Biomedical subjects

H Molina

Publications and source records attributed to H Molina.

At least 37 records · Page 2Linked to original sources

PubMed1999

[Chronic inflammatory demyelinating polyneuropathy. Findings in 30 patients].

Chronic demyelinating inflammatory polineuropathy (CIDP) is a disease which was recognized several years ago. However, the mechanism underlying its pathogenesis remains poorly understood. Nevertheless, there are some clues which strongly suggest that it constitutes an autoimmune disease. Since 1992 we have studied 30 cases. All them were clinically assessed and submitted to laboratory investigations encompassing nerve conduction studies, sera proteins immunoelectrophoresis, spinal fluid analysis and sural nerve biopsies. Upon clinical examination the usual findings were weakness, muscle atrophy, absence or diminished tendon jerks, paresthesias and hyposthesias. Electrophysiological studies disclosed marked slowing of the nerve conduction velocities, suggesting demyelination. Sera immunoelectrophoresis detected monoclonal gammopathy in 17% of the studied patients, which was not associated with lymphoproliferative illnesses. Of the patients 79% had increased levels of spinal fluid proteins. Seventeen patients gave their consent for performing a sural nerve biopsy; all the samples showed demyelination. In conclusion, we think that CDIP is a disease which can be recognized when the clinical assessment, the nerve conduction studies and the spinal fluid findings suggest the diagnosis. Although nerve biopsy may be strongly supporting, we believe that it has to be performed only if doubts arise from the clinical, electrophysiological or spinal fluid observations. It is worth noting that its early detection may benefit the patient through the administration of the right therapy precluding the eventual sequelae of the disease.

Adolescent↗

PubMed1998

Expression of complement receptors 1 and 2 on follicular dendritic cells is necessary for the generation of a strong antigen-specific IgG response.

Two mechanisms could account for the impaired humoral immune response found in Cr2-/- mice. The absence of complement receptors 1 and 2 (CR1, CR2) on B cells could affect their activation. Alternatively, impaired Ag trapping by follicular dendritic cells (FDC) could affect B cell maturation into Ig-secreting or memory B cells. To compare the roles of CR1 and CR2 on B cells vs FDC in this abnormal response, bone marrow (BM) chimeric mice were generated and immunized with specific T-dependent Ags. The primary and secondary Ab response was measured. Cr2+/+ animals reconstituted with a Cr2-/- BM generated a diminished but detectable humoral immune response compared with controls. When injected with preformed immune complexes (IC), these mice maintained follicular IC localization. Cr2-/- animals reconstituted with a Cr2+/+ BM had an initial rise in the Ab titer, but were unable to maintain it as shown by a pronounced decrease in the IgG titer. This defect persisted during the secondary immune response. Follicular IC trapping was also impaired. Despite the abnormal Ab response, germinal center formation was retained in all of the chimeric animals. These experiments are the first to demonstrate an absolute requirement for CR1 and CR2 expression on FDC in the generation of a normal humoral immune response.

Animals↗

PubMed1998

Gamma-glutamyl transpeptidase, an ecto-enzyme regulator of intracellular redox potential, is a component of TM4 signal transduction complexes.

CD21 (C3dg/EBV receptor) is physically associated on B cells with a complex of proteins that includes CD19 and the widely distributed tetraspan 4 (TM4) family protein CD81 as well as other TM4 proteins (CD53, CD37 and CD82). Monoclonal antibodies (mAb) were generated that blocked homotypic adhesion induced by CD21 ligands in the human B cell line Balm-1. One inhibitory mAb (3A8) was found to recognize the ecto-enzyme gamma-glutamyl transpeptidase (GGT), a membrane protein involved in recycling extracellular glutathione and regulating intracellular redox potential. Molecular associations between GGT and TM4 proteins CD81, CD53 and CD82, in addition to CD21 and CD19, were detected by co-precipitation and co-capping analysis. GGT is expressed on several B and T cell lines independently of CD21 expression. These results demonstrate that GGT is a component of widely distributed TM4 complexes, and that on B cells the GGT-containing TM4 complexes also contain CD19 and CD21.

Animals↗

PubMed1998

[WHO contribution to maternal and child health].

The conditioning and risk factors of maternal and child health are analyzed, like: undernutrition, communicable diseases, basic sanitation and health infrastructure. The policies and programmes are evaluated and the aims are described. The catalytic role of WHO is underlined.

Child↗

PubMed1997

Distinct roles of lymphotoxin alpha and the type I tumor necrosis factor (TNF) receptor in the establishment of follicular dendritic cells from non-bone marrow-derived cells.

In mice deficient in either lymphotoxin alpha (LT-alpha) or type I tumor necrosis factor receptor (TNFR-I), organized clusters of follicular dendritic cells (FDC) and germinal centers (GC) are absent from the spleen. We investigated the role of LT-alpha and TNFR-I in the establishment of spleen FDC and GC structure by using reciprocal bone marrow (BM) transfer. When LT-alpha-deficient mice were reconstituted with wild-type BM, FDC organization and the ability to form GC were restored, indicating that the LT-alpha-expressing cells required to establish organized FDC are derived from BM. The role of LT-alpha in establishing organized FDC structure was further investigated by the transfer of complement receptor 1 and 2 (CR1/2)-deficient BM cells into LT-alpha-deficient mice. Organized FDC were identified with both the FDC-M1 and anti-CR1 monoclonal antibodies in these BM-chimeric mice, indicating that these cells were derived from the LT-alpha-deficient recipient. Thus, expression of LT-alpha in the BM-derived cells, but not in the non-BM-derived cells, is required for the maturation of FDC from non-BM precursor cells. In contrast, when TNFR-I-deficient mice were reconstituted with wild-type BM, they showed no detectable FDC clusters or GC formation. This indicates that TNFR-I expression on non-BM-derived cellular components is necessary for the establishment of these lymphoid structures. TNFR-I-deficient BM was able to restore FDC organization and GC formation in LT-alpha-deficient mice, indicating that formation of these structures does not require TNFR-I expression on BM-derived cells. The data in this study demonstrate that FDC organization and GC formation are controlled by both LT-alpha-expressing BM-derived cells and by TNFR-I-expressing non-BM-derived cells.

Animals↗

PubMed1997

Lymphotoxin-alpha (LTalpha) supports development of splenic follicular structure that is required for IgG responses.

LTalpha-deficient (LTalpha-/-) mice show altered splenic microarchitecture. This includes loss of normal B cell-T cell compartmentalization, of follicular dendritic cell (FDC) clusters, and of ability to form germinal centers (GC). LTalpha-/- mice immunized with sheep red blood cells (SRBC) produced high levels of antigen-specific IgM but no IgG in either primary or secondary responses, demonstrating failure of Ig class switching. This inability to switch to IgG could have been due to the altered splenic microarchitecture in these mice. Alternatively, it could have been due directly to a requirement for LTalpha expression by lymphocytes cooperating in the antibody response. To investigate this, we performed reciprocal spleen cell transfers. When irradiated LTalpha-/- mice were reconstituted with wild-type splenocytes and immunized immediately with SRBC, splenic microarchitecture remained disturbed and there was no IgG response. In contrast, when irradiated wild-type animals received splenocytes from LTalpha-/- mice, follicle structure and a strong IgG response were retained. These data indicate that LTalpha-deficient B cells and T cells have no intrinsic defect in ability to generate an IgG response. Rather, the altered microenvironment characteristic of LTalpha-/- mice appears to result in impaired ability to switch to a productive IgG response. To investigate whether prolonged expression of LTalpha could alter the structure and function of spleen follicles, reciprocal bone marrow (BM) transplantation was performed. Six weeks after reconstitution of LTalpha-/- mice with wild-type BM, spleen follicle structure was partially restored, with return of FDC clusters and GC. B cell/T cell compartmentalization remained abnormal and white pulp zones were small. This was accompanied by restoration of IgG response to SRBC. Reconstitution of wild-type mice with LTalpha-/- BM resulted in loss of FDC clusters and GC, and loss of the IgG response, although compartmentalized B cell and T cell zones were largely retained. Thus, defective IgG production is not absolutely associated with abnormal B cell and T cell compartmentalization. Rather, expression of LTalpha supports the maturation of spleen follicle structure, including the development and maintenance of FDC clusters, which supports Ig class switching and an effective IgG response.

Animals↗

PubMed1997

Independent signals regulate development of primary and secondary follicle structure in spleen and mesenteric lymph node.

Lymphotoxin-alpha-deficient (LT-alpha-/-) mice manifest congenital absence of lymph nodes (LNs) and Peyer's patches and disturbed spleen follicle structure. The splenic white pulp areas show loss of discrete T and B lymphocyte zones, of follicular dendritic cell (FDC) clusters, and of germinal centers (GCs). Tumor necrosis factor receptor I-deficient (TNFR-I-/-) mice show similar absence of FDC clusters and GCs but retain segregation of T and B cell zones. Rarely are mesenteric LNs found in LT-alpha-/- mice. These mesenteric LNs show segregation of T and B cell zones similar to wild-type mice. In contrast, mesenteric LNs in TNFR-I-/- mice manifest grossly disturbed organization of T and B cells. Both LT-alpha-/- and TNFR-I-/- mice lacked FDC clusters in LNs and spleen. Interestingly, although both LT-alpha-/- and TNFR-I-/- mice that had been immunized with sheep red blood cells failed to form GCs in the spleen, they both developed GC-like clusters of peanut agglutinin-positive (PNA+) cells in their LNs. Furthermore, when lethally irradiated recombination activating gene (RAG)-1-deficient (RAG-1(-/-)) mice that had received spleen cells from LT-alpha-/- mice were immunized with sheep red blood cells, they failed to generate PNA+ clusters in the reconstituted spleen but showed robust PNA+ clusters in the reconstituted LNs. These data demonstrate that the signals that regulate the development of distinct T and B cell zones as well as the signals that regulate B cell activation to produce clusters of PNA+ cells differ between the spleen and LNs.

Animals↗

PubMed1997

Enzymatic defenses of the rat heart against lipid peroxidation.

Normal ageing is associated with different changes in the cardiovascular system that lead to an increase in pathological processes such as hypertension and heart failure. Therefore the importance of glutathione peroxidase and catalase for protection against peroxidation was studied in the rat heart. Each of the these enzymes was regulated by feeding rats a low selenium diet either unsupplemented or supplemented with 0.4 parts per million of selenium, with or without the catalase inhibitor, sodium fluoride, in their drinking water. After 2 months, selenium deficient rats had 87% reductions in mitochondrial and cytosolic glutathione peroxidase activities. These reductions were accompanied by increased peroxidation in heart homogenates and mitochondrial suspensions. Since increased mitochondrial peroxidation only occurred when both the cytosolic and mitochondrial glutathione peroxidase activities were involved, these selenoenzymes appear to work in tandem and reductions in both are a prerequisite for increased peroxidation in the heart. Peroxidation did not occur in sodium fluoride treated rats even though cytosolic catalase activity was inhibited by 70%. Moreover, inhibition of catalase activity did not exacerbate the level of peroxidation in selenium deficient rats depleted of glutathione peroxidase activity. Because increased peroxidation was only associated with reductions in glutathione peroxidase activity irrespective of catalase activity, the selenoenzyme appears to be more important for detoxification of hydrogen peroxide in the heart.

Aging↗

PubMed1997

Lymphotoxin-alpha-deficient and TNF receptor-I-deficient mice define developmental and functional characteristics of germinal centers.

Mice deficient in LT alpha (LT alpha-/-) lack lymph nodes and Peyer's patches. This action of LT alpha in lymph node organogenesis appears to be mediated by the membrane form of LT using a mechanism independent of TNF receptor I (TNFR-I) or II (TNFR-II). In contrast, normal Peyer's patch development appears to require both LT alpha and TNFR-I, with TNFR-I-/- mice showing hypoplastic Peyer's patch structures. LT alpha-/- mice also fail to support the normal segregation of T-cell and B-cell zones within the splenic white pulp. Again, this occurs via a mechanism independent of TNFR-I or TNFR-II. Additionally, follicular dendritic cell (FDC) clusters or germinal centers fail to develop in the spleen of LT alpha-/- animals. Mice deficient in either TNF alpha or TNFR-I also fail to develop splenic FDC clusters and germinal centers, indicating that signaling by both LT alpha and TNF alpha is required for development of these specialized lymphoid tissue structures. Finally, the splenic white pulp areas in LT alpha-/- mice lack the marginal zone of monoclonal antibody MOMA-1-staining metallophilic macrophages, whereas TNFR-I-deficient mice have preserved MOMA-1 staining. Thus, certain actions of LT alpha to regulate spleen white pulp architecture are mediated by receptors other than TNFR-I, most likely by the LT beta R or a closely related receptor. We tested whether germinal centers are essential for maturation of T-cell-dependent antibody responses. When LT alpha-/- mice were immunized with low doses of NP-ovalbumin (NP-OVA) adsorbed to alum, there was dramatically impaired production of high affinity anti NP IgG; however, after immunization with high doses of NP-OVA adsorbed to alum, LT alpha-/- mice mounted a high affinity NP-specific serum IgG response similar to wild-type mice, all in the absence of germinal centers or clustered FDC. Thus, although germinal centers enhance the processes required for maturation of the humoral immune response, the mechanisms responsible for affinity maturation are not absolutely dependent on the presence of germinal centers.

Animals↗

PubMed1997

[Severe cardiac failure in Kearns-Sayre syndrome].

Mitochondrial disorders are a group of diseases that can affect virtually all organ systems. A 19 year old man was seen in 1993 with neurologic abnormalities consisting of impaired function of muscles, diplopia, progressive loss of vision, impaired phonation and swallowing, during the last 10 years. Physical examination disclosed moderate wasting of the four limb muscles, mild motor weakness of neck muscles, symmetrical hyporeflexia, cerebellar dysfunction, severe external ophtalmoplegia and ptosis. Fundii oculi examination showed retinitis pigmentosa. The electromyogram demonstrated myopathic changes with normal nerve conduction velocities. The cerebrospinal fluid was normal, except for a mild increase in lactic acid. Histochemical study of a muscle biopsy specimen demonstrated ragged red fibers and increase of the subsarcolemal oxidative activity of mitochondriae. The diagnosis of Kearns-Sayre disease was confirmed and he was discharged advising physical therapy. On February 1995, he was again admitted, this time with right cardiac failure and worsening of all his previous symptoms and signs. He complained of myalgias and his muscle weakness was more striking on clinical examination. Echocardiography showed biventricular dilatation and left ventricular hypertrophy with preserved systolic function. A new muscle biopsy revealed an heteroplasmic deletion of 5 Kb with 80% of mutant mitochondrial DNA. In brief, we report a patient with the clinical phenotype of Kearns-Sayre syndrome who presented an acute congestive cardiac failure due to cardiomyopathy, an association which has seldom been, reported in the literature.

Adult↗

PubMed1997

Lower motor neuron syndrome associated with anti-GM1 antibodies.

It has been recently recognized that increased titers of serum anti-GM1 antibodies may be associated with motoneurone diseases or with multiple motor neuropathy with or without conduction block and also with chronic sensorimotor neuropathy and Guillain-Barré syndrome. Santoro et al. were the first to note that anti-GM1 antibodies were able to bind to the nodes of Ranvier of the sural nerve of a patient with clinical signs and symptoms mostly resembling amyotrophic lateral sclerosis who also showed, in nerve conduction studies, multifocal motor nerve fibers conduction block and serum IGM anti-GM1 antibodies. The two patients presented in this report had asymetrical motor neurone disease with signs and symptoms of lower motoneurone involvement, and other signs, in the first patient, which suggested the existence of upper motoneurone damage. Besides, the second patient also had clinical sensory impairment in the lower limbs. Electrophysiologically, none of them had nerve conduction block but both showed inexcitable median and sural nerve sensory fibers. Both had high titers of anti-GM1. A sural biopsy of both patients showed immunoglobulins into the sensory fibers. However, we do not know whether the anti-GM1 antibodies bind to a cross-reactive glycolipid other than the GM1 itself. In any case, it seems that the presence of anti-GM1 antibodies might be a marker signalling a potentially treatable immune disorder which may have signs of lower and upper motor neurone disease and, also, clinical and electrophysiological evidences of peripheral sensory involvement.

Aged↗

PubMed1996

Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2.

Complement receptor 1 (CR1, CD35) and complement receptor 2 (CR2, CD21) have been implicated as regulators of B-cell activation. We explored the role of these receptors in the development of humoral immunity by generating CR1- and CR2-deficient mice using gene-targeting techniques. These mice have normal basal levels of IgM and of IgG isotypes. B- and T-cell development are overtly normal. Nevertheless, B-cell responses to low and high doses of a T-cell-dependent antigen are impaired with decreased titers of antigen-specific IgM and IgG isotypes. This defect is not complete because there is still partial activation of B lymphocytes during the primary immune response, with generation of splenic germinal centers and a detectable, although reduced, secondary antibody response. These data suggest that certain T-dependent antigens manifest an absolute dependence on complement receptors for the initiation of a normally robust immune response.

Animals↗

PubMed1995

Characterization of a complement receptor 2 (CR2, CD21) ligand binding site for C3. An initial model of ligand interaction with two linked short consensus repeat modules.

Human CR2 (CD21, EBV receptor) is an approximately 145-kDa receptor and a member of the regulators of complement activation gene family. Regulators of complement activation proteins are characterized by the presence of repeating motifs of 60 to 70 amino acids that are designated short consensus repeats (SCR). CR2 serves as a receptor for four distinct ligands. Three of these ligands (complement C3, gp350/220 of EBV, and CD23) interact with the amino terminal 2 of 16 SCR (SCR 1 and 2). Previous studies have determined that at least four sites are important in allowing CR2 to efficiently bind EBV. Two of these sites are also important for binding mAb OKB7, a reagent that blocks both EBV and iC3b/C3dg binding to CR2. We have identified and characterized important sites of iC3b ligand binding by utilizing human-mouse CR2 chimeras, a rat anti-mouse CR2 mAb designated 4E3 that blocks receptor binding to C3, and human CR2-derived peptides. In addition to demonstrating an important role for the same sequence in SCR 1 that is part of the mAb OKB7 and EBV binding site, we have identified a new region within SCR 2 that interacts with C3. These results, when compared with a model of a dual SCR solution structure derived from human factor H SCR, predict that two distinct largely surface-exposed sites on CR2 interact with iC3b. A relative twist of 130 degrees about the long axis of the second SCR in this model would be necessary for these sites to form a single patch for iC3b binding on CR2.

Amino Acid Sequence↗

PubMed1995

Mouse complement regulatory protein Crry/p65 uses the specific mechanisms of both human decay-accelerating factor and membrane cofactor protein.

Normal host cells are protected from the destructive action of complement by cell surface complement regulatory proteins. In humans, decay-accelerating factor (DAF) and membrane cofactor protein (MCP) play such a biologic role by inhibiting C3 and C5 convertases. DAF and MCP accomplish this task by specific mechanisms designated decay-accelerating activity and factor I cofactor activity, respectively. In other species, including mice, structural and/or functional homologues of these proteins are not yet well characterized. Previous studies have shown that the mouse protein Crry/p65 has certain characteristics of self-protecting complement regulatory proteins. For example, Crry/p65 is expressed on a wide variety of murine cells, and when expressed on human K562 erythroleukemic cells, it prevents deposition of mouse C3 fragments on the cell surface during activation of either the classical or alternative complement pathway. We have now studied factor I cofactor and decay-accelerating activities of Crry/p65. Recombinant Crry/p65 demonstrates cofactor activity for factor I-mediated cleavage of both mouse C3b and C4b. Surprisingly, Crry/p65 also exhibits decay-accelerating activity for the classical pathway C3 convertase strongly and for the alternative pathway C3 convertase weakly. Therefore, mouse Crry/p65 uses the specific mechanisms of both human MCP and DAF. Although Crry/p65, like MCP and DAF, contains tandem short consensus repeats (SCR) characteristic of C3/C4 binding proteins, Crry/p65 is not considered to be a genetic homologue of either MCP or DAF. Thus, Crry/p65 is an example of evolutionary conservation of two specific activities in a single unique protein in one species that are dispersed to individual proteins in another. We propose that the repeating SCR motif in this family has allowed this unusual process of evolution to occur, perhaps driven by the use of MCP and DAF as receptors by human pathogens such as the measles virus.

Animals↗

PubMed1995

Familial dwarfism and painful muscle spasms.

We report a family with a disorder characterized by limbs and truncal undulating painful muscle spasms, short stature, fine and sparse hair in the scalp, absence of body hair, low implanted ears, big nose, pitched voice, enlarged heart ventricles and increased fasting glucose levels. Symptoms began in childhood and did not progress after the third decade of life. This disorder represents a new clinical phenotype among the several forms of dwarfism associated with neurological manifestations already described in the literature.

Adult↗

PubMed1995

CLECOS_P: clinical evolution control system on Parkinsonian patients undergoing neural transplantation.

The CLECOS_P system was conceived for registering and automating the processing of clinical evaluations performed on patients with Parkinson's disease who undergo functional neurosurgery and/or neural transplant. CLECOS_P represents the first time a computerized system is able to offer--with high precision and considerable time-savings--an integral analysis of the evolutive behavior of the universe in integrated variables at the core assessment program for intracerebral transplantations (CAPIT). CAPIT is used internationally for the evaluation and follow-up of patients with this pathology who have undergone neural transplant. We used the so-called MEDSAC methodology for the preparation of this system. The methodology that was used for the design of an intelligent system aimed at medical decision-making was based on the quantitative analysis of the clinical evolution. At the present moment, there are 20 patients controlled by this system: 11 bilaterally transplanted, 9 unilaterally (registered in ranks of 3 months before operation up to 1, 2, 3, 6, 9, 12, 18, and 24 months after operation). The application of CLECOS_P to these patients permitted the evaluation of 400 clinical variables, where a better evolutive characterization of the patients was obtained, thus getting most favorable results with personalized therapeutic methods aimed at raising their quality of life. CLECOS_P is used in a multi-user environment on a local area network running Novell Netware version 3.11.

Brain Tissue Transplantation↗

PubMed1994

Analysis of C3b/C3d binding sites and factor I cofactor regions within mouse complement receptors 1 and 2.

Human and murine CR1 and CR2 are defined as evolutionary homologues on the basis of their in vitro activities and a shared structural motif known as a short consensus repeat (SCR). To identify additional similarities between the two species, we analyzed the functional domains within the mouse receptors by constructing mouse-human chimeric cDNAs in which the C3 binding site of human CR2 has been replaced by different regions within the first eight SCRs of mouse CR1. Rosette analysis of cells expressing chimeric proteins, with erythrocytes bearing different mouse C3 fragments, coupled with rosette inhibition studies using specific anti-mouse CR1/CR2 mAbs reveal a weak C3b binding site within SCRs 1 and 2 of mouse CR1. There is no independent C3b interacting domain within SCRs 3 to 6, but their presence enhances C3 binding. A molecule that contains only the first six SCRs of mouse CR1 also binds C3b, but with less efficiency. There is no C3d binding area within the first six SCRs, but our data confirms previous studies indicating an additional C3b/C3d binding region within SCRs 7 and 8 of mouse CR1 (SCRs 1-2 of mouse CR2). The presence of SCRs 1 to 4 is required for C3 cofactor activity. 8C12, a mAb which blocks C3b erythrocyte rosette binding and the C3 cofactor activity of mouse CR1, binds only to chimeras containing SCRs 3 to 4.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Stereotactic retransplantation in Parkinson's disease: clinical, imaging and electrophysiological evidence of adrenal brain graft viability.

In March 1993, a patient with idiopathic Parkinson disease who had received an adrenal brain autograft 6 years before underwent bilateral stereotactic transplantation of a mesencephalic cell suspension into the striatum, in order to prevent further deterioration in his neurological condition. During the CT-guided surgical planning and the transplantation procedures, electrophysiological evidence of the adrenal graft viability was assessed. Based on these findings, we drew the preliminary conclusion that the chromaffin tissue implanted in April 1987 is still functional, which explains the clinical evolution of this patient during the postoperative long-term follow-up.

Adrenal Medulla↗