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Biomedical subjects

H Rosen

Publications and source records attributed to H Rosen.

At least 19 recordsLinked to original sources
PubMed1992

Prenatal stress selectively alters the reactivity of the hypothalamic-pituitary adrenal system in the female rat.

A study was made of the effects of prenatal stress on the reactivity of the hypothalamic-pituitary adrenal (HPA) axis in male and female offspring. Rat dams were subjected to noise and light stress on an unpredictable basis throughout pregnancy. At 28 days of age mRNA for POMC, proenkephalin and prodynorphin were measured in the hypothalamus of the offspring. A marked reduction was found in POMC mRNA in PS females (PSF) but not in males (PSM), but the other mRNA's did not differ from controls (C). At 60 days of age, PSF has 3 times higher resting levels of serum corticosterone (COR) and significantly lower dexamethasone (DEX)3H hippocampal binding sites than CF. Overnight adrenalectomy abolished the difference in DEX binding. After 10 min exposure to open field PS males and females voided more fecal pellets and made fewer center entries than C offspring, testifying to increased emotionality. Open field stress caused a 3-5-fold rise in circulating COR in all groups within 15 min, which returned to baseline by 90 min in all rats except PSF. These data show that prenatal stress can cause permanent alterations in the behavior of both sexes in stressful situations but appears to cause a selective effect on the HPA axis in the female rat.

Animals↗
PubMed1992

Cytochrome b-245 is a flavocytochrome containing FAD and the NADPH-binding site of the microbicidal oxidase of phagocytes.

The NADPH oxidase of phagocytic cells is important for the efficient killing and digestion of ingested microbes. A very unusual low-potential cytochrome b (b-245) is the only redox molecule to have been identified in this system. The FAD-containing flavoprotein that binds NADPH and transfers electrons to the cytochrome has eluded identification for three decades. We show here that the haem/FAD ratio in the membranes does not change significantly on activation of this oxidase, indicating that the FAD is present in the membranes from the outset and not recruited from the cytosol. The FAD content of membranes from cells of patients with X-linked chronic granulomatous disease (CGD) lacking the cytochrome b was roughly one-quarter of that in normal subjects and in autosomal recessive CGD patients lacking the cytosolic protein p47-phox. Similar low amounts of FAD were present in uninduced promyelocytic (HL60) cells, suggesting that the low amount of FAD in cells from X-CGD patients was probably unrelated to this oxidase system. Cytochrome b-245 appears to bind both the haem and FAD, in a molar ratio of 2:1. The e.p.r. signal of the purified cytochrome was weak and had an asymmetric g(z) peak at g = 3.31. The purified cytochrome could be partially reflavinated (about 20%) in the presence of lipid. Amino acid sequence homology was detected between the beta-subunit of this cytochrome b and the ferredoxin-NADP+ reductase (FNR) family of reductases in the putative NADPH- and FAD-binding sites. 32P-labelled 2-azido-NADP was used as a photoaffinity label for the NADPH-binding site. Labelling that was competed off with NADP was observed in the region of the beta-subunit of the cytochrome. No labelling was seen in this region in X-CGD in three subjects in whom this cytochrome was missing and in a third in whom it was present but bore a Pro-His transposition in the putative NADPH-binding site. These studies indicate that cytochrome b-245 is a flavocytochrome, the first described in higher eukaryotic cells, bearing the complete electron-transporting apparatus of the NADPH oxidase.

Amino Acid Sequence↗
PubMed1992

Antibody against the Leu-CAM beta-chain (CD18) promotes both LFA-1- and CR3-dependent adhesion events.

The Leukocytic cell-adhesion molecule (beta 2 integrin) family of adhesion molecules play a key role in the intercellular adhesive interactions necessary for normal immune cell function. In this study, we report an antibody that recognizes an epitope on the Leukocytic cell-adhesion molecule common beta-chain (CD18) and promotes both lymphocyte function-associated Ag-1- and CR3-dependent adhesion events. The antibody recognizes a temperature-sensitive epitope that is not dependent on the presence of divalent cations. It is proposed that antibody binding promotes a conformational change in both lymphocyte function-associated Ag-1 and CR3, which may mimic a natural activation mechanism, resulting in increased cellular adhesion.

Antibodies, Monoclonal↗
PubMed1992

Nuclear pleomorphism, a strong prognostic factor in axillary node-negative small invasive breast cancer.

We have evaluated established risk factors (tumor size, menopausal status, receptor status, tumor histology, and grading according to Bloom & Richardson including subfactor analysis) as well as local therapeutic procedures in a series of 121 patients with axillary node-negative (ANN) breast cancer stage T1a and T1b. The patients were operated on at a single institution (Department of Surgery, Hanuschkrankenhaus, Vienna) from 1969 to 1989. After a median observation time of 185 months, a total of 16 patients (13%) had a recurrence; of these, 6 had died of the primary disease by the control date (Dec 1, 1990). Grading (distant recurrence-free survival (DRFS) p = 0.01, overall survival (OS) p = 0.006, mitosis rate (DRFS p = 0.006, OS p = 0.02), and particularly nuclear pleomorphism (DRFS p = 0.0002, OS p = 0.00001) proved to have prognostic impact on distant recurrence-free survival and/or overall survival (Mantel-Cox log rank test; level of significance: p = 0.006 after adjustment for multiple testing by Bonferroni correction). Therapeutic procedures had a borderline-significant impact on local recurrence (p = 0.09). No other parameters had statistically significant impact. Thus, our long-term analysis confirms the superior prognostic relevance of histologic grading and nuclear pleomorphism in patients with ANN breast cancer stage T1a and T1b.

Adult↗
PubMed1992

A model for the investigation of factors influencing haemorrhagic necrosis mediated by tumour necrosis factor in tissue sites primed with mycobacterial antigen preparations.

Mycobacterial lesions and skin sites challenged with soluble mycobacterial antigen are very sensitive to the necrotizing effect of tumour necrosis factor (TNF). We have used a model that permits separate quantitative assessment of swelling and haemorrhage to show that when these reactions are elicited in mice that have not been deliberately immunized, pretreatment of the mice with lipopolysaccharide (LPS), or with a MoAb to CR3 which blocks emigration of myeloid cells into the tissues, will block both the swelling and the haemorrhage. On the other hand, treatment with an inhibitor of platelet-activating factor (PAF), or with misoprostol (a synthetic prostaglandin E1 analogue), or with cobra venom factor (CVF) which depletes complement, preferentially blocks the haemorrhagic component, while leaving the swelling relatively unaltered. As swelling occurs before the haemorrhage is seen, it is possible that these factors act at a late stage in the cascade of events leading to the tissue damage. However, LPS and CVF were able to inhibit swelling and haemorrhage in the massive reactions elicited in pre-immunized animals, whereas the PAF inhibitor had no detectable effect.

Animals↗
PubMed1992

Protective immunity and granuloma formation are mediated by two distinct tumor necrosis factor alpha- and gamma interferon-dependent T cell-phagocyte interactions in murine listeriosis: dissociation on the basis of phagocyte adhesion mechanisms.

Listeria-immune mice are able to express protective immunity in the absence of CD4+ T cells and an apparent granulomatous inflammation. Using a monoclonal antibody (5C6) able to inhibit the recruitment of myelomonocytic cells into inflammatory foci by binding to complement receptor type 3 (CR3/CD11b), we could show that protective immunity and granuloma formation indeed depend on two distinct types of T cell-phagocyte interactions. Listeria-specific CD8+ T lymphocytes, possibly in collaboration with CD4- CD8- T cells, rapidly interact with myelomonocytic cells infiltrating infected tissues in a CR3/CD11b-dependent manner. This interaction results in potent antilisterial protection but not in granuloma formation. On the contrary, CD4+ T cells are able to induce adhesion mechanisms that allow the accumulation of monocytes in granulomatous lesions even in the presence of monoclonal antibody 5C6. However, the protective capacity of these CR3/CD11b-independent T cell-mediated immune mechanisms is low in listeriosis. Tumor necrosis factor alpha and gamma interferon, known to be essential for the expression of both resistance and acquired immunity, are shown to be necessarily involved in granuloma formation, too. It therefore remains to be explained why CD8+ T cells, able to secrete both cytokines, do not induce granuloma formation. The data point to the presence of an as yet undefined CD4+ T cell-derived granuloma-inducing factor and favor the hypothesis that CD8+ T cells, in collaboration with circulating phagocytes, mediate immunity by rapidly liberating listeriae from permissive cells or protecting them from becoming infected.

Animals↗
PubMed1992

Influence of valve surgery on female fertility.

Pregnancies following cardiac valve surgery represent a considerable maternal and fetal risk. The present paper is a report of 163 women in child-bearing age who underwent cardiac valve surgery. Congenital (14.7%) and acquired (85.3%) cardiac defects required a total of 72 alloplastic and 16 bioprosthetic valve implantations. In 69 patients, purely instrumental correction was performed, in 6 patients conduits were placed. Thirty-four pregnancies were observed and led to the delivery of 18 healthy infants. The birth weight was always in the 2-sigma normal range or slightly above. Three cesarean sections were performed due to the cardiac defect, in 6 patients vacuum extraction or forceps delivery was done, and in 9 patients delivery was spontaneous. We observed 4 cases of spontaneous abortion, and in 12 cases interruption of pregnancy. 75.1% women never became pregnant. Potential risks in terms of endocarditis, repeated valve implantation and anticoagulation are emphasized, methods to decrease the physical strain during delivery are discussed.

Bioprosthesis↗
PubMed1992

On enactment.

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Family↗
PubMed1992

Regulation of proenkephalin expression in cultured skin mesenchymal cells.

Proenkephalin, a classically defined opioid encoding gene, is transiently expressed in nondifferentiated mesodermal cells during organogenesis. We examined the hypothesis that this expression is associated with mesenchymal cell proliferation. For this purpose, we established a cell culture derived from fetal skin mesenchyme that specifically expresses proenkephalin mRNA in correlation with hypodermis development. These mesenchymal cells also produce and secrete significant amounts of proenkephalin-derived peptides. Using this model system, we observed a marked increase in proenkephalin mRNA expression in response to serum. This effect is time dependent and reaches peak levels during the G1/S transition. Similarly, 12-O-tetradecanoyl-phorbol-13-ester, whose biological actions have been shown to be mediated by the activity of protein kinase C (PKC), up-regulates proenkephalin expression. Desensitization of PKC by prolonged exposure of cells to 12-O-tetradecanoyl-phorbol-13-ester attenuates the serum induction of proenkephalin. The results presented in this report demonstrate that proenkephalin expression in mesenchymal cells is regulated by serum factors via mechanisms that involve PKC activity. A possible association between proenkephalin expression and cell proliferation is suggested.

Animals↗
PubMed1992

Expression and regulation of a proenkephalin beta-galactosidase fusion gene in the reproductive system of transgenic mice.

A fusion gene containing 3 kilobases of human proenkephalin 5'-flanking sequences and 1 kilobase of human proenkephalin 3'-flanking sequence and the easily visualized histochemical marker, Escherichia coli beta-galactosidase, was used to study the function of cis-regulatory elements within the human proenkephalin gene in transgenic mice. Here data are presented on expression and regulation of this fusion gene in the reproductive system of three independent lines of transgenic mice. Within the male reproductive system, the fusion gene is expressed in the proximal epididymis and in developing germinal cells but not in mature or elongating spermatids. In the female reproductive system, the transgene was expressed at low basal levels, but expression was dramatically stimulated in the ovary and oviduct by hormonal stimulation and pregnancy; additionally, expression was induced at the uteroplacental junction in pregnant mice. Taken together these observations suggest that critical sequences for expression and regulation of the proenkephalin gene within the reproductive system are contained within sequences of the construct.

Animals↗
PubMed1992

Posttraumatic tibial osteomyelitis: a comparison of three treatment approaches.

The treatment of 25 tibias in 25 patients with posttraumatic chronic osteomyelitis was reviewed. The approaches to soft tissue management fell into three groups: 1) muscle flap coverage; 2) primary closure with suction irrigation; and 3) open cancellous bone grafting. Treatment success was judged by the presence or absence of drainage and the local signs or symptoms of infection, and by the status of the tibial nonunion. Overall, 19 of 25 tibias (76%) had successful treatment. We found flap coverage to have a higher success rate (80%) than either primary closure with suction irrigation (45.5%) or open cancellous bone grafting (40%). These results further attest to the refractory nature of chronic osteomyelitis.

Adult↗
PubMed1991

Hypochlorous acid and myeloperoxidase-catalyzed oxidation of iron-sulfur clusters in bacterial respiratory dehydrogenases.

Hypochlorous acid and related oxidants derived from myeloperoxidase-catalyzed reactions contribute to the microbicidal activities of phagocytosing neutrophils and monocytes. Microbial iron-sulfur (Fe/S) clusters have been suggested as general targets of myeloperoxidase-derived oxidations, but no susceptible Fe/S site has yet been identified. In this study, the effects of HOCl and myeloperoxidase-catalyzed peroxidation of chloride ion upon EPR-detectable Fe/S clusters in Escherichia coli and Pseudomonas aeruginosa were examined. Increasing amounts of oxidant produced progressive loss of signal amplitudes from the S-1 and S-3 Fe/S clusters of succinate:ubiquinone oxidoreductase in respiring membrane fragments. These changes were compared to loss of microbial viability, succinate uptake rates, succinate dehydrogenase activity and succinate-dependent respiration. The amounts of oxidant required to destroy Fe/S clusters exceeded the amounts required to kill organisms or inhibit respiratory function by factors of four or five. Power saturation characteristics of the S-1 signal indicated that the S-2 signal was also resistant to modification, even in highly oxidized membranes. Loss of succinate-dependent respiration was closely associated with HOCl and myeloperoxidase-mediated microbicidal activity against P. aeruginosa and was also an early event in the oxidant-mediated metabolic dysfunctions of E. coli. However, these effects were not caused by the destruction of the Fe/S clusters within the succinate:ubiquinone oxidoreductase. Rather, the major respiration-inhibiting lesion(s) appeared to reside at points in the respiratory chain between the Fe/S clusters and the ubiquinone reductase site.

Electron Spin Resonance Spectroscopy↗
PubMed1991

Phagocytosis of opsonized oil droplets by neutrophils. Adaptation to a microtiter plate format.

A previously described assay for neutrophil phagocytosis of oil droplets labeled with the lipophilic red dye, oil red O, has been adapted to a microtiter plate format. Oil laden neutrophils are fixed to the plate with glutaraldehyde, washed free of uningested oil, and evaluated for degree of oil red O uptake by direct determination of light absorption at 540 nm in a microtiter plate reader. Advantages of the modified procedure include the ability to determine rates of phagocytosis (multiple determinations) under diverse conditions, simultaneously and with greater facility. Multiple centrifugation steps are eliminated and the requirement for extraction of oil red O from each cell pellet prior to quantitation becomes optional. The system has been evaluated for oil droplets emulsified with lipopolysaccharide alone or with lipopolysaccharide together with bovine serum albumin. For droplets emulsified with lipopolysaccharide alone, efficient opsonization was accomplished with fresh serum alone, through heat labile, presumably complement-dependent, pathways. For droplets emulsified with lipopolysaccharide and bovine serum albumin, specific antiserum to bovine serum albumin was a considerably more efficient opsonin than non-immune fresh serum. A third system is described in which tetanus toxoid was introduced into oil droplets that had been previously emulsified with lipopolysaccharide. Inclusion of toxoid antigens rendered the oil droplets susceptible to opsonization with tetanus immune globulin, making the assay system possibly applicable to evaluation of immunoglobulin function in humans.

Azo Compounds↗
PubMed1991

Virulence of non-beta-lactamase-mediated ampicillin-resistant Haemophilus influenzae.

We questioned whether strains of ampicillin-resistant, non-beta-lactamase-producing (AmpR NBLP) Haemophilus influenzae with lower affinity penicillin-binding proteins (PBPs) might have altered virulence. The virulence of resistant transformant strains and the susceptible recipient was compared using infant rats. Following intraperitoneal inoculation, there was a significantly lower mortality rate and incidence and magnitude of bacteremia with two of three transformants compared to the recipient strain. Reduced virulence was not associated with greater bactericidal activity of serum or human neutrophils or faster clearance of the transformant following intravenous injection. Heated rat or human plasma supported exponential growth of the recipient, but not the transformant, suggesting deficient in vivo multiplication. We conclude that H. influenzae with altered PBPs are less virulent in an infant rat model which may be related to differences in in vivo growth.

Ampicillin Resistance↗
PubMed1991

Proenkephalin A in bone-derived cells.

Enkephalins, a group of small peptides with opiate-like activity, have been defined originally as neuropeptides. Recent reports showed, using in situ hybridization, that the enkephalin-encoding gene, proenkephalin A (pEnkA), is expressed in nondifferentiated cells of diverse mesodermal lineages. The transient expression of pEnkA in these tissues during organogenesis suggests that this gene is involved in processes such as differentiation and/or cell proliferation. In situ hybridization revealed that bone and cartilage are among the tissues that express pEnkA most actively during organogenesis. Here we show that pEnkA mRNA is abundant in normal calvaria-derived cells and in osteosarcoma-derived cell lines ROS 17/2.8 and ROS 25/1. In addition, pEnkA-derived peptides are synthesized and secreted by these cells, as revealed by specific RIA. pEnkA expression in ROS cells is decreased by osteogenin, an osteoinductive factor, and by the calcium-regulating hormone, 1,25-dihydroxyvitamin D3, whereas the osteoblastic phenotype marker, alkaline phosphatase, is increased by these factors. These results together with the inhibitory effects of pEnkA-derived peptides on alkaline phosphatase activity in ROS 17/2.8 cells suggest that pEnkA is involved in bone development and provide a model system for further analysis of pEnkA expression during this process.

Alkaline Phosphatase↗
PubMed1991

Tumor suppression after tumor cell-targeted tumor necrosis factor alpha gene transfer.

The tumor necrosis factor alpha (TNF-alpha) gene was introduced by retroviral gene transfer into the TNF-alpha-insensitive tumor cell line J558L. Production of 40 pg/ml TNF-alpha by clone J2T12 consistently did not change the growth rate in vitro, but drastically suppressed tumor growth when injected into syngeneic BALB/c mice. Within 2 wk, 90% of the mice inoculated with J558L cells developed a tumor, but none of the mice injected with J2T12 did so. Within the observation period (greater than 3 mo), 60% of the mice inoculated with J2T12 did not develop a tumor. In the other 40% of the mice, tumor manifestation was significantly delayed. Mice injected simultaneously with J2T12 cells and an anti-TNF-alpha monoclonal antibody developed tumors similar to parental J558L cells. Similarly, the tumor-suppressive effects of TNF-alpha were abolished, e.g., by injection of an anti-type 3 complement receptor (CR3) monoclonal antibody that is known to prevent migration of inflammatory cells. These results and the observation of tumor-infiltrating macrophages suggest that lack of tumorigenicity of J2T12 cells is due to the TNF-alpha secretion by the tumor cells and that TNF-alpha acts indirectly by a mechanism that involves chemotactic recruitment and activation of cells, predominantly of macrophages. In contrast, the tumor growth was not affected when, instead of TNF-alpha, interleukin 6 was expressed by J558L cells. Together, our results support the concept of tumor cell-targeted cytokine gene transfer as a tool for cancer treatment, and particularly demonstrate that extremely low doses of TNF-alpha produced by tumor cells are sufficient to inhibit tumor growth without detectable side effects.

Alkaline Phosphatase↗