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Biomedical subjects

T Brenner

Publications and source records attributed to T Brenner.

At least 19 recordsLinked to original sources
PubMed2006

Fully integrated whole blood testing by real-time absorption measurement on a centrifugal platform.

We present a novel microfluidic concept to enable a fast colorimetric alcohol assay from a single droplet of whole blood. The reduced turn-around time of 150 seconds is, on the one hand, achieved by a full process integration including metering, mixing with reagents, and sedimentation of cellular constituents. On the other hand, our novel total internal reflection (TIR) scheme allows to monitor the increase of the absorbance values in real-time. Thus, the saturation values can be predicted accurately based on an extrapolation of real-time measurements acquired during a 100 second initial period of rotation. Additionally, we present a metering structure to define nanolitre sample volumes at a coefficient of variation (CV) below 5%.

Blood Chemical Analysis↗
PubMed2003

Antibodies to glatiramer acetate do not interfere with its biological functions and therapeutic efficacy.

Glatiramer acetate (GA) previously known as Copolymer 1 (Cop 1), a synthetic amino acid copolymer, suppresses experimental autoimmune encephalomyelitis (EAE) and shows a beneficial effect in relapsing-remitting type of multiple sclerosis (MS). GA acts as a specific immunomodulator by binding to MHC Class II molecules, inducing specific T suppressor (Ts) cells and interfering with T cell responses to myelin antigens. MS patients treated with GA developed GA reactive antibodies, which peaked at three months and decreased at six months. In order to find out whether anti-GA antibodies may neutralize the therapeutic effect of GA, we tested both polyclonal (mouse and human) and monoclonal GA specific antibodies for their ability to interfere with the biological activity of GA in several assay systems. None of the antibodies interfered with GA activities either in vitro (binding to MHC molecules and T cell stimulation) or in vivo (blocking of EAE). Furthermore, 53 samples of sera obtained from 34 MS patients that participated in the open label trial in Israel, and all developed GA specific antibodies, were tested for their ability to inhibit the proliferation response of GA specific Ts cell clone and to interfere with GA competitive inhibition of the response to peptide 84-102 of myelin basic protein (MBP). None of the sera inhibited and some even enhanced the in vitro activities of GA. Furthermore, representative MS sera with high titer of GA reactive antibodies did not neutralize the biological activities of GA and did not inhibit Th2 cytokine secretion by human GA specific clone. These results are consistent with the findings that the therapeutic effect of GA is not affected by GA reactive antibodies and is sustained upon long term treatment.

Animals↗
PubMed2001

Choline deficiency induced by Mycoplasma fermentans enhances apoptosis of rat astrocytes.

A choline uptake system accumulating free choline in an energy-dependent process is described in Mycoplasma fermentans. The uptake system has a K(m) of 2.2x10(-5) M and a V(max) of 0.15 nmol 10 min(-1) mg(-1) cell protein and the choline incorporated could be recovered in the soluble fraction as free choline, phosphorylcholine and CDP-choline. Choline accumulation by M. fermentans resulted in a marked choline depletion of the growth medium. The choline depletion of an astrocyte cell culture induced by M. fermentans was associated with the apoptotic death of the cells. Apoptosis was not obtained with heat-inactivated mycoplasmas and could be reversed by the addition of free choline to the growth medium.

Animals↗
PubMed2001

Humoral and cellular immune responses to Copolymer 1 in multiple sclerosis patients treated with Copaxone.

Humoral and cellular immune responses were followed in multiple sclerosis patients treated with Copolymer 1 (Cop1, glatiramer acetate, Copaxone) who participated in three different clinical trials. All patients (130) developed Cop1 reactive antibodies, which peaked at 3 months after initiation of treatment, decreasing at 6 months and remaining low. IgG1 antibody levels were 2-3-fold higher than those of IgG2. The proliferative response of Peripheral Blood Mononuclear Cells (PBMC) to Cop1 was initially high and gradually decreased during treatment. Antibodies and T cell responses to MBP were low and did not change significantly during the treatment. The humoral and cellular immunological responses to Cop1 do not correlate with the side effects and do not affect its therapeutic activity. The preferential production of IgG1 over IgG2 antibodies may indicate that Th2 responses are involved in mediating the clinical effect of Cop1.

Adult↗
PubMed2000

Gabapentin may be hazardous in myasthenia gravis.

A patient with painful neuropathy developed ocular, facial, and masticatory weakness and fatigue after 3 months of gabapentin (GBP) treatment (400 mg/day). An elevated level of serum acetylcholine receptor antibodies (AChR-Ab) was detected. The patient recovered following pyridostigmine therapy and withdrawal of GBP and, 2 years later, is practically asymptomatic despite positive AChR-Ab. Because of this clinical observation, we gave 150 mg/kg GBP to rats with experimental autoimmune myasthenia gravis (EAMG). Repetitive nerve stimulation at 3-Hz was performed, and the 5th/1st amplitude ratio was used to calculate the decremental response. In all EAMG rats, GBP induced a transient, abnormal decrement (7-20%) 90 to 240 min after administration. No decrement was induced by GBP in normal rats. Thus, GBP aggravates the decrement in EAMG. The mechanism involved in the hitherto unreported possible unmasking of myasthenia gravis (MG) by GBP is unknown. Gabapentin should be used with caution in this disease.

Acetates↗
PubMed2000

Inhibitory effect of carbamazepine on inflammatory mediators produced by stimulated glial cells.

Exposure of rat glial cells to lipopolysaccharide (LPS) induces the production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)), the inflammatory mediators implicated in the pathogenesis of seizures and epilepsy. To determine the effect of the anticonvulsant drug carbamazepine (CBZ) on the inflammatory process, LPS-stimulated rat primary glial cultures were exposed to this agent. Dose-dependent inhibition of NO and PGE(2) production was observed of up to 77 and 88%, respectively. Furthermore, a prominent (94%) decline in the secretory isoform of phospholipase A(2) (sPLA(2)) activity was found in response to CBZ and could contribute to the inhibition of PGE(2) production. Cumulatively, our findings point to the anti-inflammatory effect of CBZ on non-neuronal cells, which might, in part, contribute to its anticonvulsive effect.

Animals↗
PubMed2000

Effects of sex hormones on experimental autoimmune myasthenia gravis.

To examine whether exacerbation of myasthenia gravis (MG) can be induced by changes in sex hormone levels we immunized 20 female Lewis rats with torpedo antigen to induce experimental autoimmune MG (EAMG). Ten of the animals underwent surgical ovariectomy prior to the induction of EAMG and 10 served as controls. Anti-acetylcholine receptor antibody (AChR-ab) titres and the degree of decrement on repetitive stimulation electromyography (REMG) at 3 Hz were obtained at base line and compared between rats with and without ovariectomy and a second control group of naïve rats. Three rats in each group were then injected with excess oestrogen and progesterone for one week, and three of the remaining rats in each group were given sham injections, and the degree of decrement on REMG and AchR-ab titres were re-evaluated. Immune reactivity of peripheral lymphocytes and splenic lymphocytes from all groups and controls was also determined. A comparable number of animals with and without ovariectomy developed clinical and electromyographic EAMG. The extent of decrement on REMG and AChR-ab titres did not change following hormonal replacement. Lymphocyte reactivity was similar for rats with and without ovariectomy. In conclusion, sex hormones do not appear to have an influence on the susceptibility to and the severity of MG.

Animals↗
PubMed1999

A novel antigen-toxin chimeric protein: myelin basic protein-pseudomonas exotoxin (MBP-PE 40) for treatment of experimental autoimmune encephalomyelitis.

Myelin basic protein (MBP), is a major component of the central nervous system (CNS) myelin. MBP can stimulate T cells that migrate into the CNS, initiating a cascade of events that result in perivascular infiltration and demyelination. EAE is an inflammatory and demyelinating autoimmune disease of the CNS that serves as a model for the human disease Multiple Sclerosis (MS). Taking advantage of the fact that EAE can be mediated by T cells, able to recognize MBP or its peptides, we developed a new approach to target anti-MBP T cells by fusing an MBP-sequence to a toxin. In the new chimeric protein, an oligonucleotide coding for the guinea pig MBP encephalitogenic moiety (residues 68-88) was fused to a cDNA encoding a truncated form of the PE gene (PE40). The chimeric gene termed MBP-PE was expressed in E. coli and highly purified. MBP-PE chimeric protein was cytotoxic to various anti-MBP T cells. Moreover, treatment with the novel MBP-toxin blocked the clinical signs of EAE as well as CNS inflammation and demyelination. A chimeric protein such as MBP-PE40 presents a novel prototype of chimeric proteins, composed of antigen/peptide-toxin, that could prove to be an efficient and specific immunotherapeutic agent for autoimmune diseases in which a known antigen is involved.

ADP Ribose Transferases↗
PubMed1999

Dehydroepiandrosterone selectively inhibits production of tumor necrosis factor alpha and interleukin-6 [correction of interlukin-6] in astrocytes.

Dehydroepiandrosterone (DHEA) is a native neurosteroid with immunomodulating activity. DHEA effectively protects animals from several viral, bacterial and parasitic infections and it was suggested that its age-associated decline is related with immunosenescence. In the present study we examined the ability of DHEA to inhibit the production of inflammatory mediators by mycoplasma-stimulated glial cells and to change the course of acute central nervous system (CNS) inflammatory disease in vivo. Addition of DHEA (10 microg/ml) markedly inhibited tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production (98 and 95%, respectively), whereas nitric oxide (NO) and prostaglandin E2 (PGE2) production was not affected. However, daily administration of 0.5 mg DHEA to mice or 5 mg to rats did not change the clinical outcome of experimental autoimmune encephalomyelitis (EAE).

Adjuvants, Immunologic↗
PubMed1999

Mycoplasma fermentans-induced inflammatory response of astrocytes: selective modulation by aminoguanidine, thalidomide, pentoxifylline and IL-10.

Exposure of primary rat glial cells, mostly astrocytes, to heat-inactivated Mycoplasma fermentans triggers the production of tumor necrosis factor alpha (TNFalpha) nitric oxide (NO) and prostaglandin E2 (PGE2). To attenuate the production of these proinflammatory mediators, four agents: aminoguanidine, pentoxifylline, thalidomide and IL-10 were added to astrocyte cultures. Aminoguanidine (1 and 3 mM), an inhibitor of inducible nitric oxide synthase (iNOS), suppressed the production of the three mediators. TNFalpha was the most sensitive to thalidomide, showing dose-response inhibition at concentrations of 20 microg/ml, 50 microg/ml and 250 microg/ml. PGE2 was affected only by concentrations of 50 microg/ml and 250 microg/ml, whereas NO responded solely to the highest amount of this inhibitor. The cytokine IL-10, at 10 U and 50 U, inhibited only TNFalpha production. Our results imply that selective suppression of proinflammatory mediators by various agents may prove feasible for amelioration of central nervous system inflammatory diseases.

Animals↗
PubMed1999

Lack of vancomycin-associated nephrotoxicity in newborn infants: a case-control study.

OBJECTIVE: The purpose of this study was to compare the incidence of nephrotoxicity, defined as doubling of baseline serum creatinine concentration, in newborn infants with peak vancomycin serum concentrations </=40 microg/mL at steady state to infants with peak vancomycin serum concentrations >40 microg/mL. A secondary objective was to correlate concomitant disease states and potentially nephrotoxic drug therapy with rises in serum creatinine in vancomycin recipients. METHODS: Newborn infants with culture-proven Staphylococcus aureus or coagulase-negative staphylococcal septicemia who received vancomycin therapy for >3 days between 1985 and 1995 were identified from an existing database and a review of medical record. All 69 patients included in the study had serial serum creatinine determinations, including a baseline value within 48 hours of starting treatment with vancomycin, and serum vancomycin concentrations determined after at least three doses, with peak and trough concentrations determined 1 hour after a 60-minute infusion and 15 to 30 minutes before a dose, respectively. Infants with congenital renal or cardiac anomalies were excluded. Demographic characteristics, vancomycin dosing regimen, serum vancomycin concentrations and sample times, concomitant drug therapy, and disease states were recorded. Patients were divided into group A (peak vancomycin concentration </=40 microg/mL) and group B (peak vancomycin concentration >40 microg/mL). The change in serum creatinine concentration between the start and end of vancomycin therapy was determined. Nephrotoxicity was identified if serum creatinine doubled at any time from the start to the end of vancomycin therapy. Alternative definitions of nephrotoxicity (any rise in serum creatinine to >0.6 mg/dL or new abnormalities of urine sediment) were used in additional analyses. RESULTS: A total of 69 evaluable patients (gestational age, 28.9 +/- 3.0 weeks; birth weight, 1219 +/- 516 g) were identified, 61 in group A and 8 in group B. Six patients in group A underwent doubling of serum creatinine concentration during vancomycin therapy, whereas none in group B did so. Serum creatinine doubled to >0.6 mg/dL in only 3 infants (all in group A). Any increase in serum creatinine to >0.6 mg/dL was seen in 10 infants, 9 of whom were in group A. No confounding variable, including previous or concomitant underlying disease states associated with renal dysfunction or treatment with other potentially nephrotoxic agents, were associated with a significant rise in serum creatinine. CONCLUSION: Vancomycin-associated nephrotoxicity is rare in neonates, even with serum peak concentrations >40 microg/mL.

Anti-Bacterial Agents↗
PubMed1998

Mycoplasma fermentans glycolipid triggers inflammatory response in rat astrocytes.

Mycoplasma fermentans glycolipid (MfGL-II) is a major lipid in the membranes of this AIDS-associated mycoplasma and constituting up to 20% of the total phospholipids of this organism. It was recently shown that MfGL-II, mainly through its phosphocholine moiety, is responsible for the attachment of M. fermentans to host cells. We now show that MfGL-II is also associated with the secretion of inflammatory mediators by cells of the central nervous system. Stimulation of primary rat astrocytes by MfGL-II caused activation of protein kinase C, secretion of nitric oxide (NO) and prostaglandin E2, and augmented glucose utilization and lactate formation in a dose-dependent manner. In an attempt to define the minimal structural requirements for MfGL-II activity, the two O-acylated fatty acids in the molecule were removed. Deacylation pronouncedly reduced the stimulatory activity of the glycolipid, suggesting that the fatty acyl residues are essential. Incubation of MfGL-II with polyclonal anti-MfGL-II antiserum or with monoclonal anti-phosphocholine antibody diminished NO release, whereas incubation of MfGL-II with normal rabbit serum had no effect. It is, therefore, likely that the terminal phosphocholine moiety plays an important role in MfGL-IIs stimulation of glial cells.

Animals↗
PubMed1998

Glial cells production of inflammatory mediators induced by Streptococcus pneumoniae: inhibition by pentoxifylline, low-molecular-weight heparin and dexamethasone.

Exposure of primary rat glial cells to heat inactivated Streptococcus pneumoniae, induced dose-dependent production of tumor necrosis factor alpha (TNF alpha), nitric oxide (NO) and prostaglandin E2 (PGE2). Concomitant addition of the bacterium and the synthetic glucocorticoid dexamethasone resulted in complete suppression of TNF alpha, NO and PGE2 production. Pentoxifylline, a phosphodiesterase inhibitor completely blocked TNF alpha secretion, whereas NO and PGE2 were not affected. Low-molecular-weight heparin enoxaparin caused 25-64% inhibition in TNF alpha production, up to 30% inhibition of NO secretion and a 10% reduction in PGE2. Thus, Streptococcus pneumoniae, the pathogen most commonly associated with meningitis in the Western world can be added to the list of agents causing direct stimulation of glial cells. Pentoxifylline and enoxaparin in addition to dexamethasone may limit the central nervous system local inflammatory responses and could improve the effort towards reducing the dismal outcome of patients with pneumococcal meningitis.

Animals↗
PubMed1998

Differential effects of central and peripheral nerves on macrophages and microglia.

The poor ability of injured central nervous system (CNS) axons to regenerate has been correlated, at least partially, with a limited and suppressed postinjury inflammatory response. A key cell type in the inflammatory process is the macrophage, which can respond in various ways, depending on the conditions of stimulation. The aim of this study is to compare the activities of macrophages or microglia when encountering CNS and peripheral nervous systems (PNS), on the assumption that nerve-related differences in the inflammatory response may have implications for tissue repair and thus for nerve regeneration. Phagocytic activity of macrophages or of isolated brain-derived microglia was enhanced upon their exposure to sciatic (PNS) nerve segments, but inhibited by exposure to optic (CNS) nerve segments. Similarly, nitric oxide production by macrophages or microglia was induced by sciatic nerve segments but not by optic nerve segments. The previously demonstrated presence of a resident inhibitory activity in CNS nerve, could account, at least in part, for the inhibited phagocytic activity of blood-borne macrophages in CNS nerve as well as of microglia resident in the brain. It seems that the CNS microglia are reversibly immunosuppressed by the CNS environment, at least with respect to the activities examined here. It also appears from this study that the weak induction of early healing-related activities of macrophages/microglia in the environment of CNS might explain the subsequent failure of this environment to acquire growth-supportive properties in temporal and spatial synchrony with the needs of regrowing axons.

Animals↗
PubMed1998

Suppression of experimental autoimmune encephalomyelitis by tyrphostin AG-556.

Tyrosine kinase blockers from the AG 126/AG-556 tyrphostin family are shown to inhibit the lipopolysaccharide (LPS)-induced production of tumor necrosis factor alpha (TNFalpha), nitric oxide (NO), and prostaglandin E2 (PGE2) in primary rat astrocytes cultures. The tyrphostin AG-556 which was previously shown to be effective against sepsis in mice and dogs also show excellent efficacy in inhibiting experimental autoimmune encephalomyelitis (EAE) in mice. AG-556 does not block the activation of JNK/SAPK and of p38/HOG and therefore seems to act at a target down stream to these kinases which is activated in stress or at a target on an obligatory parallel pathway. These findings together with previous results showing inhibition of sepsis in mice and dogs suggest that protein tyrosine kinase (PTK) blockers of the AG-556 family may be considered in the management of human autoimmune disorders such as multiple sclerosis (MS).

Animals↗