumour doses, as estimated by the partition model, than in the group with lower estimated tumour doses. Thus the radiation doses estimated by the partition model can be used to predict (a) complication rate, (b) response rate and (c) duration of survival in the same manner as the actual radiation doses measured with a beta probe at open surgery. The partition model has made selective internal radiation therapy using 90Y microspheres safe and repeatable without laparotomy.

Adult↗
PubMed1997

Longitudinal analysis of multiple indicators of health decline among spousal caregivers.

The hazards for experiencing major health events were studied longitudinally among 150 spousal caregivers of Alzheimer's disease (AD) patients and 46 married control participants. Based on longitudinal assessments from one to six years, the hazards of reaching any of three health events (extended physical illness or disability > 1 month, unhealthy medical rating from a nurse interview, or hospitalization) were not significantly different in a group comparison of caregivers to controls (Cox proportional hazards assumption, p > .05). However, there was a trend [X2(1, N = 107) = 3.13, p = .08] for caregivers to have a greater hazard for serious illness. Among caregivers only, a greater hazard for reaching at least one of these health events was associated with providing more activities of daily living (ADL) assistance [X2(1, N = 125) = 3.83, p = .05] but not with problem behaviors of the AD patient (p > .05). These results suggest that providing extensive ADL assistance may have health implications for spousal AD caregivers, while caregiving, per se, does not. Furthermore, these physical health impacts of caregiving may be best characterized using multidimensional assessments. Contrary to our guiding hypothesis, caregivers encountering more problem behaviors of their AD spouse were less likely to be hospitalized, X2(1, N = 145) = 5.88, p = .02. This finding may reflect a reluctance by caregivers to schedule necessary medical care when their spouses are most problematic, and this may have further long-term health implications for caregivers.

Activities of Daily Living↗
PubMed1997

Assessment of proliferating cell nuclear antigen in nasopharyngeal carcinoma tissue and its relation to clinical findings.

47 newly diagnosed patients with nasopharyngeal carcinoma (NPC) were studied using the proliferating cell nuclear antigen (PCNA) immunostaining technique. The results were reproducible as shown by assessment of three separate sections performed for each patient. No statistical correlation was found between PCNA labelling index (LI) and Ho's clinical staging or time required to achieve complete remission of the local disease. A higher PCNA LI was associated with a poorer disease-free survival. The literature on the use of PCNA in human tumours is reviewed.

Adolescent↗
PubMed1997

'Hepatoma-specific' alphafetoprotein may permit preclinical diagnosis of malignant change in patients with chronic liver disease.

The only hope for effective treatment of hepatocellular carcinoma (HCC or 'hepatoma') lies in early diagnosis. Measurement of the serum alphafetoprotein (AFP) level is potentially a useful screening test. When grossly raised, it is almost diagnostic of HCC. However, modestly elevated levels may also arise in patients with benign chronic liver disease, and this markedly decreases the test's specificity and hence its clinical value. In 582 consecutive attendees at an outpatient clinic for people with chronic liver disease, a single blood sample was taken for analysis of 'total' AFP and the 'hepatoma-specific' AFP isoform. Using ultrasonography as the primary screening method, patients with AFP levels > or = 50 ng ml-1 were followed up throughout the study or until HCC was diagnosed on the basis of conventionally defined criteria. On entry into the study, 53 patients had an AFP concentration > = or 50 ng ml-1 and the 'hepatoma-specific' AFP isoform was detected in 26 of these. During an 18-month follow-up period, a diagnosis of HCC was established by conventional methods in 19 (17 'definite' and two 'probable') of these 26 patients. In only two cases was there ultrasound evidence of tumour development at the time AFP was first found to be elevated; in the remainder a diagnosis of HCC, based on ultrasound screening, was established at a median time of 3.6 months (range 1-18 months) after entry into the study. Among those 27 without the 'hepatoma-specific' isoform, one developed a 'definite' HCC and two developed 'probable' tumours. With the application of 'hepatoma-specific' AFP, the positive predictive value of the test was 73.1%, compared with only 41.5% using the conventional 'total' AFP test. Application of this test for the 'hepatoma-specific' AFP markedly increases the positive predictive value of AFP and, in some cases, permits the presence of tumour to be inferred before it could be detected by routine ultrasound examination.

Carcinoma, Hepatocellular↗
PubMed1997

Semiquantification of circulating hepatocellular carcinoma cells by reverse transcriptase polymerase chain reaction.

Hepatocellular carcinoma (HCC) is one of the most common and rapidly fatal malignancies worldwide. Treatment options are severely limited by the frequent presence of metastases. If hepatocyte-specific mRNAs are detected in the circulation, it is possible to infer the presence of circulating, presumably malignant, liver cells. If these can be quantified, it is possible to predict the likelihood of haematogenous metastasis. In this investigation, we have attempted to gain an index of the mass of circulating HCC cells (with reference to the number of hepatoblastoma cells) by measuring the amounts of PCR products for albumin (alb) mRNA and alpha-fetoprotein (afp) mRNA by reverse transcriptase polymerase chain reaction (RT-PCR) and Southern blot analysis. For calibration, total RNA from 1-10(6) HepG2 cells was mixed with total RNA from 10(6) normal peripheral mononuclear cells. A linear relationship was demonstrated between the amount of alb- or afp PCR product and the level of HepG2 total RNA spiked. The assay is sensitive down to a detection level of one HepG2 cell. Alb mRNA was detected in 50% of 18 normal subjects and afp mRNA in only two normal subjects. The alb mRNA cut-off level for the normal was exceeded by seven normal subjects and 34 out of 64 HCC patients, and that for afp mRNA was exceeded by six HCC patients but none of the normal subjects. The level of alb mRNA detected was not linearly proportional to the amount of afp mRNA detected in peripheral blood of the same patients, suggesting heterogeneous expression of alb and afp genes in different circulating tumour cells. In addition, no significant linear association between the levels of afp mRNA and serum AFP was observed. Semiquantification of both mRNA markers for HCC cell detection may prove useful in prediction of metastases.

Biomarkers, Tumor↗
PubMed1997

Tumour-to-normal uptake ratio of 90Y microspheres in hepatic cancer assessed with 99Tcm macroaggregated albumin.

The selective delivery of a high dose of radiation to malignant hepatic tumours by infusion of non-biodegradable yttrium-90 (90Y) microspheres via the hepatic artery while sparing the non-tumorous liver parenchyma depends on the tumour-to-normal uptake ratio (T/N) of the therapeutic radiopharmaceutical. Using intrahepatic arterial technetium-99m macroaggregated albumin (99Tcm-MAA), the effect of tumour type, tumour vascularity assessed by hepatic angiography (HAG), tumour size and the degree of extrahepatic shunting on the T/N was investigated in 377 patients with hepatocellular carcinoma (HCC) and 25 patients with colorectal liver metastases. HCC was shown to have a wider range of T/N (0.2-26.5) compared with liver metastases (2.3-7.2). HCC with vascularity grade 1 on HAG had significantly lower T/N but there was no significant difference in HCC with higher vascularity grades. This confirmed that vascularity on HAG does not predict T/N. Overall there was no correlation between T/N and tumour size. Large tumours (> 20 cm) had a significantly lower T/N, probably due to necrosis in the tumour centres. A decrease in mean T/N with increasing percentages of lung shunting was observed in HCC. Determination of T/N by simulation with 99Tcm-MAA is recommended before internal radiation therapy with 90Y microspheres.

Carcinoma, Hepatocellular↗
PubMed1997

Cytokine gene expression profile of circulating CD4+ T cells in active pulmonary tuberculosis.

T lymphocytes, particularly CD4+ cells, are thought to play an important role in the immune defense against Mycobacterium tuberculosis through the release of their wide array of cytokines. In vitro studies suggest that Mycobacterium-specific T-cell clones are of the TH1 subtype. Using the technique of reverse transcription-polymerase chain reaction, we have investigated the capacity for cytokine gene expression profile in ex vivo circulating CD4+ T cells from 20 patients with active pulmonary tuberculosis compared with that of 30 normal healthy tuberculin-positive volunteers. Venous blood samples were collected from the former prior to the initiation of chemotherapy. A significant increase in interleukin (IL-2) expression (p < 0.001) and a significant decrease in IL-5 expression (p < 0.0001) were observed in patients with tuberculosis but no differences were seen in the expression of IL-4 and interferon gamma between the two study groups. Our data support a TH1-like immune response in active tuberculosis.

Adolescent↗
PubMed1997

Preliminary longitudinal assessment of quality of life in patients with major depression.

This study examines the longitudinal relationships between a health-related quality of life measure and depressive symptoms in patients with major depression. One hundred eighteen patients with primary major depression and 81 controls were evaluated. The patients were divided into three groups based on Diagnostic Interview Schedule criteria for a major depressive episode at baseline (T1) and 6 months later (T2). Results indicate that the Quality of Well-Being (QWB) measure is sensitive to different levels of depressive symptoms over a 6-month period. The QWB is a health-related quality of life and cost/utility measure that may be useful for pharmacoeconomic analysis. The reduction in quality of life associated with symptoms of depression is comparable to that observed with chronically physically ill patients. As a generic symptom/function measure, the QWB may be very useful in evaluating public health policy.

Depressive Disorder↗
PubMed1997

Arteriovenous shunts in patients with hepatic tumors.

UNLABELLED: The study aimed to investigate the influence of tumor type, tumor size, tumor vascularity and treatment on arteriovenous shunts between the liver and lungs in patients with hepatic cancer. METHODS: Our previous assessment of the degrees of lung shunting using intra-arterial 99mTc-macroaggregated albumin in 125 patients with hepatocellular carcinoma (HCC) was extended to include 377 patients with HCC and 25 patients with colorectal liver metastases. Patients were given 111 MBq (3 mCi) of 99mTc-macroaggregated albumin during hepatic angiography. The lungs and the liver were localized as regions of interest on the digitized gamma scintigraphic image. The total counts taken over the lungs divided by the total counts taken over both the lungs and the liver gave the percentage of lung shunting. Tumor size was measured by computerized tomography or ultrasound scan. Tumor vascularity was assessed based on the degree of neovascularization. Linear regression and Wilcoxon rank test were used for statistical analysis. RESULTS: Patients with HCC had a higher median (7.6%) and a wider range (< 1-75.4%) of percentages of lung shunting when compared with those with colorectal liver metastases (median, 4.7%; range, < 1-23.9%). The lung shunting correlated with the tumor size in the 377 patients with HCC (r = 0.359; p < 0.0001). Excluding one outlier, we found a similar correlation in 24 patients with colorectal metastases (r = 0.686; p < 0.0001). In HCC, the mean lung shunting increased with increasing tumor size, up to 15 cm, and then remained almost unchanged, up to a size of > 20 cm. The mean lung shunting also increased with increasing vascularity grades, as assessed by hepatic angiography. The difference between any two vascularity grades was statistically significant (p = 0.0001-0.0148). Similar analysis by subgroups in colorectal liver metastases was impossible because of the small number of patients. Lung shunting decreased in HCC patients after the tumors were treated, but it might increase or decrease when the disease recurs. CONCLUSION: The lung shunting was influenced by the type, size and vascularity of the hepatic tumor. The change in lung shunting with the status of the tumor after treatment further suggests a neoplastic nature of the blood vessels involved in the arteriovenous shunt.

Carcinoma, Hepatocellular↗
PubMed1996

Somatic mutations in human Ig variable genes correlate with a partially functional CD40-ligand in the X-linked hyper-IgM syndrome.

X-linked hyper-IgM (HIGM-1) syndrome is a rare disorder resulting from mutations in the CD40-ligand (CD40L) gene. This defect is associated with normal or elevated serum levels of IgM, and with low to undetectable levels of serum IgG, IgA, and IgE. We analyzed the somatic mutation status in Ig V genes from three unrelated HIGM-1 patients by reverse-transcription PCR and sequence analysis. Two patients (B.S. and P.S.) expressed unmutated VH6 genes. In contrast, one patient (A.T.) was found to express mutated VH6 genes. Whether the presence of somatic mutations in this patient was related to a functional CD40L was assessed by deriving T cell clones from his peripheral blood cells. Upon activation, these T cell clones expressed weakly and transiently surface CD40L, and were able to induce limited isotype switch of normal native B cells, indicating residual CD40L function. Altogether, our results 1) confirm the central role played by CD40L in the generation of somatic mutation (patients B.S. and P.S.), 2) provide an unusual illustration of the relative dissociation between somatic mutation and isotype switching (patient A.T.), and 3) demonstrate a further complexity of the X-linked HIGM syndrome that may occur despite a partially functional CD40L.

B-Lymphocytes↗
PubMed1996

Four IgG anti-islet human monoclonal antibodies isolated from a type 1 diabetes patient recognize distinct epitopes of glutamic acid decarboxylase 65 and are somatically mutated.

The selective destruction by an autoimmune process of the beta cells in the pancreas is the hallmark of the type 1 insulin-dependent diabetes mellitus. What triggers islet cell-specific autoreactive T and B cells, however, remains unclear. Identification of the targets of the anti-islet cell autoantibodies frequently found in insulin-dependent diabetes mellitus patients and analysis of their sequences should provide some insights into the nature of this disease. We have combined EBV transformation with CD40 activation of peripheral B cells from one patient with insulin-dependent diabetes mellitus to isolate four B cell clones that secrete islet cell-specific autoantibodies, These four human monoclonal autoantibodies are of the IgG1 isotype, and they each recognize a different epitope of the glutamic acid decarboxylase enzyme. Analysis of their variable gene sequences shows that, while clonally unrelated, three of the four human monoclonal autoantibodies use a member of the VH4 family, and two have rearranged the same delta light chain variable gene. The IgG1 isotype of the four autoantibodies as well as the presence of somatic mutations in both heavy and light chain genes provide concrete evidence for their derivation by a T cell-dependent immune response.

Adult↗
PubMed1996

B-chronic lymphocytic leukemias can undergo isotype switching in vivo and can be induced to differentiate and switch in vitro.

B-chronic lymphocytic leukemias (B-CLL) represent expanded clones of resting B lymphocytes that mostly express surface IgM (sIgM). The present study shows that B-CLL cells, freshly isolated from two patients, were sIgM+, sIgG-, and sIgA- but expressed IgG and IgA transcripts. cDNA cloning and sequencing showed that the VDJ segments associated to gamma and alpha heavy chain transcripts are identical to those from mu transcripts, thus showing that B lymphocytes giving rise to CLL cells have undergone isotype switching in vivo. Stimulation of these B-CLL cells through surface CD40 in the presence of interleukin-10 induced them to secrete IgG and IgA, proving that they can also differentiate into Ig-secreting cells. Finally, CD40-stimulated B-CLL cells were induced to switch towards IgE in response to interleukin-4, as shown by the presence of specific VDJ-C epsilon transcripts and the secretion of IgE. Therefore, B-CLL cells tested herein can undergo isotype switching in vivo and can be induced to undergo further isotype switching and differentiation in vitro.

Base Sequence↗