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Biomedical subjects

I Sanz

Publications and source records attributed to I Sanz.

At least 19 recordsLinked to original sources
PubMed2006

The restorative effects of pulsed infrared light therapy on significant loss of peripheral protective sensation in patients with long-term type 1 and type 2 diabetes mellitus.

Pulsed infrared light therapy (PILT) has been shown to increase peripheral sensation in diabetic patients with diabetic peripheral neuropathy (DPN). However, most studies last for very short periods, with the subjects receiving only 6-20 treatments. The purpose of this study was to evaluate the effectiveness of an eight-week course of PILT in reversing long-standing, profound DPN in patients with type 1 and type 2 diabetes. Twenty-two subjects with a diagnosis of type 1 (n=2) or type 2 (n=20) diabetes participated in the study. PILT was administered to one foot chosen at random with the other foot serving as a within-subject control (no treatment). Patients underwent 24 treatments (3 times/week, for eight weeks) for 30 min per treatment. Changes in peripheral protective sensation (PPS) were measured using Semmes-Weinstein monofilaments (SWM) ranging from 3.7 to 6.48. PILT improved PPS even in patients with long-standing chronic neuropathies whose initial pre-study sensation was not measurable with a 200-g SWM. PILT significantly improves PPS. While the exact mechanism of action is not understood, infrared light may improve peripheral neuropathies by improving foot perfusion by stimulating nitric oxide production.

Body Mass Index↗
PubMed2004

B lymphocytes in systemic lupus erythematosus: lessons from therapy targeting B cells.

Systemic lupus erythematosus (SLE) is a complex disease characterized by numerous autoantibodies and clinical involvement in multiple organ systems. Autoantibodies are usually present in serum for years before the onset of clinical disease. Autoimmunity begins with a limited number of autoantibodies and evolves to become progressively more diverse. Eventually clinical disease ensues. The immunological events triggering the onset of clinical manifestations have not yet been defined. While undoubtedly T cells and dendritic cells appear to play major roles in SLE, a central role for B cells in the pathogenesis of this disease has been brought to the fore in the last few years by work performed both in mice and humans by multiple laboratories. As a result, there is little doubt about the importance of B cells in the development of SLE. Yet much remains to be learned about their role in the ongoing disease process and the merit of targeting B cells for the treatment of SLE. This article will review the role of B cells in human SLE as well as the currently available data on the treatment of SLE by depleting B cells with anti-CD20 (rituximab).

Antibodies, Monoclonal↗
PubMed2001

Regulation of inherently autoreactive VH4-34 B cells in the maintenance of human B cell tolerance.

The study of human B cell tolerance has been hampered by difficulties in identifying a sizable population of autoreactive B lymphocytes whose fate could be readily determined. Hypothesizing that B cells expressing intrinsically autoreactive antibodies encoded by the VH4-34 heavy chain gene (VH4-34 cells) represent such a population, we tracked VH4-34 cells in healthy individuals. Here, we show that naive VH4-34 cells are positively selected and mostly restricted to the follicular mantle zone. Subsequently, these cells are largely excluded from the germinal centers and underrepresented in the memory compartment. In healthy donors but not in patients with systemic lupus erythematosus (SLE), these cells are prevented from differentiating into antibody-producing plasma cells. This blockade can be overcome ex vivo using cultures of naive and memory VH4-34 cells in the presence of CD70, IL-2, and IL-10. VH4-34 cells may therefore represent an experimentally useful surrogate for autoantibody transgenes and should prove valuable in studying human B cell tolerance in a physiological, polyclonal environment. Our initial results suggest that both positive and negative selection processes participate in the maintenance of tolerance in autoreactive human B cells at multiple checkpoints throughout B cell differentiation and that at least some censoring mechanisms are faulty in SLE.

B-Lymphocytes↗
PubMed2000

Delineation of the human systemic lupus erythematosus anti-Smith antibody response using phage-display combinatorial libraries.

The anti-Smith (Sm) autoantibody response is highly specific for systemic lupus erythematosus and is predominantly targeted to the Sm-B/B' and -D1 polypeptides. In all animal species thus far studied, anti-Sm Abs initially recognize proline-rich epitopes in the carboxyl terminus of the Sm-B/B' protein and subsequently to multiple other epitopes in B/B' and D. The absence of appropriate mAbs has limited our understanding of the genetic and structural basis of this autoimmune response. Using phage-display technology and lymphocytes from a systemic lupus erythematosus patient we have generated the first and only panel of human IgG anti-Sm mAbs thus far available. These Abs reproduced to a remarkable extent the serological reactivity of the patient. Epitope mapping and genetic studies revealed that the anti-Sm response is produced by distinct B cell clones with restricted epitope reactivity. All of the Abs in our study were exclusively encoded by different members of the V(H)4 gene family. On the aggregate, our results demonstrate that combinatorial libraries can recapitulate the immune repertoire of peripheral blood B memory cells and that epitope spreading appears to occur through the sequential recruitment of nonclonally related autoreactive B cell clones.

Amino Acid Sequence↗
PubMed2000

Anticardiolipin antibodies and recurrent coronary events: a prospective study of 1150 patients. Thrombogenic Factors, and Recurrent Coronary Events Investigators.

BACKGROUND: The association of anticardiolipin (aCL) antibodies with coronary artery disease has been shown in several studies but remains controversial. We evaluated the association of aCL and anti-beta(2)-glycoprotein I (abeta(2)GPI) antibodies with the risk of recurrent cardiac events in postinfarction patients. METHODS AND RESULTS: The study population consisted of 1150 patients with acute myocardial infarction. Levels of IgG and IgM aCL and abeta(2)GPI antibodies were determined on sera collected before hospital discharge. There were 131 recurrent cardiac events (nonfatal myocardial infarctions or cardiac deaths) over a mean follow-up period of 24.6 months. Patients with elevated IgG aCL antibodies had a higher event rate than patients with low levels (P:=0.05). Multivariate Cox analysis after adjustment for relevant clinical covariates showed that elevated levels of IgG aCL (hazard ratio=1. 63; P:=0.01) and low levels of IgM aCL (hazard ratio of 1.76; P:=0. 02) antibodies contribute independent risks for recurrent cardiac events. Patients with elevated IgG aCL and low IgM aCL antibody levels had a 3-fold higher risk of recurrent cardiac events than patients with low IgG aCL and elevated IgM aCL antibody levels (P:<0. 001). There was no significant association of the abeta(2)GPI antibodies with recurrent cardiac events. CONCLUSIONS: In postinfarction patients, elevated IgG aCL and low IgM aCL antibodies are independent risk factors for recurrent cardiac events. Patients with both elevated IgG aCL and low IgM aCL antibodies have the highest risk. These findings shed additional light on the mechanistic role of aCL antibodies in coronary artery disease in patients without autoimmune diseases.

Adult↗
PubMed2000

NF-kappa B regulates VCAM-1 expression on fibroblast-like synoviocytes.

Expression of VCAM-1 on synovial fibroblasts is a clinical hallmark of rheumatoid arthritis. The interaction of VCAM-1 and its integrin receptor very late Ag-4 is believed to be critically involved in the recruitment and retention of immune cells in the inflamed joints. To study the regulation of VCAM-1 in synovial fibroblasts, fibroblast-like synoviocytes (FLS) were isolated from the knee joints of normal mice and passaged repeatedly to obtain a homogeneous cell population. We have found that VCAM-1 is constitutively expressed on mouse FLS (mFLS) and that its surface expression is further increased after exposure to TNF-alpha. Nuclear translocation of transcription factor NF-kappa B including P50/P50 homodimer and P65/P50 heterodimer was activated by TNF-alpha treatment. In mFLS stably expressing a dominant-negative mutant of the inhibitory protein I-kappa B alpha- (mI-kappa B), which does not undergo proteolytic degradation, NF-kappa B remains in the cytosol and its activation in response to TNF-alpha is abolished. VCAM-1 protein expression after TNF-alpha stimulation was blocked in cells expressing the mI-kappa B. This effect is likely due to the loss of NF-kappa B-mediated transcription of VCAM-1, because the 5-fold increase in mRNA levels in response to TNF-alpha is absent in the mutant cells. To confirm these findings, we transduced mFLS with an adenoviral vector containing the mI-kappa B transgene. VCAM-1 expression was also blocked by mI-kappa B in this system, whereas cells transduced with a control adenoviral vector remained responsive to TNF-alpha. These results indicate that NF-kappa B mediates TNF-alpha-induced VCAM-1 expression on mFLS.

Adenoviridae↗
PubMed2000

Characterization of human anti-acetylcholine receptor monoclonal autoantibodies from the peripheral blood of a myasthenia gravis patient using combinatorial libraries.

Myasthenia gravis (MG) is an autoimmune disease caused by autoantibodies against the nicotinic acetylcholine receptor (AChR). Using phage-display technology we have characterized the largest panel of anti-AChR monoclonal antibodies thus far isolated from a single patient. Despite having been isolated with either Torpedo AChR or a human peptide, the recombinant antibodies shared with the donor's serum the ability to recognize human AChR expressed in its native configuration on the surface of TE671 cells. Their specificity for the main immunogenic region (MIR) of the AChR was demonstrated using a synthetic peptide corresponding to the region 67-76 of the human AChR alpha subunit and by inhibition of a highly pathogenic rat anti-MIR monoclonal antibody (mAb35). This work demonstrates the value of combinatorial libraries in isolating pathogenic autoantibodies from peripheral blood lymphocytes. Future genetic, structural, and functional analyses of the monoclonal antibodies reported herein should enhance our understanding of the pathogenesis of MG.

Animals↗
PubMed2000

In vivo cell penetration and intracellular transport of anti-Sm and anti-La autoantibodies.

Anti-nuclear autoantibodies (ANA) are the hallmark of systemic autoimmune diseases. Yet, the in vivo function of ANA remains controversial to a large extent due to the intracellular nature of their antigenic targets. It has been reported that a subset of autoantibodies can penetrate live cells and translocate into the subcellular compartments containing the corresponding antigens. The studies presented herein show that murine anti-Sm and anti-La monoclonal autoantibodies can also enter a variety of cell types from different animal species and that the cell penetration activity is not isotype-restricted. Interestingly, only mAb with cross-reactivity against double-stranded DNA did enter cells. Both these autoantibodies rapidly accumulate in the nucleus of viable cells but display different penetration kinetics. In co-localization experiments, monoclonal autoantibodies did not accumulate significantly within endocytic vesicles containing dextran, suggesting that they are internalized by mechanisms distinct from conventional receptor-mediated endocytosis. This report represents the first evidence that anti-La and anti-Sm autoantibodies are capable of entering live cells. Our observations support the notion that the phenomenon of intracellular autoantibodies may have a larger scope than previously reported and are consistent with a potential pathogenic role for ANA.

Amino Acid Sequence↗
PubMed2000

Ablation of tumor necrosis factor receptor type I (p55) alters oxygen-induced lung injury.

Hyperoxic lung injury, believed to be mediated by reactive oxygen species, inflammatory cell activation, and release of cytotoxic cytokines, complicates the care of many critically ill patients. The cytokine tumor necrosis factor (TNF)-alpha is induced in lungs exposed to high concentrations of oxygen; however, its contribution to hyperoxia-induced lung injury remains unclear. Both TNF-alpha treatment and blockade with anti-TNF antibodies increased survival in mice exposed to hyperoxia. In the current study, to determine if pulmonary oxygen toxicity is dependent on either of the TNF receptors, type I (TNFR-I) or type II (TNFR-II), TNFR-I or TNFR-II gene-ablated [(-/-)] mice and wild-type control mice (WT; C57BL/6) were studied in >95% oxygen. There was no difference in average length of survival, although early survival was better for TNFR-I(-/-) mice than for either TNFR-II(-/-) or WT mice. At 48 h of hyperoxia, slightly more alveolar septal thickening and peribronchiolar and periarteriolar edema were detected in WT than in TNFR-I(-/-) lungs. By 84 h of oxygen exposure, TNFR-I(-/-) mice demonstrated greater alveolar debris, inflammation, and edema than WT mice. TNFR-I was necessary for induction of cytokine interleukin (IL)-1beta, IL-1 receptor antagonist, chemokine macrophage inflammatory protein (MIP)-1beta, MIP-2, interferon-gamma-induced protein-10 (IP-10), and monocyte chemoattractant protein (MCP)-1 mRNA in response to intratracheal administration of recombinant murine TNF-alpha. However, IL-1beta, IL-6, macrophage migration inhibitory factor, MIP-1alpha, MIP-2, and MCP-1 mRNAs were comparably induced by hyperoxia in TNFR-I(-/-) and WT lungs. In contrast, mRNA for manganese superoxide dismutase and intercellular adhesion molecule-1 were induced by hyperoxia only in WT mice. Differences in early survival and toxicity suggest that pulmonary oxygen toxicity is in part mediated by TNFR-I. However, induction of specific cytokine and chemokine mRNA and lethality in response to severe hyperoxia was independent of TNFR-I expression. The current study supports the prediction that therapeutic efforts to block TNF-alpha receptor function will not protect against pulmonary oxygen toxicity.

Animals↗
PubMed2000

Empirical advantages of adeno associated viral vectors in vivo gene therapy for arthritis.

OBJECTIVE: To evaluate the utility of the adeno associated viral (AAV) vector for gene delivery to joint cells in vivo and in vitro, and to assess its potential as a vector for arthritis gene therapy. METHODS: A recombinant AAV (rAAV) vector expressing the bacterial beta-galactosidase (beta-gal) gene (rAAV-CMV-LacZ) was directly introduced into healthy-normal mouse knees, or arthritic knees in mice overexpressing tumor necrosis factor-alpha (hTNFalpha-Tg). Beta-gal expression levels were determined by immunohistochemistry and chemiluminescence. The transduction efficiency of this vector on primary fibroblast-like synoviocytes (FLS) in vitro was determined by FACS. The effects of UV and gamma-irradiation as well as TNF-alpha on transduction efficiency were determined using the same methods. RESULTS: We found little evidence of rAAV transduction in the joint cells of healthy mice. Target gene expression was detected in all animals at Day 3, and peaked at Day 7 before returning to baseline levels 21 days after injection. In contrast, synoviocytes, articular chondrocytes, and meniscal cells of diseased mice were transduced by rAAV-CMV-LacZ in hTNFalpha-Tg animals. Transduction efficiencies correlated with joint damage, and target gene expression was up to 10-fold greater than that seen in the normal mice. In vitro, we found that rAAV transduction of FLS can be enhanced by pretreatment with UV or gamma-irradiation and TNF-alpha stimulation. CONCLUSION: We find that rAAV vectors have several empirical advantages for in vivo gene therapy for arthritis: (1) rAAV preferentially transduces arthritic joint cells in vivo. (2) rAAV can transduce both FLS and chondrocytes in vivo. (3) rAAV transduction of FLS can be augmented by pretreatment with agents that induce DNA repair enzymes.

Adenoviridae↗
PubMed1999

Tumor necrosis factor alpha receptor I is important for survival from Streptococcus pneumoniae infections.

Tumor necrosis factor alpha (TNF-alpha) is important in resistance to various microorganisms and provides signals to the target cells through two different receptors, TNF-alpha receptor I (TNFRI) (p55 receptor) and TNFRII (p75 receptor). To delineate the significance of the two different signaling pathways in resisting infections with extracellular bacteria, we examined the resistance of mice to Streptococcus pneumoniae (serotype 6B). TNF-alpha needs to be present early in infections, since one injection of wild-type mice with anti-TNF-alpha leads to an increased susceptibility of these mice to S. pneumoniae. TNF-alpha signaling through the p55 receptor (but not the p75 receptor) is crucial in resisting S. pneumoniae infections, because intraperitoneal injection of 100 CFU/mouse killed p55-deficient mice by day 2 of infection, whereas 1,000,000 CFU/mouse was needed to kill half of the control mice. p55-deficient mice do not show evidence of a deficient acute-phase response. All three types of mice (p55 deficient, p75 deficient, and normal) showed comparable rises in the levels of two acute-phase proteins (serum amyloid P and C3) at 24, 48, and 72 h after the experimental infections, and all of the mice showed comparable influxes of neutrophils to the site of infection. Finally, it was demonstrated that p55-deficient mice can be protected from the lethal effects of S. pneumoniae infection by injection of antibodies specific for S. pneumoniae polysaccharide capsule.

Acute-Phase Reaction↗
PubMed1999

Antimicrobial and antioxidant compounds in the nonvolatile fraction of expressed orange essential oil.

Three permethoxylated flavones, dehydroabietic acid and linoleil monoglyceride were isolated from the nonvolatile residue of orange essential oil. All of them exhibited antifungal activity against phytopathogenic species and food contaminants. The isolated hexa- and heptamethoxy flavones exhibited important fungicidal activity against Geotrichum candidum, which is not inhibited by the commercial broadspectrum fungicide Benomyl (methyl-1-[butylcarbamoyl]-2-benzimidazolecarbamate); in addition, these compounds also exhibited effective antioxidant activities, similar to that shown by tert-butyl-4-hydroxyanisol, one of the most commonly used synthetic antioxidants; alpha-tocopherol, the most widely used natural antioxidant, was also isolated.

Antifungal Agents↗
PubMed1999

[In vitro immunosuppressive effect of low density lipoproteins].

BACKGROUND: Immune cells participate in the formation of atheromatous plate, however little is known about the effects of native or oxidatively modified lipoproteins on these cells. AIM: To study the effects of lipoproteins on in vitro mononuclear cell proliferation. MATERIAL AND METHODS: Peripheral blood mononuclear cells were obtained from 10 patients with type 2 diabetes mellitus (aged 52 +/- 9 years old with a disease duration of 8.2 +/- 5.7 years and a mean glycosilated hemoglobin of 9.3 +/- 2.2%) and 10 non diabetic healthy controls (aged 50.3 +/- 7.1 years old). These were stimulated with phytohemagglutinin (PHA) alone or in the presence of native LDLS, malondialdehyde modified LDLs or glycated LDLs. Proliferation was measured as 3H-thymidine incorporation and expressed as Stimulation Index (SI). RESULTS: SI of patients and healthy subjects, after PHA stimulation were similar: (57.5 +/- 29.8 and 61.1 +/- 23.5) respectively LDLs did not induce proliferation in neither group. Native LDLs produced a 98% inhibition of PHA induced proliferation. Malondialdehyde modified and glycated LDLs caused a 50% inhibition. The suppressive effect was maintained when lipoproteins were incorporated to culture media 60 min prior or after PHA stimulation. CONCLUSIONS: Lipoproteins inhibit in vitro PHA induced peripheral blood mononuclear cell proliferation both in diabetic and in non diabetic subjects.

Adult↗
PubMed1998

[Cervical metastasis of choriocarcinoma].

Neck metastatic adenopathy involves to set off a protocol aiming to specify the growth's origin. Complete ENT-examination facing a hard, movable, laterocervical lump is compulsory. Lacking the primary next comes fine needle biopsy and if it's not clear enough a cervicotomy must be performed. We report the diagnosis, the treatment and the follow-up of a testicle choriocarcinoma case, diagnosed through neck biopsy. Perusal of the bibliography.

Adult↗
PubMed1997

Human Ig heavy chain CDR3 regions in adult bone marrow pre-B cells display an adult phenotype of diversity: evidence for structural selection of DH amino acid sequences.

Ig repertoires generated at various developmental stages differ markedly in diversity. It is well documented that Ig H chain genes in human fetal liver are limited with regard to N-regional diversity and use of diversity elements. It is unclear whether these characteristics persist in pre-B cell H chain genes of adult bone marrow. Using Ig H chain CDR3 fingerprinting and sequence analysis, we analyzed the diversity of Ig H chain third complementarity determining regions (HCDR3) in adult bone marrow pre-B and mature B lymphocytes. Pre-B cell HCDR3 sequences exhibited adult characteristics with respect to HCDR3 size, distribution of N regions and usage of diversity elements. This suggested that pre-B cells in adults are distinct from fetal B cell precursors with regard to Ig H chain diversification mechanisms. At the DNA sequence level, HCDR3 diversity in mature B cells was similar to that in pre-B cells. Pre-B HCDR3s, however, frequently contained a consecutive stretch of hydrophobic amino acids, which were rare in mature B cells. We propose that highly hydrophobic pre-B HCDR3s may be negatively selected on the basis of structural limitations imposed by the antigen binding site. At the same time, usage of hydrophilic HCDR3 sequences (thought to support HCDR3 loop formation) may be promoted by positive selection.

Adult↗
PubMed1996

Gas generation and preconcentration coupled to gas phase molecular absorption spectrometry: a powerful tool for the simultaneous determination of analytes forming volatile compounds.

Different methods for a simultaneous determination of several analytes forming volatile compounds at room temperature are described. The main steps of these methods are: continuous generation, collection in a cryogenic trap, revolatilization, measurement of the volatile compounds by Gas Phase Molecular Absorption Spectrometry and resolution by multi-wavelength methods. Several mixtures containing 2, 3 or 4 components have been studied: 1) elements forming covalent hydrides; 2) arsenic organometallic compounds forming volatile gases with a similar structure to arsine; and 3) sulphur species that can evolve volatile compounds. Under the optimum conditions obtained for each mixture, detection limits range from 0.8 ng/mL (dimethylarsinic acid) to 2 microg/mL (SCN(-)).

Journal Article↗