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PubMed1998

P-CIP1, a novel protein that interacts with the cytosolic domain of peptidylglycine alpha-amidating monooxygenase, is associated with endosomes.

The cytosolic domain of the peptide processing enzyme peptidylglycine alpha-amidating monooxygenase (PAM) contains signals that direct its trafficking in the secretory and endosomal pathways. Using the yeast two-hybrid system, Alam et al. (Alam, M. R., Caldwell, B. D., Johnson, R. C., Darlington, D. N., Mains, R. E., and Eipper, B. A. (1996) J. Biol. Chem. 271, 28636) identified three proteins that interact with a fragment of the PAM cytosolic domain containing these targeting signals. We cloned the rat and human cDNAs encoding PAM COOH-terminal interactor protein-1 (P-CIP1). Both cDNAs contain an open reading frame that encodes a novel protein of 435 amino acids. The P-CIP1 protein is highly conserved from rat to human (85% identity) but does not display significant homology to proteins in the GenBank data base. In vitro, P-CIP1 interacts with the cytosolic domain of wild type PAM-1, but does not interact with mutant PAM-1 proteins that fail to target correctly when expressed in endocrine cells. P-CIP1 contains multiple consensus serine/threonine phosphorylation sites and a region predicted to form a coiled-coil at the COOH terminus. When expressed in endocrine cells or fibroblasts, P-CIP1 is distributed in a punctate pattern in the perinuclear area but does not significantly overlap the distribution of transfected wild type PAM-1. The distribution of P-CIP1 displays significant overlap with the distribution of the secretory carrier membrane proteins, internalized Texas Red-conjugated transferrin, and Rab11. The data suggest that P-CIP1 associates with vesicles in the recycling endosomal pathway, and may play a role in regulating the trafficking of integral membrane PAM.

Amino Acid Sequence↗

PubMed1999

Enhancement through mutagenesis of the binding of the isolated kringle 2 domain of human plasminogen to omega-amino acid ligands and to an internal sequence of a Streptococcal surface protein.

In the background of the recombinant K2 module of human plasminogen (K2(Pg)), a triple mutant, K2(Pg)[C4G/E56D/L72Y], was generated and expressed in Pichia pastoris cells in yields exceeding 100 mg/liter. The binding affinities of a series of lysine analogs, viz. 4-aminobutyric acid, 5-aminopentanoic acid, epsilon-aminocaproic acid, 7-aminoheptanoic acid, and t-4-aminomethylcyclohexane-1-carboxylic acid, to this mutant were measured and showed up to a 15-fold tighter interaction, as compared with wild-type K2(Pg) (K2(Pg)[C4G]). The variant, K2(Pg)[C4G/E56D], afforded up to a 4-fold increase in the binding affinity to these same ligands, whereas the K2(Pg)[C4G/L72Y] mutant decreased the same affinities up to 5-fold, as compared with K2(Pg)[C4G]. The thermal stability of K2(Pg)[C4G/E56D/L72Y] was increased by approximately 13 degrees C, as compared with K2(Pg)[C4G]. The functional consequence of up-regulating the lysine binding property of K2(Pg) was explored, as reflected by its ability to interact with an internal sequence of a plasminogen-binding protein (PAM) on the surface of group A streptococci. A 30-mer peptide of PAM, containing its K2(Pg)-specific binding region, was synthesized, and its binding to each mutant of K2(Pg) was assessed. Only a slight enhancement in peptide binding was observed for K2(Pg)[C4G/E56D], compared with K2(Pg)[C4G] (K(d) = 460 nM). A 5-fold decrease in binding affinity was observed for K2(Pg)[C4G/L72Y] (K(d) = 2200 nM). However, a 12-fold enhancement in binding to this peptide was observed for K2(Pg)[C4G/E56D/L72Y] (K(d) = 37 nM). Results of these PAM peptide binding studies parallel results of omega-amino acid binding to these K2(Pg) mutants, indicating that the high affinity PAM binding by plasminogen, mediated exclusively through K2(Pg), occurs through its lysine-binding site. This conclusion is supported by the 100-fold decrease in PAM peptide binding to K2(Pg)[C4G/E56D/L72Y] in the presence of 50 mM 6-aminohexanoic acid. Finally, a thermodynamic analysis of PAM peptide binding to each of these mutants reveals that the positions Asp(56) and Tyr(72) in the K2(Pg)[C4G/E56D/L72Y] mutant are synergistically coupled in terms of their contribution to the enhancement of PAM peptide binding.

Bacterial Proteins↗

PubMed2001

Response of an integral granule membrane protein to changes in pH.

A key feature of the regulated secretory pathway in neuroendocrine cells is lumenal pH, which decreases between trans-Golgi network and mature secretory granules. Because peptidylglycine alpha-amidating monooxygenase (PAM) is one of the few membrane-spanning proteins concentrated in secretory granules and is a known effector of regulated secretion, we examined its sensitivity to pH. Based on antibody binding experiments, the noncatalytic linker regions between the two enzymatic domains of PAM show pH-dependent conformational changes; these changes occur in the presence or absence of a transmembrane domain. Integral membrane PAM-1 solubilized from rat anterior pituitary or from transfected AtT-20 cells aggregates reversibly at pH 5.5 while retaining enzyme activity. Over 35% of the PAM-1 in anterior pituitary extracts aggregates at pH 5.5, whereas only about 5% aggregates at pH 7.5. PAM-1 recovered from secretory granules and endosomes is highly responsive to low pH-induced aggregation, whereas PAM-1 recovered from a light, intracellular recycling compartment is not. Mutagenesis studies indicate that a transmembrane domain is necessary but not sufficient for low pH-induced aggregation and reveal a short lumenal, juxtamembrane segment that also contributes to pH-dependent aggregation. Taken together, these results demonstrate that several properties of membrane PAM serve as indicators of granule pH in neuroendocrine cells.

Animals↗

PubMed1992

An interspecies comparison of the phagocytosis and dissolution of 241AmO2 particles by rat, dog and monkey alveolar macrophages in vitro.

Because of the role that alveolar macrophages (PAM) play in the pulmonary clearance of inhaled particles via mechanical transport and dissolution, understanding the uptake and dissolution of particles by these cells might provide insight into the mechanisms of particle dissolution in lungs of various species and hence facilitate the extrapolation of animal data to humans. Therefore, experiments were conducted to study the phagocytosis and dissolution of 241AmO2 particles by rat, dog and monkey PAM in vitro. Rat, dog and monkey PAM were exposed for up to 72 h to 0.19, 0.93 or 4.6 kBq/ml 241Am, after which cell viability was determined. The 241Am concentration, 4.63 kBq/ml, was used for the phagocytosis and dissolution experiments. The phagocytosis and dissolution of 241AmO2 particles were followed up to 20 and 72 h, respectively. Dog and monkey PAM took up 241AmO2 particles at similar rates, whereas rat PAM phagocytosed only 60% of the amount phagocytosed by dog and monkey PAM at 20 h. The PAM of the three species dissolved 241AmO2 particles at similar rates; 8-10% was dissolved by 72 h. The results of the 241AmO2 uptake in vitro may reflect in vivo situations, where the differences in uptake seen in vitro would probably diminish at later times after exposure. The dissolution results imply that the dissolution of 241AmO2 particles by alveolar macrophages of the three species might be species-independent. This, at least, might be true for dog and monkey, where in vivo data have shown that 241AmO2 was translocated similarly in both species. Finally, the alveolar macrophage culture system provides a useful simulation to investigate uptake and dissolution of inhaled particles.

Americium↗

PubMed1979

Origin, Kinetics, and characteristics of pulmonary macrophages in the normal steady state.

Pulmonary macrophages of mice in the steady state were isolated by lavage with PBS containing EDTA and subsequent enzymatic digestion of tissue with pronase and DNA-ase. By this method, the total pulmonary macrophage population was obtained in two cell suspensions, one with a pure population of pulmonary alveolar macrophages (PAM) and the other with a mixed population of pulmonary alveolar and pulmonary tissue macrophages (PTM). The morphological, cytochemical, and functional characteristics of both PAM and PTM were like those of mature tissue macrophages except for the presence of C3 receptors. These receptors were almost absent on PAM and present on a larger number of cells in the mixed population of PAM and PTM. The total pulmonary macrophage population of mice in the steady state is approximately equal to 2 x 10(6), of which about 93% are PAM and about 7% are PTM. In labeling experiments with 3H-thymidine, the low in vitro labeling indices (less than 3%) for both PAM and the mixture of PAM and PTM, showed that both are essentially nondividing cells. In vivo labeling studies showed an increase in the number of labeled macrophages that can only be attributed to labeled monocytes migrating into the lungs. Additional evidence was provided by a decrease in the labeling indices of pulmonary macrophages when mice were treated with hydrocortisone acetate, which causes a severe monocytopenia, thus preventing monocyte influx into the lungs. Confirmation of the bone marrow origin was obtained in mice labeled after x-irradiation with partial bone marrow shielding: labeled pulmonary macrophages were found in the exposed lungs. In all experiments, the labeling indices were identical in the two macrophage populations isolated. These results show that the influx of monocytes is the source of cell renewal for the pulmonary macrophages. No indications for an interstitial division or maturation compartment in the lung were found. Quantitation of the efflux of labeled monocytes from the blood, and the number of labeled pulmonary macrophages, showed that in the steady state about 15% of the monocytes leaving the circulation become pulmonary macrophages and that the turnover time of pulmonary macrophages is approximately equal to 27 d.

Animals↗

PubMed1993

Downregulation of the antigen presenting cell function(s) of pulmonary dendritic cells in vivo by resident alveolar macrophages.

Class II major histocompatibility complex (Ia)-bearing dendritic cells (DC) from airway epithelium and lung parenchyma express low-moderate antigen presenting cell (APC) activity when freshly isolated. However, this function is markedly upregulated during overnight culture in a manner analogous to epidermal Langerhans cells. The in vitro "maturation" process is inhibited by coculture with pulmonary alveolar macrophages (PAM) across a semipermeable membrane, and the degree of inhibition achieved can be markedly increased by the presence of tumor necrosis factor alpha. In addition, PAM-mediated suppression of DC function is abrogated via inhibition of the nitric oxide synthetase pathway. Functional maturation of the DC is accompanied by increased expression of surface Ia, which is also inhibited in the presence of PAM. Prior elimination of PAM from DC donors via intratracheal administration of the cytotoxic drug dichloromethylene diphosphonate in liposomes, 24-72 h before lung DC preparation, achieves a comparable upregulation of APC activity, suggesting that (consistent with the in vitro data) the resident PAM population actively suppresses the APC function of lung DC in situ. In support of the feasibility of such a regulatory mechanism, electron microscopic examination of normal lung fixed by intravascular perfusion in the inflated state (which optimally preserves PAM in situ), revealed that the majority are preferentially localized in recesses at the alveolar septal junctions. In this position, the PAM are in intimate association with the alveolar epithelial surface, and are effectively separated by as little as 0.2 microns from underlying interstitial spaces which contain the peripheral lung DC population. A similar juxtaposition of airway intraepithelial DC is demonstrated with underlying submucosal tissue macrophages, where the separation between the two cell populations is effectively the width of the basal lamina.

Animals↗

PubMed1990

DNA adenine adducts induced by nitrogen mustards and their role in transcription termination in vitro.

Previous studies have demonstrated that three cancer chemotherapeutic compounds of the nitrogen mustard class, melphalan (L-PAM), nitrogen mustard (HN2) and chlorambucil (CBC), each generated DNA lesions that prematurely terminate in vitro transcription. Sites of these lesions were inconsistent with sites of N7 guanine monoadducts formed by these compounds, and in the cases of L-PAM and CBC were suggestive of adenine lesions. The present study is an attempt to identify and characterize nitrogen mustard-induced non-N7 guanine DNA adducts, and in particular adenine DNA adducts, and to assess their role in drug-induced in vitro transcription termination. Data from studies using a modified Maxam-Gilbert DNA sequencing technique demonstrate that L-PAM and CBC, but not HN2, generate heat-labile, alkaline-stabilized adenine adducts at nearly every adenine in a region of a defined DNA template examined. Comparison of sites of L-PAM- and CBC-induced adenine adducts to known sites of drug-induced transcription termination in the same DNA template show that L-PAM- and CBC-induced transcription termination is associated not with drug lesions at single adenines, but rather with drug-induced adducts at neighboring adenines. Additional in vitro transcription studies using a small DNA molecule generated by polymerase chain reaction-mediated DNA amplification demonstrate that none of the transcription-terminating lesions induced by L-PAM and CBC in this molecule are interstrand in nature. These results suggest that some, but not all, nitrogen mustard compounds can generate heat-labile adenine lesions in DNA, and that bifunctional nitrogen mustards that can form heat-labile adenine adducts also form adducts consistent with intrastrand adenine-adenine crosslinks. These adducts at pairs of adenines in turn appear to be responsible for L-PAM- and CBC-induced transcription termination in vitro.

Amino Acid Sequence↗

PubMed1996

Prevalence and significance of pancreatic acinar metaplasia at the gastroesophageal junction.

Pancreatic acinar metaplasia (PAM), defined as nodules of glandular tissue forming acini composed of cells with coarse apical eosinophilic granules, with or without mucous cells, was recently recognized in gastric mucosa, but its significance is not known. As part of a study on intestinal metaplasia at the gastroesophageal junction (GEJ), we evaluated the prevalence and clinical and histologic correlates of PAM in biopsy specimens from the gastroesophageal squamocolumnar junction. All adult patients having elective upper gastrointestinal endoscopy over a 6-month period were invited to participate. Clinical data and endoscopic findings were recorded. Biopsy specimens, obtained from both sides of the apparent squamocolumnar junction, were processed routinely and reviewed (without knowledge of the clinical data) to evaluate types of epithelium, types and degree of inflammation, and the presence of PAM. The presence or absence of PAM was then correlated with the other histologic findings and with the clinical and endoscopic data. The study comprised 155 patients (79 women, 76 men; 139 white patients, nine black patients, and seven patients of other ethnic groups). Their mean age was 52 years (range: 18-89 years). PAM was present in 37 patients (24%). PAM was not associated with any of the reported symptoms, endoscopic evidence of esophagitis or columnar epithelium in the distal esophagus, or any of the histologic features evaluated, including active esophagitis, intestinal metaplasia at the GEJ, active and chronic gastritis, intestinal metaplasia in the stomach, and Helicobacter infection. Although PAM is present in a considerable proportion (24%) of patients with mucosal biopsy specimens from the squamocolumnar junction, it appears to be an incidental finding unrelated to clinical or histologic abnormalities. We therefore suggest a congenital, rather than an acquired, origin for this entity.

Adult↗

PubMed2001

Buthionine sulfoximine and myeloablative concentrations of melphalan overcome resistance in a melphalan-resistant neuroblastoma cell line.

BACKGROUND: Alkylator resistance contributes to treatment failure in high-risk neuroblastoma. Buthionine sulfoximine (BSO) can deplete glutathione and synergistically enhance in vitro sensitivity to the alkylating agent melphalan (L-PAM) for many neuroblastoma cell lines, but optimal use of this combination needs to be defined because clinical responses have been less frequent and not durable. PATIENTS AND METHODS: The authors established and characterized a neuroblastoma cell line (CHLA-171) from a patient who died of progressive disease after treatment with BSO and low-dose L-PAM. RESULTS: CHLA-171 lacks MYCN amplification, expresses PGP (P-glycoprotein) 9.5 RNA, and shows cell surface antigen expression (human leukocyte antigen class I weakly positive, but HSAN 1.2 (hybridoma, SAN 1.2) and anti-GD2 (anti-ganglioside GD2 antibody) strongly positive) characteristic of neuroblastoma cell lines. Twenty-four hours of BSO treatment (0-1,000 micromol/L) maximally depleted CHLA-171 glutathione to 36% of baseline. The cytotoxic response of CHLA-171 to BSO and L-PAM, alone and in combination, was measured by digital image microscopy (DIMSCAN) over a range of drug concentrations and compared with drug levels obtained in the patient during BSO/L-PAM therapy. As single agents, CHLA-171 was highly resistant to L-PAM (LD90 = 42 micromol/L; peak plasma concentration in the patient equals 3.9 micromol/L) and moderately resistant to BSO (LD90 = 509 micromol/L; steady-state concentration in the patient equals 397 micromol/L). Treatment with a 10:1 (BSO:L-PAM) fixed ratio combination synergistically overcame resistance (3-4 logs of cell kill, combination index <1) at clinically achievable levels of BSO (100-400 micromol/L) and levels of L-PAM (10-40 micromol/L) clinically achievable only with hematopoietic stem cell support. CONCLUSIONS: The in vitro results obtained for CHLA-171 suggest that BSO/L-PAM therapy may be optimally effective for drug-resistant neuroblastoma using myeloablative doses of L-PAM.

Antimetabolites, Antineoplastic↗

PubMed2002

Roles of the plasminogen activator streptokinase and the plasminogen-associated M protein in an experimental model for streptococcal impetigo.

Primary infection by group A streptococci (GAS) takes place at either the throat or skin of the human host, often leading to pharyngitis or impetigo, respectively. Many GAS strains differ in their preference for throat and skin tissue sites. Previous epidemiological findings show that many of the strains displaying strong tropism for the skin have a high-affinity binding site for plasminogen, located within M protein (PAM), a prominent surface fibril. Plasminogen bound by PAM interacts with streptokinase, a plasminogen activator secreted by GAS, to yield bacterial-bound plasmin activity. In this study, PAM and streptokinase were tested for their roles in infection using an experimental model that closely mimics human impetigo. Inactivation of genes encoding either PAM or streptokinase led to a partial, but significant, loss of virulence in vivo, as measured by net growth of the bacteria and pathological alterations. The relative loss in virulence in vivo was greater for the streptokinase mutant than for the PAM mutant. However, the PAM mutant, but not the streptokinase mutant, displayed a partial loss in resistance to phagocytosis in vitro. The combined experimental and epidemiological data provide evidence that PAM and streptokinase play a key role in mediating skin-specific infection by GAS. In addition, secreted cysteine proteinase activity due to SpeB leads to degradation of streptokinase in stationary phase broth cultures. Since SpeB is also a determinant of tissue-specific GAS infection at the skin, direct interactions between these two proteolytic pathways may constitute an important pathogenic mechanism. An integrated model for superficial infection at the skin is presented.

Animals↗

PubMed1982

Evidence for the pulmonary origin of alveolar macrophages.

This paper supports the hypothesis that some form of pulmonary alveolar macrophage (PAM) production occurs within the lung in the normal steady state. The study involved monitoring the change in number of labelled PAMs following two modes of irradiation--the first with the thorax being irradiated and the rest of the mouse shielded, the second with the thorax shielded and the body irradiated. Also measurements of monocyte and PAM numbers after a single bone marrow irradiation were carried out. Finally, the labelling indices of monocytes in both control and thorax irradiated mice were measured. Both the number of monocytes and PAMs, along with the labelling indices of monocytes and PAMs after irradiation, indicate the independence of PAMs from a monocyte precursor population, and also provide evidence for a pulmonary origin of PAMs.

Animals↗

PubMed2006

Attributable fractions for premature mortality avoidable through public health action: updated estimates by Australian public health physicians.

OBJECTIVE: To determine whether previously published estimates of attributable fractions of primary avoidable mortality (PAM) and secondary avoidable mortality (SAM) were valid to Australian public health physicians. DESIGN: Self-administered survey. SETTING: Australia-wide survey. PARTICIPANTS: 331 Fellows of the Australasian Faculty of Public Health Medicine (71.8% response rate). RESULTS: Tobias and Jackson's cited estimates for PAM and SAM for lung cancer were the least contested by respondents (62% 'no change' for PAM estimate; 67% 'no change' for SAM estimate). By contrast, 39% indicated that the PAM estimate of 30% for diabetes required change. Those most-contested PAM estimates also typically elicited significantly different responses by gender (breast cancer, diabetes and falls), age (breast cancer, stroke and diabetes) and training (stroke, diabetes, mental health). The proportion of respondents who agreed with the cited estimates either for PAM or SAM for any of the 10 selected conditions never differed significantly according to current primary role ('practitioner' v 'researcher' v 'other'). CONCLUSIONS: PAM and SAM represent the key action areas for public health. We conclude that the estimates of Tobias and Jackson are generally robust among Australian public health physicians, invoking confidence that their advocacy will engage practitioners, policy makers and citizens seeking better governance of health system performance.

Age Factors↗

PubMed2006

Synergistic activities of azithromycin and amphotericin B against Naegleria fowleri in vitro and in a mouse model of primary amebic meningoencephalitis.

Naegleria fowleri is responsible for producing a rapidly fatal central nervous system infection known as primary amebic meningoencephalitis (PAM). To date, amphotericin B, an antifungal agent, is the only agent with established clinical efficacy in the treatment of PAM. However, amphotericin B is not always successful in treating PAM and is associated with severe adverse effects. We previously found azithromycin to be more effective than amphotericin B in a mouse model of PAM. We therefore investigated the combination of amphotericin B and azithromycin in vitro and in a mouse model of PAM. For the in vitro studies, 50% inhibitory concentrations were calculated for each drug alone and for the drugs in fixed combination ratios of 1:1, 3:1, and 1:3. We found amphotericin B and azithromycin to be synergistic at all three of the fixed combination ratios. In our mouse model of PAM, a combination of amphotericin B (2.5 mg/kg of body weight) and azithromycin (25 mg/kg) protected 100% of the mice, whereas amphotericin B alone (2.5 mg/kg) protected only 27% of mice and azithromycin alone (25 mg/kg) protected 40% of mice. This study indicates that amphotericin B and azithromycin are synergistic against the Lee strain of N. fowleri, suggesting that the combined use of these agents may be beneficial in treating PAM.

Amphotericin B↗

PubMed2001

Assessing the risk of primary amoebic meningoencephalitis from swimming in the presence of environmental Naegleria fowleri.

Free-living Naegleria fowleri amoebae cause primary amoebic meningoencephalitis (PAM). Because of the apparent conflict between their ubiquity and the rarity of cases observed, we sought to develop a model characterizing the risk of PAM after swimming as a function of the concentration of N. fowleri. The probability of death from PAM as a function of the number of amoebae inhaled is modeled according to results obtained from animals infected with amoeba strains. The calculation of the probability of inhaling one or more amoebae while swimming is based on a double hypothesis: that the distribution of amoebae in the water follows a Poisson distribution and that the mean quantity of water inhaled while swimming is 10 ml. The risk of PAM for a given concentration of amoebae is then obtained by summing the following products: the probability of inhaling n amoebae x the probability of PAM associated with inhaling these n amoebae. We chose the lognormal model to assess the risk of PAM because it yielded the best analysis of the studentized residuals. Nonetheless, the levels of risk thereby obtained cannot be applied to humans without correction, because they are substantially greater than those indicated by available epidemiologic data. The curve was thus adjusted by a factor calculated with the least-squares method. This provides the PAM risk in humans as a function of the N. fowleri concentration in the river. For example, the risk is 8.5 x 10(-8) at a concentration of 10 N. fowleri amoebae per liter.

Amebiasis↗

PubMed1984

Abnormal phagolysosome fusion in pulmonary alveolar macrophages of rats exposed chronically to cigarette smoke.

Cigarette smoking is strongly associated with functional and morphologic changes in pulmonary alveolar macrophages (PAM). Phagocytic activity is a primary function of PAM, and although the ingestion of particles appears to be normal in the PAM of cigarette smokers, published data suggest that antimicrobial activity of these cells might be diminished. Because phagolysosome fusion (PLF) is an important aspect of the phagocytic process subsequent to the ingestion phase, PLF was evaluated in PAM lavaged from the lungs of male Fisher 344 rats that had been exposed for 8 wk to whole cigarette smoke, to the gas phase of cigarette smoke, or to air as a sham control. Using the acridine orange assay with viable yeast as the phagocytic challenge, we found no difference in the numbers of PAM from each group that had phagocytic activity after a 2-h challenge. However, PLF expressed as the number of orange-fluorescing phagosomes per total number of yeast-containing phagosomes was 35 +/- 1% (X +/- SE) for the group exposed to whole smoke, 53 +/- 2% for the gas phase group, and 65 +/- 1% for the control group. These differences are highly significant, with p less than 0.001 for the whole smoke versus control and p less than 0.01 for the gas phase versus control. Tight phagosomal membranes suggest normal PLF, whereas loose membranes suggest that PLF is inhibited. When the structure of yeast-containing phagosomes was examined and PLF was calculated with the number of phagosomes with tight membranes substituted for the number of orange-fluorescing phagosomes, PLF in smoke-exposed PAM was found to be significantly (p less than 0.01) different from that in sham-exposed control PAM.(ABSTRACT TRUNCATED AT 250 WORDS)

Acridine Orange↗

PubMed1975

Effects of oxygen exposure on it vitro function of pulmonary alveolar macrophages.

Bacterial infection may complicate pulmonary oxygen (O2) toxicity, and animals exposed to high O2 concentrations show depressed in vivo pulmonary bacterial inactivation. Therefore, in vitro studies were undertaken to define the mechanism by which O2 alters pulmonary antibacterial activity. Normal and BCG pretreated rabbits were exposed to 100% O2 for 24, 48, and 72-h periods. Pulmonary alveolar macrophages (PAM) were obtained from the experimental animals and from nonoxygen exposed controls by bronchopulmonary lavage. O2 exposure did not alter cell yield or morphology. PAMs were suspended in 10% serum-buffer, and phagocytosis of (14C)Staphylococcus aureus 502A and (14C)Pseudomonas aeruginosa was measured. Comparison of the precent uptake of the 14C-labeled S. aureus after a 60-min incubation period demonstrated that normal PAMs exposed to O2 for 48 h showed a statistically significant increase in phagocytosis when compared to their controls (43.5 vs. 29.2%). A similar, but smaller increase was seen after 24-h O2 exposures. 48 and 72-h O2 exposures produced no significant changes in phagocytosis in PAMs from BCG-stimulated rabbits. Normal PAMs also showed an increased phagocytosis of Ps. aeruginosa after 48-h oxygen exposure. No impairment of in vitro bactericidal activity against either S. aureus 502A or Ps. aeruginosa could be demonstrated in PAMs from normal rabbits exposed to O2 for 48 h. These results indicate that the in vitrophagocytic and bactericidal capacity of the rabbit PAM is relatively resistant to the toxic effects of oxygen, and that imparied in vivo activity may possibly be mediated by effects other than irreversible metabolic damage to these cells. The mechanism for the observed stimulation of phagocytosis remains to be determined.

Animals↗

PubMedDate not supplied

Accuracy of the potential acuity meter in predicting the visual outcome in cases of cataract associated with macular degeneration.

In order to ascertain the accuracy and specificity of the Potential Acuity Meter (PAM) in the preoperative evaluation of likely postoperative visual acuity in cases of cataract associated with age-related macular degeneration (ARMD), we studied the results in 130 cases, 54 of whom had preoperatively proved or suspected ARMD associated with a cataract. All of them were operated with extracapsular extraction and implantation of an intraocular lens (IOL), and final visual acuity was established when all the patients were visited three months postoperatively. A positive linear correlation was found between normal ocular fundus and PAM prediction (r = 0.77), and in the group of patients with preoperatively confirmed ARMD (r = 0.77). No difference was found between the preoperative PAM estimation and the final visual acuity in both groups. The PAM prediction was less accurate in cases with doubtful preoperative ARMD (r = 0.58) for whom showed PAM the highest score of false negatives in favor of the final visual acuity. Our results show that PAM is a reliable clinical technique for the prediction of visual results after cataract surgery in cases with preoperatively proved or doubtful macular pathology. To the best of our knowledge, this is the first report regarding the sensitivity and specificity of the PAM in diseased or suspicious maculas associated with cataract.

Aged↗

PubMed1985

Hormonal, drug, and dietary factors affecting peptidyl glycine alpha-amidating monooxygenase activity in various tissues of the adult male rat.

The factors controlling levels of peptidyl glycine alpha-amidating monooxygenase (PAM) activity in its major tissue sources in the adult male rat were investigated by carrying out a variety of endocrine, pharmacological, and dietary manipulations. Levels of PAM activity and alpha MSH immunoactivity in the neurointermediate lobe of the pituitary gland rose and fell in parallel in rats treated with the dopamine antagonist haloperidol or the dopamine agonist bromocriptine, respectively. PAM activity in the anterior pituitary lobe was increased after adrenalectomy or castration and decreased after thyroidectomy or treatment with haloperidol. PAM activity in the submandibular gland was increased after treatment with the alpha-adrenergic antagonist phenoxybenzamine and decreased after treatment with the alpha-adrenergic agonist phenylephrine. Serum levels of PAM activity were unaltered after hypophysectomy, adrenalectomy, sialectomy, or castration, but rose after thyroidectomy and declined after treatment with the ganglionic blocker chlorisondamine or phenoxybenzamine. Chronic dietary copper deficiency in rats resulted in increased PAM activity in homogenates of anterior pituitary lobe and submandibular gland assayed under optimized conditions; chronic dietary ascorbate deficiency in guinea pigs did not produce consistent changes in PAM activity in the tissues examined.

Animals↗