Biomedical subjects
R Guzman
Publications and source records attributed to R Guzman.
Cytomegalovirus infection of rats increases the neointimal response to vascular injury without consistent evidence of direct infection of the vascular wall.
BACKGROUND: Previous studies suggest that infection may play a role in restenosis and atherogenesis; cytomegalovirus (CMV) is one of the implicated pathogens. To determine a potential causal role of CMV in these disease processes, we assessed whether CMV infection increases the neointimal response to injury of the rat carotid artery. METHODS AND RESULTS: Carotid injury was performed on 60 rats; immediately thereafter, 30 rats were infected with rat CMV, and the other 30 were mock-infected. Six weeks later, rats were euthanized, and the salivary glands, spleen, and carotid arteries were harvested. CMV infection was associated with significant exacerbation of the neointimal response to injury (neointimal to medial ratio 0.81+/-0. 59 versus 0.31+/-0.38 in CMV-infected versus control rats; P<0.0001). This occurred despite absence of infectious virus from vascular tissues and detection of CMV DNA by polymerase chain reaction in the injured artery only at day 3 after infection. Persistent distant infection, associated with systemic cytokine response, was evidenced by isolation of infectious virus from homogenates of both salivary glands and spleen and by higher serum levels of interleukin (IL)-2 and IL-4 (but not interferon-gamma and tumor necrosis factor-alpha) in infected versus noninfected rats. CONCLUSIONS: CMV infection of immunocompetent adult rats increases the neointimal response to vascular injury, suggesting that CMV may play a causal role in atherosclerosis/restenosis. Importantly, this CMV-induced response occurs even without the presence of virus in the vascular wall, suggesting that inflammatory and immune responses to infection of nonvascular tissues may contribute to the vascular response to injury.
Concurrent deregulation of gelsolin and cyclin D1 in the majority of human and rodent breast cancers.
Decreased gelsolin and increased cyclin D1 are among the most common defects found in human and rodent breast cancers. Our purpose was to determine the frequency of concurrence of these 2 alterations in this malignancy. Our results demonstrate that gelsolin protein and mRNA were significantly reduced in 80-100% of rodent mammary carcinomas that developed spontaneously, following oncogene introduction, or after treatment with viral, chemical or hormonal agents. The reduction in gelsolin most likely occurs during the transition from preneoplasia to carcinoma because hyperplasias had normal levels of gelsolin whereas microtumors had reduced expression. Southern analysis revealed no major mutations in the gelsolin gene of tumors with low expression. Cyclin D1 mRNA was increased in 50-100% of these rodent mammary tumors, although the cyclin D1 gene was not amplified. By nuclear runon assay, downregulation of gelsolin in both human and mouse mammary cancer cells involved diminished transcription and, conversely, human breast cancer cells expressing high levels of cyclin D1 had increased initiation of cyclin D1 transcription compared with cyclin D1 low expressors. Thus, alteration in the rate of transcription appears to be an important factor underlying the dysfunction of these genes. According to our data, concurrent deregulation of gelsolin and cyclin D1 is highly prevalent among breast cancers of humans and rodents, with both defects present in 89% of the neoplasms analyzed in this study. In fact, most tumors in every rodent model of mammary tumorigenesis examined had the 2 alterations.
Striatal grafts in a rat model of Huntington's disease: time course comparison of MRI and histology.
Survival and integration into the host brain of grafted tissue are crucial factors in neurotransplantation approaches. The present study explored the feasibility of using a clinical MR scanner to study striatal graft development in a rat model of Huntington's disease. Rat fetal lateral ganglionic eminences grown as free-floating roller-tube cultures were grafted into the quinolinic acid-lesioned striatum, and T1- and T2-weighted sequences were acquired at 2, 7, 21, and 99 days posttransplantation. MR images were then compared with images of corresponding histological sections. The lesion-induced striatal degeneration caused a progressive ventricle enlargement, which was significantly different from controls at 21 days posttransplantation. Seven days posttransplantation, T1-weighted images revealed a defined liquid-isointense signal surrounded by a hyperintense rim at the site of graft placement, which was found unaltered for the first 21 days posttransplantation, whereas a hypointense graft signal was detected at 99 days posttransplantation. At 2 days posttransplantation, T2-weighted images showed the graft region as a hyperintense area surrounded by a rim of low signal intensity but at later time-points graft location could not be further verified. Measures for graft size and ventricle size obtained from MR images highly correlated with measures obtained from histologically processed sections (R = 0.8, P < 0.001). In conclusion, the present study shows that fetal rat lateral ganglionic eminences grown as free-floating roller-tube cultures can be successfully grafted in a rat Huntington model and that a clinical MR scanner offers a useful noninvasive tool for studying striatal graft development.
Glucose tolerance during pregnancy and birth weight in a Hispanic population.
OBJECTIVE: To assess the effect of screening glucose values and gestational diabetes mellitus (GDM) on birth weight in a community-based population of pregnant Hispanic women and infants in Detroit, Michigan. METHODS: In a prospective cohort study of 372 mother-infant pairs, analysis of variance and multiple linear and logistic regression were used to examine the effects of maternal screening glucose and GDM status on mean birth weight and the risk of large for gestational age (LGA) and small for gestational age (SGA) births. RESULTS: Screening glucose values of at least 135 mg/dL were found in 26.6% of the mothers and GDM in 5.1%. There was a significant relation between increasing maternal screening glucose level and adjusted mean birth weight (P < .005). As glucose level increased, there was a significant trend toward an increasing percentage of LGA infants and a decreasing percentage of SGA infants (Cochran-Armitage test for trend, P = .001 and P = .009, respectively). Among nondiabetic women, a 10-mg/dL increase in glucose value was associated with an adjusted 30.5-g increase in birth weight (standard error 9.0; P < .001), increased adjusted odds of LGA (adjusted odds ratio [OR] 1.17; 95% confidence interval [CI] 1.02, 1.34), and decreased adjusted odds of SGA (adjusted OR 0.69; 95% CI 0.52, 0.93). CONCLUSION: Our findings showed a high prevalence of glucose abnormality and an independent effect of maternal glucose level on birth weight in our Hispanic population. Maternal glucose level should be included in studies of factors that affect birth weight, and appropriate prenatal care provided to Hispanic women with abnormal and borderline metabolic status.
Establishing LA VIDA: a community-based partnership to prevent intimate violence against Latina women.
LA VIDA--the Southwest Detroit Partnership to Prevent Intimate Violence Against Latina Women--evolved in response to community concern about the problem of intimate partner violence (IPV) and the lack of culturally competent preventive and support services for Latino women and men in southwest Detroit. Since 1997, diverse organizations have mobilized as a community-academic partnership to ensure the availability, accessibility, and utilization of IPV services. This article describes and analyzes the evolution of LA VIDA within a community-based participatory research framework using a case study approach that draws on multiple data sources including group and individual interviews and field notes. The challenges and lessons learned in addressing a complex multifaceted problem such as IPV in an ethnic minority community are highlighted in an examination of the process of mobilizing diverse organizations, conducting community diagnosis and needs assessment activities, establishing goals and objectives within a social ecological framework, and integrating evaluation during the development phase.
Tuberculous mycotic aneurysm of the aorta: review of published medical and surgical experience.
To define the epidemiology, pathogenesis, pathology, presentation, and management of tuberculous mycotic aneurysm of the aorta (TBAA) in the therapeutic era, we reviewed all of the cases reported in the English language literature from 1945 to the present. To the 39 cases in the published literature, we add two cases of our own. Although it is exceedingly rare, the prevalence of this lesion has remained relatively constant. In 75% of the cases, TBAA appeared to result from erosion of the aortic wall by a contiguous focus; 25% from direct seeding of the aortic intima or of the adventitia or media (via the vasa vasorum). Most of the aneurysms were saccular (90%) and false (88%). The thoracic and abdominal aortas were affected with equal frequency. The mean (+/- SD) age of the patients was 50+/-16 years. Twenty-two were men, and 19 were women. In 63% of the cases, tuberculosis (TB) was diagnosed at presentation. Disseminated TB was present in 46% of the cases. One or more of three clinical scenarios suggested TBAA: persistent pain, major bleeding, and a palpable or radiographically visible para-aortic mass, especially if it is expanding or pulsatile. In turn, each of these findings suggested a complication of TBAA that may be an indication for surgical intervention. Among the patients who were offered both medical and surgical treatment, 20 of 23 (87%) survived. Among those who were offered only one form of treatment or were offered no treatment at all there were no survivors. Both in situ reconstruction with a prosthetic graft, and extra-anatomic bypass appeared to offer excellent results, provided that an effective regimen of antituberculous drugs was delivered postoperatively. We offer our conclusions: (1) symptomatic TBAA is a rare but uniformly fatal lesion if not diagnosed promptly, (2) in the context of active TB, and especially miliary TB, TBAA should be suspected whenever one or more of the three clinical scenarios are present, and (3) combined medical and surgical therapy appears to offer the best chance of a cure.
An intracranial aneurysm on the feeding artery of a cerebellar hemangioblastoma. Case report.
A case of cerebellar hemangioblastoma with a coexistent arterial aneurysm on the feeding artery of the tumor is reported. The patient presented with an acute onset of headache, loss of consciousness, and left-sided hemiparesis due to a posterior fossa hemorrhage found adjacent to a hemangioblastoma. Four-vessel angiography revealed an aneurysm on the anterior inferior cerebellar artery (AICA), which was the main feeding vessel of the hemangioblastoma. Successful total excision of the hemangioblastoma and clipping of the AICA aneurysm achieved in a one-stage operation was demonstrated on postoperative angiography.
Production of "neometalloenzymes" by de novo biosynthesis. New ELISA method for their characterization.
Several approaches known for producing "neometalloenzymes" are classified into two categories: protein engineering using antibodies as starting materials and "de novo" biosynthesis of metal-binding antibodies with potential catalytic metal-binding structure. This latter approach is chosen in this study. Polyclonal anti-zinc-iminodiacetate [IDA-Zn(II)] antibodies are produced in rabbits and mice. Because of the absolute need for the unequivocal screening of the hapten [IDA-Zn(II)] specific antibodies, a new ELISA method was developed using a biheaded polyethylene glycol with biotin on one end and the hapten on the other end. The parameters for optimizing the immunization and the ELISA technique are discussed and the method is validated with rabbit and mice sera.
Comparison of mesencephalic free-floating tissue culture grafts and cell suspension grafts in the 6-hydroxydopamine-lesioned rat.
Ventral mesencephalon (VM) of fetal rat and human origin grown as free-floating roller-tube (FFRT) cultures can survive subsequent grafting to the adult rat striatum. To further explore the functional efficacy of such grafts, embryonic day 13 ventral mesencephalic tissue was grafted either after 7 days in culture or directly as dissociated cell suspensions, and compared with regard to neuronal survival and ability to normalize rotational behavior in adult rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. Other lesioned rats received injections of cell-free medium and served as controls. The amphetamine-induced rotational behavior of all 6-OHDA-lesioned animals was monitored at various time points from 18 days before transplantation and up to 80 days after transplantation. Tyrosine hydroxylase (TH) immunostaining of the histologically processed brains served to assess the long-term survival of grafted dopaminergic neurons and to correlate that with the behavioral effects. Additional cultures and acutely prepared explants were also fixed and stored for histological investigation in order to estimate the loss of dopaminergic neurons in culture and after transplantation. Similar behavioral improvements in terms of significant reductions in amphetamine-induced rotations were observed in rats grafted with FFRT cultures (127%) and rats grafted with cell suspensions (122%), while control animals showed no normalization of rotational behavior. At 84 days after transplantation, there were similar numbers of TH-immunoreactive (TH-ir) neurons in grafts of cultured tissue (775 +/- 98, mean +/- SEM) and grafts of fresh, dissociated cell suspension (806 +/- 105, mean +/- SEM). Cell counts in fresh explants, 7-day-old cultures, and grafted cultures revealed a 68.2% loss of TH-ir cells 7 days after explantation, with an additional 23.1% loss after grafting, leaving 8.7% of the original number of TH-ir cells in the intracerebral grafts. This is to be compared with a survival rate of 9.1% for the TH-ir cells in the cell-suspension grafts. Immunostaining for the calcium-binding proteins calretinin, calbindin, and parvalbumin showed no differences in the neuronal expression of these proteins between the two graft types. In conclusion, we found comparable dopaminergic cell survival and functional effects of tissue-culture grafts and cell-suspension grafts, which currently is the type of graft most commonly used for experimental and clinical grafting. In this sense the result is promising for the development of an effective in vitro storage of fetal nigral tissue, which at the same time would allow neuroprotective and neurotrophic treatment prior to intracerebral transplantation.
Sister chromatid exchanges induced in vitro and in vivo by an extract of black pepper.
Black pepper is a spice widely used in human food. The aim of this investigation was to determine whether an alcoholic extract of the mature berries of black pepper induced genotoxic damage in vivo and in vitro. The first aspect was evaluated in mouse bone marrow cells and the second one in human lymphocytes. In both cases the rate of sister chromatid exchange (SCE) and the replicative index were determined. For the in vivo assay, ip doses of 7.0, 14.0, 28.0 and 56.0 mg/kg body weight were tested, with the following results: (1) a significant increase of SCE frequency in all doses tested compared with the control level (the highest dose produced almost a duplication of the basal rate of SCEs); (2) a similar pattern with regard to cell proliferation kinetics at all doses tested, without significant differences between them. For the in vitro assay, doses of 25.0, 50.0, 75.0 and 100.0 micrograms/ml were tested, with the following results: (1) a significant increase in the frequency of SCEs at all doses tested; a linear regression analysis of the data produced a correlation coefficient of 0.98; (2) a significant reduction in the replicative index, at the two high doses. These results demonstrated that the extract of black pepper was genotoxic in both systems.
A new method of synthesizing biopolymeric affinity ligands.
(1) A new concept for producing soluble polymeric affinity ligands is proposed and exemplified. By solid-phase synthesis, an insoluble hydrophilic polymer is converted into an affinity gel. The gel is hydrolytically degraded to water-soluble affinity polymeric ligands which are recovered and purified. (2) A water-soluble biopolymeric metal-affinity carrier based on an iminodiacetic acid (IDA) derivative of dextran has been synthesized through the modification of Sephadex G-200 by IDA, followed by hydrolysis with dextranase and size-exclusion-chromatographic purification of the high-molecular-mass fragments. (3) The molecular size of the soluble products as a function of hydrolysis time with dextranase from Penicillium sp. was determined. The range of molecular size of the biopolymeric chelating ligand varies from around 200 Da to greater than 580 kDa. (4) The influence of three metal ions chelated with the Sephadex derivative on the hydrolysis rate and the molecular-size distribution of end products was studied. Eu3+ was found to improve the rate of solubilization. Ni2+ and Cu2+ decreased the hydrolysis rate, as compared with that of the metal-free IDA-Sephadex. (5) The method introduced here has the potential of being developed and applied as a general technology for synthesis of soluble multifunctional affinity ligands. Such ligands should be useful for liquid-phase extraction as well as for the synthesis of adsorbents with localized multiple binding sites. Other possible fields of applications are to be found in medicine, where they could be used for slow drug delivery or detoxification, and in analytical chemistry, where they could be used in various assays.
Sensitivity and specificity of in situ bacterial chain reaction (BCR) in detecting sparse human tumor cells in peripheral blood.
We report here the development of bacterial chain reaction (BCR), a system using micro organisms as nanodevices to amplify and visualize signals from molecular bioprobes such as antibodies, binding proteins, lectins, and oligonucleotides. Unlike conventional enzyme-linked amplification systems in which the amount of enzyme is a constant parameter, in the BCR an enzyme (penicillinase) is used to trigger a proliferative chain reaction producing an exponential increase in enzyme. The detection limits and specificity of BCR were determined using a model system designed to detect and enumerate MCF-7 (a human breast adenocarcinoma cell line) cells disseminated at extremely low frequency (e.g., one tumor cell per million normal cells) among monocluclear cells (MNCs) of human peripheral blood. Results of testing 83 specimens of peripheral blood from presumably healthy donors showed 97.6% specificity. The system was capable of detecting tumor cells at a frequency of 2 x 10(-7).
Representativeness of microorgans from human colorectal tumors.
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Treatment of non-Hodgkin's lymphoma of Waldeyer's ring: radiotherapy versus chemotherapy versus combined therapy.
Treatment of stage IA non-Hodgkin's lymphoma (NHL) of Waldeyer's ring remains controversial, probably because of the small number of patients and the scarcity of controlled studies. Between 1981 and 1991, 316 patients with stage I NHL of Waldeyer's ring were randomised for treatment with radiotherapy alone (extended fields), 101 patients; combined chemotherapy with a regimen of CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) or CHOP-like (epirubicin instead of doxorubicin), 106 patients; and combined therapy (radiotherapy followed by the same combination chemotherapy), 109 patients. Median follow-up was 6.8 years. Complete response was achieved in 93, 87 and 97%, respectively. Relapses were least frequent in patients treated with combination therapy. The 5-year rate for failure-free survival was 48% for radiation therapy, 45% for the patients who were treated with chemotherapy, which was statistically significantly less than the 83% for patients treated with combined therapy (P < 0.001). Overall survival was also better in the combined therapy arm: 90%, statistically different to 58% for the patients treated with chemotherapy alone and 56% for patients treated with radiation therapy (P < 0.001). Toxicity was mild and late side-effects were not observed in any patients. From these results combined therapy should be considered as the best therapeutic approach in patients with localised NHL of Waldeyer's ring.
Interferon alpha 2b as maintenance therapy in low grade malignant lymphoma improves duration of remission and survival.
We assessed the efficacy and toxicity of interferon alpha 2b (IFN) as maintenance therapy in patients with low grade malignant lymphoma. Between March 1986 and December 1989, 98 patients with low-grade malignant lymphoma in complete remission after conventional chemotherapy were randomly assigned to received IFN, 5.0 MU three times a week for one year, as maintenance therapy (n = 48), or to receive no treatment (control group, n = 50). In March 1994, the median duration of response had not yet been reached in the patients treated with IFN compared to 46 months in the control group. At 9-years 62% of the patients in the IFN arm remain in first complete remission compared to only 25% in the control group (p <.001). In addition, the median duration of survival has not yet been reached in either the IFN arm compared to 74 months in the control group (p <.001). Quality of life was excellent in both groups and severe side effects secondary to IFN treatment were not observed. All patients completed the planned dose of IFN. We conclude that IFN as maintenance therapy in low-grade malignant lymphoma is an excellent therapeutic option because it improves the duration of remission and survival without producing severe side effects or reducing the quality of life.
Technetium-99m-pertechnetate uptake by intrathyroidal parathyroid adenoma.
A 57-yr-old woman was referred for preoperative scintigraphic localization of a parathyroid adenoma. Double-phase 99mTc-sestamibi imaging was performed followed by a separate-day [99mTc]pertechnetate thyroid scan. There was marked accumulation of both tracers by a right lower pole ¿thyroid' nodule which, at surgery, proved to be an intrathyroidal parathyroid adenoma. Hypervascularity is the presumed explanation for rare cases of pertechnetate-avid parathyroid adenomas.
Preoperative localization of a parathyroid adenoma with Tc-99m sestamibi imaging in a patient with concomitant nontoxic multinodular goiter.
Preoperative localization of parathyroid adenomas is useful in patients undergoing parathyroidectomy. The authors report a patient with hyperparathyroidism and an associated nontoxic nodular goiter. Technetium-99m sestamibi scintigraphy localized and differentiated the parathyroid adenoma from the multinodular goiter. Excellent correlation was found between preoperative radionuclide imaging and surgical pathology. Technetium-99m sestamibi parathyroid imaging may be a simple and helpful test in the surgical management of parathyroid adenomas, particularly in patients with nontoxic multinodular goiter.