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Biomedical subjects

D Schiller

Publications and source records attributed to D Schiller.

At least 19 recordsLinked to original sources
PubMed2006

Combined treatment of colorectal tumours with agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and radiotherapy: enhanced effects in vitro and dose-dependent growth delay in vivo.

We and others have demonstrated already that TRAIL (TNF-related apoptosis-inducing ligand) is a very promising candidate for molecular targeted anticancer therapy, especially when combined with ionizing radiation or other DNA-damaging agents. Agonist monoclonal antibodies that activate and are specific for the death signaling TRAIL receptors are an alternative method to stimulate the programmed cell death pathway. Phase 1 clinical trials have subsequently been conducted and shown a very good tolerability of these antibodies. In order to assess the efficacy of TRAIL receptor stimulation to induce cell death by this alternate method, we studied the combination of the agonistic-TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 with radiation in vitro and in vivo. Induction of apoptosis after combined treatment with TRAIL receptor antibodies HGS-ETR1 and/or HGS-ETR2 (0.01, 0.1, 1.0 mg/ml) and irradiation with 2, 5 or 10 Gy was determined by fluorescence microscopy and Western blot analysis of caspase-8 and PARP. The colorectal tumour cell lines Colo 205, HCT 116 and HCT-15 were used for in vitro experiments. Growth delay experiments were performed with combined treatment with fractionated irradiation (days 1-5 and 3 Gy single dose/day) and the receptor antibodies (intraperitonially, three different concentrations, application on days 1, 4 and 8) on Colo 205 xenograft-bearing NMRI (nu/nu) nude mice. HGS-ETR1 and HGS-ETR2 induced apoptotic cell death in a dose-dependent fashion and significantly increased cell death in combination with irradiation in vitro when compared to either irradiation or antibody treatment alone. The efficacy of the combined treatment seems to be at least partially Bax-dependent. Similar to the results from cell culture experiments, in vivo experiments demonstrated a dose-dependent delay in tumour growth after combined treatment. In vivo, in the Colo205 xenograft model, HGS-ETR2 revealed a higher activity than HGS-ETR1. This is the first study to demonstrate significant efficacy of combined treatment with the monoclonal agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and ionising radiation in in vitro and in vivo models. We postulate that HGS-ETR1 and HGS-ETR2 will be very promising new agents in the field of molecular targeted multi-modality anticancer therapy.

Antibodies, Monoclonal↗
PubMed2004

Projection structure and oligomeric state of the osmoregulated sodium/glycine betaine symporter BetP of Corynebacterium glutamicum.

The high-affinity glycine betaine uptake system BetP, an osmosensing and osmoregulated sodium-coupled symporter from Corynebacterium glutamicum, was overexpressed in Escherichia coli with an N-terminal StrepII-tag, solubilized in beta-dodecylmaltoside and purified by streptactin affinity chromatography. Analytical ultracentrifugation indicated that BetP forms trimers in detergent solution. Detergent-solubilized BetP can be reconstituted into proteoliposomes without loss of function, suggesting that BetP is a trimer in the bacterial membrane. Reconstitution with E.coli polar lipids produced 2D crystals with unit cell parameters of 182A x 154A, gamma=90 degrees exhibiting p22(1)2(1) symmetry. Electron cryo-microscopy yielded a projection map at 7.5A. The unit cell contains four non-crystallographic trimers of BetP. Within each monomer, ten to 12 density peaks characteristic of transmembrane alpha-helices surround low-density regions that define potential transport pathways. Small but significant differences between the three monomers indicate that the trimer does not have exact 3-fold symmetry. The observed differences may be due to crystal packing, or they may reflect different functional states of the transporter, related to osmosensing and osmoregulation. The projection map of BetP shows no clear resemblance to other secondary transporters of known structure.

Affinity Labels↗
PubMed2004

Lesions to the basolateral amygdala and the orbitofrontal cortex but not to the medial prefrontal cortex produce an abnormally persistent latent inhibition in rats.

Repeated nonreinforced preexposure to a stimulus interferes with the establishment of conditioned responding to this stimulus when it is subsequently paired with reinforcement. This stimulus-preexposure effect is known as latent inhibition (LI). Rather remarkably, LI appears to be resistant to the effects of numerous lesions, including the prefrontal cortex (PFC) and the basolateral amygdala (BLA). However, intact behavioral expression of LI following damage to given brain regions does not preclude the possibility that such regions participate in the regulation of LI expression in the intact brain. The present study showed that lesions of the BLA and the orbitofrontal cortex (OFC) but not of the medial PFC (mPFC) led to an abnormally persistent LI which emerged under conditions that disrupted LI in control rats. LI was measured in a thirst motivated conditioned emotional response procedure by comparing suppression of drinking in response to a tone in rats which received 0 (nonpreexposed) or 40 tone presentations (preexposed) followed by either two or five tone-shock pairings. Control rats showed LI with 40 preexposures and two conditioning trials, but raising the number of conditioning trials to five disrupted LI. OFC- and BLA-lesioned rats showed LI under the former condition but in addition persisted in exhibiting LI under the latter condition. Rats with lesion of the mPFC did not show persistent LI. Thus, although LI does not depend on the integrity of BLA and OFC (because it is present in BLA- and OFC- lesioned rats even under conditions disrupting the phenomenon in normal rats), these regions play an important role in the modulation of its expression, more specifically, in the control of the non-expression of LI when the impact of conditioning increases beyond a certain level.

Amygdala↗
PubMed2003

A comparison of drug effects in latent inhibition and the forced swim test differentiates between the typical antipsychotic haloperidol, the atypical antipsychotics clozapine and olanzapine, and the antidepressants imipramine and paroxetine.

Current animal models of antipsychotic activity that have the capacity to dissociate between typical and atypical antipsychotic drugs (APDs) have two drawbacks: they require previous administration of a psychotomimetic drug, and they achieve the dissociation by demonstrating effectiveness of atypical but not typical APDs, thus losing specificity and selectivity for APDs. The present experiments were designed to solve these problems by using two non-pharmacological tests: latent inhibition (LI), in which potentiation of the deleterious effects of non-reinforced stimulus pre-exposure on its subsequent conditioning served as a behavioral index for a common action of typical and atypical APDs (antipsychotic), and the forced swim test (FST), in which reduction of immobility served as a behavioral index for a dissimilar action of these drugs (antidepressant). The typical APD haloperidol (0.1 mg/kg), the atypical APDs clozapine (2.5 mg/kg) and olanzapine (0.6 mg/kg), and the antidepressants imipramine (10 mg/kg) and paroxetine (7.0 mg/kg), produced distinct patterns of action in the two tests: haloperidol potentiated LI and increased immobility in the FST, clozapine and olanzapine potentiated LI and decreased immobility in the FST, and imipramine and paroxetine decreased immobility in the FST and did not potentiate LI. Thus, the comparison of drug effects in LI and FST enabled a discrimination between typical and atypical APDs without losing selectivity for APDs.

Animals↗
PubMed2001

[Birbeck granules in epidermal Langerhans cells of elderly patients with decubital ulcers].

UNLABELLED: Birbeck granules (Bg), known also as Langerhans cell (L) granules are special organelles found in the L cells' cytoplasm, which serve as a marker for their identification. These organelles have been studied in epidermal L cells in elderly patients with pressure sores and were compared to those found in epidermal L cells of healthy volunteers who served as controls. RESULTS: There was an increase of about 47% in the number of B granules in patients' L cells from sacral epidermis near lesion (p < 0.01) and an increase of about 68% of the number of B granules in patients' L cells from normal epidermis (p < 0.005) was found as compared to healthy control L cells. Part of the B granules in patients' L cells were of similar morphology to those of controls. They were found throughout the cytoplasm as simple rods or rackets. In addition, in patients' epidermis some irregularly shaped granules were observed, such as: racket structure common to two or more rod structures; rod shaped granules in direct continuity with mitochondria, and others with lysosomes. Moreover, B granules in continuity with the cell plasma membrane and groups of closely opposed rod shaped granules were observed. These two last shaped structures apparently reflected formative stages of B granules. It is suggested that an increase of the number of B granules indicated an active state of L cells in the epidermis of patients studied. It is not clear whether the morphologic alterations of B granules influence the L cell functions in antigen presentation. It is possible that they may be partly involved in infections which occur frequently in patients with decubital ulcers. It is also possible that the increase in the number of B granules and the altered structures found among them in patients' epidermis express a reaction of L cells to inflammation.

Aged↗
PubMed2000

The effect of highly active antiretroviral therapy on binding and neutralizing antibody responses to human immunodeficiency virus type 1 infection.

The effect on humoral immune responses of highly active antiretroviral therapy (HAART) commenced during primary or chronic human immunodeficiency virus type 1 (HIV-1) infection was investigated. HAART inhibited the development of anti-gp120 antibodies when initiated during primary infection and could sometimes reduce antibody titers in patients treated within 2 years of HIV-1 infection. Conversely, antibody responses in patients infected for several years were less sensitive to HAART. Administering HAART during primary infection usually did not substantially affect the development of weak neutralizing antibody responses against autologous virus. However, 2 patients treated very early after infection did not develop neutralizing responses. In contrast, 3 of 4 patients intermittently adherent to therapy developed autologous neutralizing antibodies of unusually high titer, largely coincident with brief viremic periods. The induction of strong neutralizing antibody responses during primary HIV-1 infection might require the suppression of virus replication by HAART, to allow for the recovery of immune competency, followed by exposure to native envelope glycoproteins.

Anti-HIV Agents↗
PubMed2000

The latent inhibition model dissociates between clozapine, haloperidol, and ritanserin.

Latent inhibition (LI), i.e., retarded conditioning to a stimulus following its nonreinforced preexposure, is impaired in some subsets of schizophrenia patients and in amphetamine-treated rats. Typical and atypical antipsychotic drugs (APD's) potentiate LI, but to date the model has not dissociated between them. This study demonstrates such a dissociation using haloperidol (0.1 mg/kg), clozapine (5 mg/kg), and ritanserin (0.6 mg/kg) administered in preexposure and/or conditioning. Under conditions which did not yield LI in vehicle controls (40 preexposures and five conditioning trials), both haloperidol and clozapine, but not ritanserin, led to LI when administered in conditioning. Under conditions which led to LI in vehicle controls (40 preexposures and two conditioning trials), clozapine and ritanserin, but not haloperidol, abolished LI when administered in preexposure. It is suggested that LI potentiation via conditioning detects the "typical" action of APD's whereas LI disruption via preexposure detects the "atypical" action of APD's.

Acoustic Stimulation↗
PubMed2000

Effect of zinc supplementation on epidermal Langerhans' cells of elderly patients with decubital ulcers.

In the present study, Langerhans' cells (LCs) in the sacral epidermis, 8-10 cm from lesions of patients (mean age 71 years) with decubital ulcers, were compared ultrastructurally and morphometrically with those in the patients' own normal epidermis from the upper leg, before and after supplementation with 50 mg/day elementary zinc (in the form of a 220-mg tablet of Avazinc, administered once daily) for four months. Zinc intake resulted in from 80% to full healing of the decubital ulcers in the patients studied. The percentages of LCs were low in both perilesional sacral epidermis (2.07 +/- 0.71%) and in control leg epidermis (2.71 +/- 1.38%) before zinc supplementation and also afterward (2.12 +/- 0.16% and 2.59 +/- 0.88%, respectively). LCs demonstrated a more dendritic morphology after zinc supplementation: 68.15 +/- 9.28% and 77.0 +/- 3.45% of sacral and of control leg epidermal LCs, respectively, had dendrites before, and 91.52 +/- 3.43% and 84.15 +/- 3.64% of sacral and of control leg epidermal LCs, respectively, had dendrites after zinc supplementation. The LC section area in the sacral epidermis near the lesion as well as in the control leg epidermis and the number of LC granules in LC sections were not affected by zinc supplementation. The higher percentage of LCs having dendrites in the epidermis of patients with decubital ulcers after zinc supplementation may indicate that these LCs are in a more motile state, which might affect the healing process of the lesions.

Administration, Oral↗
PubMed2000

Polyamine transport and role of potE in response to osmotic stress in Escherichia coli.

When transport of polyamines in Escherichia coli was examined, putrescine excretion was observed under two different physiological conditions: (i) strictly correlated to growth and (ii) following a hyperosmotic shock. Spermidine was not excreted. Characterization of a deletion mutant showed that PotE is not involved in these transport processes.

Antiporters↗
PubMed2000

Chronic indwelling catheter replacement before antimicrobial therapy for symptomatic urinary tract infection.

PURPOSE: We determined whether routine replacement of a chronic indwelling catheter before instituting antimicrobial therapy leads to an improved bacteriological or clinical outcome when treating symptomatic urinary tract infection in elderly nursing home residents. MATERIALS AND METHODS: We performed a prospective randomized open clinical trial at 2 long-term care facilities. Patients were randomized to indwelling catheter replacement before initiating antimicrobial therapy or no replacement. Urine and blood cultures were done before antimicrobial therapy began. Clinical and microbiological outcomes were assessed after 3 days of therapy, and 7 and 28 days after therapy was complete. RESULTS: Enrolled in our study were 21 male and 33 female nursing home residents with a mean age of 72.6 years, a chronic indwelling catheter and a clinical diagnosis of urinary tract infection. A total of 27 cases were randomized to either catheter replacement and no replacement before antimicrobial therapy. Polymicrobial bacteriuria significantly decreased 3 days after therapy was initiated, and 7 and 28 days after it was discontinued in 24 versus 8 (p = 0.002), 18 versus 9 (p = 0.01) and 13 versus 5 (p = 0.02) patients with and without catheter replacement, respectively. Catheter replacement was also associated with a shorter time to afebrile status, improved clinical status 72 hours after the initiation of therapy in 25 versus 11 patients (p <0.001) and a lower rate of symptomatic clinical relapse 28 days after therapy in 3 versus 11 (p = 0.015). CONCLUSIONS: Clinical and bacteriological outcomes are improved when long-term indwelling catheters are replaced before initiating antimicrobial therapy for symptomatic urinary tract infection.

Aged↗
PubMed1995

Barnett continent intestinal reservoir. Multicenter experience with an alternative to the Brooke ileostomy.

PURPOSE: Since 1988, surgeons at five hospitals have been performing the Barnett continent intestinal reservoir (BCIR). The BCIR includes modifications to the original Kock pouch, designed to reduce the incidence of valve slippage and fistula formation. Principle modifications include an intestinal collar, an isoperistaltic valve, and a lateral pouch design. METHOD: This unique collaborative study includes 510 ulcerative colitis or familial polyposis patients, with a follow-up time from one to five years postoperatively. RESULTS: Ninety-two percent still have functioning reservoirs. Six and one-half percent have had their pouches removed and replaced with conventional Brooke ileostomies. Reoperation rate for major pouch-related complications (other than pouch removal) was 12.8 percent. These complications included slipped valve (6.3 percent), valve fistulas (4.5 percent), and pouch fistulas (6.3 percent). Several questions were administered to patients whose responses revealed a significant improvement in general quality of life, state of mind, and overall health. CONCLUSIONS: The BCIR represents a successful alternative to patients with a conventional Brooke ileostomy or those who are not candidates for the ileal pouch-anal anastomosis.

Adenomatous Polyposis Coli↗
PubMed1992

Species-specific binding of CD4 to the beta 2 domain of major histocompatibility complex class II molecules.

Exon-shuffled constructs between mouse (IA beta b) and human (DR3 beta) class II beta chains were made to study the interaction sites between CD4 and major histocompatibility complex (MHC) class II molecules, and to determine whether a species barrier is involved. The overall structure and the peptide binding groove appeared to be unaffected by the exon shuffling procedure as determined by monoclonal antibody and peptide binding assays, respectively. While purified CD4+ BALB/c T cells responded strongly in a mixed leukocyte reaction to transfectants expressing the whole IA molecule, the response to IA molecules containing a DR beta 2 domain was substantially reduced. In addition, the presence of an IA beta 2 domain in DR failed to restore the weak xenoreactivity to the whole DR molecule. Similar observations were made with murine HEL-specific, IA alpha k beta b-restricted T cell hybridomas which responded significantly stronger to the whole compared with the exon-shuffled IA molecules. The involvement of CD4 in these differential responses was confirmed by the observation that CD4 loss variants responded to both molecules comparably, and transfection of CD4 into these cells restored the parental phenotype. In contrast, CD4 loss variants transfected with human CD4 responded equally to both the whole and the exon-shuffled molecules. Taken together, these data imply the existence of a partial species barrier, and suggest that CD4 interacts with the beta 2 domain of MHC class II molecules, probably in addition to other contact sites. Models for the interaction of CD4 with MHC class II molecules are presented.

Binding Sites↗