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D Brenner

Publications and source records attributed to D Brenner.

At least 19 recordsLinked to original sources
PubMed2006

Sustained JNK signaling by proteolytically processed HPK1 mediates IL-3 independent survival during monocytic differentiation.

We studied monocytic differentiation of primary mouse progenitor cells to understand molecular mechanisms of differentiation. We found a tightly controlled non-apoptotic activation of caspase-3 that correlated with differentiation. Although caspase activity was already detected during monocytic differentiation, a caspase-3 target has not been identified yet. We show that hematopoietic progenitor kinase 1 (HPK1) is processed towards its N- and C-terminal fragments during monocytic differentiation. While HPK1 is an immunoreceptor-proximal kinase in T and B cells, its role in myeloid cells is elusive. Here, we show that the N-terminal cleavage product, HPK1-N, comprising the kinase domain, confers progenitor cell survival independent of the growth factor IL-3. Furthermore, HPK1-N causes differentiation of progenitor cells towards the monocytic lineage. In contrast to full-length kinase, HPK1-N is constitutively active causing sustained JNK activation, Bad phosphorylation and survival. Blocking of caspase activity during differentiation of primary mouse progenitor cells leads to reduced HPK1-N levels, suppressed JNK activity and attenuated monocytic differentiation. Our work explains growth factor-independent survival during monocytic differentiation by caspase-mediated processing of HPK1 towards HPK1-N.

Animals↗
PubMed2006

The role of CAP3 in CD95 signaling: new insights into the mechanism of procaspase-8 activation.

Formation of the CD95 (APO-1/Fas) death inducing signaling complex (DISC) plays a central role in CD95 signaling. Previously, CD95 DISC composition was analyzed by two-dimensional gel electrophoresis and four major cytotoxicity-associated proteins (CAP1-4) were found. CAP1 and CAP2 were defined to be unmodified and phosphorylated FADD, respectively. CAP4 was identified as procaspase-8a. CAP3, however, has remained elusive. In this study, we demonstrate that CAP3 is an intermediate of procaspase-8 processing. CAP3 is generated within seconds of DISC formation and subsequently processed to the prodomain of procaspase-8a that is known as p26 (CAP5). These findings lead to new insights into the mechanism of procaspase-8 processing and apoptosis initiation.

Amino Acid Chloromethyl Ketones↗
PubMed2001

Revising the preventive paradox: the Swiss case.

AIMS: To examine Kreitman's preventive paradox of alcohol consumption and its revisions by Stockwell and colleagues and by Skog, with regard to alcohol-related social harm in Switzerland, and to shed light on the reporting of alcohol-related social harm in the low-volume drinking, non-binging subpopulation. The paper compares occurrence and severity of social harm in four subgroups defined by average consumption (volume) and binge drinking. Stage-of-change membership was used to further distinguish low-risk drinkers who might have changed their drinking patterns from those who had not. DESIGN, SETTING, AND PARTICIPANTS: Telephone interviews were conducted with 1256 current drinkers of a probabilistic two-stage sample of the general population of Switzerland. Moderate and hazardous mean consumption (volume) was defined by means of a quantity-frequency instrument. Daily average consumption of 20 g was set as the cut-off point for women, and 30 g for men. Binge drinking was defined as taking four or more drinks on an occasion for women, and five or more for men. Structural equation modelling was used to construct a severity scale of six alcohol-related consequences: work problems, accidents and problems with the police, with friends, with a partner or with the family. Explanatory factor analysis was used to assign drinkers to motivational stages of change. FINDINGS: Moderate drinkers in terms of volume reported more problems than hazardous drinkers, which confirms Kreitman's view. Binge drinkers reported more problems than non-binge drinkers, confirming the view of Stockwell and colleagues. Binge drinkers were more numerous in the moderate drinking group, which constituted the majority of drinkers, in accordance with Skog's view. Binge drinkers in the moderate-volume and hazardous-volume drinking groups did not differ significantly as to either severity or number of problems. Approximately 40% of moderate-volume, non-binge drinkers who reported alcohol-related social harm had already changed their consumption pattern, which indicated that reported harm was related to an earlier drinking pattern. CONCLUSIONS: As Skog has pointed out, the second-order preventive paradox of binge drinking reappeared, in that most binge drinkers were found to occur in the drinker group with low average consumption. Findings also indicate that, with respect to social harm, a preventive strategy aimed at the majority of the population, but on heavy-drinking occasions rather than on mean consumption, may be valuable.

Adolescent↗
PubMed2001

Estimated risks of radiation-induced fatal cancer from pediatric CT.

OBJECTIVE: In light of the rapidly increasing frequency of pediatric CT examinations, the purpose of our study was to assess the lifetime cancer mortality risks attributable to radiation from pediatric CT. MATERIALS AND METHODS: Organ doses as a function of age-at-diagnosis were estimated for common CT examinations, and estimated attributable lifetime cancer mortality risks (per unit dose) for different organ sites were applied. Standard models that assume a linear extrapolation of risks from intermediate to low doses were applied. On the basis of current standard practice, the same exposures (milliampere-seconds) were assumed, independent of age. RESULTS: The larger doses and increased lifetime radiation risks in children produce a sharp increase, relative to adults, in estimated risk from CT. Estimated lifetime cancer mortality risks attributable to the radiation exposure from a CT in a 1-year-old are 0.18% (abdominal) and 0.07% (head)-an order of magnitude higher than for adults-although those figures still represent a small increase in cancer mortality over the natrual background rate. In the United States, of approximately 600,000 abdominal and head CT examinations annually performed in children under the age of 15 years, a rough estimate is that 500 of these individuals might ultimately die from cancer attributable to the CT radiation. CONCLUSION: The best available risk estimates suggest that pediatric CT will result in significantly increased lifetime radiation risk over adult CT, both because of the increased dose per milliampere-second, and the increased lifetime risk per unit dose. Lower milliampere-second settings can be used for children without significant loss of information. Although the risk-benefit balance is still strongly tilted toward benefit, because the frequency of pediatric CT examinations is rapidly increasing, estimates that quantitative lifetime radiation risks for children undergoing CT are not negligible may stimulate more active reduction of CT exposure settings in pediatric patients.

Adolescent↗
PubMed2000

The glutathione precursor L-2-oxothiazolidine-4-carboxylic acid protects against liver injury due to chronic enteral ethanol exposure in the rat.

L-2-oxothiazolidine-4-carboxylic acid (OTC) is a cysteine prodrug that maintains glutathione in tissues. Here, its effect on alcohol-induced liver injury in an enteral alcohol feeding model was investigated. Male Wistar rats were given control high-fat or ethanol containing diets enterally for 4 weeks. Treated rats received 500 mg/kg/d of dietary OTC. Ethanol delivery, weight gain, and the cyclic pattern of ethanol in the urine were not different between the OTC-ethanol and ethanol groups. After 4 weeks, serum aspartate transaminase (AST), necrosis and inflammation were elevated significantly by ethanol compared with appropriate high-fat controls, effects blocked by OTC. Moreover, ethanol elevated hepatic tumor necrosis factor alpha (TNF-alpha) messenger RNA (mRNA) and the nuclear transcription factor nuclear factor kappaB (NFkappaB) 2-3 fold. NFkappaB in isolated Kupffer cells was also increased by ethanol. These effects were all blocked by OTC treatment. Additionally, superoxide production was higher in Kupffer cells isolated from ethanol-treated rats, an effect blunted by OTC. OTC also increased circulating glutathione (GSH) levels about 2-fold; however, GSH levels were not affected by ethanol or OTC in livers from the groups studied. Surprisingly, GSH was elevated by ethanol and OTC treatment in isolated Kupffer cells about 2-fold. Moreover, GSH (Ki-10 micromol/L) and cysteinyl-glycine, but not oxidized glutathione (GSSG) or OTC, blunted the LPS-induced increase in calcium in isolated Kupffer cells, possibly by activating a glycine-gated chloride channel due to their structural similarity with glycine. Collectively, it is concluded that GSH is protective, in part, by increasing circulating GSH, which blunts activation of Kupffer cells via the glycine-gated chloride channel.

Animals↗
PubMed2000

A polymer, random walk model for the size-distribution of large DNA fragments after high linear energy transfer radiation.

DNA double-strand breaks (DSBs) produced by densely ionizing radiation are not located randomly in the genome: recent data indicate DSB clustering along chromosomes. Stochastic DSB clustering at large scales, from > 100 Mbp down to < 0.01 Mbp, is modeled using computer simulations and analytic equations. A random-walk, coarse-grained polymer model for chromatin is combined with a simple track structure model in Monte Carlo software called DNAbreak and is applied to data on alpha-particle irradiation of V-79 cells. The chromatin model neglects molecular details but systematically incorporates an increase in average spatial separation between two DNA loci as the number of base-pairs between the loci increases. Fragment-size distributions obtained using DNAbreak match data on large fragments about as well as distributions previously obtained with a less mechanistic approach. Dose-response relations, linear at small doses of high linear energy transfer (LET) radiation, are obtained. They are found to be non-linear when the dose becomes so large that there is a significant probability of overlapping or close juxtaposition, along one chromosome, for different DSB clusters from different tracks. The non-linearity is more evident for large fragments than for small. The DNAbreak results furnish an example of the RLC (randomly located clusters) analytic formalism, which generalizes the broken-stick fragment-size distribution of the random-breakage model that is often applied to low-LET data.

Animals↗
PubMed2000

Tumor necrosis factor alpha in the pathogenesis of human and murine fulminant hepatic failure.

BACKGROUND & AIMS: The tumor necrosis factor (TNF)-alpha/TNF receptor system is critical for liver development because hepatocytes undergo apoptosis if the antiapoptotic cascades resulting in RelA NF-kappaB activation are not effective. Therefore, we studied the role of TNF-alpha in fulminant hepatic failure (FHF) and developed a new therapeutic strategy. METHODS: Serum levels and hepatic expression of TNF-alpha and both TNF receptors were determined by enzyme-linked immunosorbent assay and immunohistochemistry. Adenoviral vectors were constructed expressing dominant-negative proteins interfering with intracellular TNF-alpha-dependent pathways. The relevance of these constructs was studied in primary mouse hepatocytes and in a murine model of FHF. RESULTS: Serum levels of TNF-alpha and TNF receptors are significantly increased in FHF; this increase correlates with patient prognosis. In livers of patients with FHF, infiltrating mononuclear cells express high amounts of TNF-alpha and hepatocytes overexpress TNF receptor 1 (TNF-R1). Apoptotic hepatocytes are significantly increased in FHF, and there is a strong correlation with TNF-alpha expression, which is even more pronounced in areas of mononuclear infiltrates. In an in vivo FHF model, the Fas-associated death domain (FADD), adenovirus selectively blocked the intracellular pathway, leading to mitochondrial cytochrome c release, caspase-3 activation, and, thus, apoptosis of hepatocytes. CONCLUSIONS: The results show that the TNF-alpha/TNF-R1 system is involved in the pathogenesis of FHF in humans. Studies in this animal model indicate that FADD may serve as a molecular target to prevent liver cell death in vivo.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Functional receptors in the avian kidney for C-type natriuretic peptide.

Renal actions of avian-specific C-type natriuretic peptide (chCNP) were investigated in the conscious Pekin duck. Under conditions of steady-state renal water and salt elimination, systemic chCNP administration (6 and 30 pmol/min x kg BW for 20 min) dose dependently induced transient natriuresis and diuresis. Mean arterial pressure and heart rate remained constant throughout the experiment. Employing receptor autoradiography, binding sites specific for [125I]BH-chCNP could be localized at high density in glomeruli of both reptilian- and mammalian-type nephrons, and arterioles of the avian kidney. The distal tubular zone revealed [125I]BH-chCNP binding sites at medium, the medullary cone area at low density. Using an enriched kidney membrane fraction, competitive displacement studies with [125I]BH-chCNP as radioligand and various unlabeled peptide analogs (chANP, chCNP, rANP, rBNP, frANP, rANP(4-23)) allowed the discrimination of high-affinity (IC50 values 10(-10)-10(-9) M) and low-affinity (IC50 values 10(-8)-10(-7) M) binding sites different from typical mammalian receptor subtypes. Intracellular cyclic GMP formation could be demonstrated immunocytochemically for both types of glomeruli and cells of the distal tubular zone in fixed tissue sections after in vivo application of chCNP (0.8 nmol/min x kg BW; 5 min). The results obtained by combination of physiological in vivo studies and in vitro receptor analysis indicate an important role for chCNP in the modulation of avian kidney function.

Animals↗
PubMed1999

Thrombostatin inhibits induced canine coronary thrombosis.

Thrombostatin (RPPGF), an angiotensin converting enzyme metabolite of bradykinin, is an inhibitor of alpha-thrombin's ability to activate platelets. We examined the in vivo pharmacokinetics and pharmacodynamics of thrombostatin in rabbits and its ability to inhibit coronary thrombosis induced by electrolytic injury in dogs. Plasma half-life of thrombostatin had a t1/2alpha of 2.6 min and a t1/2beta of 24 min in rabbits. Ligating the renal arteries did not prolong clearance (t1/2alpha = 2.4 min; t1/2beta = 12 min). Thrombostatin produced a prolonged in vivo antiplatelet effect. At 30 min after a single intravenous administration in rabbits, thrombostatin's plasma concentration was <8.7 microM (5 microg/ml). However, ex vivo 20 and 40 nM gamma-thrombin-induced platelet aggregation of these rabbits' platelets was inhibited 40% for 2.75 and 1 h, respectively. In vitro, flow cytometry studies revealed that thrombostatin specifically bound to human platelets and washed human platelets treated with thrombostatin were less responsive to gamma-thrombin than control platelets. Using electrolytic injury to induce coronary artery thrombosis, dogs treated with thrombostatin, aspirin, or combined thrombostatin and aspirin occluded in 62+/-25 (mean +/- SD), 62+/-36, or 89+/-32 min versus untreated animals which occluded at 39+/-27 min, (p<0.01, p<0.01 and p<0.001, respectively). These studies show that thrombostatin binds to platelets and can delay coronary occlusion in vivo.

Amino Acid Sequence↗
PubMed1998

The pharmacokinetics of the kininogens.

Recent evidence has shown that plasma high molecular weight kininogen and both kininogens have the ability to modulate prekallikrein activation and thrombin-induced platelet activation, respectively. However, nothing is known about the plasma clearance and tissue distribution of these proteins. We examined the in vivo pharmacokinetics of high (HK) and low (LK) molecular weight kininogens in rats. 125I-HK and -LK molecular weight kininogens' clearance in rats best-fitted a biexponential model. For HK, the t1/2alpha and t1/2beta were 0.6 and 9.5 h and for LK, 0.78 and 7.4 h, respectively. 125I-kinin-free HK (cleaved HK) was cleared with a t1/2alpha and t1/2beta of 0.45 and 9.9 h, respectively. 125I-Domain 3 of kininogens was cleared with a t1/2beta and t1/2c of 0.99 and 13.3 h, respectively. HK was mostly concentrated in lung; LK, domain 3, and cleaved HK were mostly concentrated in kidney. The kininogens were also concentrated in liver, spleen, and skin. These studies indicate that protein size rather than form is the major determinant of its clearance. Furthermore, the distribution of the kininogens is where bradykinin metabolism and activity are well described.

Animals↗
PubMed1998

Molecular defects in ferrochelatase in patients with protoporphyria requiring liver transplantation.

Protoporphyria is a genetic disorder in which a deficiency of mitochondrial ferrochelatase activity causes accumulation of protoporphyrin that produces severe liver damage in some patients. In this study, mutations of the ferrochelatase gene were examined in eight unrelated patients who had liver transplantation. RNA was prepared from liver and/ or lymphoblasts, and specific reverse transcriptase-nested polymerase chain reactions amplified and sequenced ferrochelatase cDNAs. Products shorter than normal resulted from an exon 3 deletion in three patients, exon 10 deletion in two, exon 2 deletion in one, and deletion of five nucleotides in exon 5 in one. Sequence of normal-size products revealed no other mutations. Western blot showed a reduced quantity of normal-size ferrochelatase protein in protoporphyria liver compared with normal liver (19-51%, mean 32% of normal). Levels of the mitochondrial protein F1-ATPase beta-subunit were not decreased to a similar degree. Liver ferrochelatase activity was reduced more than could be explained by the decrease in ferrochelatase protein (4-20%, mean 9% of normal). These results establish genetic heterogeneity in the most severe phenotype of protoporphyria. However, the gene mutations found share the property of causing a major structural alteration in the ferrochelatase protein.

Adolescent↗
PubMed1998

Sublethal damage repair times for a late-responding tissue relevant to brachytherapy (and external-beam radiotherapy): implications for new brachytherapy protocols.

PURPOSE: Data were analyzed from recent experiments with the end point of late rectal obstruction in rats, involving acute and various protracted radiation exposures. Because the end point is of direct relevance both for brachytherapy as well as external beam radiotherapy, the goal was to estimate the linear-quadratic (LQ) parameters alpha/beta and T1/2, which are of importance for designing improved protraction/fractionation schemes. METHODS AND MATERIALS: The data were fit to the LQ model, both in its standard form and in a form in which two different components of sublethal damage repair-fast and slow-are assumed. The design of the experiments was such that both slow and reasonably fast sublethal damage repair components should be separately estimated, if they were contributing to a significant degree. RESULTS: LQ parameter estimates were alpha/beta = 4.6 Gy [4.0, 5.5] and T1/2 = 70.2 min [59.1, 91.4]. Despite the experimental design facilitating detection of a rapid component of repair, no statistically robust evidence for a very fast repair component was found. CONCLUSIONS: The long estimated repair time for a late-responding normal-tissue end point with direct relevance to brachytherapy suggests a variety of possible brachytherapy protocols that may be more efficacious than continuous low dose rate irradiation. Just as a difference in alpha/beta ratios between early- and late-responding tissues are a central tenet in radiotherapy, so corresponding differences in T1/2 values have the potential to be exploited, particularly for brachytherapy.

Animals↗
PubMed1998

Usage patterns of transdermal nicotine when purchased as a non-prescription medicine from pharmacies.

OBJECTIVE: To assess nicotine patch use in smokers who purchased the product as a non-prescription medicine from pharmacies. DESIGN: A questionnaire administered at the time of purchase. SETTING: Community pharmacies throughout New Zealand. SUBJECTS: A total of 805 male and female purchasers of nicotine patches aged 18 through 87 years. MAIN OUTCOME MEASURES: Patterns of usage including self-reported smoking history, previous quit-smoking attempts, previous and current use of transdermal nicotine and other products, side effects, and concomitant smoking. RESULTS: Most respondents (74%) had attempted to quit smoking previously, many of whom (53%) had used a non-prescription nicotine replacement product. Approximately 60% of purchasers were first-time users. For those continuing a course of treatment, there was no evidence of use for longer than the manufacturer's recommendation (12 weeks). Twenty-eight per cent of respondents reported continuing smoking while using transdermal nicotine, although the number of cigarettes smoked was much less than in the reported smoking history. Side effects were reported by 24% of patch users in the current course, but there was no evidence of significant safety problems. CONCLUSIONS: This survey provides preliminary data on the non-prescription usage of transdermal nicotine when purchased through pharmacies.

Administration, Cutaneous↗
PubMed1998

The role of gut-derived bacterial toxins and free radicals in alcohol-induced liver injury.

Previous research from this laboratory using a continuous enteral ethanol (EtOH) administration model demonstrated that Kupffer cells are pivotal in the development of EtOH-induced liver injury. When Kupffer cells were destroyed using gadolinium chloride (GdCl3) or the gut was sterilized with polymyxin B and neomycin, early inflammation due to EtOH was blocked. Anti-tumour necrosis factor (TNF)-alpha antibody markedly decreased EtOH-induced liver injury and increased TNF-mRNA. These findings led to the hypothesis that EtOH-induced liver injury involves increases in circulating endotoxin leading to activation of Kupffer cells. Pimonidazole, a nitro-imidazole marker, was used to detect hypoxia in downstream pericentral regions of the lobule. Following one large dose of EtOH or chronic enteral EtOH for 1 month, pimonidazole binding was increased significantly in pericentral regions of the liver lobule, which was diminished with GdCl3. Enteral EtOH increased free radical generation detected with electron spin resonance (ESR). These radical species had coupling constants matching alpha-hydroxyethyl radical and were shown conclusively to arise from EtOH based on a doubling of the ESR lines when 13C-EtOH was given. Alpha-hydroxyethyl radical production was also blocked by the destruction of Kupffer cells with GdCl3. It is known that females develop more severe EtOH-induced liver injury more rapidly and with less EtOH than males. Female rats on the enteral protocol exhibited more rapid injury and more widespread fatty changes over a larger portion of the liver lobule than males. Plasma endotoxin, ICAM-1, free radical adducts, infiltrating neutrophils and transcription factor NFkappaB were approximately two-fold greater in livers from females than males after 4 weeks of enteral EtOH treatment. Furthermore, oestrogen treatment increased the sensitivity of Kupffer cells to endotoxin. These data are consistent with the hypothesis that Kupffer cells participate in important gender differences in liver injury caused by ethanol.

Animals↗
PubMed1997

Use of topical NSAIDs in patients receiving systemic NSAID treatment: a pharmacy-based study in Germany.

Topical non-steroidal anti-inflammatory drugs NSAID account for two-thirds of the most frequently prescribed NSAIDs in Germany. Nevertheless, the extent of use and the benefit of local NSAIDs are viewed critically. We described the use of topical NSAIDs in people with systemic NSAID therapy. The study population consisted of 526 people with an average age of 57 years; two-thirds of the patients were women. We observed that the elderly (60 years and older) and patients with osteo- and/or rheumatoid arthritis had an increased likelihood of being treated with both topical and systemic NSAIDs. We suggest that the frequent use of topical NSAIDs in these patients is based on their supportive therapeutic effect rather than on their efficacy. Further research is needed in order to investigate the potential beneficial effects of topical NSAIDs in NSAID therapy.

Administration, Topical↗
PubMed1997

Modeling the cornea with the topographic modeling system videokeratoscope.

The algorithms and models used by the Topographic Modeling System (TMS) corneal topography systems are described. The systems are calibrated to report the power at a number of points along each of 256 meridians. The power reported is the power of an equivalent sphere. From the radius of the equivalent sphere and the optical properties of the videokeratoscope, shape and a more accurate estimate of power are calculated. The TMS differs from most other videokeratoscopic systems in that it estimates the power and does not use axial distance.

Cornea↗