Biomedical subjects

D Gu

Publications and source records attributed to D Gu.

At least 19 recordsLinked to original sources

PubMed1999

Necrotizing myopathy induced by overexpression of interferon-gamma in transgenic mice.

A transgenic mouse model has been established in which the cytokine interferon-gamma (IFN-gamma) is overexpressed through the action of the acetylcholine receptor epsilon promoter acting at the neuromuscular junction. While originally developed as a model for the study of the pathogenesis of myasthenia gravis, there are important differences from both human myasthenia gravis and its animal model, experimental autoimmune myasthenia gravis. By 4 months of age there was a well-established inflammatory, predominantly necrotizing myopathy, with marked dystrophic calcification. Dystrophic and degenerative changes in terminal axons and adjacent Schwann cells were also apparent. The acetylcholine receptor was not the primary target of the inflammatory response, since at 10 weeks of age the receptor content was not decreased and antibodies were not detected bound to the receptor. The IFNgamma transgenic mouse model may provide a clinically relevant model of necrotizing myopathy for investigation of the pathological changes associated with, and presumably precipitated by, overexpression of the pro-inflammatory cytokine interferon-gamma on the neuromuscular junction, intramuscular nerves and myofibers.

Animals↗

PubMed1997

Interdecadal Climate Fluctuations That Depend on Exchanges Between the Tropics and Extratropics

The unexpected and prolonged persistence of warm conditions over the tropical Pacific during the early 1990s can be attributed to an interdecadal climate fluctuation that involves changes in the properties of the equatorial thermocline arising as a result of an influx of water with anomalous temperatures from higher latitudes. The influx affects equatorial sea-surface temperatures and hence the tropical and extratropical winds that in turn affect the influx. A simple model demonstrates that these processes can give rise to continual interdecadal oscillations.

Journal Article↗

PubMed1997

Endocrine/exocrine intermediate cells in streptozotocin-treated Ins-IFN-gamma transgenic mice.

To trace the ontogeny of beta cell regrowth in adult transgenic mice that produce interferon-gamma in the islets (ins-IFN-gamma), their existing beta cells were depleted by treatment with high doses of streptozotocin (STZ). Initially, beta cell necrosis and degranulation were apparent in STZ-treated mice of both the BALB/c and the ins-IFN-gamma transgenic strains. The newly emerging transitional cells were then characterized by ultrastructural analysis. Interestingly, transitional cells harboring both exocrine and endocrine granules appeared frequently in ins-IFN-gamma transgenics after high-dose STZ treatment. New beta cells were produced primarily by the formation of new islets from the small pancreatic ducts. Beta cell regeneration in the ins-IFN-gamma transgenic mouse model is thus explained primarily by the budding of new islets from the ducts with acinar cells as possible precursors of islet cells.

Animals↗

PubMed1997

alpha-Cell neogenesis in an animal model of IDDM.

Currently there is debate regarding the capacity of pancreatic islets to regenerate in adult animals. Because pancreatic endocrine cells are thought to arise from duct cells, we examined the pancreatic ductal epithelium of the diabetic NOD mouse for evidence of islet neogenesis. We have evidence of duct proliferation as well as ductal cell differentiation, as suggested by bromodeoxyuridine-labeling and the presence of glucagon-containing cells within these ducts. In addition, the ductal epithelia in diabetic NOD mice expressed the neuroendocrine markers neuropeptide Y and tyrosine hydroxylase. These ducts also expressed the homeobox gene product, insulin promoter factor 1. Ductal cell proliferation and expression of these markers was not observed in transgenic NOD mice (NOD-E), which do not develop clinical or histopathological symptoms of IDDM. This suggests that the observed ductal cell proliferation and differentiation was a direct result of beta-cell destruction and insulin insufficiency in these adult diabetic mice, which further suggests that these events are recapitulating islet ontogeny observed during embryogenesis. It is possible that comparable processes occur in the human diabetic pancreas.

Animals↗

PubMed1997

Long-term prognosis of percutaneous transluminal coronary angioplasty in 229 cases.

OBJECTIVE: To evaluate long-term efficacy of percutaneous transluminal coronary angioplasty (PTCA) and the factors affecting its efficacy in Chinese patients. METHODS: Two hundred and twenty-nine patients who underwent successful PTCA in this institution were followed-up by direct interview or letters. The rate of follow-up was 95%. The period of follow-up were 0.5-8.4 (with mean of 2.3 +/- 1.8 years). RESULTS: Angina Pectoris recurred in 76 (33.2%) of the patients. Cox regression analysis revealed that the relative risk of recurrence of angina pectoris was increased among the patients with triple vessel disease and with history of hypertension. During the period of follow-up, 2 (0.9%) patients died, 6 (2.6%) had non-fatal acute myocardial infarction, 4 (1.7%) had coronary artery bypass graft surgery and 29 (12.7%) had repeat PTCA. The cardiac event-free survival rate calculated by Kaplan-Meier method was 84.8% at the first year and 70.5% at the eighth year. Cox regression analysis revealed that there were positive correlation between the relative risks of cardiac events and stenosis of lesions before PTCA and residual stenosis of LAD after PTCA. CONCLUSION: The long-term efficacy of PTCA in Chinese patients was good. The results of this study suggest that to decrease the residual stenosis of LAD during procedures could probably decrease the relative risk of cardiac events during follow-up.

Adult↗

PubMed1997

[An approach to operative treatment for acute abdomen complicated by malignant hemopathy].

The experience of operative treatment in 14 cases of acute abdomen complicated by malignant hemopathy was reported. Primary diseases consisted of AL, NHL, MM, MH and MDS-RA, 13 cases of them were at progressing stage. The acute abdominal conditions included acute appendicitis, acute pancreatitis, acute cholecystitis, peritonitis secondary to intestinal perforation, intestinal obstruction, primary peritonitis and ileocecal syndrome. The type of acute abdomen was related with primary desease and chemotherapy. 8 cases were operated and 2 of them died of complications after operation. Biopsy of excised tissue showed tumor cells in 2 cases. The rate of correllation between preoper active and postoperative diagnosis was 62.5%. These findings suggest that malignant infiltration in the viscera, duration of abdominal pain before operation and the change of blood picture are the major factors for determining operative indication and the postoperative prognosis.

Abdomen, Acute↗

PubMed1996

Determination of nerve conduction velocity distribution from sampled compound action potential signals.

The sampled compound action potential (CAP) data sequence was expressed as the circular convolution of the delay sequence and the sampled single fiber action potential (SFAP) data sequence. An algorithm, based on Hirose's method [1], was then developed to separate the delay sequence from the sampled CAP data sequence, and the nerve conduction velocity distribution (NCVD) was consequently calculated from the delay sequence. The NCVD was found to be the product of the amplitude of the SFAP and the number of fibers. Simulations show that the estimated results were in good agreement with the calculated results. Experiments were performed on ten sciatic nerves from five bullfrogs (Rana pipens) using two independent variables: interelectrode distance and stimulus current strength. The results estimated from CAP's recorded under each condition reflect the corresponding feature of NCVD of the condition. The advantage of the technique is to provide detailed information about both slow and fast conducting fibers. This technique also offers the possibility to directly calculate the nerve fiber diameter distribution from the sampled CAP data sequences.

Action Potentials↗

PubMed1996

Growth factors in the regenerating pancreas of gamma-interferon transgenic mice.

We examined the distribution of several relevant growth factors in gamma-interferon transgenic mice, which undergo continual growth and differentiation in the pancreas. As a result, epidermal growth factor (EGF), TGF-alpha, and the EGF receptor were identified as potentially important in mediating some of these regenerative changes. Transient up-regulation of EGF, TGF-alpha, and the EGF receptor were observed in acini undergoing differentiation into duct-like structures. These ducts have been shown to proliferate and potentiate regeneration of the pancreatic islet mass.

Animals↗

PubMed1996

Structural alterations of resistance vessels of spontaneously hypertensive rats and protective effects of captopril.

OBJECTIVE: To observe the structural alterations of resistance vessels in spontaneously hypertensive rats (SHRs) and to evaluate the effects of captopril on them. METHODS: 15-week-old male SHRs were treated with oral captopril (100 mg/kg/day) for 12 weeks. Age- and sex-matched SHRs and Wistar-Kyoto rats (WKY) were fed under the same conditions without captopril administration for the same duration. All rats were killed at the age of 27 weeks. The structural parameters included media width, lumen diameter, media-lumen ratio, vascular collagen area (VCA) and vascular collagen density (VCD). The media width, lumen diameter and media-lumen ratio were measured in hhematoxylin and eosin staining sections under a direct light microscope and VCA and VCD in picrosirius red staining sections under a polarizing light microscope. All the values were processed with a computer image analyzer. RESULTS: There were thicker media width, smaller lumen diameter, higher media-lumen ratio and larger VCA in untreated SHRs than in WKY. Captopril inhibited media thickening, with lumen diameter decreasing, media-lumen ratio increasing and VCA enlarging. There was no significant difference in VCD among the three groups. CONCLUSIONS: Adverse structural alterations occur in resistance vessels of SHRs and captopril may prevent their progression.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1995

Prevalence of hypertension and its trends in Chinese populations.

The third nation-wide survey of blood pressure level and hypertension was carried out in China in 1991. In total, 950,356 residents aged > or = 15 years were examined. Sampling population were composed of half urban and half rural from 27 provinces or autonomous regions and three municipalities. The results showed that: (1) the age-adjusted prevalence rate of hypertension (systolic blood pressure > or = 140 mmHg or diastolic blood pressure > or = 90 mmHg) was 11.26% (male 12.15%, female 10.32%) and the definite hypertension rate (systolic blood pressure > or = 160 mmHg or diastolic blood pressure > or = 95 mmHg, or on medication) was 5.29% (male 5.38%, female 5.21%); rate of borderline hypertension was evaluated from 2.82% to 6.15% during the 10-year period from 1979/1980 to 1991; (2) the prevalence rate was progressively increased with age, especially after age 35; prevalence rates were generally higher in men than women before about age 44, however by age 60, women had a higher prevalence of hypertension; (3) a general trend of decrease in prevalence from north-eastern to south-western China was confirmed; (4) there were significantly lower rates in rural than in urban areas. Results of preliminary analysis for prevalence of hypertension among different occupations, nationalities, and educational levels were presented.

Adolescent↗

PubMed1995

Cellular and humoral immune responses to adenoviral vectors containing factor IX gene: tolerization of factor IX and vector antigens allows for long-term expression.

Recombinant adenoviruses containing the canine factor IX (FIX) cDNA were directly introduced in the hind leg muscle of mice. We show that (i) in nude mice, high expression (1-5 micrograms/ml in plasma) of FIX protein can be detected for > 300 days; (ii) in contrast, expression of FIX protein was transient (7-10 days) in normal mice; (iii) CD8+ lymphocytes could be detected within 3 days in the infected muscle tissue; (iv) use of beta 2-microglobulin and immunoglobulin M heavy chain "knockout" mice showed that lack of sustained expression of FIX protein is due to cell-mediated and humoral immune responses; (v) normal mice, once infected with recombinant adenovirus, could not be reinfected efficiently for at least 30 days due to neutralizing viral antibodies; and, finally, (vi) using immunosuppressive drugs, some normal mice can be tolerized to produce and secrete FIX protein for > 5 months. We conclude that currently available adenoviral vectors have serious limitations for use for long-term gene therapy.

Adenoviridae↗

PubMed1995

Myasthenia gravis-like syndrome induced by expression of interferon gamma in the neuromuscular junction.

Abnormal humoral responses toward motor end plate constituents in muscle induce myasthenia gravis (MG). To study the etiology of this disease, and whether it could be induced by host defense molecules, we examined the consequences of interferon (IFN) gamma production within the neuromuscular junction of transgenic mice. The transgenic mice exhibited gradually increasing muscular weakness, flaccid paralysis, and functional disruption of the neuromuscular junction that was reversed after administration of an inhibitor of acetylcholinesterase, features which are strikingly similar to human MG. Furthermore, histological examination revealed infiltration of mononuclear cells and autoantibody deposition at motor end plates. Immunoprecipitation analysis indicated that a previously unidentified 87-kD target antigen was recognized by sera from transgenic mice and also by sera from the majority of human MG patients studied. These results suggest that expression of IFN-gamma at motor end plates provokes an autoimmune humoral response, similar to human MG, thus linking the expression of this factor with development of this disease.

Animals↗

PubMed1995

The role of infiltrating macrophages in islet destruction and regrowth in a transgenic model.

The expression of interferon-gamma (IFN-gamma) in pancreatic beta cells leads to a complex pathology that represents the processes of both islet destruction and islet regeneration. Inflammatory cells and the factors elicited from them participate in the development of pathology in this transgenic model. To dissect the role of infiltrating macrophages in these events, the monoclonal directed against the type 3 complement receptor (5C6) was utilized to inhibit the extravasation of macrophages. This was approached by treating transgenic mice with 5C6 for 3 or 4 months, starting from 5-7 days of age. The data presented in this report demonstrate that infiltrating macrophages are important in the observed induction of diabetes in our transgenic model. We also found that infiltrating macrophages did not play a major role in the observed proliferation and islet regeneration, but some interesting subtleties regarding the regulation of this proliferative process emerged.

Animals↗

PubMed1995

Transgenic mice expressing IFN-gamma in pancreatic beta-cells are resistant to streptozotocin-induced diabetes.

In 28 adult Ins-IFN-gamma transgenic mice, injection of high doses of streptozotocin (STZ; first injection, 300 microgram/g body weight; second injection, 200 microgram/g body weight 4 h later) failed to induce severe hyperglycemia. To the contrary, 28 BALB/c mice developed diabetes mellitus after identical injections of STZ. Because the STZ-induced islet damage was partially inhibited in Ins-IFN-gamma transgenic mice, their glycemia levels became normal 4 days after STZ administration. Both transgenic and BALB/c mice lost weight after receiving STZ, but the body weights of transgenic mice then returned to pretreatment levels in a nearly parallel manner with the glycemia. Immunolabeling with insulin identified an unusual spreading pattern of insulin immunoreactivity. Ultrastructural observations confirmed that beta-cell necrosis and degranulation were more severe in STZ-treated BALB/c than in Ins-IFN-gamma transgenic mice. Moreover, regeneration of pancreatic duct cells and islet neogenesis were observed in the transgenic mice. Therefore, after STZ treatment, the Ins-IFN-gamma transgenic mice apparently were resistant to the induction of severe diabetes, whereas their BALB/c age-matched counterparts succumbed to the disease.

Animals↗

PubMed1995

Treatment of IFN-gamma transgenic mice with anti-IFN-gamma reveals the remodeling capacity of the adult pancreas.

Pancreatic expression of gamma-interferon (IFN-gamma) initiates a cascade of pathogenic changes that include pancreatic inflammation, islet cell destruction, hyperglycemia, and islet regeneration. In this study, we explore the developmental plasticity of the adult pancreas and particularly its ability to return to normoglycemia and to remodel itself from an advanced pathogenic state. This was approached by treating adult transgenic mice with a pulse of anti-IFN-gamma antibody and determining the functional and morphological status of the pancreas. We demonstrated that anti-IFN-gamma antibody administration led to the reduction of hyperglycemic blood glucose levels in transgenic mice. We also observed that the pancreas returned from a profoundly perturbed state toward normality. Analysis of the mitotic index indicated that cell proliferation previously associated with islet cell regeneration was greatly reduced after anti-IFN-gamma administration. Our results highlight the ability of the adult pancreas to remodel itself and return from a complex pathological state to normalcy once the trophic signal inducing this pathology is removed. These data also suggest that anti-IFN-gamma administration may have important clinical implications for treatment of chronic pancreatitis in humans.

Animals↗

PubMed1995

Accumulation of extracellular matrix and developmental dysregulation in the pancreas by transgenic production of transforming growth factor-beta 1.

Transgenic mice expressing transforming growth factor-beta 1 (TGF-beta 1) in the pancreatic beta-islet cells directed by human insulin promoter were produced to study in vivo effects of TGF-beta 1. Fibroblast proliferation and abnormal deposition of extracellular matrix were observed from birth onward, finally replacing almost all the exocrine pancreas. Cellular infiltrates comprising macrophages and neutrophils were also observed. Plasminogen activator inhibitor was induced in the transgenic pancreas as well as fibronectin and laminin, partly explaining accumulation of extracellular matrix. TGF-beta 1 inhibited proliferation of acinar cells in vivo as evidenced by decreased bromodeoxyuridine incorporation. Development of pancreatic islets was dysregulated, resulting in small islet cell clusters without formation of normal adult islets; however, the overall islet cell mass was not significantly diminished. Additional transgenic lines with less pronounced phenotypes had less expression of TGF-beta 1 transgene. These findings suggest that TGF-beta 1 might be a mediator of diseases associated with extracellular matrix deposition such as chronic pancreatitis, and this mouse model will be useful for further analysis of the in vivo effects of TGF-beta 1, including its potential for immunosuppression.

Animals↗

PubMed1994

A transgenic model for studying islet development.

The regeneration of islet cells in a transgenic mouse strain harboring the interferon-gamma gene (IFN-gamma) linked to the insulin promoter DNA fragment (ins-IFN-gamma) is described. The regeneration follows the loss of islets by an immune response provoked by IFN-gamma and manifests in the proliferation of duct cells, the presence of progenitor cells, and the formation of buds and isletlike structure. All three types (A, B, and D) of four endocrine cells identified by immunolabeling are present. The progenitor cells express neuronal enzymes, tyrosine hydroxylase (TH) and glutamic acid decarboxylase (GAD), as revealed by specific antibodies. The results indicate that the islet regeneration closely resembles the embryonic islet differentiation and serves as a model for studying islet development. The expression of neuronal enzymes by islet progenitor cells signifies yet unknown relationships to the nervous tissue. GAD, recognized as an autoantigen in insulin-dependent diabetes mellitus (IDDM) and stiff-man syndrome, may provide a clue to the mechanism of autoimmune disease.

Animals↗

PubMed1994

Postnatal anti-interferon-gamma treatment prevents pancreatic inflammation in transgenic mice with beta-cell expression of interferon-gamma.

beta-Cell-targeted expression of interferon-gamma (IFN-gamma) leads to pancreatitis and immune sensitization to beta-cells. This transgenic model is used to explore the possible role of locally produced IFN-gamma in loss of tolerance to beta-cell-specific antigens in insulin-dependent diabetes mellitus (IDDM). The aim of the present study was to test if postnatal treatment with antibodies against IFN-gamma could inhibit morphological changes in the IFN-gamma transgenic pancreas, even though the transgene is expressed during embryogenesis. Treatment with a monoclonal rat anti-mouse IFN-gamma antibody for 6 weeks, starting from 5 to 7 days of age, completely inhibited IFN-gamma-induced morphological changes in the pancreas, and only a modest inflammatory reaction emerged after prolonged treatment for 12 weeks. The lack of morphological changes may reflect the ability of nonterminally differentiated neonatal pancreatic cells to compensate for transgene-induced pathological alterations occurring in utero prior to the antibody treatment. We conclude that inflammation and altered pancreas morphology in the transgenic mice is the result of the biological actions of IFN-gamma and not by disrupted islet development due to transgene overexpression in the pancreatic beta-cells. Furthermore, our treatment schedule can serve as a model for future intervention studies in the transgenic mice, elaborating the role of IFN-gamma in localized inflammatory reactions, IDDM in particular.

Animals↗