Interferon-beta 1b augments activation-induced T-cell death in multiple sclerosis patients.
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Cell Death↗
Biomedical subjects
T Berger
Publications and source records attributed to T Berger.
Bioavailability of interferon beta 1b in MS patients with and without neutralizing antibodies.
BACKGROUND: Neutralizing antibodies (NAB) to interferon beta (IFNbeta) occur in about one-third of MS patients treated with IFNbeta-1b and there is an association with a loss of clinical and MRI efficacy. However, there are no data regarding the bioavailability of IFNbeta-1b in patients with and without NAB. METHODS: The authors measured MxA in whole blood by ELISA, and serum-binding antibodies (SBA) by Western blot and ELISA in 134 samples of MS patients on IFNbeta-1b and 54 control subjects, and correlated the MxA levels and SBA titers with the NAB titer. RESULTS: In the IFNbeta group 84 samples were NAB negative, 21 were NAB positive (i.e., titer of > or =20), and 29 had detectable NAB (i.e., titer between 10 and 20). The median MxA concentration in NAB-negative patients was 4.09 ng/10(5) peripheral blood leukocytes (PBL), 2.37 ng/10(5) PBL in samples with detectable NAB, 0.36 ng/10(5) PBL in NAB-positive samples, and 0.27 ng/10(5) PBL in control subjects. There was no significant difference between NAB-positive samples and control subjects, otherwise the groups differed significantly from each other. SBA occurred in 49% of NAB-negative samples, in 79% of samples with detectable NAB, and in all NAB-positive samples. With regard to the SBA titer, all groups differed significantly from each other. In none of the control samples were SBA detected. CONCLUSION: The conversion of SBA into NAB depends to some degree on the SBA titer, but other mechanisms may be involved. Once NAB have developed, the bioavailability of IFNbeta as measured by MxA is completely inhibited.
Antibodies↗
Encephalitogenic and neuritogenic T cell responses to the myelin-associated glycoprotein (MAG) in the Lewis rat.
Autoimmune responses to the myelin-associated glycoprotein (MAG) are implicated in the immunopathogenesis of both multiple sclerosis (MS) and certain peripheral neuropathies. In this study we demonstrate that T cell responses to defined epitopes of MAG mediate a pathological inflammatory response in the nervous system of the Lewis rat. Peptide-specific T cells were generated against four different MAG epitopes, three of which are common to both L- and S-isoforms of MAG (amino acid (a.a.) sequence: 20-34, 124-137, 354-377) whilst the fourth epitope (a.a. sequence: 570-582) is located in the C-terminal sequence of S-MAG. The adoptive transfer of T cells specific for these epitopes initiated a mild but dose-dependent inflammatory response in the central nervous system (CNS) of naive recipients. Clinical disease was only observed in those animals injected with T cells specific for the a.a. sequence 20-34 (MP1.1), which also initiated an inflammatory response in the peripheral nervous system (PNS). Co-transfer of MP1.1 (a.a. sequence 20-34)-specific T cells with the myelin oligodendrocyte glycoprotein (MOG)-specific monoclonal antibody 8-18C5 enhanced disease severity and induced widespread demyelination in the CNS. In contrast, co-transfer of T cells with the MAG-specific mAb 513 failed to induce demyelination, but had a moderate effect on the local inflammatory response. The ability of MAG to initiate an autoaggressive T cell response in the Lewis rat supports the concept that MAG-specific autoimmune responses may play a role in the pathogenesis of immune mediated diseases of the nervous system in man.
Amino Acid Sequence↗
Alterations in HIV expression in AIDS patients with psoriasis or pruritus treated with phototherapy.
BACKGROUND: Ultraviolet light (UVL) upregulates HIV transcription in vitro and in transgenic mice. AIDS-associated psoriasis and pruritus respond to phototherapy. OBJECTIVE: Our goal was to determine the effect of phototherapy on viral load and immunologic parameters in HIV-positive patients. METHODS: T cell subsets, p24, plasma cytokines, serum or plasma HIV-RNA, dosage, and antivirals were assessed in HIV-positive patients and negative controls receiving 6 weeks of phototherapy with UVB and in untreated controls. RESULTS: Phototherapy improved skin conditions without significantly affecting T cell numbers. Plasma p24 increased 2-fold (P = .055) and HIV-RNA levels 4-fold (P = .022) 6 weeks from baseline in patients who entered the trial before March 1995. Later patients who were mostly receiving combination antiviral therapy showed a 4-fold reduction in serum HIV-RNA (P = .012) at 2 weeks. The effect of UVB on viral load at 6 weeks was dependent on the baseline level (P = .006). IL-10 increased and was inversely related to HIV-RNA levels (P = .0267). CONCLUSION: Phototherapy is associated with HIV load alterations, depending on patients' initial HIV-RNA, antiviral therapy, skin type, and UVL dosage.
Acquired Immunodeficiency Syndrome↗
Expression of CD30 mRNA, CD30L mRNA and a variant form of CD30 mRNA in restimulated peripheral blood mononuclear cells (PBMC) of patients with helminthic infections resembling a Th2 disease.
It has been proposed that CD30, a member of the tumour necrosis factor (TNF) receptor superfamily, is preferentially up-regulated on Th2-type human T cells. In order to investigate a correlation between infection with Echinococcus multilocularis and CD30 expression, we analysed regulation of CD30 mRNA, a variant form of CD30 mRNA (CD30v) and CD30 ligand (CD30L) mRNA expression on PBMC from patients with alveolar echinococcosis (AE) using reverse transcriptase-polymerase chain reaction (RT-PCR). In PBMC of patients with AE as well as healthy donors, spontaneous expression of CD30L mRNA and the CD30v mRNA could be detected. However, the intact form of CD30 mRNA could be detected neither in freshly isolated PBMC of patients nor in PBMC of healthy individuals. Expression of CD30L mRNA and the variant form of CD30 mRNA was frequently detected at individual time points during 72 h of culture of PBMC stimulated with crude Echinococcus antigen. In contrast to CD30v or CD30L mRNA expression, induction of CD30 mRNA expression was detected only in three out of six (50%) healthy donors and in 10 out of 21 (48%) patients with alveolar echinococcosis after 72 h of incubation. As a control, mitogenic stimulation of PBMC of both healthy individuals and infected patients led to expression of intact CD30 mRNA within 24 h of culture. These data demonstrate the different expression of two different forms of CD30 mRNA in PBMC of human individuals. The specific induction of CD30 expression is correlated only in rare cases with the clinical status of patients with AE, indicating the lack of a general induction of CD30 mRNA in this Th2-type-dominated helminthic disease. The data provide further evidence that the CD30 receptor is not an exclusive marker for a Th2-type response.
Adult↗
Plant polyketide synthases: a chalcone synthase-type enzyme which performs a condensation reaction with methylmalonyl-CoA in the biosynthesis of C-methylated chalcones.
Heterologous screening of a cDNA library from Pinusstrobus seedlings identified clones for two chalcone synthase (CHS) related proteins (PStrCHS1 and PStrCHS2, 87.6% identity). Heterologous expression in Escherichia coli showed that PStrCHS1 performed the typical CHS reaction, that it used starter CoA-esters from the phenylpropanoid pathway, and that it performed three condensation reactions with malonyl-CoA, followed by the ring closure to the chalcone. PstrCHS2 was completely inactive with these starters and also with linear CoA-esters. Activity was detected only with a diketide derivative (N-acetylcysteamine thioester of 3-oxo-5-phenylpent-4-enoic acid) that corresponded to the CHS reaction intermediate postulated after the first condensation reaction. PstrCHS2 performed only one condensation, with 6-styryl-4-hydroxy-2-pyrone derivatives as release products. The enzyme preferred methylmalonyl-CoA against malonyl-CoA, if only methylmalonyl-CoA was available. These properties and a comparison with the CHS from Pinus sylvestris suggested for PstrCHS2 a special function in the biosynthesis of secondary products. In contrast to P. sylvestris, P. strobus contains C-methylated chalcone derivatives, and the methyl group is at the position predicted from a chain extension with methylmalonyl-CoA in the second condensation of the biosynthetic reaction sequence. We propose that PstrCHS2 specifically contributes the condensing reaction with methylmalonyl-CoA to yield a methylated triketide intermediate. We discuss a model that the biosynthesis of C-methylated chalcones represents the simplest example of a modular polyketide synthase.
Acyl Coenzyme A↗
Dentate gyrus basket cell GABAA receptors are blocked by Zn2+ via changes of their desensitization kinetics: an in situ patch-clamp and single-cell PCR study.
Although GABA type A receptors (GABAARs) in principal cells have been studied in detail, there is only limited information about GABAARs in interneurons. We have used the patch-clamp technique in acute rat hippocampal slices in combination with single-cell PCR to determine kinetic, pharmacological, and structural properties of dentate gyrus basket cell GABAARs. Application of 1 mM GABA (100 msec) to nucleated patches via a piezo-driven fast application device resulted in a current with a fast rise and a marked biexponential decay (time constants 2.4 and 61.8 msec). This decay could be attributed to strong receptor desensitization. Dose-response curves for the peak and the slow component yielded EC50 values of 139 and 24 microM, respectively. Zn2+ caused a marked blocking effect on both the peak and the slow component via a noncompetitive mechanism (IC50 values of 8 and 16 microM). This led to an acceleration of the slow component as well as a prolongation of recovery from desensitization. Zn2+ sensitivity was suggested to depend on the absence of gamma-subunits in GABAARs. To test this hypothesis we performed single-cell reverse transcription PCR that revealed primarily the presence of alpha2-, beta2-, beta3-, gamma1-, and gamma2-subunit mRNAs. In addition, flunitrazepam increased the receptor affinity for its agonist, indicating the presence of functional benzodiazepine binding sites, i.e., gamma-subunits. Thus, additional factors seem to co-determine the Zn2+ sensitivity of native GABAARs. The modulatory effects of Zn2+ on GABAAR desensitization suggest direct influences on synaptic integration via changes in inhibition and shunting at GABAergic synapses.
Animals↗
Purpuric nodules and macules on the extremities of a young woman. Cutaneous polyarteritis nodosa.
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Adult↗
4-Hydroxy-2-pyrone formation by chalcone and stilbene synthase with nonphysiological substrates.
Valerophenone synthase (VPS) is a polyketide synthase that catalyzes the formation of the phloroglucinol derivatives in the synthesis of the bitter acids in hop (Humulus lupulus). The reaction uses isovaleryl-CoA or isobutyryl-CoA, but otherwise it is identical to that of the chalcone synthase in flavonoid biosynthesis. Our study showed that chalcone synthase can perform the function of VPS, but not perfectly, because the majority of the reactions terminated after two condensation reactions (products: 4-hydroxy-2-pyrone derivatives). The same experiments with stilbene synthase yielded exclusively the 4-hydroxy-2-pyrone derivatives, not the products expected from three condensation reactions. The results are discussed in the context of the functional diversity and evolution in the family of CHS-related polyketide synthases.
Acyltransferases↗
Sperm plasma membrane receptors for the porcine oocyte plasma membrane.
In vitro fertilisation (IVF) was used to assess the ability of solubilised sperm plasma membrane (PM) proteins to inhibit the interaction of intact gametes. This is a first step before evaluating the ability of individual isolated proteins to competitively inhibit sperm-oocyte interaction as part of the process of studying the molecular events of fertilisation. Porcine oocytes were aspirated from ovaries, matured for 48 h in Medium 199, and the zona pellucida (ZP) was removed by exposure to acid Tyrode's solution. ZP-free matured oocytes were exposed to 200-800 micrograms/ml sperm PM protein for 1 h prior to insemination and during gamete co-incubation. Twenty-four hours after insemination with 5 x 10(5) capacitated sperm/ml, the oocytes were fixed, stained and examined. Sperm PM protein clearly inhibited IVF in a concentration-dependent manner (r = -0.87). The inhibition index (I50%), representing the sperm PM protein concentration necessary to inhibit IVF to 50% of the control value, was 310 micrograms/ml. These results demonstrate that solubilised sperm PM protein inhibits the interaction of intact gametes as one might expect for receptor-ligand interactions. Furthermore, the complement of sperm PM proteins appeared maximally effective at a calculated concentration of 690 microns/ml, providing a foundation for further studies with individual proteins.
Animals↗
Improving primary care residents' proficiency in the diagnosis of skin cancer.
OBJECTIVE: To determine whether a brief, multicomponent intervention could improve the skin cancer diagnosis and evaluation planning performance of primary care residents to a level equivalent to that of dermatologists. PARTICIPANTS: Fifty-two primary care residents (26 in the control group and 26 in the intervention group) and 13 dermatologists completed a pretest and posttest. DESIGN: A randomized, controlled trial with pretest and posttest measurements of residents' ability to diagnose and make evaluation plans for lesions indicative of skin cancer. INTERVENTION: The intervention included face-to-face feedback sessions focusing on residents' performance deficiencies; an interactive seminar including slide presentations, case examples, and live demonstrations; and the Melanoma Prevention Kit including a booklet, magnifying tool, measuring tool, and skin color guide. MEASUREMENTS AND MAIN RESULTS: We compared the abilities of a control and an intervention group of primary care residents, and a group of dermatologists to diagnose and make evaluation plans for six categories of skin lesions including three types of skin cancer-malignant melanoma, squamous cell carcinoma, and basal cell carcinoma. At posttest, both the intervention and control group demonstrated improved performance, with the intervention group revealing significantly larger gains. The intervention group showed greater improvement than the control group across all six diagnostic categories (a gain of 13 percentage points vs 5, p < .05), and in evaluation planning for malignant melanoma (a gain of 46 percentage points vs 36, p < .05) and squamous cell carcinoma (a gain of 42 percentage points vs 21, p < .01). The intervention group performed as well as the dermatologists on five of the six skin cancer diagnosis and evaluation planning scores with the exception of the diagnosis of basal cell carcinoma. CONCLUSIONS: Primary care residents can diagnose and make evaluation plans for cancerous skin lesions, including malignant melanoma, at a level equivalent to that of dermatologists if they receive relevant, targeted education.
Clinical Competence↗
Changes in glial K+ currents with decreased extracellular volume in developing rat white matter.
Whole cell patch-clamp recordings of K+ currents from oligodendrocyte precursors in 10-day-old rats (P10) and, following myelination, in mature oligodendrocytes from 20-day-old rats (P20) were correlated with extracellular space (ECS) diffusion parameters measured by the local diffusion of iontophoretically injected tetramethylammonium ions (TMA+). The aim of this study was to find an explanation for the changes in glial currents that occur with myelination. Oligodendrocyte precursors (P10) in slices from corpus callosum were characterized by the presence of A-type K+ currents, delayed and inward rectifier currents, and lack of tail currents after the offset of a voltage jump. Mature oligodendrocytes in corpus callosum slices from P20 rats were characterized by passive, decaying currents and large tail currents after the offset of a voltage jump. Measurements of the reversal potential for the tail currents indicate that they result from increases in [K+]e by an average of 32 mM during a 20 msec 100 mV voltage step. Concomitant with the change in oligodendrocyte electrophysiological behavior after myelination there is a decrease in the ECS of the corpus callosum. ECS volume decreases from 36% (P9-10) to 25% (P20-21) of total tissue volume. ECS tortuosity lambda = (D/ADC)0.5, where D is the free diffusion coefficient and ADC is the apparent diffusion coefficient of TMA+ in the brain, increases as measured perpendicular to the axons from 1.53 +/- 0.02 (n = 6, mean +/- SEM) to 1.70 +/- 0.02 (n = 6). TMA+ non-specific uptake (k') was significantly larger at P20 (5.2 +/- 0.6 x 10(-3) s(-1), n = 6) than at P10 (3.5 +/- 0.4 x 10(-3) s(-1), n = 6). It can be concluded that membrane potential changes in mature oligodendrocytes are accompanied by rapid changes in the K+ gradient resulting from K+ fluxes across the glial membrane. As a result of the reduced extracellular volume and increased tortuosity, the membrane fluxes produce larger changes in [K+]e in the more mature myelinated corpus callosum than before myelination. These conclusions also account for differences between membrane currents in cells in slices compared to those in tissue culture where the ECS is essentially infinite. The size and geometry of the ECS influence the membrane current patterns of glial cells and may have consequences for the role of glial cells in spatial buffering.
Animals↗
Functional properties of AMPA and NMDA receptors expressed in identified types of basal ganglia neurons.
AMPA- and NMDA-type glutamate receptors (AMPARs and NMDARs) mediate excitatory synaptic transmission in the basal ganglia and may contribute to excitotoxic injury. We investigated the functional properties of AMPARs and NMDARs expressed by six main types of basal ganglia neurons in acute rat brain slices (principal neurons and cholinergic interneurons of striatum, GABAergic and dopaminergic neurons of substantia nigra, globus pallidus neurons, and subthalamic nucleus neurons) using fast application of glutamate to nucleated and outside-out membrane patches. AMPARs in different types of basal ganglia neurons were functionally distinct. Those expressed in striatal principal neurons exhibited the slowest gating (desensitization time constant tau = 11.5 msec, 1 mM glutamate, 22 degrees C), whereas those in striatal cholinergic interneurons showed the fastest gating (desensitization time constant tau = 3.6 msec). The lowest Ca2+ permeability of AMPARs was observed in nigral dopaminergic neurons (PCa/PNa = 0.10), whereas the highest Ca2+ permeability was found in subthalamic nucleus neurons (PCa/PNa = 1.17). NMDARs of different types of basal ganglia neurons were less variable in their functional properties; those expressed in nigral dopaminergic neurons exhibited the slowest gating (deactivation time constant of predominant fast component tau1 = 150 msec, 100 microM glutamate), and those of globus pallidus neurons showed the fastest gating (tau1 = 67 msec). The Mg2+ block of NMDARs was similar; the average chord conductance ratio g-60mV/g+40mV was 0.18-0.22 in 100 microM external Mg2+. Hence, AMPARs expressed in different types of basal ganglia neurons are markedly diverse, whereas NMDARs are less variable in functional properties that are relevant for excitatory synaptic transmission and neuronal vulnerability.
Animals↗
Treatment guidelines in central nervous system Whipple's disease.
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Anti-Bacterial Agents↗
Induction of experimental autoimmune encephalomyelitis by CD4+ T cells specific for an astrocyte protein, S100 beta.
S100 beta protein is a calcium binding protein that is not only expressed by astrocytes in the CNS, but also in many other tissues including the eye, thymus, spleen and lymph nodes. Despite this tissue distribution, which was expected to induce a firm state of self-tolerance to S100 beta, the Lewis rat mounts a strong T cell response to this autoantigen. The pathogenicity of this T cell response was demonstrated by the adoptive transfer of S100 beta-specific T cells which induced an inflammatory response in the CNS and eye of naive syngeneic recipients. The distribution of lesions in this novel model of EAE resembles that seen in some patients with MS, suggesting that the initial autoimmune insult in MS may be directed against a non-myelin antigen co-expressed in the CNS and extra-neural tissues.
Adoptive Transfer↗
Neurological monitoring of neurotoxicity induced by paclitaxel/cisplatin chemotherapy.
To evaluate the neurotoxicity of paclitaxel/cisplatin chemotherapy, we studied neurological and electrophysiological functions in 14 patients who had been treated with 1-7 courses of paclitaxel/cisplatin. The cumulative paclitaxel and cisplatin doses ranged from 175 to 1225 mg/m2 and 100-700 mg/m2, respectively. Neurological examinations as well as motor nerve conduction studies of the peroneal nerve were performed and summarised by means of a peripheral neuropathy score. Neurotoxicity with onset usually after the second treatment cycle occurred in 13 patients. 12 patients complained about sensory symptoms, 13 patients had impaired vibration sense and 8 patients developed additional muscle weakness, predominantly of the legs. Dysfunction of peroneal motor nerve conduction occurred in 13 patients. Reduction of amplitudes as well as slowing of conduction velocities were seen in 13 patients and prolonged distal latencies in 10 patients. The peripheral neuropathy score was elevated in 13 patients. Neurological symptoms, impairment of both vibration sense and tendon reflexes, and the peripheral neuropathy score increased with the cumulative doses of paclitaxel/cisplatin. Serial analysis among selected patients also revealed an increase in neurotoxicity with increasing cumulative drug doses. These data indicate the development of neurotoxicity in most patients treated with paclitaxel/cisplatin and also suggest that early signs of neurotoxicity can be detected by clinical examination with emphasis on symptoms as well as vibration sense and can be well documented by electrophysiological investigations.
Adult↗
Serum antibodies against gangliosides and Campylobacter jejuni lipopolysaccharides in Miller Fisher syndrome.
Seven patients with Miller Fisher syndrome (MFS), six in the acute phase and one in the recovery phase, were investigated for serum antibodies against gangliosides and purified lipopolysaccharides (LPS) from different strains of Campylobacter jejuni, including the MFS-associated serotypes O:2 and O:23. Immunoglobulin G antibodies against gangliosides GT1a and GQ1b were found in five of six patients in the acute phase of disease. Three of these patients also displayed antibodies to ganglioside GD2, a finding not previously reported for MFS. All anti-GT1a- and anti-GQ1b-seropositive patients showed antibody binding to C. jejuni LPS, predominantly to O:2 and O:23 LPS. Antibody cross-reactivity between gangliosides GT1a and GQ1b and O:2 and O:23 LPS was demonstrated by adsorption studies. This cross-reactivity between gangliosides and C.jejuni LPS, which is obviously due to oligosaccharide homologies, may be an important pathogenetic factor in the development of MFS after C. jejuni infection.
Adult↗