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Biomedical subjects

M Haas

Publications and source records attributed to M Haas.

At least 73 records · Page 4Linked to original sources
PubMed1999

Involvement of nuclear factor-kappaB in a murine model for the acute form of autoimmune-like toxic oil syndrome.

The toxic oil syndrome (TOS) represents an exogenously induced autoimmune disease with acute or chronic symptoms similar to systemic lupus erythematosus or scleroderma. When genetically different mouse strains were exposed to oleic acid anilide (OAA), it was possible to mimic the different syndrome manifestations. The aim of the present study was to examine the role of NF-kappaB/Rel transcription factors in the development of the severe acute wasting disease observed in A/J mice. Within a week of OAA exposure, the A/J, but not B10.S strain, displayed weight loss, cachexia, apathy, reduced activity, and breathing difficulties. In affected A/J mice we observed a marked increase in NF-kappaB activation (p50/p65 dimers) both in splenic T cells and peritoneal macrophages as well as in tissue from aorta and gut. Incubation of splenocytes with OAA in vitro induced a dose-dependent removal of IkappaB-alpha, accompanied by NF-kappaB activation, whereas Sp-1 binding was not affected. Furthermore, we demonstrated the increased expression of the two NF-kappaB target genes IL-6 and IL-1beta in OAA-exposed mice and a transient OAA-induced accumulation of TNFalpha in vitro. This is the first report which implicates NF-kappaB/Rel in acute forms of chemically induced autoimmune-like disease and may serve as a paradigm for the involvement of this transcriptional system in acute processes associated with autoimmunity, suggesting possible avenues of therapeutic intervention.

Acute Disease↗
PubMed1999

4-Hydroxynonenal prevents NF-kappaB activation and tumor necrosis factor expression by inhibiting IkappaB phosphorylation and subsequent proteolysis.

Extensively oxidized low density lipoprotein (ox-LDL), a modulator of atherogenesis, down-regulates the lipopolysaccharide (LPS)-induced activation of transcription factor NF-kappaB. We investigated whether 4-hydroxynonenal (HNE), a prominent aldehyde component of ox-LDL, represents one of the inhibitory substances. NF-kappaB activation by stimuli such as LPS, interleukin (IL)-1beta, and phorbol ester, but not tumor necrosis factor (TNF), was reversibly inhibited by HNE in a dose-dependent manner in human monocytic cells, whereas AP-1 binding was unaffected. Using similar HNE concentrations, LPS-induced kappaB- and TNF or IL-8 promoter-dependent transcription was prevented. Furthermore, pretreatment with HNE suppressed TNF production but not lactate dehydrogenase levels. Under these conditions the binding of LPS to monocytic cells was not significantly affected. However, induced proteolysis of the inhibitory proteins IkappaB-alpha, IkappaB-beta, and, at a later time point, IkappaB-epsilon was prevented. This is not due to inhibition of the proteasome, the major proteolytic activities of which remain unaffected, but rather to a specific prevention of the activation-dependent phosphorylation of IkappaB-alpha. This is the first report which demonstrates that HNE specifically inhibits the NF-kappaB/Rel system. Down-modulation of NF-kappaB-regulated gene expression may contribute at certain stages of atherosclerosis to low levels of chronic inflammation and may also be involved in other inflammatory/degenerative diseases.

Aldehydes↗
PubMed1999

p53 function influences the effect of fractionated radiotherapy on glioblastoma tumors.

PURPOSE: Glioblastoma multiforme brain tumors (GM) are treated with a spectrum of fractionation regimens based on the clinical and anatomical characteristics of the tumor but rarely based on the molecular characteristics of the individual neoplasm. This study tests the hypothesis that the response of cell lines derived from GM to fractionated radiotherapy depends on the function of wild-type p53 (wt p53), a tumor suppressor gene frequently mutated in GM tumors. METHODS & MATERIALS: Isogenic derivatives of glioblastoma cells differing only in p53 function were prepared using a retroviral vector expressing a dominant negative mutant of p53 (mt p53). Radiation survival in vitro was quantitated using linear quadratic and repair-saturation mathematical models. Apoptosis was assayed by a terminal deoxynucleotide transferase-labeling technique and chromatin morphology. RESULTS: We have previously reported the generation of isogenic GM cell lines differing only in p53 function. U87-175.4, lacking wt p53 function, had a significantly lower alpha/beta value than U87-LUX.8, expressing functional wt p53, leading us to hypothesize that fractionated irradiation would preferentially spare GM cells harboring mt p53 compared with those expressing functional, wt p53. Survival curves following either 2.0 Gy or 3.5 Gy/fraction demonstrated that lack of functional wt p53 was associated with resistance to fractionated irradiation. Radiation-induced apoptosis could not account for the observed differences in clonogenic survival. Rather, our data suggested that a deficit in the G1-checkpoint contributed to increased resistance to fractionated irradiation of cells expressing mutant p53. CONCLUSIONS: The effect of fractionated radiotherapy in GM may depend on the function of the tumor suppressor gene p53. A potential clinical consequence of these findings is that hyperfractionation regimens may provide a therapeutic advantage specifically for tumors expressing wt p53 whereas a radiotherapy course of fewer, larger fractions may be appropriate for the treatment of tumors carrying p53 mutations. Further studies are needed to confirm our proposal that the p53 status of GM tumors can be used to guide our choice of fractionation schemes.

Apoptosis↗
PubMed1999

Drug-induced acute interstitial nephritis in renal allografts: histopathologic features and clinical course in six patients.

Drug-induced acute interstitial nephritis is a common cause of dysfunction in native kidneys, but is rarely reported in renal allografts. This report describes six renal transplant recipients with acute renal allograft dysfunction or delayed allograft function in whom a renal transplant biopsy showed histopathologic features of drug-induced interstitial nephritis with no diagnostic evidence of acute rejection, cyclosporine or tacrolimus nephrotoxicity, or other lesion that could account for the graft dysfunction. In five of the six patients, interstitial nephritis occurred within 4 weeks of transplantation. All the patients were receiving trimethaprim-sulfamethoxazole and/or other drugs associated with interstitial nephritis. After discontinuation of these drugs and short-term corticosteroid treatment, all patients showed improvement in renal function, although the time course of this improvement varied considerably, with three patients showing a return to baseline serum creatinine level within 2 weeks and two patients showing a gradual improvement over 8 weeks. Four of the five patients followed up for more than 1 year (range, 14 to 33 months) after the episode of interstitial nephritis had good allograft function (serum creatinine level </= 1.6 mg/dL) at most recent follow-up, with one patient who had graft loss because of severe rejection 7.5 months after the development of interstitial nephritis. These findings suggest drug-induced interstitial nephritis may be an infrequent cause of graft dysfunction in kidney transplant recipients. Drug-induced interstitial nephritis is a reversible lesion that should be considered in the differential diagnosis of acute renal allograft dysfunction.

Acute Disease↗
PubMed1999

Smooth muscle-specific actin levels in the urine of renal transplant recipients: correlation with cyclosporine or tacrolimus nephrotoxicity.

Cyclosporine A (CSA) and tacrolimus (FK506) are powerful immunosuppressive agents that have proven useful for antirejection therapy in patients with solid organ transplants, including kidney. However, both drugs are nephrotoxic, each producing similar histological patterns of injury to renal tubules and preglomerular arterioles, and this toxicity is a major cause of renal allograft dysfunction. A renal transplant biopsy presently represents the most reliable means of diagnosing nephrotoxicity caused by CSA or tacrolimus and distinguishing it from acute rejection. Because CSA and tacrolimus nephrotoxicity often involve arteriolar smooth muscle, whereas vascular smooth muscle is rarely involved in acute rejection, we investigated if the appearance of a smooth muscle-specific isoform of alpha-actin (SMA) in the urine of renal transplant recipients about to undergo a biopsy for graft dysfunction correlated with biopsy evidence of CSA or tacrolimus toxicity. Eighty-nine urine samples from 61 patients, plus 6 samples from healthy control subjects, were analyzed in a blinded manner by enzyme-linked immunosorbent assay using a specific anti-SMA monoclonal antibody. For the patient samples, the results of these assays were then correlated with the biopsy findings. Those 40 cases in which the biopsy showed evidence of CSA or tacrolimus nephrotoxicity had a significantly (P < 0.01) greater SMA level in the corresponding urine samples (0.089 +/- 0.126 microgram/mL; mean +/- SD) than the 49 cases without toxicity (0.018 +/- 0.027 microgram/mL) or 6 control subjects (0.003 +/- 0.007 microgram/mL), although there was considerable overlap of SMA values among these groups. The greatest SMA levels were seen in patients with CSA or tacrolimus nephrotoxicity that was likely to be relatively acute, namely those with thrombotic microangiopathy and those without previous biopsy evidence of toxicity. SMA levels correlated significantly with the estimated severity of arteriolopathy on biopsy. In patients with tubular but not arteriolar lesions of CSA or tacrolimus toxicity, the mean SMA level was not significantly greater than that in patients without toxicity. Urine SMA levels in patients with a biopsy specimen showing acute rejection were not significantly different from those in patients without rejection, and there was no correlation between urine SMA level and severity of rejection. Whereas the degree of overlap of SMA levels in patients with and without nephrotoxicity was far too great to consider this assay as a potential alternative to renal transplant biopsy for the diagnosis of nephrotoxicity, the assay may have potential as a marker for active arteriolar injury in renal transplant recipients and other patients receiving CSA or tacrolimus therapy.

Actins↗
PubMed1999

Inhibition of T-cell acute lymphoblastic leukemia proliferation in vivo by re-expression of the p16INK4a tumor suppressor gene.

T-cell acute lymphoblastic leukemia (T-ALL) is characterized by the presence of differentiation-inhibited pro- and pre-T-cell blasts. The p16INK4a tumor suppressor gene has been shown to be frequently deleted in human T-ALL cases. Deletion of p16INK4a may be associated with poor prognosis and relapse of the disease. Radiation-induced murine T-ALL in C57B1/6 mice shares pathogenetic and molecular characteristics with the human disease. We used the murine disease as a model to study the status of the INK4/ARF gene locus and to examine the effect of p16INK4a-re-expression in T-ALL cells on their leukemic potential in vivo. In 9 of 17 radiation-induced murine T-ALL cell lines, the p16INK4a protein was not expressed as determined by immunoblotting. Southern blot analysis revealed homozygous deletions of the p16INK4a gene locus in three of the nine lines, along with the genes encoding p15INK4b and p19ARF. Transduction of p16INK4a-negative T-ALL lines with retrovirus encoding p16INK4a significantly inhibited their in vitro proliferation by inducing G1-arrest. Importantly, re-expression of p16INK4a in p16INK4a-negative T-ALL cells obliterated the induction of lethal disseminated leukemia in syngeneic mice. This is the first demonstration that re-establishment of p16INK4a expression is critical for in vivo growth regulation of T-ALL cells.

3T3 Cells↗
PubMed1999

Field intercomparison of diffusive samplers for measuring ammonia.

Agricultural production systems are recognised as a major source of atmospheric ammonia. Deposition of ammonia and ammonium may contribute to undesired changes in oligotrophic ecosystems. The continuous measurement of atmospheric ammonia requires expensive and sophisticated techniques and is performed only in a very restrict number of ambient air stations in Europe. Therefore, the application of passive samplers, which have the advantage of being easy to handle and cost-efficient, is useful. In the past the comparability of different passive samplers must be considered as rather scarce. In a joint European project under the leadership of the GSF-Forschungszentrum für Umwelt und Gesundheit, Neuherberg, in 1997 a comparison of different passive ammonia monitoring methods was carried out in a prealpine rural site near Garmisch-Partenkirchen. It was considered valuable to include not only well established systems but also methods still being developed. For the comparative test ten working groups with different methods took part. A wet annular denuder system, which has been developed by the Netherlands Energy Research Foundation for on-line measurement of atmospheric ammonia, served as reference of passive methods. The experiment, which started in June and finished in December, showed that most of the passive samplers fulfil the requirements and can be recommended for further measurements. Additional measurements of meteorological parameters were performed to check the influences of different weather conditions on passive sampling.

Agriculture↗
PubMed1999

Lipid-lowering therapy in membranous nephropathy.

Membranous nephropathy (MN) is a very common cause of nephrotic syndrome in adults, and lipid abnormalities are, therefore, frequently found in these subjects. Although efficient lipid-lowering therapy is available, almost nothing is known about the contribution of hyperlipidemia in the pathogenesis of progressive renal failure in MN. Studies in an experimental animal model of human MN, Heymann nephritis, have shown that lipids play an essential role in the pathogenesis of proteinuria. Local production of reactive oxygen species after subepithelial immune complex deposition leads to the formation of lipid peroxidation (LPO) adducts, which ultimately alter the composition of the glomerular basement membrane. As the magnitude of urinary protein excretion is associated with the long-term prognosis, a normalization of glomerular permselective properties has been used as a surrogate parameter for the beneficial effects of treatment. Probucol, a drug with LPO inhibitor potential, is able to reduce urinary protein excretion in rats with passive Heymann nephritis. In humans with MN, preliminary data also support this observation. It remains to be determined, however, if this intervention, which does not interfere with immune complex formation, will reduce the number of the patients reaching end-stage renal failure because of MN. In conclusion, lipids may contribute to glomerular injury in MN, as LPO might be an especially important factor, opening the possibility for new therapeutic interventions, thereby avoiding the side-effects of the currently used treatment regimen.

Glomerulonephritis, Membranous↗
PubMed1999

Persistent antihypertensive effect of oral nitrite supplied up to one year via the drinking water in spontaneously hypertensive rats.

The hypothesis was studied whether the chronic administration of nitrite lowers the blood pressure of spontaneously hypertensive rats (SHR) and prevents secondary hypertension-induced organ lesions. For this purpose totally 96 SHR received 50 to 75 mmol/l NaNO2 or equimolar amounts of NaHCO3 in their drinking water during 4, 8 or 12 months. At each point of time arterial blood pressure, determined with the tail cuff method, was significantly lower in the NaNO2-group in comparison to the controls indicating that no significant tolerance towards nitrite had developed. There was also a tendency towards reduced cardiac hypertrophy and renal atrophy in the NaNO2-group, however without reaching the level of significance. Drinking water containing 75 mmol NaNO2/l was not well tolerated by young rats in contrast to 50 mmol/l. Possible beneficial effects of high dietary nitrate/nitrite levels are discussed with respect to the low frequency of hypertension observed in vegetarians.

Administration, Oral↗
PubMed1999

The relationship of untreated borderline infiltrates by the Banff criteria to acute rejection in renal allograft biopsies.

The relationship of borderline infiltrates to acute rejection by Banff criteria in renal allografts of patients receiving only maintenance immunosuppression is not clear. Renal allograft biopsies with borderline lesions that were not treated with additional anti-rejection therapy were retrospectively studied. Sixty-five such biopsies were identified from 50 patients, and their outcome was determined by serum creatinine and/or histologic findings in subsequent biopsies, up to 40 d after the initial biopsy. In addition to the borderline infiltrates, there was evidence of acute cyclosporine or tacrolimus toxicity (58%), acute tubular necrosis (12%), and urinary obstruction (12%). Forty-day follow-up after 30 (46%) biopsies revealed serum creatinine < 110% of baseline, and repeat biopsies were not indicated. In 17 (26%), the serum creatinine initially decreased, then increased, and follow-up biopsies showed acute rejection in nine. In 18 (28%), the creatinine remained elevated and follow-up biopsies revealed acute rejection in nine. The untreated borderline infiltrates were thus nonprogressive after 47 biopsies (72%) and progressed to histologic acute rejection after 18 (28%). When there was increasing or persistently elevated creatinine after the initial biopsy, 51% of cases (18 of 35) progressed to acute rejection. Infiltrates that progressed to rejection had more frequent glomerulitis (7 of 18 versus 3 of 47, P = 0.003) and Banff acute score indices (i+t+v+g) >2 (16 of 18 versus 29 of 47, P = 0.03). A majority (72%) of borderline infiltrates not given additional anti-rejection therapy did not progress to acute rejection over 40 d of follow-up, suggesting that conservative management of these lesions, at least in the short term, may be more appropriate than routine treatment as acute rejection.

Adolescent↗
PubMed1999

Building a dialysis facility within the confines of a skilled nursing facility.

Creating a dialysis facility within an existing SNF will cost more money then building an independent dialysis facility. If a new building is created and is physically attached to the existing SNF, it will have to meet the regulations that apply to the SNF. It is possible to build a new building adjacent to but not connected with the SNF without having to meet SNF requirements. If this is an option, then it is imperative to determine with the local authorities how much space must be between the structures. If the decision is made to build within the physical confines of the existing SNF, the SNF may no longer meet current regulations. In some cases I have seen, the SNF facility was older and had been grandfathered under current regulations. When the building inspector and fire marshall inspected the new dialysis unit, they made the determination that the SNF had to be upgraded to meet some of the current regulations. This was a very costly situation for the SNF. If the organization is considering creating a dialysis unit in conjunction with a SNF, I would recommend the dialysis unit be constructed as a new, separate building on the campus rather then within the existing building. The combination of these two types of care can be very positive both for the patients and the organizations.

Ambulatory Care Facilities↗
PubMed1998

Enrichment for DNA mismatch repair-deficient cells during treatment with cisplatin.

In addition to playing a role in tumorigenesis, loss of DNA mismatch repair results in low-level intrinsic resistance to cisplatin and carboplatin. We used a mismatch repair-deficient (clone B) and -proficient (clone B/rev) pair of Chinese hamster ovary sublines to determine the ability of cisplatin to enrich for repair-deficient cells during growth in vitro and in vivo. Clone B cells were 1.8-fold resistant to cisplatin as measured by a clonogenic assay. These cells were molecularly engineered to express constitutively the green fluorescent protein, and changes in the fraction of these repair-deficient cells were monitored by flow cytometric analysis. A single 1-hr exposure to cisplatin at an IC50 concentration enriched populations initially containing either 5 or 10% clone B cells by 81 and 75%, respectively, when measured at 5 days. Enrichment increased as a function of drug concentration to 158 and 169%, respectively, following an IC90 exposure. When grown as a xenograft, a single LD10 dose of cisplatin enriched the tumors by 48% from 4.6 to 6.8% repair-deficient cells (p = 0.04). To determine whether similar enrichment occurs during the treatment of human ovarian cancer patients, paired tumor samples were obtained from 38 patients before and after treatment with a minimum of 3 cycles of platinum drug-based primary chemotherapy and analyzed immunohistochemically for changes in the fraction of tumor cells expressing hMHL1. Following treatment there was a reduction in hMLH1 staining in 66% of the cases (p = 0.0005). Our results demonstrate that, despite the fact that loss of mismatch repair yields only modest levels of cisplatin resistance, even a single exposure to cisplatin produces quite a marked enrichment for repair-deficient cells in vitro and in vivo. Our results are consistent with the concept that treatment with cisplatin or carboplatin selects for preexisting mismatch repair-deficient cells, and that this contributes to the frequent development of clinical resistance.

Adaptor Proteins, Signal Transducing↗