PubMed Health⌕ Search

Biomedical subjects

C Hofmann

Publications and source records attributed to C Hofmann.

At least 91 records · Page 5Linked to original sources
PubMed1994

Glucose transporters (GLUT1, 2, & 4) in fat, muscle and liver in a rat model of endotoxic shock.

To explore the mechanisms for hypoglycemia in our rat model of septic shock, we examined whether changes occur in glucose transporter isoform protein level. Total membrane protein fractions were collected from tissues 6 to 8 hours after endotoxin injection at which time animals exhibited hypoglycemia (7.2 +/- 0.5 vs. 2.6 +/- 1.2mM) and lactacidemia (1.0 +/- 1.0 vs. 5.1 +/- 1.8mM/L) as compared to saline-treated controls. The protein level of glucose transporter isoforms GLUT1 and 4 in fat did not significantly change in septic shock when compared to control animals (126 +/- 22% and 114 +/- 79%, respectively). Likewise, no change was seen in GLUT1 or 4 in muscle (124 +/- 52% and 101 +/- 28%, respectively). The protein abundance of isoforms GLUT1 and 2 in liver were not significantly altered (123 +/- 35% and 101 +/- 23%, respectively). Septic shock induced hypoglycemia cannot be directly explained by changes in total glucose transporter protein levels.

Adipose Tissue↗
PubMed1994

Phase I study of the novel distamycin derivative tallimustine (FCE 24517).

BACKGROUND: Tallimustine, a benzoyl nitrogen mustard derivative of the antiviral agent distamycin A, is a new alkylating agent which binds to A-T rich regions of DNA in the minor groove producing highly sequence-specific alkylations. Its main preclinical features are a significant antitumor activity in animal models and a lack of cross-resistance in vitro and in vivo with L-PAM. Myelotoxicity was dose-limiting in animals, with a more than 100-fold difference in bone marrow sensitivity between mice and dogs. PATIENTS AND METHODS: Forty adult patients (pts) with solid malignancies were entered in the study. The drug was administered as an IV bolus every 4 weeks. CBC was repeated twice a week and serial assessments of renal function were performed in the week following the first cycle. From the starting dose of 50 micrograms/m2, corresponding to 1/3 of the highest non-toxic dose (HNTD) in dogs, there were increases through 10 dose levels, with reliance only on the features of the myelotoxicity observed. RESULTS: The main toxic effect was neutropenia which was dose-limiting, selective and short-lasting. Only previously-untreated pts received doses of 750 micrograms/m2 or more, with grade 4 neutropenia occurring in > or = 75% of the cycles. The maximally tolerable dose (MTD) was defined as 1250 micrograms/m2, with 3 of 3 pts developing febrile neutropenia requiring IV antibiotics. A platelet count of < 100 x 10(3)/microliters was observed in only one pt. Bone marrow aspiration performed in selected pts on days 8 and 15 confirmed a highly selective impairment by tallimustine of the myeloid lineage, with rapid recovery of the proliferative compartment. Pharmacokinetic studies performed at 1000 micrograms/m2 and 1250 micrograms/m2 showed a rapid fall of the plasma levels within the first 2 hours with drug concentrations between 100 ng/ml and 400 ng/ml within the first hour. A partial response of 4 months' duration was reported in one previously-untreated pt with cutaneous recurrences of malignant mesothelioma. CONCLUSIONS: The report of some antitumour efficacy, the high selectivity of neutropenia, the lack of significant non-hematological toxic effects and the occurrence of detectable but still low plasma drug concentrations suggest that further clinical evaluation of higher doses of tallimustine in combination with colony-stimulating factors would be justified.

Adult↗
PubMed1994

Altered gene expression for tumor necrosis factor-alpha and its receptors during drug and dietary modulation of insulin resistance.

As obesity is a major risk factor for noninsulin-dependent diabetes mellitus, adipose tissue may generate a mediator that influences the activity of insulin on various target tissues. Recent evidence suggests that a cytokine, tumor necrosis factor-alpha (TNF alpha), may serve this role. This study investigates whether the expression of TNF alpha and its receptors is modulated during drug treatment to reduce insulin resistance. The effects of moderate weight loss by dietary restriction were also examined. We show here that a marked induction of TNF alpha mRNA occurs in adipose tissues from a mouse model of obesity-linked diabetes (KKAy) compared to that in nondiabetic mice (C57). Likewise, RNA transcripts encoding TNF R2 receptors (p75) were significantly increased in fat tissues of the obese diabetic animals. In muscle from these diabetic animals, RNA transcripts encoding both TNF R1 (p55) and R2 were significantly elevated, although R2 transcript abundance was less elevated than in fat. We also observed that the overexpression of mRNA for TNF alpha and both of its receptors could be at least partly normalized by treatment of the diabetic animals with the insulin-sensitizing agent pioglitazone. Treating of the obese diabetic animals by food restriction reduced the expression of mRNA for TNF R2 in muscle, but not fat. These results clearly indicate that gene expression for the TNF systems can be regulated by an insulin-sensitizing drug and reduction of body weight. Such findings support a role for this cytokine in the insulin-resistant diabetic state and show its modulation by therapies that reverse the disorder.

Animals↗
PubMed1994

[The peripartal disease complex of the mother sow in the industrial swine facility. 3. Slaughter findings of old sows with anamnesis of peripartal diseases].

In an industrial pig production unit ten sows were selected at random. All the sows had a puerperal disease in their anamnesis. The sows were slaughtered after weaning and subjected to pathological examination. The mammary glands, uteri and bladder of ten slaughtered sows were examined for gross pathological alterations. All the sows showed symptoms of chronic mastitis (abscess, granuloma, fibrosis or cysts). Four of the examined uteri showed pathological alterations. Nine out of the ten bladders examined revealed pathological findings.

Abattoirs↗
PubMed1994

[The peripartum disease complex of the sow in industrial swine breeds. 1. Peripartum course of bacteriuria of sows with vaginal-vulvar discharge in a modern swine breeding facility].

In an industrial pig production unit ten sows were selected at random. All the sows had puerperal disease in their anamnesis and all of them revealed at the time of selection--during their late pregnancy--Urinary Tract Infection (UT)I and vaginal-vulvar discharge (VD). Mid-stream early morning urine samples were collected during four days ante partum and during four days post partum. The samples were semiquantitatively examined for E. coli and gram positive cocci. Three sows showed ante partum non significant bacteriuria which turned into significant bacteriuria post partum. The majority of the reminding sows revealed a significant bacteriuria during the whole period of examination.

Animals↗
PubMed1994

[The peripartum disease complex of the sow in commercial swine breeding. 2. The effect of prepartum bacteriuria on the peripartum and postpartum occurrence of puerperal diseases in the sow with anamnesis of urinary tract infection and vaginal-vulvar discharge].

In an industrial pig production unit ten sows were selected at random. All the sows had puerperal disease in their anamnesis and all of them revealed at the time of selection--during their late pregnancy--urinary tract infection (UTI) and vaginal-vulvar discharge (VD) and most of them had significant bacteriuria a.p. All the sows were evaluated using Bilkei's MMA early detection system. The majority of the sows which have had significant bacteriuria a.p. developed a puerperal disease.

Animals↗
PubMed1993

[Topical treatment of psoriasis with calcipotriol. Report of clinical experience].

BACKGROUND: Numerous clinical studies have demonstrated the efficacy of calcipotriol, a synthetic vitamin D3 analogue, in the treatment of mild to moderate chronic psoriasis. METHOD: Report on clinical experience of 40 psoriasis patients treated with calcipotriol, alone or in combination with phototherapy. RESULTS: After four weeks of treatment, the condition had largely cleared up in eleven out of 18 patients (61%) receiving calcipotriol alone, and in 20 out of 22 patients (91%) receiving combination treatment with UVB or UVA plus UVB. The new anti-psoriasis agent was well tolerated and readily accepted by the patients. CONCLUSION: Calcipotriol represents a valuable addition to the available therapy spectrum in chronic psoriasis.

Administration, Topical↗
PubMed1993

Antidiabetic agent pioglitazone enhances adipocyte differentiation of 3T3-F442A cells.

Adipocytes play an important role in normal physiology as a major site for systemic energy homeostasis. In disorders such as diabetes, adipocyte function is markedly altered. In this study, we investigated the effect of pioglitazone, a novel antidiabetic agent known to lower plasma glucose in animal models of diabetes mellitus, on cellular differentiation and expression of adipose-specific genes. Treatment of confluent 3T3-F442A preadipocyte cultures for 7 days with pioglitazone (Pio; 1 microM) and insulin (Ins; 0.17 microM) resulted in > 95% cell differentiation into lipid-accumulating adipocytes in comparison with 60-80% cell differentiation by treatment with either agent alone. Analysis of triglyceride accumulation showed increases of triglyceride content over time above untreated preadipocytes by treatment of the cells with Ins, Pio, and especially with Ins + Pio. Basal glucose transport, as measured by cellular uptake of 2-deoxy-D-[14C]glucose, was likewise enhanced in a time-dependent manner by treatment of preadipocytes with Ins, Pio, or Ins + Pio, such that a synergistic effect resulted from the combined treatment with both agents. It was further determined that RNA transcript abundance for genes encoding glucose transporters GLUT-1 and GLUT-4, as well as the adipose-specific genes encoding adipsin and aP2, were increased by the Ins, Pio, or Ins + Pio treatment. Taken together, these findings indicate that pioglitazone is a potent adipogenic agent. By promoting differentiation, this agent may move cells into a state active for glucose uptake, storage, and metabolism.

3T3 Cells↗
PubMed1993

The antidiabetic agent pioglitazone increases expression of glucose transporters in 3T3-F442A cells by increasing messenger ribonucleic acid transcript stability.

Whereas adipocytes normally play an important role as a major site for systemic energy homeostasis, adipocyte function is markedly altered in disorders such as diabetes. In this study, we investigated the effect of pioglitazone, a novel antidiabetic agent known to lower plasma glucose in animal models of diabetes mellitus, on expression of glucose transporters GLUT1 and GLUT4 in 3T3-F442A cells. Treatment of confluent 3T3-F442A preadipocyte cultures for 7 days with pioglitazone (1 microM) and insulin (1 microgram/ml) resulted in nearly 100% differentiation of cells to lipid-accumulating adipocytes, and such adipocytes showed a markedly increased capacity for glucose uptake. Analysis of messenger RNA transcripts encoding GLUT1 and GLUT4 glucose transporters over the 7-day differentiation period indicated time-dependent increases in abundance of each type that were maximal at more than 5-fold with the combined presence of insulin and pioglitazone. In accord, GLUT1 and GLUT4 protein levels also increased to maximal levels of 10-fold and 7-fold, respectively, over those in undifferentiated preadipocytes. Increased messenger RNA half-lives from 2.2 to greater than 24 h for GLUT1 and from 1.2 to greater than 24 h for GLUT4 correlated with this induced adipocyte differentiation. Taken together, these findings indicated that pioglitazone markedly enhanced expression of cellular glucose transporters, and the mechanism for this action was mainly stabilization of transporter messenger RNA transcripts. Such increased expression of glucose transporters in adipocytes establishes the cells in a state active for glucose uptake, thus ultimately facilitating storage and metabolism as well.

3T3 Cells↗
PubMed1993

9-cis-retinoic acid, a potent inducer of digit pattern duplications in the chick wing bud.

The effects of retinoids are mediated by two types of receptors, the retinoic acid receptors (RARs) and the retinoid-X-receptors (RXRs). The physiological ligand of the RARs is all-trans-retinoic acid whereas RXRs have high affinity for 9-cis-retinoic acid, a naturally occurring retinoid isomer. RXRs are broadly expressed in embryonic and adult tissues, and they are capable of forming homodimers as well as heterodimers with RARs and other nuclear hormone receptors. The role of 9-cis-retinoic acid in regulating the activity of RXR homodimers and RXR-containing heterodimers is poorly understood in vivo. To begin to explore the function of 9-cis-retinoic acid in morphogenesis, we have examined the activity of this isomer in the chick wing. Using reverse transcriptase polymerase chain reaction analyses, we show that RXR gamma is expressed in stage 20 wing buds. Similar to all-trans-retinoic acid, the 9-cis-isomer induces pattern duplications when locally applied to chick wing buds, but the 9-cis isomer is about 25 times more potent than the all-trans form. Furthermore, applied all-trans-retinoic acid is converted to the 9-cis isomer in the wing bud. The ratio of 9-cis to all-trans-retinoic acid established in the tissue is approximately 1:25. This quantitative agreement between the degree of conversion and the 25-fold higher efficacy of the 9-cis isomer, raises the possibility that, at least in part, the effects of all-trans-retinoic acid on the wing pattern result from a conversion to the 9-cis isomer.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1992

Expression of anchorin CII, a collagen-binding protein of the annexin family, in the developing chick embryo.

Expression of anchorin CII, a collagen-binding protein of the annexin family, was followed in the developing chick embryo using Northern and in situ hybridization and Western blotting. During chick somite development, anchorin CII mRNA was detected by Northern blotting as early as stage 11. At stage 24, anchorin mRNA accumulated in the anterior part of the somite sclerotome near the resegmentation line, as shown by in situ hybridization. The presence of anchorin CII protein during stages 11 to 20 was confirmed by Western blotting. In situ hybridization identified anchorin CII also in the otic vesicle adjacent to the site of contact with the statoacoustic ganglion and in the mandibular mesenchyme. The level of anchorin CII mRNA in differentiated hyaline cartilage, exemplified by sternal cartilage, was lower than that in differentiating somites or cultured chondrocytes. These findings are consistent with our notion that anchorin CII may be involved in cell-matrix interactions preceding chondrogenic differentiation events in the chick embryo. A significant level of anchorin CII mRNA and protein synthesis was also found in cultured myoblasts, but less than that in chondroblasts. This distribution pattern is different from that reported for a related protein, p34, or calpactin, the major protein substrate for tyrosine kinase phosphorylation in chick chondrocytes and fibroblasts. The results confirm suggestions from previous sequencing studies that anchorin CII and p34 are different proteins of the annexin/calpactin family.

Animals↗
PubMed1992

Manometric characteristics of cervical dysphagia in a patient with the Kearns-Sayre syndrome.

The manometric findings of deglutitive pharyngoesophageal function in a patient with the Kearns-Sayre syndrome and cervical dysphagia are described. These findings indicate that striated muscles of the pharynx, upper esophageal sphincter (UES), and proximal esophagus are involved. Near absence of pharyngeal peristalsis, abnormally low UES resting pressure, and absence of proximal esophageal peristalsis characterize the manometric findings in this patient. It is conceivable that in mild cases, a combination of various degrees of severity of the above findings may exist.

Adult↗
PubMed1991

Altered glucose transporter mRNA abundance in a rat model of endotoxic shock.

To better understand molecular mechanisms of glucose transport in shock, we studied glucose transporter isoform mRNA abundance after injection of S. enteritidis endotoxin (40 mg/kg) or saline. Six to 8 hours after injection, endotoxin-treated animals compared to controls became hypoglycemic (44 +/- 6 vs. 111 +/- 4 mg/dl) and lactacidemic (5.9 +/- 0.5 vs. 1.3 +/- 0.1). At such times, tissue RNA was isolated and hybridized to Riboprobes for GLUT1 (erythrocyte), GLUT2 (liver), and GLUT4 (muscle/fat) glucose transporter isoforms and expressed as percent of control. GLUT1 mRNA abundance was increased in fat (660%, p less than .05), soleus muscle (314%, p less than .05), and liver (871%, p less than .001) of endotoxin-treated rats. Soleus muscle GLUT4 mRNA levels were increased (+33%, p less than .02), while liver GLUT2 mRNA levels were markedly decreased (-58%, p less than .01). The overall increase in GLUT1 mRNA abundance accompanied by lowered liver GLUT2 mRNA levels may either cause or reflect profoundly altered glucose transport.

Adipose Tissue↗
PubMed1991

Glucose transport deficiency in diabetic animals is corrected by treatment with the oral antihyperglycemic agent pioglitazone.

Insulin-stimulated glucose uptake into muscle and fat involves regulation of the subcellular distribution and the expression of a specific facilitative glucose transporter protein (GLUT4). Peripheral glucose uptake is lowered in diabetes, and the expression of GLUT4 is depressed in animals that have been made diabetic (i.e. insulin deficient) by destruction of the pancreatic beta-cells. In the present study we found that GLUT4 expression is also decreased in an animal model for type II diabetes mellitus (noninsulin-dependent diabetes mellitus), KKAY obese mice. These KKAY mice have elevated circulating insulin levels, but target cell resistance to the metabolic actions of insulin. Treatment of both types of diabetic animals with pioglitazone, a new antihyperglycemic compound, corrects deficits in glucose transport and GLUT4 mRNA and protein abundance. Such corrections are, however, more readily detected in fat than in muscle. Increases in GLUT4 mRNA and protein levels and glucose transport function by pioglitazone are dependent upon the presence of circulating insulin. Treatment with pioglitazone alone is sufficient for correction of glucose transport in hyperinsulinemic insulin-resistant animals, but hypoinsulinemic animals require insulin therapy along with pioglitazone treatment for similar corrections. In these insulin-deficient animals, neither treatment with the drug alone nor minimal insulin replacement therapy results in substantial correction. Since insulin and this antihyperglycemic agent seem to work synergistically, it is likely that pioglitazone acts to amplify cellular responses to insulin.

Administration, Oral↗
PubMed1991

A rapid, accurate, nonradioactive method for quantitating RNA on agarose gels.

In order to study quantitative gene expression with Northern blots, it is important to have an internal standard that can be used to verify even loading or to correct for uneven loading between lanes. In this study it is shown that two-dimensional quantitation of ethidium bromide-intercalated 28S rRNA fluorescence can be used for such standardization. It was found that the film response of the fluorescence was linear with respect to total loaded RNA in the range of 2.5-12.5 micrograms RNA under the conditions used, after which the linear relationship falls off. This method eliminates the use of radiation for internal standardization of Northern blots.

3T3 Cells↗