Biomedical subjects
Publications and source records attributed to H Rosen.
Ticlopidine, a platelet aggregation inhibitor, has been approved to decrease the risk of thrombotic stroke. We describe a 75-year-old white woman who developed acute renal failure 10 days after initiating ticlopidine therapy. A renal biopsy revealed interstitial infiltrates containing lymphocytes and eosinophils. To our knowledge this is the first report of ticlopidine-induced acute interstitial nephritis.
Patients who underwent potential curative surgery for colonic adenocarcinoma were enrolled in a prospectively randomised, controlled clinical trial of combined intraperitoneal (i.p.) plus systemic intravenous (i.v.) chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV). We investigated whether this adjuvant treatment approach, specifically addressing the risk of peritoneal and hepatic recurrence, could improve disease-free and overall survival. Between May 1988 and December 1990, 121 patients with resected stage III or high-risk stage II (T4N0M0) colon cancer were randomly assigned for observation (which was considered standard care until the NIH consensus conference) or adjuvant chemotherapy with LV (200 mg/m2) plus 5-FU (350 mg/m2), both given i.v. (days 1-4) and i.p. (days 1 and 3) every 4 weeks for a total of six courses. After a median follow-up time of 4.6 years, a comparative analysis between the two groups of patients suggested both an improvement in disease-free survival (75% versus 58%; P = 0.06) and a survival advantage (78% versus 63%; P = 0.05) in favour of adjuvant chemotherapy. The sites of recurrence were also different, i.e. local regional and intrahepatic tumour recurrences were observed in only 6/58 (10%) and 5/58 (9%) adjuvant treated patients as compared to 11/60 (18%) and 10/60 (17%) observed patients. The overall benefit of adjuvant therapy appeared to be greatest in patients with stage III colon cancer. Treatment-associated toxicity was infrequent and generally mild with only 5% experiencing severe (WHO grade 3) adverse reactions. Interim results of this adjuvant trial suggest that combined i.p. plus systemic i.v. chemotherapy with 5-FU and LV represents a potentially effective adjuvant regimen in stage II/III colon cancer.
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Operative fixation of 22 nonunited fractures was undertaken in 21 obese patients. Eleven patients were women and 10 were men, with an average age of 46.3 years (range 25-74). The average body mass index in this group of patients was 37.9 kg/m2 (range 33.2-57.1). Two patients were classified as morbidly obese and 19 as severely obese. The management of these patients proved to be fraught with difficulties related to their obesity. There were a number of occurrences believed to be related to poorly protective positioning and prolonged ischemic pressure under the patient's body weight during the administration of anesthetic, including a peroneal compartment syndrome, a gluteal compartment syndrome with sciatic nerve palsy, bilateral brachial plexus stretch injuries, an anterior interosseous nerve palsy, and the postoperative development of a patch of scalp alopecia. There were two wound separations and no episodes of thromboembolic disease. Sixteen nonunited fractures healed after the index procedure at an average time to healing of 5.6 months (range 2-14). Five nonunited fractures required a second procedure to gain union [average total time to healing 17 months (range 10-31)]. A single fracture remains ununited. Awareness of the unique technical demands and operative and anesthetic risks encountered when undertaking an operative procedure in a severely obese patient is imperative for the safe and successful treatment of orthopaedic surgical problems in these patients.
Between March 1989 and August 1993, 16 distal femoral nonunions (16 patients) were treated using the supracondylar intramedullary nail. The time between the initial event and retrograde nailing averaged 33 months. The nonunion level was infraisthmal in four patients and supracondylar in 12. Operative technique involved retrograde insertion of a reamed supracondylar intramedullary nail through the intercondylar notch. Follow-up was available on all patients and averaged 20 months (range 9-46). Four nonunions (25%) united with a single surgery at an average of 17 months. A fifth nonunion united at 21 months after nail dynamization and subsequent nail breakage. The nonunions of two additional patients united after exchange of a broken retrograde nail. Additional surgical procedures were performed in six of the remaining nine patients in an attempt to gain union. At an average follow-up of 16 months (range 9-23), none of the nine had united. Nine nails fractured at an average of 11 months, all through a screw hole near the nonunion. Based on these results, we cannot recommend use of the supracondylar intramedullary nail in its present form for the treatment of distal femoral nonunions.
A technique for removing a fractured abutment screw and salvaging the endosseous implant is presented. Two commercially available screw retrieval kits are described and discussed.
Proenkephalin (PENK), a classically defined opioid gene, was originally thought to be expressed almost exclusively in the mature nervous and neuroendocrine systems. In the last few years, it was demonstrated, however, that high levels of PENK messenger RNA and PENK-derived peptides are expressed in embryonic mesenchymal tissues during differentiation into mature tissues and organs. Shortly after birth, as development progresses, PENK expression drops in those tissues to undetectable levels. Very little is known about the molecular mechanisms regulating this transient expression. To investigate those mechanisms, we used primary cell cultures of calvaria-derived osteoblasts. These cultures express PENK and exhibit a normal pattern of osteoblastic differentiation. In the present study we demonstrate that 1) a reciprocal interrelationship exists between PENK expression and osteoblastic differentiation in vivo, ex vivo, and in vitro; namely, PENK expression is down-regulated upon cellular differentiation; 2) PENK promoter usage and messenger RNA splicing function similarly in osteoblasts and in neural cells; 3) osteoblastic PENK expression is modulated by bone-targeting hormones; and 4) this down-regulation is inhibited by the serine/threonine kinase inhibitor H-8. The link between osteoblastic differentiation and down-regulation of PENK expression together with our preliminary findings indicating the existence of an osteoblastic opioid receptor suggest that opioids act in an autocrine/paracrine mechanism on undifferentiated osteoblasts and play a significant role in bone development.
BACKGROUND: Severe liver failure is associated with high mortality. Orthotopic liver transplantation (OLT) is the only effective therapeutic modality; there is a need for a 'bridge' system to support patients until an organ becomes available. METHODS: A bioartificial liver (BAL) was used to treat 10 patients with severe liver failure. A plasmapheresis system was used to pump patient plasma through a module with porcine hepatocytes. Each treatment lasted 6-7 h. RESULTS: All patients tolerated the procedure(s) well. Eight patients underwent OLT following BAL treatment(s). There were two late deaths after recovery from liver failure. Five patients with increased intracranial pressure (ICP) and decerebration had ICP normalization, increased cerebral perfusion pressure and full neurologic recovery after OLT. There was improvement in the level of encephalopathy and a significant decrease in serum ammonia after BAL treatment(s). CONCLUSIONS: BAL treatment is safe and beneficial and can be successfully used as a 'bridge' to transplantation.
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The control of tuberculosis has become more elusive with the increased incidence of HIV, and the continued selection of multidrug-resistant organisms. The intracellular pathogenesis of, and host-response to Mycobacterium tuberculosis present challenges to both classical chemotherapeutic and vaccination approaches, with the organism able to replicate in an unrestricted manner in lung but not other tissues. Adequate control of this pathogen, that has evolved so successfully for its symbiotic exploitation of man, will require complex approaches including additional chemotherapeutics of more acceptable toxicity and efficacy, vaccination and commitment to public health measures. In this review, the worldwide scope of the disease is outlined, and its direct and indirect costs considered. The organism enjoys the protective advantages of a slow replication and of a specialized phagolysosomal intracellular niche, requiring a host-response capable of breaching these cellular barriers. The challenges of current vaccine approaches, including live vaccines, target antigen selection and the antigen delivery and adjuventation necessary to elicit adequate pulmonary responses are discussed. Our current understanding is inadequate to control TB and the rekindling of fundamental experimental approaches to the organism, and the host response it evokes, are essential to generate the preventative and therapeutic means necessary for its worldwide control.
C5a is a 74-amino acid glycoprotein generated on activation of the C system. The responses evoked by C5a, both in vitro and in vivo, and its association with inflammatory diseases, suggest that a receptor antagonist would be of considerable therapeutic importance. However, efforts at generating antagonists have so far been unsuccessful. Structure/activity studies of the C terminus of C5a have generated peptide analogues with nanomolar affinities, but all of these retain strong agonist properties. We now report hexapeptides of the form NMePhe-Lys-Pro-dCha-X-dArg in which increasing aromaticity at position 5 leads to a progressive loss of agonism with little change in binding affinity. The different responses induced by C5a are lost in the order: degranulation before Ca(2+)-flux before chemotaxis. We also describe the first full antagonist of C5a, because the peptide in which x = Trp is not only devoid of all agonist properties, but it inhibits C5a induced degranulation and C5a stimulated G protein activation.
Activation of the immune system in response to either infection or lipopolysaccharide (LPS) produces neurophysiological, neuroendocrine and behavioral changes. Some of the physiological consequences of LPS are mediated by endogenous opioid peptides. The following studies were designed to characterize the effects of LPS in several behavioral paradigms, and to determine the role of opioids in mediating these effects. The effects of LPS on locomotor and self-care activity were assessed in the open field test. Rats were injected with either saline or a dose of LPS (25, 50, 100, or 1000 micrograms/kg). 4 h later, the animals were placed in an open field and the numbers of line crossings, rearings and grooming episodes were counted. LPS significantly suppressed the three open field behaviors in a dose-related manner. The effect of LPS on sensitivity to pain was determined using the hot-plate and tail-flick tests. Administration of LPS (200 micrograms/kg) increased pain sensitivity in the hot plate test 30 min after drug administration, but produced a significant analgesic response 4 h after drug administration in both tests. Further characterization of LPS-induced analgesia demonstrated that it began about 2 h after and disappeared 30 h after the administration of LPS. Administration of naltrexone completely blocked the analgesic effects of LPS 4 h after its administration, but had no effect on LPS-induced suppression of activity in the open field. The effect of LPS on body temperature was biphasic, producing hypothermia at 2 h and hyperthermia at 8-30 h after its administration. Naltrexone had no effect on the body temperature changes induced by LPS.(ABSTRACT TRUNCATED AT 250 WORDS)
The binding domain of the human C5a receptor consists of two distinct and physically separable subsites. One of these sites binds the C-terminal 8 amino acids of C5a and is as yet undefined, while the second site lies in the N terminus of the receptor and interacts with the core of C5a. Two deletion mutants were prepared to probe the importance of this second site. Removal of residues 2-22 decreased the binding affinity for C5a by 600-fold, while extending the deletion through residue 30 caused a further 75-fold decrease. Thus, the N terminus is responsible for at least 45% of the total energy for the binding of C5a. The five aspartic acids present in the deleted segments appear to be critical residues, as their conversion to alanines accounts for most of the affinity lost in the two truncations. Despite its importance for binding, the N terminus is not necessary for signal transduction, as a C-terminal peptide analog of C5a was able to stimulate G protein activation and to generate a Ca2+ flux through a receptor lacking residues 2-22. However, intact C5a was a very poor activator of this truncated receptor. These results imply that interaction between the N terminus of the receptor and C5a produces a conformational change in C5a that allows it's C terminus to properly interact with and activate the receptor.
In this report we show that interferon gamma treatment of U937 cells induces increased expression of the gamma-subunit of the high-affinity Fc receptor for IgG (Fc gamma RI). Interferon treatment results in a 10-fold increased expression of the gamma-subunit and induces expression of a phosphorylated form (gamma 1). The increased expression of the gamma-subunit correlates with its ability to transmit a signal via Fc gamma R, as measured by activation of the respiratory burst using insoluble immune complexes. During Fc gamma R activation, a mobility shift occurs in the phosphorylated form of this gamma 1-subunit. Phosphoamino acid analysis demonstrates that this gamma 1 subunit is threonine phosphorylated in resting differentiated U937 cells and becomes predominantly serine phosphorylated on Fc receptor activation. The mobility shift in the gamma-subunit can be induced by treating U937 cells with phorbol 12-myristate 13-acetate or by monoclonal antibody cross-linking of Fc gamma RI. Hence the gamma-subunit is serine phosphorylated in response to Fc gamma RI and protein kinase C activation. Therefore the gamma-subunit, initially described as a subunit of Fc epsilon RI, now appears to be involved in signal transduction via Fc gamma RI. The data also suggest that the gamma-subunit, in contrast with the zeta-subunit of the T-cell receptor-CD3 complex, is a substrate for serine/threonine kinase(s) in the cell. The serine phosphorylation of the gamma-subunit suggests a divergence of structure and function between the gamma-subunit and its homologue, the zeta-subunit of the T-cell receptor. Phosphorylation of the gamma-subunit on serine may play some regulatory role in Fc gamma RI signal transduction in myeloid cells.
Eosinophilic differentiation of a pro-eosinophilic HL-60 cell line resulted in the induction of a high affinity RANTES/macrophage inflammatory protein-1 alpha receptor. The induced receptor is biochemically indistinguishable in RANTES equilibrium-binding studies from the monocytic receptor expressed on THP-1 cell membranes. Continued expression of the receptor requires the continuous presence of the inducing stimulus, and receptor site number declines without a loss of binding affinity with a t1/2 of 11.5 h on withdrawal of the inducing stimulus. The induced receptor is capable of three physiologic measures of receptor coupling, namely, ligand-induced Ca2+ fluxes, priming of the respiratory burst, and chemotaxis. Dose-dependent Ca2+ fluxes were elicited upon increasing concentrations of RANTES and MIP-1 alpha whereas no response was measured upon addition of MIP-1 beta or MCP-1. In addition, desensitization studies demonstrated that previous exposure to either RANTES or MIP-1 alpha almost completely inhibits a Ca2+ flux upon subsequent exposure to either ligand. Priming of the respiratory burst to PMA in differentiated cells by human rRANTES was more effective than priming by IL-5 or granulocyte-macrophage-CSF, whereas undifferentiated cells failed to secrete superoxide anion. In addition, differentiated cells underwent chemotaxis in response to RANTES. This provides the first evidence for the induction of a C-C chemokine receptor upon eosinophilic differentiation of a leukocyte cell line, and is in keeping with the demonstrated ability of human RANTES to induce the rapid formation of eosinophilic inflammatory sites.
BACKGROUND: Because of experimental and preliminary clinical evidence that additional modulation of the biochemical pharmacology and cytotoxicity of 5-fluorouracil (5-FU) and leucovorin (LV) may be possible by combination of these agents with cisplatin (CDDP), the authors undertook a prospective randomized trial in patients with colorectal cancer. METHODS: Between 1989 and 1992, 138 patients with advanced measurable colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either 5-FU (425 mg/m2) and LV (20 mg/m2) for 5 days, or the combination of 5-FU and LV in the same daily dose plus cisplatin (20 mg/m2), each drug given for 4 consecutive days. In both treatment arms, courses were administered every 28 days, if toxicity allowed, for a total of 6 months or until evidence of tumor progression. RESULTS: The overall responses (complete and partial response) were 19% and 28% for the 5-FU/LV and the 5-FU/LV/CDDP treatment arms, respectively. Although the three-drug combination appeared superior to 5-FU/LV for time to progression or death (8.5 versus 5.2 months; P = 0.042), there was no evidence that the adoption of cisplatin will translate into a definite survival advantage. A comparative analysis of the toxicities experienced by the patients in the two treatment groups showed a comparable rate, although severe side effects (P < 0.05), specifically stomatitis (P = 0.013), were noticed more frequently in patients treated with 5-FU/LV for 5 days. CONCLUSIONS: These results suggest that the therapeutic index of 5-FU/LV in metastatic colorectal cancer may be improved with the addition of cisplatin. However, the somewhat better therapeutic activity and lower incidence of severe gastrointestinal side effects have to be weighed against additional pharmaceutical charges and the need for a more intense antiemetic regimen.
The guanine nucleotide-binding protein-coupled receptor superfamily binds a vast array of biological messengers including lipids, odorants, catecholamines, peptides, and proteins. While some small molecules bind to these receptors at a single interhelical site, we find that the binding domain on the receptor for the inflammatory protein C5a is more complex and consists of two distinct subsites. This more elaborate motif appears to be an evolutionary adaptation of the simpler paradigm to which a second interaction site has been added in the receptor N terminus. Surprisingly, occupation of only one of the subsites is required for receptor activation. The two-site motif is not unique to the C5a receptor but appears to be widely used by the superfamily to accommodate macromolecular ligands.
Proenkephalin encode a group of small peptides with opiate-like activity, the endogenous opioids, known to function as neurohormones, neuromodulators, and neurotransmitters. Recently, we have demonstrated that in addition to its abundance in fetal brain tissue, proenkephalin is highly expressed in nondifferentiated mesodermal cells of developing fetuses. We identified the skeletal tissues, bone, and cartilage as major sites of proenkephalin expression. To examine the possibility that proenkephalin is involved in bone development we have studied the expression of this gene in bone-derived cells, its modulation by bone active hormones, and the effects of enkephalin-derived peptides on osteoblastic phenotype. Our studies revealed that osteoblastic cells synthesize high levels of proenkephalin mRNA which are translated, and the derived peptides are secreted. Reciprocal interrelationships between osteoblast maturation and proenkephalin expression were established. These results together with our observations demonstrating inhibitory effects of proenkephalin-derived peptides on osteoblastic alkaline phosphatase activity, strongly support the notion that proenkephalin is involved in bone development. A different direction of research by other investigators has established the capability of the opioid system in the periphery to participate in the control of pain. On the basis of these two lines of observation, we would like to present the following hypothesis: The potential of embryonic skeletal tissue to synthesize proenkephalin-derived peptides is retained in the adult in small defined undifferentiated cell populations. This potential is realized in certain situations requiring rapid growth, such as remodeling or fracture repair. We suggest that in these processes, similarly to the situation in the embryo, the undifferentiated dividing cells produce the endogenous opioids. In the adult these peptides may have a dual function, namely participating in the control of tissue regeneration and in the control of pain.