Search PubMed⌕ Search

Biomedical subjects

M Lotze

Publications and source records attributed to M Lotze.

36 records · Page 2Linked to original sources
PubMed1999

Daily rhythm of temporal resolution in the auditory system.

Over a period of 24 hours, fusion thresholds (click durations 100 micros) were assessed in 7 subjects. Over the same period, order thresholds (click duration of 1 ms) were measured in 10 subjects (12 independent sessions). Auditory fusion thresholds showed a diurnal rhythm with a maximum performance (shortest intervals) around midnight. In contrast, order thresholds appear to be independent on the time of day. Sex specific differences in threshold levels were only observed in order thresholds but not in fusion thresholds.

Acoustics↗
PubMed1999

Activation of cortical and cerebellar motor areas during executed and imagined hand movements: an fMRI study.

Brain activation during executed (EM) and imagined movements (IM) of the right and left hand was studied in 10 healthy right-handed subjects using functional magnetic resonance imagining (fMRI). Low electromyographic (EMG) activity of the musculi flexor digitorum superficialis and high vividness of the imagined movements were trained prior to image acquisition. Regional cerebral activation was measured by fMRI during EM and IM and compared to resting conditions. Anatomically selected regions of interest (ROIs) were marked interactively over the entire brain. In each ROI activated pixels above a t value of 2.45 (p<0.01) were counted and analyzed. In all subjects the supplementary motor area (SMA), the premotor cortex (PMC), and the primary motor cortex (M1) showed significant activation during both EM and IM; the somatosensory cortex (S1) was significantly activated only during EM. Ipsilateral cerebellar activation was decreased during IM compared to EM. In the cerebellum, IM and EM differed in their foci of maximal activation: Highest ipsilateral activation of the cerebellum was observed in the anterior lobe (Larsell lobule H IV) during EM, whereas a lower maximum was found about 2-cm dorsolateral (Larsell lobule H VII) during IM. The prefrontal and parietal regions revealed no significant changes during both conditions. The results of cortical activity support the hypothesis that motor imagery and motor performance possess similar neural substrates. The differential activation in the cerebellum during EM and IM is in accordance with the assumption that the posterior cerebellum is involved in the inhibition of movement execution during imagination.

Adult↗
PubMed1998

fMRI reveals amygdala activation to human faces in social phobics.

Functional magnetic resonance imaging was used to determine the activation of the amygdala while seven social phobics and five healthy controls were exposed to slides of neutral faces as well as aversive odor stimuli. The amygdala was selectively activated in the social phobics during presentation of the face stimuli. The data show for the first time that the amygdala is active in human phobics when they are exposed to potentially fear-relevant stimuli. Further research is needed to determine the extent to which overactivation of the amygdala precedes or is a consequence of phobia.

Adult↗
PubMed1997

Prevalence of infection with Cryptosporidium parvum and Cyclospora cayetanensis among international travellers.

BACKGROUND: Cryptosporidium parvum and Cyclospora cayetanensis are recognised as possible pathogens of traveller's diarrhoea. AIMS: To identify the prevalence of C parvum and Cyc cayetanensis in travellers returning from developing countries. PATIENTS: Nine hundred and seventy eight stool samples wer taken from 795 patients returning from developing countries. METHODS: Microscopy (iron-haematoxylin stain, SAF concentration, modified acid fast stain) and a commercially available enzyme linked immunosorbent assay (ELISA) kit for the detection of Cryptosporidium antigen in stool. RESULTS: Of the 795 patients in the study, 469 suffered from diarrhoea. Infection with Cyc cayetanensis could be detected in five subjects (1.1%) by acid fast stain, and 13 patients (2.8%) were infected with C parvum. On evaluation, the antigen capture ELISA turned out to be clearly less sensitive for detection of C parvum than microscopy. All patients with either C parvum or Cyc cayetanensis infection suffered from watery diarrhoea. CONCLUSIONS: C parvum and Cyc cayetanensis are not major causes of diarrhoea in international travellers. In cases of persistent watery diarrhoea, however, these pathogens should be taken into account in the differential diagnosis.

Animals↗
PubMed1997

Interleukin-2-based therapy for metastatic renal cell cancer: the Cytokine Working Group experience, 1989-1997.

PURPOSE: This article reviews long-term follow-up data from three phase II studies conducted by the Cytokine Working Group from 1989 to 1995 that evaluated various recombinant interleukin-2 (rIL-2) -based regimens in patients with metastatic renal cell cancer. Response rates, long-term response duration, and toxicity are compared. PATIENTS AND METHODS: The Cytokine Working Group studies reviewed here investigated the safety and efficacy of two high-dose intravenous rIL-2-based regimens and two moderate-dose outpatient subcutaneous rIL-2-based regimens in patients with progressive metastatic renal cell cancer. A randomized phase II study, initiated in 1989, investigated the safety and efficacy of high-dose intravenous rIL-2 alone and high-dose intravenous rIL-2 plus recombinant interferon-alpha (rIFN-alpha). A second phase II study, initiated in 1992, tested the safety and efficacy of moderate-dose subcutaneous rIL-2 plus subcutaneous rIFN-alpha in the outpatient setting. The third trial, initiated in 1995, investigated a regimen consisting of the previous subcutaneous rIL-2 plus rIFN-alpha regimen alternating with intravenous bolus 5-fluorouracil (5-FU) plus subcutaneous rIFN-alpha. Median follow-up for these studies is 72 months, 48 months, and 24 months, respectively. RESULTS: The overall response rates observed with each of these regimens were similar (17% with high-dose rIL-2 alone, 11% with high-dose rIL-2/rIFN-alpha, 17% with outpatient subcutaneous rIL-2/rIFN-alpha, and 16% with outpatient rIL-2/rIFN-alpha, plus 5-FU/rIFN-alpha). However, the high-dose rIL-2 regimen produced a 7% complete response rate, compared with 0%, 4%, and 4%, respectively, with each of the other regimens. Median response duration was also much longer with high-dose intravenous rIL-2 alone (53 months), compared with 7 months, 12 months, and 9 months, respectively, with each of the other regimens. CONCLUSION: Complete response rate and response duration appear to favor the high-dose intravenous rIL-2 regimen. This will require verification in a randomized study comparing the best high-dose arm (rIL-2 alone) with the best outpatient regimen (rIL-2/IFN-alpha). The Cytokine Working Group is currently conducting such a study.

Adult↗
PubMed1997

Prospective randomized trial of lisofylline for the prevention of toxicities of high-dose interleukin 2 therapy in advanced renal cancer and malignant melanoma.

The therapeutic application of high-dose interleukin (IL) 2 in human malignancy is limited by severe multiorgan toxicities that are mediated, in part, by tumor necrosis factor (TNF) and IL-1. CT1501R (lisofylline; LSF) is one of several methyl xanthine congeners that inhibit the effects of TNF by the interruption of specific signal transduction pathways. This randomized, placebo-controlled trial was designed to assess the activity of LSF in reducing the toxicities of high-dose IL-2 therapy. Fifty-three patients with metastatic renal cancer or malignant melanoma were treated with i.v. bolus IL-2, 600, 000 IU/kg every 8 h for 5 days (14 doses), followed by 9 days of rest and another 5-day course of IL-2. Patients were randomly assigned to LSF, 1.5 mg/kg i.v. bolus, or placebo every 6 h during IL-2 therapy. All patients were to be treated to individual maximum tolerance of IL-2 at the intensive care unit level of support. The end points for statistical analysis were the number of IL-2 doses administered during the first cycle of treatment (maximum, 28) and the toxicities experienced by each group after the first 8 planned IL-2 doses. There was no difference between the LSF and placebo groups in the mean number of IL-2 doses tolerated in the entire first cycle of therapy (19.6 +/- 5.4 versus 19.5 +/- 5.8, P = 0.86) or in the first or second 5-day course of IL-2. The only significant difference in toxicities occurring through the eighth dose of IL-2 was in the maximum elevation of serum creatinine (mean, 1.7 +/- 0.8 for placebo versus 1.5 +/- 0.6 mg/dl for LSF, P = 0.013). A Monte Carlo analysis of major toxicities over the first 14-dose course of therapy showed a statistically significant difference favoring the LSF-treated group (P = 0.025). LSF was well tolerated, associated only with mildly increased nausea (P = 0.006 after eight IL-2 doses, but not significant for the entire first cycle). The antitumor activity was comparable in both groups (objective responses, 2 of 28 with LSF versus 4 of 24 with placebo). The mean peak plasma concentrations of LSF on days 1, 5, and 19 were 6.24, 3.83, and 5.04 micromol/liter, respectively. In conclusion, with this dose and schedule, LSF did not alter the toxicities of high-dose i.v. IL-2 sufficiently to impact the overall dose intensity of IL-2. Successful IL-2 toxicity modulation may require the use of higher doses of LSF, the development of agents with more potent anti-TNF activity, and/or combined modulating agents that function via distinct mechanisms to interrupt cytokine-mediated signaling.

Adult↗
PubMed1991

Lysis of autologous melanoma cells by tumor-infiltrating lymphocytes: association with clinical response.

Tumor-infiltrating lymphocytes (TILs) can be grown in vitro in medium containing interleukin-2 (IL-2). In clinical trials at the Surgery Branch of the National Cancer Institute, patients with metastatic malignant melanomas were treated with IL-2 plus the adoptive transfer of autologous TILs. At the time of treatment, TILs were assayed for in vitro lysis of fresh autologous and allogeneic melanoma cells and Daudi cells. Patients were evaluated for clinical response 4-8 weeks later. Lysis of autologous tumor cells by TILs was significantly higher for responding than for nonresponding patients. Tumor cells from responding and nonresponding patients were equally sensitive to lysis by allogeneic lymphokine-activated killer (LAK) cells. There was no difference between TILs from responding and nonresponding patients for lysis of LAK-sensitive Daudi cells, which was low in most cases and demonstrated that TIL lysis of autologous tumor cells was not due to LAK cells. The observed association of autologous tumor cell lysis by TILs with clinical response suggests that the development of culture methods to optimize lysis of autologous tumors may lead to increased response rates using this TIL treatment regimen.

Cell Division↗
PubMed1991

Lymphocytes as cellular vehicles for gene therapy in mouse and man.

The application of bone marrow gene therapy has been stalled by the inability to achieve stable high-level gene transfer and expression in the totipotent stem cells. We show that retroviral vectors can stably introduce genes into antigen-specific murine and human T lymphocytes in culture. Murine helper T cells were transduced with the retroviral vector SAX to express both neomycin-resistance and human adenosine deaminase genes. These cells were expanded in culture and selected for expression of neomycin resistance with G418. The gene insertion, selection, and culture expansion did not alter antigen specificity or growth characteristics of the T cells in vitro. To determine if cultured T cells might be used for gene therapy, their persistence and continued expression of the introduced genes was evaluated in nude mice transplanted with the SAX-transduced T cells. G418-resistant cells could be readily recovered from the spleens of recipients of transduced T cells for several months. In addition, recovered cells continued to produce human adenosine deaminase. Based on these observations, we studied cultured human tumor-infiltrating lymphocytes as a candidate cell for a trial of gene transfer in man. Exponential cultures of interleukin-2-stimulated tumor-infiltrating lymphocytes were efficiently transduced with the neomycin-resistance gene using the retroviral vector N2. Gene insertion and subsequent G418 selection did not substantially alter the growth characteristics, interleukin 2 dependence, membrane phenotype, or cytotoxicity profile of the transduced T cells. These studies provided a portion of the experimental evidence supporting the feasibility of the presently ongoing clinical trials of lymphocyte gene therapy in cancer as well as in patients with adenosine deaminase deficiency.

Animals↗
PubMed1988

Interleukin-2 administration causes reversible hemodynamic changes and left ventricular dysfunction similar to those seen in septic shock.

Interleukin-2, a lymphocyte product, has well demonstrated antitumor activity in humans. Early clinical studies showed hemodynamic alterations in patients receiving the drug as antitumor immunotherapy. We serially assessed interleukin-2-associated hemodynamic parameters and left ventricular ejection fractions in five patients with neoplastic diseases unresponsive to conventional therapies. By day 4 of therapy, compared with baseline (preinterleukin-2), all patients developed tachycardia (p less than 0.01), decreased mean arterial blood pressure (p less than 0.05), increased cardiac index (p less than 0.05), and decreased systemic vascular resistance (p less than 0.01). In addition, left ventricular ejection fraction fell from 58.0 +/- 4.7 to 36.4 +/- 4.0 percent (0.05 less than p less than 0.10), which was associated with a trend toward left ventricular dilatation manifested by an increase in left ventricular end-diastolic volume index. Transient renal dysfunction was noted in all five patients, and one developed transient respiratory failure; both types of organ dysfunction recovered to baseline values after cessation of immunotherapy. Thus, interleukin-2 induces multiple reversible cardiovascular abnormalities that are similar to the hemodynamic manifestations of human septic shock.

Adult↗
PubMed1983

Rheumatoid arthritis in a Chippewa band. II. Field study with clinical serologic and HLA-D correlations.

We present an in-depth study of rheumatoid arthritis (RA) in a Chippewa band. Of the 227 band members, 168 (74%) were evaluated. The unusually high prevalence of RA was confirmed in 7.1% of those studied or, minimally, 5.3% with a 100% completion rate without additional cases found. Seropositivity in those with clinically definite RA was 92% relative to rheumatoid factor and 75% for ANA. Despite the high prevalence (68%) of HLA-DR4 in this closed population, there was a significant correlation of DR4 with RA (100%). The implications of these observations in this population isolate are discussed.

Adolescent↗
PubMed1981

Rheumatoid arthritis in a Chippewa Band. I. Pilot screening study of disease prevalence.

The Mille Lacs Band of Chippewa Indians in central Minnesota was screened for rheumatoid arthritis, with a 77% completion rate of the reservation census. Rheumatoid arthritis was found in marked excess, namely 6.8% of those evaluated or, minimally, 5.3% of the total band if all persons had been evaluated with no additional cases identified. This relatively closed population thus provides an opportunity to assess genetic and environmental factors of significance in this disease.

Adolescent↗
PubMedDate not supplied

Monoacetyldapsone inhibition of dapsone N-hydroxylation by human and rat liver microsomes.

Dapsone (DDS) is metabolized by N-hydroxylation and N-acetylation to DDS hydroxylamine (DDS-NOH) and monoacetyldapsone (MAD), respectively. The activities of these two alternative and independent reactions vary widely between individuals and show an inverse relationship during chronic DDS therapy. Toxicity observed during DDS therapy has been attributed to DDS-NOH. The observation of reduced toxicity in rapid acetylators, who are also poor hydroxylators, therefore, raised the possibility that MAD may be inhibiting DDS-NOH formation. This hypothesis was tested in human and rat liver microsomes. Human liver microsomes hydroxylated DDS with a lower affinity (KM 2-fold greater) and lower maximal catalytic activity (Vmax 12-fold lower) than that of the rat. The relative catalytic activity (Vmax/KM) was 22-fold higher in rat compared with human liver microsomes. Furthermore, MAD was a potent inhibitor of DDS N-hydroxylation by rat liver microsomes (52% inhibition at 0.01 mM MAD) compared with human liver microsomes (23% inhibition at 0.4 mM MAD). Human, but not rat, liver microsomes deacetylated MAD to DDS by an NADPH independent mechanism. These results show that substantial differences exist in DDS N-hydroxylase between rats and humans, with respect to substrate affinity, enzyme activity, and susceptibility to inhibition, such that information obtained from the rat should not be extrapolated to humans. We conclude that MAD is a potent inhibitor of DDS-NOH formation in rat liver microsomes. The degree of inhibition in human microsomes, however, suggest that MAD is unlikely to be a significant modulator of enzyme activity in vivo.

Animals↗
PubMedDate not supplied

A phase II study of recombinant human interleukin-4 for advanced or recurrent non-small cell lung cancer.

PURPOSE: Recombinant human interleukin-4 is a pleiotropic cytokine that has shown antitumor activity in preclinical models and activity in phase I clinical trials. PATIENTS AND METHODS: This was a randomized phase II study testing two doses of recombinant human interleukin-4 (0.25 microgram/kg and 1.0 microgram/kg) administered subcutaneously three times per week in advanced non-small cell lung cancer. RESULTS: Sixty-three patients were enrolled (22 receiving 0.25 microgram/kg and 41 taking 1.0 microgram/kg); the median age was 61 years. Tumor histology included adenocarcinoma (41 patients), squamous cell carcinoma (12 patients), and other types (10 patients). The initial stage of disease was IIIb in 11 patients and IV in 52. Forty-four patients had received prior combination chemotherapy, predominantly cisplatin based. Recombinant human interleukin-4 was well tolerated, with no myelosuppression or elevations of liver enzymes, bilirubin, or blood glucose. The most frequent symptoms (any grade) in the 0.25-microgram dose were fatigue (13/22) and fever (8/22). Severe vomiting and dyspnea were observed in one patient each. In the 1.0-microgram dose group, a similar toxicity pattern (any grade) was seen, with fatigue (18/41), fever (14/41), and anorexia (12/41). One patient each had severe hypotension and chest pain. One patient was withdrawn from the study because of a perforated duodenal ulcer. Fifty-five patients were evaluable for response. In the 1.0-microgram group, there was one partial response of > 5.5 years' duration, and eight patients had stable disease of 106 to 350 days' duration. All patients had stage IV disease, and 24 patients had progressed during previous chemotherapy. In the 0.25-microgram group, one patient had stable disease. DISCUSSION: Recombinant human interleukin-4 can be administered safely and may have antitumor activity in non-small cell lung cancer. The higher dose (1.0 microgram/kg) may be associated with a higher incidence of stable disease. In view of the low toxicity seen at both dose levels, a phase II study investigating higher recombinant human interleukin-4 doses is ongoing. Recombinant human interleukin-4 should be explored further, alone or in combination with other cytokines, chemotherapy, or radiotherapy.

Adult↗