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Biomedical subjects

M Ma

Publications and source records attributed to M Ma.

At least 19 recordsLinked to original sources
PubMed1997

Increased susceptibility to endotoxin shock in complement C3- and C4-deficient mice is corrected by C1 inhibitor replacement.

Endotoxin shock is a life-threatening syndrome associated with a Gram-negative infection and mediated by a systemic inflammatory response. As a major effector of inflammation, the complement system has been implicated in both the pathogenesis and the protection from endotoxin shock. To clarify the role of complement in endotoxin shock, we have used mice totally deficient in either complement component C3 or C4. We found that both the C3- and C4-deficient mice were significantly more sensitive to endotoxin than wild-type controls. The endotoxin-challenged complement-deficient mice failed to clear endotoxin efficiently from the circulation and this led to excess consumption of C1 inhibitor protein (C1 INH), a major regulator of both complement and the contact system of blood coagulation. Replacement of C1 INH rescued the endotoxin-challenged complement-deficient mice from shock and death. These findings suggest a novel therapy for treatment of endotoxemia with C1 INH protein.

Animals↗
PubMed1997

Breast cancer management: is volume related to quality? Clinical Advisory Panel.

A method of carrying out region-wide audit for breast cancer was developed by collaboration between the cancer registry, providers and purchasers as part of work to fulfill the 'Calman-Hine' recommendations. In order to test the audit method, a retrospective audit in North Thames East compared practice in 1992 against current guidelines. The analysis compared care in specialist and non-specialist centres. A stratified random sample comprising 28% of all breast cancer patients diagnosed in 1992 was selected from the population-based Thames Cancer Registry. The data for 309 patients with stage I-III tumours were analysed by hospital type using local guidelines. No difference between specialist (high volume) and non-specialist centres was detected for factors important in survival. Pathological staging was good with over 70% reporting tumour size and grade. A small number of patients were undertreated; after conservative surgery, 10% (19) of women did not receive radiotherapy, and 15% (8) of node-positive premenopausal women did not receive chemotherapy or ovarian ablation. In contrast, a significant trend with hospital volume was found for several quality of life factors. These included access to a specialist breast surgeon and specialist breast nurses, availability of fine-needle aspiration (FNA), which ranged from 84% in high-volume to 42% in low-volume centres, and quality of surgery (axillary clearance rates ranged from 51% to 8% and sampling of less than three nodes from 3% to 25% for high- and very low-volume centres respectively). Confidential feedback of results to surgeons was welcomed and initiated change. The summary information gave purchasers information relevant to the evaluation of cancer services. While the audit applied present standards to past practice, it provided the impetus for prospective audit of current practice (now being implemented in North Thames).

Breast Neoplasms↗
PubMed1997

Molecular determinants for cellular uptake of Tat protein of human immunodeficiency virus type 1 in brain cells.

We measured the cellular uptake of 125I-labeled full-length Tat (amino acids 1 to 86) (125I-Tat(1-86)) and 125I-Tat(1-72) (first exon) in human fetal astrocytes, neuroblastoma cells, and human fetal neurons and demonstrated that the uptake of 125I-Tat(1-72) without the second exon was much lower than that of 125I-Tat(1-86) (P < 0.01). This suggests an important role for the C-terminal region of Tat for its cellular uptake. 125I-Tat uptake could be inhibited by dextran sulfate and competitively inhibited by unlabeled Tat but not by overlapping 15-mer peptides, suggesting that Tat internalization is charge and conformationally dependent. Interestingly, one of 15-mer peptides, Tat(28-42), greatly enhanced 125I-Tat uptake. These findings are important for understanding the neuropathogenesis of human immunodeficiency virus type 1 infection and in the potential application of Tat for drug delivery to cells.

Amino Acid Sequence↗
PubMed1997

Commonly prescribed salt intake in continuous ambulatory peritoneal dialysis patients is too restrictive: results of a double-blind crossover study.

Salt restriction in continuous ambulatory peritoneal dialysis (CAPD) patients is widely prescribed and thereby may reduce quality of life. It is presumed that this has a beneficial effect on BP and reduces the need for hypertonic dialysate. However, this has never been formally evaluated. A double-blind crossover study of placebo versus sodium chloride pills (60 mEq of sodium per day) is presented in 20 stable CAPD patients, 10 of whom were hypertensive. Dietary sodium was quantified throughout the study by 3-d dietary histories and remained unaltered throughout. There was a clinically unimportant but statistically significant rise in BP with added salt: 135/77 to 144/82 (P < 0.05). No rise in BP occurred in the hypertensive patients. Weights, use of hypertonic dialysate, and BP medications remained unaltered throughout the study. In conclusion, 200 mEq of sodium per day, i.e., a normal sodium intake, is easily tolerated in stable CAPD patients, and the recommended sodium intake commonly prescribed is too restrictive.

Aged↗
PubMed1997

Human immunodeficiency virus type 1 Tat protein induces death by apoptosis in primary human neuron cultures.

Neuronal loss in HIV encephalopathy remains a mystery since HIV-1 productively infects macrophage and microglia and only rarely infects neurons in the central nervous system. Apoptosis is a mechanism which may account for the loss of neurons in HIV-1 infected brain. Putative toxic factors that result in neuronal cell death in HIV-1 infection include the regulatory protein Tat, since this protein is known to be released from HIV-1 infected cells. Here we show that Tat induces cell death by apoptosis in cultured human fetal neurons producing characteristic morphological and biochemical features associated with apoptosis. These findings suggest that Tat may play an important role as a secreted, soluble neurotoxin in HIV-1 associated dementia.

Apoptosis↗
PubMed1996

Immunoglobulin G-mediated inflammatory responses develop normally in complement-deficient mice.

The role of complement in immunoglobulin G-triggered inflammation was studied in mice genetically deficient in complement components C3 and C4. Using the reverse passive Arthus reaction and experimental models of immune hemolytic anemia and immune thrombocytopenia, we show that these mice have types II and III inflammatory responses that are indistinguishable from those of wild-type animals. Complement-deficient and wild-type animals exhibit comparable levels of erythrophagocytosis and platelet clearance in response to cytotoxic anti-red blood cell and antiplatelet antibodies. Furthermore, in the reverse passive Arthus reaction, soluble immune complexes induce equivalent levels of hemmorhage, edema, and neutrophillic infiltration in complement-deficient and wild-type animals. In contrast, mice that are genetically deficient in the expression of Fc receptors exhibit grossly diminished reactions by both cytotoxic antibodies and soluble immune complexes. These studies provide strong evidence that the activation of cell-based Fc gamma R receptors, but not complement, are required for antibody-triggered murine inflammatory responses.

Anemia, Hemolytic↗
PubMed1996

Regulation of the B cell response to T-dependent antigens by classical pathway complement.

Mice deficient in complement components C3 (C3 -/-) and C4 (C4 -/-) were found to have a profound defect in their Ab response to a T-dependent Ag (bacteriophage (phi X174). Characterization of the deficient mice demonstrated a diminished level of peanut agglutinin+ germinal centers and a failure in isotype switching despite normal B cell signaling in vitro. The nature of the defect was found to lie at the B cell level, as the T cells were primed in C3- and C4-deficient mice as well as those in wild-type mice. These results, and the finding that the defect could be partly reversed by a 10-fold increase in Ag dose, support the hypothesis that covalent attachment of complement ligands, i.e., C3b and C3d to the Ag-Ab complex, increases its immunogenicity.

Animals↗
PubMed1996

The role of K+ currents in frequency-dependent spike broadening in Aplysia R20 neurons: a dynamic-clamp analysis.

The R20 neurons of Aplysia exhibit frequency-dependent spike broadening. Previously, we had used two-electrode voltage clamp to examine the mechanisms of this spike broadening (Ma and Koester, 1995). We identified three K+ currents that mediate action-potential repolarization: a transient A-type K+ current (I(Adepol)), a delayed rectifier current (IK-V), and a Ca(2+)-sensitive K+ current(IK-CA). A major constraint in that study was the lack of completely selective blockers for I(Adepol) and I(K-V), resulting in an inability to assess directly the effects of their activation and inactivation on spike broadening. In the present study, the dynamic-clamp technique, which employs computer simulation to inject biologically realistic currents into a cell under current-clamp conditions (Sharp et al., 1993a,b), was used either to block I(Adepol) or I(K-V) or to modify their inactivation properties. The data in this paper, together with earlier results, lead to the following hypothesis for the mechanism of spike broadening in the R20 cells. As the spike train progresses, the primary responsibility for spike repolarization gradually shifts from I(Adepol) to I(K-V) to I(K-Ca). This sequence can be explained on the basis of the relative rates of activation and inactivation of each current with respect to the constantly changing spike durations, the cumulative inactivation of I(Adepol) and I(K-V), and the progressive potentiation of I(K-Ca). Positive feedback interactions between spike broadening and inactivation contribute to the cumulative inactivation of both I(Adepol) and I(K-V). The data also illustrate that when two or more currents have similar driving forces and partially overlapping activation characteristics, selectively blocking one current under current-clamp conditions can lead to a significant underestimate of its normal physiological importance.

Action Potentials↗
PubMed1996

Reperfusion injury of ischemic skeletal muscle is mediated by natural antibody and complement.

Reperfusion of ischemic tissue induces an acute inflammatory response that can result in necrosis and irreversible cell injury to both local vascular endothelium and parenchyma. To examine the pathogenesis of ischemia/reperfusion injury, we have used mice deficient in complement components C3, C4, or serum immunoglobulin in a hindlimb model of ischemia. We found that mice homozygous deficient in C3 or C4 were equally protected against reperfusion injury based on a significant reduction in leakage of radiolabeled albumin out of the vasculature. This demonstrates that classical pathway complement is an important factor in the initiation of inflammation following reperfusion. Furthermore, mice deficient in serum immunoglobulin were equally protected and this protection could be reversed by reconstitution with serum from normal mice. Thus, this report describes a novel mechanism for reperfusion injury that involves antibody deposition and activation of complement leading to inflammation permeability.

Animals↗
PubMed1996

Antibody response to a T-dependent antigen requires B cell expression of complement receptors.

Several lines of evidence indicate that antibody responses to T-dependent antigens require complement receptors expressed on either B lymphocytes or follicular dendritic cells. We have used RAG-2 deficient blastocyst complementation to create mice specifically lacking B cell complement receptors. Despite normal expression of complement receptor 1 (CR1[CD35]) and CR2 (CD21) on follicular dendritic cells, these mice have a profound defect in their capacity to mount a T-dependent antibody response. This is the first direct demonstration in vivo that B cell expression of complement receptors is required for a humoral immune response. This is the first direct demonstration in vivo that B cell expression of complement receptors is required for a humoral immune response. This suggests that CD21 and/or CD35 on B lymphocytes may be required for cellular activation, adsorptive endocytosis of antigen, recruitment to germinal centers, and/or protection from apoptosis during the humoral response to T-dependent antigens.

Animals↗
PubMed1996

Micronuclei induced in round spermatids of mice after stem-cell treatment with chloral hydrate: evaluations with centromeric DNA probes and kinetochore antibodies.

The chromosomal effects of chloral hydrate (CH) on germ cells of male mice were investigated using two methods to detect and characterize spermatid micronuclei (SMN); (a) anti-kinetochore immunofluorescence (SMN-CREST) and (b) multicolor fluorescence in situ hybridization with DNA probes for centromeric DNA and repetitive sequences on chromosome X (SMN-FISH). B6C3F1 mice received single intraperitoneal (i.p.) injections of 82.7, 165.4, or 413.5 mg/kg and round spermatids were sampled at three time intervals representing cells treated in late meiosis, early meiosis, or as spermatogonial stem cells. No increases in the frequencies of SMN were detected for cells treated during meiosis using either SMN-CREST or SMN-FISH methods. After spermatogonial stem-cell treatment, however, elevated frequencies of SMN were detected by both methods. With SMN-FISH, dose trends were observed both in the frequencies of spermatids containing micronuclei and in the frequency of spermatids carrying centromeric label. These findings corroborate the recent report by Allen and colleagues [Allen JW et al.(1994): Mutat. Res. 323:81-88] that CH treatment of spermatogenic stem cells induced SMN. Furthermore, our findings suggest that chromosomal malsegregation or loss may occur in spermatids long after CH treatment of stem cells. Further studies are needed to understand the mechanism of action of the CH effect on stem cells and to determine whether similar effects are induced in human males treated with CH.

Anesthetics, Intravenous↗
PubMed1996

Immunolocalization of the oostatic and prothoracicostatic peptide, Neb-TMOF, in adults of the fleshfly, Neobellieria bullata.

The hexapeptide Neb-TMOF (H-NPTNLH-OH, trypsin modulating oostatic factor of the gray fleshfly, Neobellieria bullata)2 occurs in vitellogenic ovaries and is involved in negative feedback regulation of trypsin biosynthesis in the gut of late vitellogenic females. Polyclonal antisera were raised against the synthetic peptide and were used to identify and immunolocalize Neb-TMOF epitopes in different fleshfly tissues. Neb-TMOF-immunoreactive material first appears in the cortical layer of young vitellogenic oocytes and later spreads over the yolk granules. This suggests a pinocytosis with the three yolk polypeptides (vitellogenins). Controls treated with the preimmune sera or with anti-Neb-TMOF antiserum preadsorbed to Neb-TMOF peptide coupled to a solid phase support did not stain. There was no immunostaining in the central nervous system (brain and ventral nerve cord), the retrocerebral complex, the fat body, or the testes. Western blot analysis showed that the anti-Neb-TMOF antisera specifically recognize a putative hormone precursor polypeptide (Mr 75 kDa) from vitellogenic ovaries. This protein is virtually absent from the hemolymph. It is not immunologically related to the three yolk polypeptides, since it is not recognized by yolk polypeptides antisera. In adult females the ovary appears to be the only site of synthesis of Neb-TMOF and of its precursor. Immunopositive staining is found in the apical areas of ovarian follicle cells, suggesting these cells as a site of hormone precursor biosynthesis. This is the first demonstration that a protein colocalized with yolk proteins might act as a precursor for a folliculostatic hormone.

Animals↗
PubMed1996

Disruption of the Cr2 locus results in a reduction in B-1a cells and in an impaired B cell response to T-dependent antigen.

Covalent attachment of activated products of the third component of complement to antigen enhances its immunogenicity, but the mechanism is not clear. This effect is mediated by specific receptors, mCR1 (CD35) and mCR2 (CD21), expressed primarily on B cells and follicular dendritic cells in mice. To dissect the role of mCR1 and mCR2 in the humoral response, we have disrupted the Cr2 locus to generate mice deficient in both receptors. The deficient mice (Cr2-/-) were found to have a reduction in the CD5+ population of peritoneal B-1 cells, although their serum IgM levels were within the range of normal mice. Moreover, Cr2-/- mice had a severe defect in their humoral response to T-dependent antigens that was characterized by a reduction in serum antibody titers and in the number and size of germinal centers within splenic follicles. Reconstitution of the deficient mice with bone marrow from MHC-matched Cr2+/+ donors corrected the defect, demonstrating that the defect was due to B cells themselves. These results indicate an obligatory role of B cell complement receptors in responses of the B cells to protein antigens.

Animals↗
PubMed1996

Enhanced vasocontraction of rat tail arteries by toxoflavin.

1. It has been suggested that the toxic effect of toxoflavin (TXF) produced by Pseudomonas cocovenenas is mainly due to the impairment of electron transfer of the mitochondrial respiratory chain. However, the cardiovascular effect of TXF is unknown. In the present study, the effect of TXF on the isometric contraction of rat isolated tail artery strips and the underlying mechanisms were investigated. 2. The basal force of the tissues was not affected by the toxin. However, the application of TXF before or during KCl (60 mM) stimulation potentiated KCl-induced vasocontraction, specifically the tonic phase of the contraction. 3. When the vessel strips were precontracted with phenylephrine (Phe), TXF further enhanced the tonic contraction of the tissue. Pretreatment of tissues with TXF also potentiated subsequent vasocontraction induced by Phe. The vasocontractor effects of TXF and Phe, however, were not additive. 4. The vascular effect of TXF was not mediated by oxygen-derived free radicals since catalase and SOD did not affect TXF-enhanced vasocontraction. In contrast, the vasocontractor effect of TXF was dependent on extracellular Ca2+ and abolished by nifedipine (a Ca2+ antagonist). TXF also had no effect on caffeine- or U46619-induced vasocontraction. 5. It is suggested that TXF may potentially contract blood vessels via its effect on Ca2+ channels. This effect of TXF depends on the contractile status of the vascular tissues.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1996

Extracellular human immunodeficiency virus type 1 Tat protein is associated with an increase in both NF-kappa B binding and protein kinase C activity in primary human astrocytes.

Human immunodeficiency virus type 1 (HIV-1) infection has been associated with an increase in the binding of the transcription factor NF-kappa B to its consensus sequence in the viral promoter. Using cultures of primary human fetal astrocytes, we show that exogenous HIV-1 Tat protein, which has been demonstrated to be released from infected cells, is associated with an increase in the binding of this transcription factor to an HIV-1 long terminal repeat kappa B sequence. This effect occurs rapidly and is independent of new protein synthesis. We also demonstrate that extracellular Tat protein is associated with an increase in protein kinase C activity. If Tat functions similarly in other cell types, such findings could relate to some of this protein's previously described physiological effects. These effects include Tat's ability to upregulate the synthesis of specific cytokines and to act as a growth factor.

Antibodies, Viral↗
PubMed1996

Fat pharms.

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Animals↗
PubMed1996

Validation of multiplex polymorphic STR amplification sets developed for personal identification applications.

Polymorphic short tandem repeat (STR) loci, which typically consist of variations in the number of 3-7 base pair repeats present at a site, provide an effective means of personal identification. Typing can be accomplished by amplification of genomic DNA using the polymerase chain reaction (PCR) and locus-specific primers, separation of amplified alleles using gel electrophoresis and their display using silver staining or fluorescent detection. Primers for several STR loci can be combined in a single multiplex reaction so typing of multiple loci can be accomplished rapidly and with less DNA than required if each locus were analyzed separately. Before such muliplex systems are used in forensic or paternity applications, it is desirable that they undergo testing for their reliability. This study evaluates the performance of two STR triplex systems, one containing the loci HUMCSF1PO, HUMTPOX, and HUMTH01, and the other containing HUMHPRTB, HUMFESFPS, and HUMVWFA31. Protocols for amplification of these two triplexes, and their corresponding monoplexes, were evaluated for sensitivity of detection, resistance to changes in the annealing temperature of the amplification protocol, and the ability to identify the minority contributor in amplification of mixed samples. In addition, five laboratories determined the alleles of twenty DNA samples, each extracted by one of four different extraction methods. The results illustrate that the two STR triplex systems and the monoplex systems contained within them can be used with as little as 0.25 ng of DNA template. Both triplexes amplified with 100% success using the Perkin Elmer Model 480 thermal cycler. With the GeneAmp 9600 System, the CTT triplex amplified with 100% success and the HFv triplex in 95.6% of attempts. These experiments meet many requirements for use in validation of DNA typing systems for forensic cases and paternity identification.

Anthropology, Physical↗