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Biomedical subjects

J J Jimenez

Publications and source records attributed to J J Jimenez.

At least 19 recordsLinked to original sources
PubMed2006

Multiple sclerosis as a vascular disease.

Multiple sclerosis (MS) has traditionally been viewed and researched as an immune-mediated disease with principal emphasis on the role of activated inflammatory cells, oligodendrocytes and astrocytes in its pathogenesis. Abnormalities of cerebral endothelial cells (CECs) is an under explored facet of MS pathogenesis and vascular abnormalities play a crucial role in formation of the MS lesions and disease progress, at least in the initial stages of disease. This review will focus on MS as a central nervous system (CNS) disease with a strong vascular constituent and examines abnormalities within CECs in MS and their role in the loss of blood-brain barrier and transendothelial migration of activated leukocytes into the CNS. One goal of this paper is to persuade and promote research on the endothelial abnormalities in pathogenesis of MS and to exploit existing knowledge on endothelial injury. A deeper understanding of endothelial pathophysiology in MS may help develop effective treatments through stabilization of endothelial function, translating into delay or arrest of MS disease onset and disability in MS patients.

Antibody Specificity↗
PubMed2005

Endothelial microparticles induce formation of platelet aggregates via a von Willebrand factor/ristocetin dependent pathway, rendering them resistant to dissociation.

Endothelial microparticles (EMP) released from activated or apoptotic endothelial cells (EC) are emerging as useful markers for detection of EC dysfunction. Our recent observation that EMP carry von Willebrand factor (vWf) led us to investigate their interaction with platelets. EMP were incubated with normal washed platelets in the presence or absence of ristocetin, then platelet aggregates were measured by flow cytometry. In the absence of ristocetin, negligible EMP conjugated with platelets (< 5%) but in the presence of ristocetin (1 mg mL(-1)), EMP induced up to 95% of platelets to aggregate. EMP-platelet interaction was 80% blocked by anti-CD42b, or by 0.1 microm filtration to remove EMP. Platelet aggregates induced by normal plasma or high molecular weight vWf (Humate-P) dissociated 50% within 15-25 min following 1:20 dilution. In contrast, aggregates formed with EMP persisted two- to threefold longer with the same treatment, indicating greater stability. A similar degree of prolongation of dissociation was observed using plasma from thrombotic thrombocytopenic purpura (TTP) patients compared with normal plasma. Addition of EMP to plasma from severe von Willebrand disease restored his ristocetin-induced platelet aggregation. Multimer analysis of vWf on EMP showed unusually large vWf (ULvWf). In summary, EMP carries ULvWf multimers, promote platelet aggregates, and increase the stability of the aggregates thus formed.

Cells, Cultured↗
PubMed2001

Elevated plasma endothelial microparticles in multiple sclerosis.

OBJECTIVE: To assess endothelial dysfunction in patients with MS and to investigate whether plasma from patients with MS induces endothelial cell dysfunction in vitro. BACKGROUND: Endothelial cell dysfunction may contribute to the pathogenesis of MS. Elevations of soluble adhesion molecules intracellular adhesion molecule, vascular cell adhesion molecule, and platelet-endothelial cell adhesion molecule-1 (CD31) have been reported as markers of blood-brain barrier (BBB) damage in MS, but direct assay of endothelium has been difficult. Endothelial cells release microparticles < approximately 1.5 microm (EMP) during activation or apoptosis. The authors developed a flow cytometric assay of EMP and studied EMP as markers of endothelial damage in MS. METHODS: Platelet-poor plasma (PPP) from 50 patients with MS (30 in exacerbation and 20 in remission) and 48 controls were labeled with fluorescein isothiocyanate (FITC)-conjugated anti-CD31 and anti-CD51 (vitronectin receptor) antibodies, and two classes of EMP (CD31+ and CD51+) were assayed by flow cytometry. For in vitro studies, patients' plasma was added to the microvascular endothelial cell (MVEC) culture and release of CD31+ and CD51+ EMP were measured in the supernatant. RESULTS: Plasma from patients in exacerbation had 2.85-fold elevation of CD31+ EMP as compared with healthy controls, returning to near control value during remission. The CD31+ EMP concentration showed a positive association with gadolinium enhancement in patients with MS. In contrast, CD51+ EMP remained elevated in both exacerbation and remission. This suggests that CD31+ EMP is a marker of acute injury, whereas CD51+ EMP reflects chronic injury of endothelium. MS plasma induced release of both CD31+ and CD51+ EMP from MVEC culture in vitro. CONCLUSION: Endothelial dysfunction is evident during exacerbation of MS, evidenced by shedding of EMP expressing PECAM-1 (CD31). The in vitro data indicate contribution of one or more plasma factors in endothelial dysfunction of MS.

Adult↗
PubMed2001

Elevated endothelial microparticles in thrombotic thrombocytopenic purpura: findings from brain and renal microvascular cell culture and patients with active disease.

Endothelial injury is believed to be a key initiating event in the pathogenesis of thrombotic thrombocytopenic purpura (TTP), leading to platelet activation and formation of platelet-rich thrombi in microvasculature. However, the nature of endothelial injury in TTP is poorly defined and clinical assays to rapidly and reliably monitor endothelial damage are not readily available. Using flow cytometry, we measured endothelial microparticles (EMPs) generated from cultured renal and brain microvascular endothelial cells (MVECs) during activation and apoptosis, and evaluated the effect of TTP plasma on them. EMPs were measured using positivity for monoclonal antibodies (mAbs) CD31 and CD51, and their procoagulant activity was assessed using a Russell viper venom assay. Both cell lines generated procoagulant EMPs when cultured with inducers of activation (tumour necrosis factor alpha; TNF-alpha) or apoptosis (mitomycin C). TTP plasma induced a five- to sixfold increase of EMP generation and a two- to threefold increase of procoagulant activity in cultured brain and renal MVECs. TTP plasma induced a threefold and 13-fold increase of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression, respectively, on renal MVECs. Procoagulant activity tended to parallel EMP numbers. The effect of TTP plasma on cell viability was similar to that of TNF-alpha, implying that it induced activation rather than apoptosis. Control plasma and idiopathic thrombocytopenic purpura (ITP) plasma had little effect. In the clinical study, EMP assay of blood from acute TTP patients showed levels markedly elevated compared with normal controls, but values returned to normal in remission. In conclusion, TTP plasma activated and induced injury to MVECs in culture, judged by production of EMP and expression of activation markers. Released procoagulant EMP may play a role in the pathogenesis of TTP. Assay of EMP may be a useful marker of disease activity and endothelial injury in TTP and possibly other thrombotic disorders.

Adult↗
PubMed2000

Determination of the 2-bromomethyl-2-(2,4-dichlorophenyl)-1, 3-dioxolan-4-yl)methyl benzoate diastereoisomers by supercritical fluid chromatography.

The study of the separation and determination of the two 2-bromomethyl-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl-methyl benzoate diastereoisomers is presented in this work. The separation was achieved using packed column supercritical fluid chromatography. Three stationary phases were checked, the C(18) packing providing the best results. The influence of several parameters (nature and percentage of modifier, temperature and pressure) on the separation were also evaluated. The baseline separation (R(s)=1.78) of the compounds was obtained in only 2 min, using a C(18) column, a pressure of 100 bar, a temperature of 35 degrees C, a flow-rate of 2. 5 ml/min and 5% of 2-propanol as organic modifier. Under these conditions the unwanted diastereoisomer (trans) was eluted before the main compound (cis), so the determination of the purity was more accurate.

2-Propanol↗
PubMed1996

Familial infantile thrombotic thrombocytopenic purpura.

PURPOSE: To further define familial infantile thrombotic thrombocytopenic purpura and clarify its pathophysiology, we describe a family with two infants presenting with this rare syndrome. RESULTS: Complete, but temporary remission followed the transfusion of whole blood in the first sibling and fresh frozen plasma (FFP) in the second. Periodic FFP transfusions have kept the surviving proband in a prolonged clinical remission. The presence of unusually large von Willebrand factor multimers was demonstrated in the proband and the processing activity of these large multimers was found to be normal. CONCLUSION: The occurrence of this rare disorder, in siblings who are products of a consanguinous union, suggests an as yet uncharacterized genetic defect.

Female↗
PubMed1995

Pretreatment with 1,25(OH)2D3 protects from Cytoxan-induced alopecia without protecting the leukemic cells from Cytoxan.

The authors previously demonstrated that pretreatment with 1,25(OH)2D3 protects from Cytoxan-induced alopecia in the rat model. The current study was designed to investigate whether 1,25(OH)2D3 protects the transplantable rat chloroleukemia (C51) cells from the cytotoxic effects of Cytoxan. In vitro, 4-hydroperoxycyclophosphamide had a dose-dependent cytotoxic effect on C51 cells. In separate experiments, preincubation with 1,25(OH)2D3 did not protect the C51 cells from the cytotoxic effects of 4-hydroperoxycyclophosphamide. In vivo, 4 groups of 10 5-day-old rats were treated as follows: Groups 1 and 2 received 0.2 micrograms of 1,25(OH)2D3 topically in ethanol daily starting on day 5 through day 10. Groups 3 and 4 received ethanol topically similarly. On day 7, all rats received 1 x 10(5) C51 cells intraperitoneally. On day 11, groups 1 and 3 received 35 mg/kg Cytoxan intraperitoneally. All rats in groups 2 and 4 were dead of leukemia by day 34. In groups 1 and 3, only 1 of 10 and 2 of 10 rats died of leukemia, respectively. Alopecia developed in all rats in group 3. In contrast, all rats in group 1 were protected from Cytoxan-induced alopecia. These results indicate that, in vivo, pretreatment with 1,25(OH)2D3 does not protect the rat chloroleukemia cells from the cytotoxic effect of Cytoxan, while protecting from Cytoxan-induced alopecia.

Alopecia↗
PubMed1992

Protection from chemotherapy-induced alopecia by 1,25-dihydroxyvitamin D3.

We have previously reported that several biological agents, when given simultaneously with cytosine arabinoside or cytoxan, will protect from cytosine arabinoside-induced but not from cytoxan-induced alopecia. In the present study we used the secosteroid 1,25-dihydroxyvitamin D3 in a different timing schedule to protect from chemotherapy-induced alopecia. In three separate experiments, 0.2 microgram of topical, 1,25-dihydroxyvitamin D3 protected rats from alopecia induced by etoposide, cytoxan, and an Adriamycin-cytoxan combination. In another experiment, 0.1 microgram protected rats from etoposide-induced alopecia at the site of application. 1,25-Dihydroxyvitamin D3 may offer a new and exciting approach to the prevention of chemotherapy-induced alopecia.

Alkylating Agents↗
PubMed1992

Interleukin 1 protects hair follicles from cytarabine (ARA-C)-induced toxicity in vivo and in vitro.

ImuVert, a biologic response modifier, and interleukin 1 (IL 1) have been shown to protect the young rat from alopecia induced by cytarabine (ARA-C). In the present study the inhibition by ARA-C of DNA synthesis in hair follicles (HFs) and the protective effect of ImuVert and IL 1 were investigated in vivo and in vitro. Both ImuVert and IL 1 were equally effective in protecting rats from ARA-C-induced alopecia. DNA synthesis in HFs isolated from ARA-C-treated animals was 10-20% of untreated controls. Follicles isolated from animals given either ImuVert or IL 1 before ARA-C exhibited normal DNA synthesis. In vitro, the incubation of normal rat HF with ARA-C resulted in 80% inhibition of [3H]-thymidine uptake. Preincubation of the follicles for 1 hr with IL 1 before the addition of ARA-C completely blocked the inhibition. Preincubation with imuVert, however, was less effective in blocking the inhibition from ARA-C.

Alopecia↗
PubMed1992

Protection from 1-beta-D-arabinofuranosylcytosine-induced alopecia by epidermal growth factor and fibroblast growth factor in the rat model.

The present study was designed to examine the effect of epidermal growth factor (EGF) and fibroblast growth factor (FGF) on 1-beta-D-arabinofuranosylcytosine (ARA-C)- and cyclophosphamide-induced alopecia in the young rat model. Seven-day-old rats were given ARA-C with or without human or murine EGF daily for 7 days. Alopecia was scored on the 12th day of the experiment. Both human and murine EGF protected rats from ARA-C-induced alopecia. The topical application of murine EFG in dimethyl sulfoxide offered significant protection limited to the treated area. In other experiments the administration of acidic FGF (aFGF) with ARA-C resulted in protection from alopecia limited to the site of FGF injection. Neither EGF nor FGF had any influence on alopecia from cyclophosphamide. It is concluded that both EGF and FGF are effective in protecting against ARA-C-induced alopecia in the rat model.

Alopecia↗
PubMed1992

IL-1 synergizes with ARA-C in aborting the development of chloroleukemia while protecting from ARA-C-induced alopecia in the rat model.

Recently, interleukin 1 (IL-1) was shown to protect rats from ARA-C-induced alopecia. The present study was designed to investigate the effect of combination rHu-IL-1 and ARA-C on transplantable chloroleukemia (C51) and at the same time evaluate the protective effect of IL-1 on the ARA-C-induced alopecia in the rat model. In vitro, IL-1 had no direct effect on growth, viability or differentiation of C51 cells, neither did IL-1 protect the C51 cells from ARA-C cytotoxicity. In vivo, the combination treatment of ARA-C + IL-1 aborted the development of transplanted chloroleukemia in 100% of rats, vs 60%, 10% and 0% survival for rats treated with IL-1, ARA-C and buffer respectively. All rates treated with ARA-C alone developed complete body alopecia. In contrast, none of the rats treated with combination IL-1 and ARA-C combination developed alopecia. Thus, IL-1 demonstrated a double beneficial effect, synergism with ARA-C against the leukemic cells on the one hand, and protection from ARA-C-induced alopecia, on the other.

Alopecia↗
PubMed1992

Protection from chemotherapy-induced neutropenia by ImuVert.

Neutropenia is a major cause of chemotherapy-induced morbidity. This study examines the effect of ImuVert on the course of neutropenia from Cytoxan and Adriamycin. In adult rats treated with either Cytoxan or Adriamycin and ImuVert, the absolute neutrophil count remained above 7,000 and 2,000, respectively, for the duration of ImuVert therapy. In contrast, in the control Cytoxan group the absolute neutrophil count reached 300/mm3 on day 5 and remained below 1,000 from day 4 through day 7. In the Adriamycin control group, the nadir absolute neutrophil count reached 600/mm3 on day 7 and remained below 100 from day 6 through day 8. C3H/EJ mice (endotoxin-hyporesponsive) treated with Cytoxan developed an absolute neutrophil count below 1,000 from day 4 through day 7. In contrast, in the group concomitantly treated with ImuVert, the nadir absolute neutrophil count remained below 1,000 only on days 4 and 5. The authors conclude that stimulation of endogenous cytokine production by ImuVert may provide a potentially useful approach to bone marrow rescue from chemotherapy.

Animals↗
PubMed1991

Role of tumor-derived cytokines on the immune system of mice bearing a mammary adenocarcinoma. II. Down-regulation of macrophage-mediated cytotoxicity by tumor-derived granulocyte-macrophage colony-stimulating factor.

Peritoneal elicited macrophages (PEM) from mammary tumor-bearing mice have a decreased capacity to become cytotoxic against syngeneic, allogeneic, and xenogeneic target cells upon in vitro stimulation with LPS, as compared with PEM of normal mice. A regulatory mechanism other than PG release is suggested because the addition of both indomethacin and LPS to macrophage cultures from tumor-bearing mice caused no changes in their cytotoxic capability. Because tumor products have been implicated in the down-regulation of immune responses, we investigated whether pretreatment with supernatants from the tumor cell line DA-3, derived from the in vivo mammary adenocarcinoma D1-DMBA-3, affects the cytolytic capacity of macrophages. This treatment inhibits, in a dose-dependent fashion, the ability of stimulated normal PEM to kill target cells. Partial purification of DA-3 cell line supernatant showed that most of the inhibitory activity was exerted by factors with a molecular mass greater than 10 kDa and less than 30 kDa. However, slight inhibition could also be observed with fractions containing molecules less than 10 kDa. The data suggest that more than one factor released by the mammary tumor cells may be involved in the down-regulation of macrophage-mediated cytotoxicity. Because the DA-3 cells constitutively produce granulocyte-macrophage CSF (GM-CSF), which has a molecular mass of 27 kDa, we pretreated PEM from normal mice in vitro with rGM-CSF for 24 h. This resulted in a dose-dependent decrease in their capacity to kill tumor target cells upon LPS stimulation. Furthermore, PEM from normal mice injected with rGM-CSF for 25 days displayed a profound decrease in their cytolytic ability against DA-3 targets upon in vitro stimulation with increasing amounts of LPS. The pretreatment of PEM from normal mice with a combination of DA-3 cell supernatants and specific anti-GM-CSF partially neutralized the inhibitory effect of the DA-3 supernatant on macrophage tumoricidal capability. These results indicate that tumor-derived GM-CSF is an important factor involved in the decreased macrophage cytotoxicity during mammary adenocarcinoma progression.

Adenocarcinoma↗