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PubMed1995

Copper deficiency alters rat peptidylglycine alpha-amidating monooxygenase activity.

Perinatal copper deficiency was studied in 1-mo-old female and male Sprague-Dawley rat offspring to investigate changes in cuproenzymes. Offspring of dams given the low Cu treatment beginning at d 7 of gestation exhibited signs characteristic of Cu deficiency, including a 90% reduction in liver Cu levels compared with Cu-adequate controls. Compared with Cu-adequate rats, Cu-deficient rats had lower activities of the cuproenzymes peptidylglycine alpha-amidating monooxygenase (PAM), cytochrome c oxidase (CCO), and Cu,Zn-superoxide dismutase (SOD) in heart and midbrain samples. Activity of dopamine-beta-monooxygenase (DBM) was higher in midbrain and lower in heart samples from Cu-deficient compared with Cu-adequate rats. Following 1 mo of Cu repletion, PAM and CCO activity were still lower in heart of Cu-replete rats. Midbrain DBM activity was still elevated in the former Cu-deficient males. A second study was conducted using weanling male Holtzman rats. After 5.5 wk of treatment, Cu-deficient rats had signs characteristic of Cu deficiency and lower PAM, CCO and DBM activities in heart but not midbrain as compared with Cu-adequate rats. The PAM activity was lower following Cu deficiency. Perhaps neuropeptide maturation is compromised by Cu deficiency.

Animals↗

PubMed2003

Comparing therapeutic and prophylactic protection against the lethal effect of paraoxon.

Prophylactic and therapeutic efficacy against organophosphorus (OP) intoxication by pralidoxime (2-PAM) and atropine were studied and compared with sterically stabilized long-circulating liposomes encapsulating recombinant organophosphorus hydrolase (OPH), either alone or in various specific combinations, in paraoxon poisoning. Prophylactic and therapeutic properties of atropine and 2-PAM are diminished when they are used alone. However, their prophylactic effects are enhanced when they are used in combination. Present studies indicate that sterically stabilized liposomes (SL) encapsulating recombinant OPH (SL-OPH) alone can provide much better therapeutic and prophylactic protection than the classic 2-PAM + atropine combination. This protection was even more dramatic when SL-OPH was employed in combination with 2-PAM and/or atropine: the magnitude of prophylactic antidotal protection was an astounding 1022 LD(50) [920 mg/kg (LD(50) of paraoxon with antagonists)/ 0.95 mg/kg (LD(50) of control paraoxon)], and the therapeutic antidotal protection was 156 LD(50) [140 mg/kg (LD(50) of paraoxon with antagonists)/0.9 mg/kg (LD(50) of control paraoxon)]. The current study firmly establishes the value of using liposome encapsulating OPH.

Animals↗

PubMed1991

NSABP trials of adjuvant chemotherapy for breast cancer. A further look at the evidence.

Two decades ago the National Surgical Adjuvant Breast Project (NSABP) began to test the hypothesis that adjuvant chemotherapy would influence favorably the postsurgical survival rates of women with breast cancer. Although the use of phenylalanine mustard (melphalan or (L-PAM) has been supplemented by other agents, the thrust to recommend adjuvant chemotherapy as standard treatment was created by an L-PAM series of five trials using L-PAM or L-PAM plus fluorouracil. Only the first trial, B-05, contained an untreated group. The main treated groups in these five trials are similar to each other in survival probabilities, and the main untreated group in B-05 is not different in survival than the combined results of these five trials. There were a total of nine comparison in each study-and in B-05 the subgroup of treated women 49 years or younger with one to three positive node was found to be different than the untreated group. Four subsequent subgroups of women who were 49 years or younger with one to three positive nodes are not similar in survival despite the fact that they were developed from similar main groups that had similar treatment. The initial treated subgroup in B-05 had a survival outcome that was never again achieved in the subsequent four studies. The untreated subgroup in B-05 was not different than three of the four subsequently treated subgroups. The NSABP now has evidence that denies the conclusion that adjuvant chemotherapy prolongs survival in premenopausal node-positive women. Recommendations that adjuvant chemotherapy become standard treatment for premenopausal node-positive women should be seriously reconsidered and probably withdrawn.

Adult↗

PubMedDate not supplied

Is patient activation associated with outcomes of care for adults with chronic conditions?

We examined the patient activation measure's (PAM's) association with process and health outcomes among adults with chronic conditions. Patients with high PAM scores were significantly more likely to perform self-management behaviors, use self-management services, and report high medication adherence, compared to patients with the lowest PAM scores. This population was 10 times more likely to report high patient-satisfaction scores, 5 times more likely to report high quality-of-life scores, and reported significantly higher physical and mental functional status scores, compared to those with the lowest scores. These results suggest that PAM scores are associated with key process and health outcome measures.

Aged↗

PubMed2000

The origin of alveolar macrophages in the transplanted lung: a longitudinal microsatellite-based study of donor and recipient DNA.

Transplanted lungs are initially populated by donor pulmonary alveolar macrophages (PAMs). These will form major antigen presenters for the recipient's suppressed immune system. They may be expected to be replaced by recipient major histocompatibility complex-compatible cells, with time. We have isolated CD14+ PAMs from bronchoalveolar lavage specimens for 6 months after transplantation and identified their origin by using microsatellite analysis. This DNA-based technology permits the reliable identification of the origin of cells from different individuals. We show that replacement of donor PAMs occurs with individual dynamics in each case. Recipient PAMs usually appeared within 2 weeks, whereas donor cells could be retained for as long as 6 months. In this limited series, there was no obvious correlation between the dynamics of this process and the occurrence of rejection episodes or infections.

Adult↗

PubMed2005

Conjunctival melanoma arising from diffuse primary acquired melanosis in a young black woman.

PURPOSE: To report a case of conjunctival melanoma arising from diffuse primary acquired melanosis (PAM) with atypia in a young black woman in the context of previously published cases of this lesion in blacks. METHODS: Retrospective case report with literature review. The number and percentage of conjunctival melanomas occurring in black patients were determined from case series in which race was specified, published from 1950 to the present. RESULTS: Nodular multifocal conjunctival melanoma in a 30-year-old black woman was treated using surgical excision and adjuvant cryotherapy. Extensive PAM with severe atypia, including areas of microinvasive melanoma, was treated using topical mitomycin C. Literature review revealed 35 cases of conjunctival melanoma occurring in black patients. No previous reports of mitomycin C use in black patients with melanoma or PAM were identified. CONCLUSIONS: Conjunctival melanoma is an exceedingly rare tumor in black patients. The current case brings the total of reported cases to 36. We successfully treated nodular melanoma and diffuse PAM in a young black woman using a combination of excision with cryotherapy and topical mitomycin C, suggesting that these lesions are amenable to the same types of therapy previously described for white patients.

Administration, Topical↗

PubMed1983

Expression of keratin genes in mouse epidermis and normal and malignantly transformed epidermal cells in culture.

Complementary DNA (cDNA) clones constructed to the 55, 59 and 67 kilodalton (K) keratins, the major keratins synthesized in newborn mouse epidermis, were used as molecular hybridization probes to examine the expression of these genes in newborn epidermis and normal and malignantly transformed epidermal cells in culture. Transcripts of these three keratin genes are abundant in newborn epidermis. However, primary cultures of epidermal cells contain very low levels of these RNAs. The decreased expression of these keratin genes in primary cells appears to be due to factors within the culture system. Unlike primary-cell cultures, the malignantly transformed cell line Pam 212 synthesizes keratin proteins and mRNAs similar to newborn epidermis, including the 67 K keratin. However, synthesis of the 67 K keratin in Pam 212 cells is modulated by culture factors. Keratin gene expression in another Pam line, 321, differs from that of Pam 212 cells in that decreased expression of these three keratin genes occurs. These results indicate that keratin genes that are normally expressed in vivo in epidermis may be expressed in malignant epidermal cells under conditions that do not permit expression of these genes in nonmalignant primary epidermal cells.

Animals↗

PubMed1987

Inhibition of the proliferation of transformed epidermal cells in culture by various prostaglandins.

Cytotoxic action of various prostaglandins (PGs) was examined on the PAM 212 transformed mouse epidermal cell line, and delta 7-PGA1 was found most active. delta 7-PGA1 exerted a dose-dependent inhibition of PAM 212 cell growth over 0.1 microgram/ml (0.3 microM). At 1.6 microgram/ml (4.6 microM) growth was completely inhibited, and the number of viable cells decreased remarkably during culture. The concentration needed for 50% growth inhibition (IC50) value of delta 7-PGA1 on PAM 212 cell growth was calculated as 0.4 microgram/ml (1.1 microM). At this concentration, the DNA synthesis in 24- and 48-h cultured cells was decreased to a half of the level in the control cells, and microscopically, remaining cells showed degenerative changes with many vacuoles in their cytoplasm. Prostaglandin D2, a major PG in mast cells, also showed potent cytotoxic activity. However, this action was expressed as 9-deoxy-delta 9,12-13,14-dihydro-PGD2 (delta 12-PGJ2), which was converted from PGD2 in plasma, and had a 3-fold stronger growth inhibitory activity than PGD2; the IC50 values of PGD2 and delta 12-PGJ2 were 2 micrograms/ml (5.7 microM) and 0.75 microgram/ml (2.1 microM), respectively. Among other PGs tested, PGA2 showed a comparable growth inhibitory activity, and PGB2, PGE1, and PGE2 less but significant activity. Prostaglandin F2 alpha and PGI2 however, had no such effect on cell proliferation at 5 micrograms/ml (14.3 microM) concentration, suggesting that cyclopentenone structure is an essential moiety of PG derivatives for cell growth inhibition. This cytotoxic action of delta 7-PGA1 and delta 12-PGJ2 appears to be independent of cyclic-AMP, since these PGs were virtually inactive in raising intracellular cyclic-AMP levels in PAM 212 cells.

Animals↗

PubMed1982

Cell kinetics of pulmonary alveolar macrophages in the mouse.

The study of pulmonary alveolar macrophages (PAMs) involves two techniques, one following the migration of a cohort of labelled PAMs from the lung and the other involves the use of a continuous labelling method with [3H]TdR. In both studies, strikingly similar, probably biphasic curves are obtained that can be interpreted as indicating the existence of two proliferating cell populations with turnover times of approximately 10 days and approximately 35 days. It is suggested that one of these compartments is an intra-alveolar PAM population whilst the other probably represents a precursor population. It is also possible to interpret the data as indicating a single, and probably solely intra-alveolar, PAM population with a very skewed distribution of cell cycle times.

Animals↗

PubMedDate not supplied

Pressor action of pyridine-2-aldoxime in malathion poisoning.

1. Intravenous injections of pyridine-2-aldoxime (PAM) produced a marked, prolonged and dose-related rise in blood pressure in anaesthetized cats treated with malathion (MT) and without malathion (NMT). 2. The pressor effect of PAM was significantly reduced by phentolamine and phenoxygenzamine, but unaffected by hexamethonium. 3. Pretreatment with guanethidine and reserpine almost completely abolished the pressor response to PAM. 4. The results indicate that PAM has a potent sympathomimetic action which appears to be mediated through release of catecholamines from storage sites.

Animals↗

PubMed2006

CD14 directly binds to triacylated lipopeptides and facilitates recognition of the lipopeptides by the receptor complex of Toll-like receptors 2 and 1 without binding to the complex.

It has demonstrated that the recognition of triacylated lipopeptides by Toll-like receptor (TLR) 2 requires TLR1 as a coreceptor. In the NF-kappaB reporter assay system in which human embryonic kidney 293 cells were transfected with TLR2 and TLR1 together with an NF-kappaB luciferase reporter gene, S-(2,3-bispalmitoyloxypropyl)-N-palmitoyl-Cys-Lys-Lys-Lys-Lys (Pam(3)CSK(4)) and Pam(3)CSSNA were recognized by TLR2/TLR1, but the recognition level was unexpectedly very low. However, cotransfection of CD14 drastically enhanced the recognition of triacylated lipopeptides by TLR2/TLR1. The CD14-induced enhancement did not occur without cotransfection of TLR1. Both CD14(dS39-A48), a mutant with deletion of the part of possible N-terminal ligand-binding pocket, and anti-CD14 monoclonal antibody reduced the CD14-induced enhancement. Transfection of a TIR domain-deficient mutant of TLR2 (TLR2(dE772-S784)) or TLR1 (TLR1(dQ636-K779)) completely abrogated the CD14-induced enhancement. Soluble recombinant CD14 added extracellularly enhanced the recognition of Pam(3)CSSNA by TLR2/TLR1. Immunoprecipitation analysis demonstrated that CD14 was not associated with TLR2 but that TLR1 was associated with TLR2. In addition, surface plasmon resonance-based assay demonstrated that CD14 binds to Pam(3)CSK(4) at a dissociation constant of 5.7 microM. This study suggests that CD14 directly binds to triacylated lipopeptides and facilitates recognition of the lipopeptides by the TLR2/TLR1 complex without binding to the receptor complex.

Cell Line↗

PubMed1995

Specific biological effects of an anti-rat PMN antiserum intraperitoneally infected into f344/n rats.

Neutropenia can be produced with antimitotic chemicals, but this method lacks specificity. An alternative is to use antibody-dependent cytotoxicity to produce neutropenia; however, this method has not been completely evaluated with respect to efficacy, specificity, and potential collateral damage, especially to constituents of bone marrow. This study used in vitro and in vivo methods to evaluate specific biological effects of a commercially available rabbit anti-rat neutrophil (PMN) antiserum in F344/N rats. The viability of rat pulmonary alveolar macrophages (PAMs), PMNs, and lymphocytes in vitro was quantified using a trypan blue dye exclusion test. Amounts of antiserum in vitro that rendered PMNs 100% nonviable did not decrease the viability or phagocytic ability of the PAMs and did not decrease the viability of the lymphocytes. Intraperitoneal (IP) injection of the antiserum into rats resulted in complete depletion of the PMNs and about a 50% depletion of the lymphocytes in circulating blood within 24 hours. The numbers of both cell types remained lowered for 5 days, but returned to control values by Day 6 after the IP injection. The antiserum had no effect on the numbers of PAMs or lymphocytes in the pulmonary alveolar airspaces, as determined by quantifying the numbers of these cell types in bronchoalveolar lavage fluid (BALF). The numbers of PMNs in BALF, however, decreased on Days 3 and 4 after IP injection of antiserum, but were not different from control values by Day 5. The viability of the PAMs in BALF of treated rats was not different from control values at any time point. There were no morphological indications that the injected antiserum damaged lung tissue or stem cells in bone marrow. Results demonstrate that the anti-rat PMN antiserum administered IP to F344/N rats depletes circulating PMNs and partially depletes lymphocytes for a period of about 6 days without adversely affecting the precursors of red or white blood cells in bone marrow. We concluded that the antiserum is a relatively specific way to temporarily render rats neutropenic without damaging precursor cells in bone marrow.

Journal Article↗

PubMed1998

[Experimental infection of Naegleria fowleri in mice].

Ten SPF mice (ddY, 4w-old, female) were infected by nasal instillation with an isolate of Naegleria fowleri that was first isolated from a patient with primary amoebic meningoencephalitis (PAM) in Japan. Of these mice, 2 showed clinical signs typical for PAM on the 4th day. On the next day, 5 mice became very ill and remained immobile; their movement and response to painful stimuli diminished progressively. All the infected mice were then examined histopathologically on the same day regardless of their clinical signs. Pathological changes due to invasion and/or proliferation of amoebae were observed in 5 mice with clinical signs. Swelling of the nasal mucosa and ulcerated nasal epithelium with inflammatory cells were observed. Proliferation of amoebae was detected to a lesser extent in nasal cavity including mucous membrane and nasal epithelium. Olfactory lobes and arteriolar hemisphere were necrotic with haemorrhage and filled with amoebae. From these findings the pathogenicity of the isolate was confirmed to develop PAM in experimental animals. It was also observed that the olfactory neuroepithelium was the route of invasion in PAM due to N. fowleri and consequently migration occurred through olfactory lobes into the cerebrum.

Amebiasis↗

PubMed2006

Anti-inflammatory effects of 4-phenyl-3-butenoic acid and 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester, potential inhibitors of neuropeptide bioactivation.

Substance P (SP) and calcitonin gene-related peptide (CGRP) are well established mediators of inflammation. Therefore, inhibition of the biosynthesis of these neuropeptides is an attractive potential strategy for pharmacological intervention against a number of inflammatory diseases. The final step in the biosynthesis of SP and CGRP is the conversion of their glycine-extended precursors to the active amidated peptide, and this process is catalyzed by sequential action of the enzymes peptidylglycine alpha-monooxygenase (PAM) and peptidylamidoglycolate lyase. We have demonstrated previously that 4-phenyl-3-butenoic acid (PBA) is a PAM inhibitor, and we have also shown that in vivo inhibition of serum PAM by PBA correlates with this compound's ability to inhibit carrageenan-induced edema in the rat. Here we demonstrate the ability of PBA to inhibit all three phases of adjuvant-induced polyarthritis (AIP) in rats; this represents the first time that an amidation inhibitor has been shown to be active in a model of chronic inflammation. We recently introduced 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid (AOPHA) as one of a new series of mechanism-based amidation inhibitors. We now report for the first time that AOPHA and its methyl ester (AOPHA-Me) are active inhibitors of serum PAM in vivo, and we show that AOPHA-Me correspondingly inhibits carrageenan-induced edema in rats in a dose-dependent manner. Neither PBA nor AOPHA-Me exhibits significant cyclooxygenase (COX) inhibition in vitro; thus, the anti-inflammatory activities of PBA and AOPHA-Me are apparently not a consequence of COX inhibition. We discuss possible pharmacological mechanisms that may account for the activities of these new anti-inflammatory compounds.

Adjuvants, Immunologic↗

PubMed1999

Differential regulation of peptide alpha-amidation by dexamethasone and disulfiram.

alpha-Amidation is essential for the function of many peptides in intercellular communication. This C-terminal modification is mediated in a two-step process by the hydroxylase and lyase activities of the bifunctional enzyme, peptidylglycine alpha-amidating monooxygenase (PAM). The first step, catalyzed by peptidylglycine-alpha-hydroxylating monooxygenase (PHM; EC 1.14.17. 3), is rate limiting in the process, and therefore subject to regulation. Dexamethasone and disulfiram (tetraethylthiuram disulfide; Antabuse) were used as in vivo treatments to study the regulation of PHM expression and activity in cardiac atrium. Our findings show that both dexamethasone and disulfiram treatment increase the activity of PHM in atrial tissue but that they do so by distinctly different mechanisms. Dexamethasone elevated tissue levels of PAM mRNA and protein concurrently, suggesting that glucocorticoids regulate PAM expression at the level of gene transcription. In contrast, disulfiram treatment, which depletes stores of alpha-amidated peptides, increased the specific activity of PHM without affecting the level of PAM expression. The catalytic efficiency of PHM was enhanced by raising the Vmax of the enzyme. Importantly, this increase in Vmax was retained through purification to homogeneity, indicating that either a covalent modification or a stable conformational change had occurred in the protein. These novel findings demonstrate that the rate-limiting enzyme in the bioactivation of peptide messengers is differentially regulated by transcriptional and post-transcriptional mechanisms in vivo. It is proposed that regulation of PHM's expression and catalytic efficiency serve as coordinated physiologic mechanisms for maintaining appropriate levels of alpha-amidating activity under changing conditions in vivo.

Animals↗

PubMed2006

Immunogenicity of Duffy binding-like domains that bind chondroitin sulfate A and protection against pregnancy-associated malaria.

Sequestration of Plasmodium falciparum-infected erythrocytes in the placenta is implicated in pathological outcomes of pregnancy-associated malaria (PAM). P. falciparum isolates that sequester in the placenta primarily bind chondroitin sulfate A (CSA). Following exposure to malaria during pregnancy, women in areas of endemicity develop immunity, and so multigravid women are less susceptible to PAM than primigravidae. Protective immunity to PAM is associated with the development of antibodies that recognize diverse CSA-binding, placental P. falciparum isolates. The epitopes recognized by such protective antibodies have not been identified but are likely to lie in conserved Duffy binding-like (DBL) domains, encoded by var genes, that bind CSA. Immunization of mice with the CSA-binding DBL3gamma domain encoded by var1CSA elicits cross-reactive antibodies that recognize diverse CSA-binding P. falciparum isolates and block their binding to placental cryosections under flow. However, CSA-binding isolates primarily express var2CSA, which does not encode any DBLgamma domains. Here, we demonstrate that antibodies raised against DBL3gamma encoded by var1CSA cross-react with one of the CSA-binding domains, DBL3X, encoded by var2CSA. This explains the paradoxical observation made here and earlier that anti-rDBL3gamma sera recognize CSA-binding isolates and provides evidence for the presence of conserved, cross-reactive epitopes in diverse CSA-binding DBL domains. Such cross-reactive epitopes within CSA-binding DBL domains can form the basis for a vaccine that provides protection against PAM.

Animals↗

PubMed1991

Differential induction of tumor necrosis factor alpha in ovine pulmonary alveolar macrophages following infection with Corynebacterium pseudotuberculosis, Pasteurella haemolytica, or lentiviruses.

Soluble mediators such as tumor necrosis factor alpha (TNF-alpha) may be important in the pathogenesis of many chronic pulmonary infections. We examined the ability of Corynebacterium pseudotuberculosis, Pasteurella haemolytica, and ovine lentiviruses (OvLV) to induce TNF-alpha secretion by pulmonary alveolar macrophages (PAM). Bronchoalveolar lavage cells, composed of greater than 90% PAM, were obtained from normal sheep. Bronchoalveolar lavage cells were cultured for 2, 24, 48, 72, or 168 h in endotoxin-free RPMI medium (with 10% autologous serum) or in medium containing one of the following additives: lipopolysaccharide, 1-micron polystyrene beads, C. pseudotuberculosis, P. haemolytica, or one of two plaque-cloned OvLV, 85/28 or 85/34. Lipopolysaccharide, C. pseudotuberculosis, and P. haemolytica induced TNF-alpha activity in PAM cultures as early as 2 h after inoculation, as assessed by a colorimetric cytotoxicity assay. This activity could be blocked by rabbit anti-recombinant bovine TNF-alpha serum. In contrast, medium alone, polystyrene beads, and productive infection by OvLV did not induce TNF-alpha activity in PAM cultures. Bacterial pathogens which infect pulmonary macrophages may elicit the secretion of TNF-alpha within the lungs and lead to the cachectic state associated with chronic pneumonia.

Animals↗

PubMed2004

Plasminogen binding by group A streptococcal isolates from a region of hyperendemicity for streptococcal skin infection and a high incidence of invasive infection.

Reports of resurgence in invasive group A streptococcal (GAS) infections come mainly from affluent populations with infrequent exposure to GAS. In the Northern Territory (NT) of Australia, high incidence of invasive GAS disease is secondary to endemic skin infection, serotype M1 clones are rare in invasive infection, the diversity and level of exposure to GAS strains are high, and no particular strains dominate. Expression of a plasminogen-binding GAS M-like protein (PAM) has been associated with skin infection in isolates elsewhere (D. Bessen, C. M. Sotir, T. M. Readdy, and S. K. Hollingshead, J. Infect. Dis. 173:896-900, 1996), and subversion of the host plasminogen system by GAS is thought to contribute to invasion in animal models. Here, we describe the relationship between plasminogen-binding capacity of GAS isolates, PAM genotype, and invasive capacity in 29 GAS isolates belonging to 25 distinct strains from the NT. In the presence of fibrinogen and streptokinase, invasive isolates bound more plasminogen than isolates from uncomplicated infections (P < or = 0.004). Only PAM-positive isolates bound substantial levels of plasminogen by a fibrinogen-streptokinase-independent pathway (direct binding). Despite considerable amino acid sequence variation within the A1 repeat region of PAM where the plasminogen-binding domain maps, the critical lysine residue was conserved.

Antigens, Bacterial↗