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PubMed1988

Predictions of outcomes from cataract surgery in elderly persons.

To determine how well visual outcomes of cataract surgery can be predicted from acuity estimations by visual instruments and an ophthalmologist, the authors compared predictions of postsurgical visual acuity with the measured acuity at 4 months in 82 elderly persons. Comparisons were made between the potential acuity meter (PAM), laser interferometer (LI), and an ophthalmologist, who predicted the final vision before surgery using screening visual information, including PAM, LI data, and results of the patient's examination. Neither instrument alone was successful in predicting postsurgical acuity +/- 1 contiguous Snellen chart line (bivariate correlation [r] = 0.03 for PAM and 0.07 for LI). The ophthalmologist was the most accurate predictor of acuity within 1 line (r = 0.41, p less than or equal to 0.001). These results indicate that the PAM and LI did not independently predict postsurgical vision in elderly cataract patients, but results of a clinical examination markedly improved the accuracy of predictions.

Aged↗

PubMed1989

Animal model of conjunctival primary acquired melanosis.

A condition clinically identical to human conjunctival primary acquired melanosis (PAM) was induced in 16 of 20 Dutch (pigmented) rabbits after weekly topical 60-microliters applications of a 1% solution of 7,12-dimethylbenz[a]anthracene (DMBA) in acetone. Pigment stippling appeared in the conjunctiva as early as 5 weeks after the initial carcinogen application. Confluent patches of flat pigmentation appeared over the palpebral conjunctiva 18 weeks after the onset of treatment and showed progressive lateral enlargement and darkening. Histologically, a spectrum of changes from increased melanin production and melanocytic hyperplasia without atypia (resembling the human condition of PAM without atypia) through atypical melanocytic hyperplasia (resembling human PAM with atypia) was identified. The development of this model permits further investigations to explore and explain the clinically observed phenomenon of waxing and waning of PAM and its promotion to conjunctival malignant melanoma.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1997

Nitric oxide production following in vitro stimulation of ovine pulmonary alveolar macrophages.

Production of inducible nitric oxide (NO) as measured by nitrite in supernatant from ovine pulmonary alveolar macrophage (PAM) cultures was assessed following stimulation of PAM with live cells and supernatants from Corynebacterium pseudotuberculosis and Pasteurella haemolytica cultures; purified bacterial lipopolysaccharide derived from both Escherichia coli and Pasteurella haemolytica alone and in combination with interferon-gamma or lymphocyte conditioned medium; or ovine lentivirus. PAM cultured ex vivo with no further stimulation for 24 h, 48 h or 72 h, produced low concentrations of NO that was not substantially increased following co-culture by the various additives. Assessment of NO production in PAM cultures containing P. haemolytica or supernatant from P. haemolytica cultures was complicated by production of high levels of nitrite in the bacterial cultures. Species differences in inducible NO production may affect the efficacy of clearance of bacterial infections and be responsible for inter-host differences in disease expression following infection by intracellular pathogens.

Animals↗

PubMed1998

Key peptide processing enzymes are expressed by a variant form of small-cell carcinoma of the lung.

Small-cell carcinoma of the lung (SCCL) is a neuroendocrine tumor characterized by having the capacity to produce and secrete a number of small neuropeptides. These peptides serve the tumor as autocrine growth factors. SCCL is known to undergo a process of dedifferentiation to a variant (drug-resistant) form, and this process is associated with loss of marker enzymes such as neuron-specific enolase (NSE) and dopa decarboxylase (DDC). The current study was designed to discover if variant SCCL, represented by cell line NCI H82, retains some capacity to generate active neuropeptides (like vasopressin) from their precursors by continuing to express the three key classes of enzymes necessary for such conversions, namely prohormone convertases (PCs), carboxypeptidases (CPs), and peptidylglycine a-amidating monooxygenase (PAM). RT-PCR for mRNAs representing PC1, PC2, CPE, and PAM was performed on total RNA extracted from NCI H82. The primers selected for PCR and partial sequencing were synthetic 20, 21, 22, and 24 oligomers designed to yield products of 533, 880, 405, and 560 base pairs (bp) for PC1, PC2, CPE, and PAM, respectively. For the conditions used, we were able to demonstrate products for all four enzymes. Each of the four products generated were of the expected size. Cloning and sequencing of these products revealed that each had a structure identical to that published for the human form of the respective enzyme. Western analysis with antibodies against PC1, PC2, CPE, and PAM, provided evidence that mRNAs for the four enzymes are translated into proteins that could represent functional forms. Our findings therefore demonstrate that key enzymes involved in the generation of active neuropeptides, unlike the marker enzymes NSE and DDC, continue to be expressed by variant SCCL.

Blotting, Western↗

PubMed1988

The effect of activation of macrophages on the advancement of experimental lung emphysema.

Experiments were carried out on 68 Wistar rats of both sexes. Five s.c. injections of BCG vaccine (once a week) were applied as macrophage mobilizing and activating agent. Papain or physiological saline was given once intratracheally after the 3rd dose of BCG. 4 weeks after the latter substances had been administered the animals were sacrificed. The lungs and the pulmonary alveolar macrophages (PAM) were examined using histological and morphometric techniques; SEM and TEM were applied for assessing ultrastructure of PAM and lung sections. In rats given BCG the number of PAM was increased, and their morphological features showed enhanced activity. In these animals the aggravated emphysematous changes induced by papain should be ascribed to the cumulation of PAM and their increased activity in the lungs.

Animals↗

PubMedDate not supplied

Predicting unsuccessful cardiopulmonary resuscitation (CPR): a comparison of three morbidity scores.

The aim of the study was to assess the usefulness of three different morbidity scores in predicting unsuccessful resuscitation. We reviewed the records of adult patients who underwent CPR between September 1994 and June 1996 in The Royal Hampshire County Hospital, Winchester. Demographic data and enough clinical data to calculate the Pre-Arrest Morbidity score (PAM), the Prognosis After Resuscitation score (PAR) and the Modified PAM Index (MPI) were collected. During the study period 264 consecutive adult patients underwent inpatient CPR. Twenty-eight (11%) of the patients survived to discharge from hospital. Patients who died had significantly higher morbidity scores than those who survived. No patient with a PAM score greater than 6/25, PAR greater than 7/28 or MPI greater than 6/24 survived. There were 47/264 patients who scored above this threshold for the PAM score giving a sensitivity for predicting unsuccessful CPR of 20%. The sensitivity of the PAR was 29% and MPI was 22%. Each score identified a different group of patients for whom CPR was unsuccessful. Using all three scores in combination identified 42% of the unsuccessful CPR attempts. Morbidity scores are likely to need further refinement in order to be a useful bedside tool for predicting success for individual patient resuscitation attempts.

Adult↗

PubMed1977

In vitro induction of aryl hydrocarbon hydroxylase in human pulmonary alveolar macrophages by benzanthracene.

Aryl hydrocarbon hydroxylase (AHH) was induced in human pulmonary alveolar macrophages (PAMs) cultured in the presence of benzanthracene. Time and dose--response curves were established for in vitro induction of this enzyme system in PAMs. In addition, a positive correlation was noted between the level of AHH activity in freshly lavaged PAMs and the in vitro inducibility of the enyzme in these cells from either nonsmokers or cigarette smokers. Measurements of the inducibility of AHH in cultured human PAMs provide an experimental system suitable for studying the mechanisms responsible for the initiation of pulmonary carcinogenesis.

Adult↗

PubMed1998

NLCQ-1, a novel hypoxic cytotoxin: potentiation of melphalan, cisDDP and cyclophosphamide in vivo.

PURPOSE: To investigate in vivo interactions between the recently developed bioreductive agent 4-[3-(2-nitroimidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1) and the chemotherapeutic agents melphalan (L-PAM), cis-platin (cisDDP) and cyclophosphamide (CPM). METHODS AND MATERIALS: EMT6 and FSaIIC tumor cells were inoculated (subcutaneously) into the leg(s) of female Balb/c and male C3H mice, respectively. Treatment was initiated at 10 mm (EMT6) and 5 mm (FSaIIC) mean tumor diameter. The in vivo-in vitro and tumor regrowth assays were used, respectively, as endpoints. Bone marrow toxicity studies were also performed when the in vivo-in vitro assay was used. Drugs were given by i.p. injection. Tumors were excised 18-h after chemotherapeutic drug administration (Balb/c mice) or measured daily until three times their original size (C3H mice). The optimum administration schedule for potentiation between NLCQ-1 and each chemotherapeutic drug, as well as dose modification factors (DMF) at the optimum time, were determined with the in vivo-in vitro assay. When the tumor regrowth assay was used, each chemotherapeutic agent was given either as a single dose or as a split dose over two consecutive days at the optimum administration time after a 10 mg/kg NLCQ-1 i.p. injection. RESULTS: NLCQ-1 (at 0.33 times MTD), strongly potentiated the antitumor effect of L-PAM, cisDDP and CPM without concurrent enhancement in bone marrow toxicity. Potentiation was strictly schedule dependent and the optimum effect (1.5 to 2 logs killing beyond additivity) was observed when NLCQ-1 was given 60-, 45-, and 110-min before L-PAM, cisDDP, and CPM, respectively. The DMF values at 30% survival were 2.5, 1.9, and 3.8 for L-PAM, cisDDP, and CPM, respectively. DMF values for bone marrow toxicity at 50% survival were ca. 1 for all chemotherapeutic drugs. Pretreatment with NLCQ-1 resulted in 4-12 days extra delay in the regrowth of FSaIIC tumors. CONCLUSIONS: These results support the clinical investigation of NLCQ-1 as a chemosensitizer.

Aminoquinolines↗

PubMed1999

Basic properties of the sound-evoked post-auricular muscle response (PAMR).

One objective electrophysiological test for deafness involves presenting a brief acoustic stimulus to a subject and measuring the electrical activity evoked in the muscle located just behind the ear (the post-auricular muscle or PAM). Although this electrical response has been known for many years, it has been ignored by most clinicians and frequently misreported in the literature. This paper presents the fundamental properties of the PAM electrical response (the PAMR) and examines ways in which its measurement can be improved by altering the standard electrode position and filtering. The response consists of a simple bipolar compound action potential with a first peak latency of between 12.5 and 15 ms, depending on the stimulus intensity and PAM muscle tone. The largest recordings can be made with an active electrode over the PAM and with the reference electrode on the dorsal surface of the pinna. It can be obtained with click and tone-burst stimuli within 20 dB of the subjective detection threshold, can be evoked with tone-bursts between 500 Hz and 16 kHz and grows either linearly with the click level or approximately exponentially with the tone-burst level, reaching a maximum of as large as 250 microV pp in some subjects. It has a frequency spectrum mostly between 25 and 200 Hz. The response is often visible in raw recordings, with as few as 20 averages required for obtaining a stable waveform. There is very little amplitude and latency difference in stimulating the ear on the same side or opposite side to the recording electrodes and the binaurally evoked response is similar to the simple arithmetic sum of the waveforms obtained with monaural stimulation. The response latency and duration are longer in very young infants, but reach adult values by 12 months of age. In a companion paper, we describe a method of enhancing the PAMR using lateral eye movement (Patuzzi and O'Beirne, 1999a).

Acoustic Stimulation↗

PubMed2002

Serotonin modulates early cortical auditory processing in healthy subjects: evidence from MEG with acute tryptophan depletion.

We studied the effects of acute tryptophan depletion (ATD) on early cortical auditory processing. Middle-latency auditory evoked fields (MAEF) were investigated in 14 healthy subjects after 5 h of ATD or control mixture ingestion in a randomized, double-blinded, controlled cross-over design study. MAEFs to monaural click stimuli (0.1-ms duration) were recorded with a 122-channel neuromagnetometer. Total plasma tryptophan (Trp), free Trp, and large neutral amino acid (LNAA) concentrations were determined by using high-performance liquid chromatography. ATD lowered the total plasma Trp levels by 75%, free Trp level by 47%, and the ratio Trp/SigmaLNAA by 92%. The control mixture increased total Trp level by 45% and free Trp by 32%, and decreased the ratio Trp/SigmaLNAA by 35%. The ratio tyrosine/SigmaLNAA did not differ between ATD and control experiment. ATD resulted in a significant main effect on Pam latencies and a near-significant main effect on Pam amplitudes. A significant Mixture ingestion X Sex interaction on Nbm amplitude and a significant Mixture ingestion X Sex X Hemisphere interaction on Pam latency were observed. ATD did not affect the MAEF source dipoles. The Pam latencies in both hemispheres had a significant negative relationship with the extent of ATD. The results suggest that the neurotransmitter serotonin is involved in early auditory cortical processing. Further, the serotonin modulation may be different in males and females.

Adult↗

PubMed2000

Lysosomal activity of pulmonary alveolar macrophages in acute experimental pancreatitis in rats with reference to positive PAF-antagonist (BN 52021) effect.

The activation of pulmonary alveolar macrophages (PAM's), might play an important role in severe complications of acute pancreatitis. The aim of our study was to assess the labilization of macrophage lysosomal membranes and release of lysosomal cathepsin B (CB) and N-acetyl-beta-D-hexosaminidase (NAH) into bronchoalveolar lavage fluid (BALF) during taurocholate acute pancreatitis (AP) in rats treated with PAF-antagonist--BN 52021. Total activity of CB increased by 374% after 6 h and by 237% after 12 h of AP in lysosomal enriched fraction of PAM's. Fractional free activity of CB increased to 40% after 6 h and to 38% after 12 h of AP. Free activity of CB was increased 5 fold in the supernatant of macrophage homogenate, and 10 fold in the supernatant of BALF after 6 h of AP. The values of NAH activity roughly paralleled that of CB. Treatment with BN 52021 (5 mg x kg(-1) every 6 h i.v.) partially normalized the measured parameters. Our results indicate that the PAF-antagonist BN 52021 reduced the increase of total and free activity of lysosomal hydrolases of PAM's and partly prevented the labilization of their lysosomal membranes. Therefore, an important mechanism of BN 52021 beneficial effect in pulmonary complications of acute pancreatitis could be dependent on the stabilization of PAM's lysosomes.

Acute Disease↗

PubMed2003

Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators.

To improve the potency of 2-pralidoxime (2-PAM) for treating organophosphate poisoning, we dimerized 2-PAM and its analogs according to Wilson's pioneering work and the 3D structure of human acetylcholinesterase (hAChE) inactivated by isoflurophate. 1,7-Heptylene-bis-N,N'-syn-2-pyridiniumaldoxime, the most potent of the alkylene-linked dimeric reactivators, was readily synthesized using bistriflate and is 100 times more potent than 2-PAM in reactivating hAChE poisoned by isoflurophate. Experimental and computational studies confirm that 2-PAM in its biologically active form adopts the syn-I configuration. Further, they suggest that the improved performance of dimeric oximes is conferred by two-site binding with one oxime pointing toward the diisopropyl ester at the catalytic site of hAChE and the other anchored at the peripheral site. This type of binding may induce a conformational change in the acyl pocket loop which modulates the catalytic site via a domino effect.

Acetylcholinesterase↗

PubMed1991

Determination of reactive nitrogen mustard anticancer drugs in plasma by high-performance liquid chromatography using derivatization.

A high-performance liquid chromatography (HPLC) method is described for the determination of reactive nitrogen mustard anticancer drugs in plasma after derivatization with diethyl-dithiocarbamic acid (DDTC). Three compounds were studied: two reactive species (mechlorethamine (HN2) and galactose 6-mustard (G-6-M] and a less reactive species (melphalan (L-PAM] included for validation experiments. Mass and NMR spectrometry confirmed that one molecule of DDTC reacts with each arm of the mustard, displacing a chlorine atom to form a stable disubstituted adduct. With the reactive mustards a 30-min incubation at 37 degrees C is recommended for greater than 90% derivatization efficiency. Gradient elution was employed to analyze all three compounds using the same conditions with a microBondapak C18 10-microns particle size column (30 cm by 3.8 mm i.d.). The retention time (tR) of HN2-DDTC2 was 13.1 min +/- 1.5% within day CV; tR of L-PAM was 7.6 min and L-PAM-DDTC2 was 14.6 min +/- 0.8% CV. G-6-M-DDTC2 yielded a double peak, tR = 10.7 min and 10.9 min +/- 2.9% CV. The limit of detection on column was 0.5 ng for HN2, 1 ng for L-PAM, and 5 ng for G-6-M. A solid-phase sample preparation technique using "Bond Elut" phenyl is described that extracts from plasma G-6-M-DDTC2 with greater than 74% efficiency and HN2-DDTC2 with greater than 90% efficiency. When the drugs were derivatized in plasma, recovery remained high for G-6-M (greater than 84%) but dropped to 50% for HN2.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗

PubMed2004

Probing the Ser-Ser-Lys catalytic triad mechanism of peptide amidase: computational studies of the ground state, transition state, and intermediate.

Peptide amidase (Pam), a hydrolytic enzyme that belongs to the amidase signature (AS) family, selectively catalyzes the hydrolysis of the C-terminal amide bond (CO-NH(2)) of peptides. The recent availability of the X-ray structures of Pam, fatty acid amide hydrolase, and malonamidase E2 has led to the proposal of a novel Ser-Ser-Lys catalytic triad mechanism for the amide hydrolysis by the AS enzymes. The molecular dynamics (MD) simulations using the CHARMM force field were performed to explore the catalytic mechanism of Pam. The 1.8 A X-ray crystal structure of Pam in complex with the amide analogue of chymostatin was chosen for the initial coordinates for the MD simulations. The five systems that were investigated are as follows: (i) enzyme.substrate with Lys123-NH(2), (ii) enzyme.substrate with Lys123-NH(3)(+), (iii) enzyme.substrate with Lys123-NH(3)(+) and Ser226-O(-), (iv) enzyme.transition state, and (v) enzyme.tetrahedral intermediate. Our data support the presence of the hydrogen bonding network among the catalytic triad residues, Ser226, Ser202, and Lys123, where Ser226 acts as the nucleophile and Ser202 bridges Ser226 and Lys123. The MD simulation supports the catalytic role of the crystallographic waters, Wat1 and Wat2. In all the systems that have been studied, the backbone amide nitrogens of Asp224 and Thr223 create an oxyanion hole by hydrogen bonding to the terminal amide oxygen of the substrate, and stabilize the oxyanion tetrahedral intermediate. The results from both our computational investigation and previously published experimental pH profile support two mechanisms. In a mechanism that is relevant at lower pH, the Lys123-NH(3)(+)-Ser202 dyad provides structural support to the catalytic residue Ser226, which in turn carries out a nucleophilic attack at the substrate amide carbonyl in concert with Wat1-mediated deprotonation and stabilization of the tetrahedral transition state by the oxyanion hole. In the mechanism operating at higher pH, the Lys123-NH(2)-Ser202 catalytic dyad acts as a general base to assist addition of Ser226 to the substrate amide carbonyl. The results from the MD simulation of the tetrahedral intermediate state show that both Ser202 and Lys123 are possible candidates for protonation of the leaving group, NH(2), to form the acyl-enzyme intermediate.

Amidohydrolases↗

PubMed1994

Inhibition of peptidylglycine alpha-amidating monooxygenase by N-substituted homocysteine analogs.

C-terminal amidation is a posttranslational modification found in many neuropeptides. Peptidylglycine alpha-amidating monooxygenase (PAM) catalyzes the synthesis of the biologically essential C-terminal amide from a glycine-extended precursor peptide. Reported herein are the first potent inhibitors of PAM. Dipeptides containing a C-terminal homocysteine and an N-acylated hydrophobic amino acid were found to inhibit PAM with IC50s in the low nanomolar range. Inhibition potency was dependent on both the carboxylate and the thiolate functionalities of the homocysteine and on the hydrophobic groups of the second amino acid. The thiolate was postulated to produce high binding affinities through coordination with the active-site copper. The compound series also exhibited potent inhibition of PAM in rat dorsal root ganglion cells as demonstrated by a dose-dependent increase in the substance P-Gly/substance P ratio. These results indicate that the compounds have sufficient potency and intracellular bioavailability to aid future studies focused on neuropeptide function and the contributions of neuropeptides to various disease processes.

Animals↗

PubMed1976

Improved delivery through biological membranes. 3. Delivery of N-methylpyridinium-2-carbaldoxime chloride through the blood-brain barrier in its dihydropyridine pro-drug form.

Administration of N-methyl-1,6-dihydropyridine-2-carbaldoxime hydrochloride, the pro-drug form of 2-PAM, resulted in an average of 13-fold increase in the amount of 2-PAM delivered into the brain of mice as compared to the administration of 2-PAM. The pro-drug which crossed the BBB resulted in a dramatic increase in the reactivation of AChE blocked by DFP. In vivo studies of the "aging" of the phosphorylated AChE in the brain of mice could also be studied using pro-2-PAM.

Acetylcholinesterase↗

PubMed2004

Effect of hydrophobically modified polymer on salt-induced structural transition in microemulsions.

The phase boundaries of the middle-phase microemulsion for NaCl/SDS/H2O/1-heptane/1-pentanol systems in the absence of polymer and in the presence of unmodified poly(acrylamide) (PAM) and hydrophobically modified poly(acrylamide) (HMPAM) have been determined at varying salt concentrations. These three middle-phase microemulsions (with HMPAM, with PAM, and without polymer) were studied using interfacial tension measurement, steady-state fluorescence, and time-resolved fluorescence quenching. Compared to the polymer-free system and the system with PAM, the addition of HMPAM significantly enlarges the range of the salt concentrations for the formation of the middle-phase microemulison and causes both the excess oil and aqueous phases to increase in volume at the expense of the middle-phase microemulsion. For the middle-phase microemulsion with HMPAM, the interfacial tensions of the microemulsion phase with the excess oil phase and with the excess aqueous phase are all ultralow and exhibit higher values than those with PAM and without polymer. At the same salt concentration, the apparent surfactant aggregation number in the middle-phase microemulsion with HMPAM has the smallest value among these three systems. All results indicate that the strong interaction of surfactant with hydrophobically modified polymer has a large effect on the formation and properties of the middle-phase microemulsion.

Acrylamide↗

PubMed1997

Pulmonary alveolar microlithiasis: review of Italian reports.

Pulmonary alveolar microlithiasis (PAM) is a rare disease of unknown etiology, characterized by the presence of calcific concretions in the alveolar spaces. A familial occurrence is frequently found so that an inherited trait is thought to be involved. The chest X-ray is characterized by a 'sandstrom' picture while the clinical state undergoes to a slow and progressive impairment resulting in respiratory failure at the end stage. We have reviewed the Italian literature of the past 50 years detecting 48 case-reports of PAM (19 males and 29 females). Only 20 out of them were documented in international journals. A familial occurrence of 43.7% was found and 18 patients were under age fifteen. There was a prevalence in the female sex (60.4%) and in the second decade of life. Chest X-ray was the most important tool to diagnose PAM revealing the characteristic picture in all patient. Bronchoalveolar lavage (BAL) and open lung biopsy respectively show the characteristic calcospherites in the recovered fluid (BALF) and in the alveolar spaces. About 300 cases of PAM are reported in the international literature. We believe these data are probably underestimated because many case-reports are not published in international literature.

Adolescent↗