bluuebunny/crossref_metadata_2025 huggingface dataset:
Distribution kinetics of solutes in the isolated in-situ perfused rat head using the multiple indicator dilution technique and a physiological two-barrier model
Authors: Foster K A , Weiss M , Roberts M S
Published: October 2002

The purpose of this study was to determine the pharmacokinetics of [14C]diclofenac, [14C]salicylate and [3H]clonidine using a single pass rat head perfusion preparation. The head was perfused with 3-[N-morpholino] propane-sulfonic acid-buffered Ringer's solution. 99mTc-red blood cells and a drug were injected in a bolus into the internal carotid artery and collected from the posterior facial vein over 28 min. A two-barrier stochastic organ model was used to estimate the statistical moments of the solutes. Plasma, interstitial and cellular distribution volumes for the solutes ranged from 1.0 mL (diclofenac) to 1.6 mL (salicylate), 2.0 mL (diclofenac) to 4.2 mL (water) and 3.9 mL (salicylate) to 20.9 mL (diclofenac), respectively. A comparison of these volumes to water indicated some exclusion of the drugs from the interstitial space and salicylate from the cellular space. Permeability-surface area (PS) products calculated from plasma to interstitial fluid permeation clearances (CLPI) (range 0.02-0.40 mL s−1) and fractions of solute unbound in the perfusate were in the order: diclofenac >salicylate >clonidine >sucrose (from 41.8 to 0.10 mL s−1). The slow efflux of diclofenac, compared with clonidine and salicylate, may be related to its low average unbound fraction in the cells. This work accounts for the tail of disposition curves in describing pharmacokinetics in the head.
Cloned human EP1 prostanoid receptor pharmacology characterized using radioligand binding techniques
Authors: Sharif Najam A , Davis Terry L
Published: October 2002

Prostaglandins such as prostaglandin E2 (PGE2) interact with EP-class prostanoid receptors including EP1, EP2, EP3 and EP4 subtypes. We have conducted a detailed pharmacological characterization of the binding of [3H]-PGE2 to recombinant human EP1 prostanoid receptors expressed in human embryonic kidney (HEk-293) cells using a broad panel of natural and synthetic prostanoids. The receptor displayed high affinity (kd = 16.0 ± 0.69 nM; n = 3) for [3H]-PGE2, and was expressed at high levels (Bmax = 3.69 ± 0.30 pmol (mg protein)−1 in cell membranes of HEk-293 cells. Specific binding constituted 97.5 ± 1.4% (n = 12) of the total binding. In competition assays, the rank order of affinities of natural prostanoids for the receptor was PGE2 > PGE1 > PGF2 > PGI2 > PGD2. PGE2 was more effective than PGE1 at displacing bound [3H]-PGE2 (ki for PGE2 = 14.9 ± 2.2 nM; ki for PGE1 = 165 ± 29 nM). The affinities of enprostil (ki = 14.5 ± 3.1 nM) and 17-phenyl-ω-trinor-PGE2 (ki = 7.3 ± 2.7 nM) for the receptor were quite similar to that of PGE2, while that of sulprostone (ki = 137 ± 13 nM) more closely resembled PGE1. Some compounds historically classified as specific for DP prostanoid receptors bound with relatively high affinity to the recombinant human EP1 receptor (e.g. Zk118182 (ki = 73.4 ± 8.6 nM) and Zk110841 (ki = 166 ± 20 nM)). All FP (e.g. travoprost acid, fluprostenol), IP (iloprost) and TP (SQ29548) receptor-specific ligands exhibited low affinity (ki ≥ 1μM).
Gastroprotective activity of oleanolic acid derivatives on experimentally induced gastric lesions in rats and mice
Authors: Astudillo Luis , Rodriguez Jaime A , Schmeda-Hirschmann Guillermo
Published: October 2002

The gastroprotective effect of the triterpene oleanolic acid (OA) was assessed on gastric ulceration in rats. The effect of a single oral dose of OA was evaluated at 50, 100 and 200 mg kg−1 in the following models: pylorus ligature (Shay), and aspirin- and ethanol-induced gastric ulcers. A single oral administration of OA at doses of 50, 100 and 200 mg kg−1 inhibited the appearance of gastric lesions induced by ethanol, aspirin and pylorus ligature. In the pylorus ligature and aspirin models, the effect of OA at the selected concentrations was comparable with that of ranitidine at 50 mg kg−1. In the ethanol-induced gastric lesion model, OA showed a dose-dependent activity, and at 100 and 200 mg kg−1 was as active as omeprazole at 20 mg kg−1. The effect of OA, its acetylated and methoxylated derivatives, oleanonic acid and its methyl ester were assessed on HCl/ethanol-induced ulcers in mice at 200 mg kg−1. OA and its methoxylated (OAM) and acetylated (OAAM, OAA) derivatives proved to be active in this animal model. The semisynthetic derivatives OAM and OAAM had the greatest gastroprotective activity, but their effect was not significantly greater than OA. In an acute toxicity test on mice, intraperitoneal administration of OA showed no toxicity at doses up to 600 mg kg−1.
Formation of a disulfide protein conjugate of the SH-group-containing metabolite (M-I) of esonarimod (kE-298) and its elimination in rats
Authors: Hasegawa Masatoshi , Omi Naoko , Endo Hiromi , Yoshida Hideo , Higuchi Shohei
Published: October 2002

The reactivity of the thiol moiety of the active main metabolite (M-I) of esonarimod (kE-298), a novel anti-rheumatic agent, was investigated in rats. After repeated oral administration of 14C-kE-298, the radioactivity decreased rapidly and no tendency towards accumulation was found, in marked contrast to other common SH-group-containing drugs. At 30 min after intravenous administration of 14C-M-I to rats, the concentration of the 14C-M-I plasma protein conjugate in plasma was extremely low at 0.143 nmol mL−1 (0.66% of total plasma radioactivity). The 14C-M-I plasma protein conjugate that formed in rat plasma was mixed disulfide with plasma protein. After intravenous administration of synthetic 14C-M-I plasma protein conjugate to rats, the radioactivity in plasma decreased rapidly, with the terminal half-life at 6.90 h. In-vitro, the 14C-M-I plasma protein conjugate was readily dissociated by the endogenous thiol compounds, cysteine and glutathione. These results suggest that the reactivity of the thiol moiety of M-I is extremely low. Furthermore, the 14C-M-I plasma protein conjugate decreased rapidly in-vivo, which would be related to interaction with endogenous thiol compounds. These properties of M-I are principally responsible for the zero accumulation in rat tissues. kE-298 could therefore be expected to have reduced adverse effects compared with other SH-group-containing anti-rheumatic drugs.
Effect of heparinoid on the production of tissue inhibitor of metalloproteinases (TIMP)-3 in rheumatoid synovial fibroblasts
Authors: Watanabe Hideki , Wada Hiromi , Itoh Masayuki , Kataoka Masanori , Kido Hiroko , Naruse Tomohiro
Published: October 2002

Heparinoid is one of the major contents of Mobilat widely used as an antirheumatic drug. To clarify the precise mechanisms of the antirheumatic effect of heparinoid, we investigated its effects on the production of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) from rheumatoid synovial fibroblasts stimulated (or not) with interleukin-1 alpha (IL-1α) at 100 units mL−1. The expression of TIMP-3 mRNA was also investigated in a similar manner. The production of both MMPs and TIMPs and the expression of TIMP-3 mRNA were investigated by western-blot analysis and northern-blot hybridization, respectively. Under the stimulation of IL-1α, heparinoid increased the production of TIMP-3 in a concentration-dependent manner, but not TIMP-1, TIMP-2, MMP-1 or MMP-3. Heparinoid did not affect the expression of TIMP-3 mRNA that was increased by the stimulation of IL-1α. These findings suggest that the anti-rheumatoid effect of heparinoid may be due to increased production of TIMP-3. This increase in TIMP-3 may help redress the imbalance between the amounts of MMPs and TIMPs as observed in the joint tissues of rheumatoid arthritis and osteoarthritis patients.
Influence of nicardipine and nifedipine on plasma carvedilol disposition after oral administration in rats
Authors: Hokama Nobuo , Hobara Norio , Sakai Masayuki , Kameya Hiromasa , Ohshiro Susumu , Sakanashi Matao
Published: October 2002

The effect of two kinds of 1,4-dihydropyridine calcium-channel blockers, nicardipine hydrochloride and nifedipine, on the disposition of carvedilol, was studied in rats. Blood samples were assayed for carvedilol levels using solid-phase extraction and high-performance liquid chromatography. The plasma carvedilol concentration was found to be significantly higher, and the area under the concentration-time curve up to 24 h (AUC0→24) was 6.7 and 3.0 times higher after simultaneous oral administration of 20 mg kg−1 carvedilol with 40 mg kg−1 nicardipine hydrochloride, or with 40 mg kg−1 nifedipine, respectively, than after administration of carvedilol alone. The pharmacokinetic interaction between carvedilol and dihydropyridine calcium-channel blockers is thought to be attributable to vasodilator-induced changes in hepatic first-pass metabolism, inhibition in the absorption barrier by P-glycoprotein and in the metabolism of carvedilol.
Free radical scavengers, anti-inflammatory and analgesic activity of Acaena magellanica
Authors: Feresin Gabriela Egly , Tapia Alejandro , Angel Gutierrez R , Delporte Carla , Erazo Nadine Backhouse , Schmeda-Hirschmann Guillermo
Published: October 2002

Extracts of the whole plant Acaena magellanica (Rosaceae) were assessed for anti-inflammatory, antipyretic and analgesic activity in animal models. At 600 mg kg−1, the global ethanolic extract (GEE), dichloromethane (DCM) and defatted methanol (MeOH) fractions showed a mild anti-inflammatory effect in the carrageenan-induced guinea-pig paw oedema. The GEE, DCM and defatted MeOH fractions significantly reduced inflammation by 43.2, 40.5 and 42.1%, respectively. The GEE did not showed any significant antipyretic activity in doses up to 600 mg kg−1. A 20% w/v infusion administered orally at 16 mL kg−1 presented analgesic effect in the acetic acid-induced abdominal constriction test in mice. The GEE and MeOH extract of A. magellanica showed free radical scavenging activity in the diphenylpicrylhydrazyl decolouration assay. Assay-guided isolation led to quercetin, Q-3-O-β-D-glucoside, Q-3-O-β-D-galactoside, ellagic acid and catechin as the free radical scavengers. The saponins tormentic acid 28-O-β-D-galactopyranoside and 28-O-β-D-glucopyranoside were isolated from the polar extract. The structures were determined by spectroscopic methods.
Mechanisms involved in the relaxant action of the ethanolic extract of propolis in the guinea-pig trachea in-vitro
Authors: Paulino Niraldo , Scremin Fernando M , Raichaski Lisiane B , Marcucci Maria Cristina , Scremin Amarilis , Calixto João B
Published: October 2002

This study examines the mechanisms by which the standardised ethanolic extract of propolis induces relaxation of the guinea-pig trachea in-vitro. In guinea-pig trachea with or without epithelium and contracted by histamine, the propolis extract caused reproducible and graded relaxation, with a mean EC50 value of 3.8 or 10.5 μg mL−1 and Emax of 100%, respectively. The propolis extract-induced relaxation was markedly reduced (26 ± 9 and 96 ± 3%) when guinea-pig tracheas were exposed to Krebs solution containing elevated K+ in the medium (40 or 80 mM). Pre-incubation of guinea-pig tracheas with tetraethylamonium (100 mM) or with 4-aminopyridine (10 mM) reduced the propolis extract-induced relaxation by 31±10% and 28 ± 2%. Likewise, apamin (0.1 μM), charybdotoxin (0.1 μM) or iberiotoxin (0.1 μM) caused marked inhibition of propolis extract-mediated relaxation in guinea-pig trachea (percentage of inhibition: 65 ± 3%, 60 ± 5% and 65 ± 9%, respectively). Also, glibenclamide (1 μM) inhibited the relaxant response caused by the propolis extract by 57 ± 4%. ω-Conotoxin GIVA (0.1 μM) or capsaicin (1 μM) produced small but significant inhibition (30 ± 5% or 47 ± 7%, respectively) of the propolis extract-induced relaxation. The vasoactive intestinal peptide (VIP) antagonist D-P-CI-Phe6, Leu17[VIP] porcine (0.1 μM) inhibited relaxation by 55 ± 5%, while propranolol (1 μM) induced a parallel rightward displacement (about 20 fold) of the propolis extract concentration-response curve. Finally, the propolis extract-induced relaxation was inhibited by the nitric oxide synthase inhibitor L-NG-nitroarginine (L-NOArg, 100 μM) (48 ± 6%), and by the soluble guanylate cyclase inhibitor methylene blue (10 μM) (37 ± 6%), while the more selective soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolol[4,3-a]quinoxalin-1-one (ODQ, 1 μM) produced only a parallel (about 3 fold) rightward displacement of the propolis extract concentration-response curve. Collectively, these results support the notion that the propolis extract-mediated relaxation in the guinea-pig trachea involves the release of nitric oxide, probably from sensory neurons, besides the activation of soluble guanylate cyclase and activation of Ca2+- and ATP-sensitive K+channels. Furthermore, the stimulation of β2-adrenergic and VIP receptors also seems to account for its relaxant action.
Clearance and disposition of indometacin in chronically instrumented fetal lambs following a 3-day continuous intravenous infusion
Authors: Krishna Rajesh , Riggs K Wayne , Kwan Eddie , Wong Harvey , Szeitz Andras , Walker Martin P R , Rurak Dan W
Published: October 2002

Indometacin is used in pregnancy for the treatment of premature labour, but there are limited data on the disposition of the drug in the fetus. In order to elucidate fetal indometacin pharmacokinetics at plasma levels and duration comparable with those occurring with use of the drug for tocolysis in humans, indometacin was administered at doses of 1.9 (low dose, LD; n = 5) or 7.5 (high dose, HD; n = 9) μg min−1 to steady state over a 3-day period in chronically instrumented fetal lambs. Indometacin concentrations in biological fluid samples were analysed by a sensitive capillary gas chromatography-electron capture detection method. The mean steady-state fetal arterial plasma indometacin concentrations were 68.6 ± 16.5 ng mL−1 in the LD infusion and 230.3 ± 28.8 ng mL−1 in the HD infusion. Indometacin concentrations in amniotic fluid were ∼10% of those in fetal plasma, and below assay detection limits in tracheal fluid. Total body clearance (TBC) in the LD and HD infusions were not different and the overall mean was 11.3 ± 1.2 mL min−1 kg−1. In the 11 experiments where paired fetal arterial and umbilical venous samples were collected, the extraction of indometacin across the placenta averaged only 5.2 ± 1.1%, indicating low placental permeability to the drug in sheep. However, fetal placental clearance (CLpl) of indometacin (10.0 ± 2.5 mL min−1 kg−1, n = 10) averaged 115.1± 41.2% of TBC in these animals and the calculated value for fetal non-placental clearance (0.6 ± 2.8 mL min−1 kg−1) was not significantly different from zero. Fetal renal clearance of intact indometacin (3.8 ± 1.1 μL min−1 kg−1; n = 12) was also very low. However, treatment of fetal urine with glucuronidase indicated the presence of glucuronide conjugates and these comprised 69.9 ± 8.2% of the total drug concentration (i.e. intact + conjugated) in urine. Thus, the fetal lamb appears to be able to glucuronidate indometacin, but the contribution of this and other non-placental routes to overall fetal elimination of the drug appear minimal. CLpl of the drug is also low owing to the physicochemical properties of indometacin (high polarity) and the permeability characteristics of the sheep placenta.
Abnormal alterations in the metabolic patterns of patients on valproate therapy
Authors: Kreher U , Darius J , Wien F
Published: October 2002

Four cases of abnormal metabolic patterns which were obtained from three infantile patients and one adult on valproate (valproic acid; 2-n-propyl-pentanoic acid) therapy are reported. Serum levels of valproate and 15 metabolites were measured by gas chromatography/mass spectrometry. A mentally retarded, 11-month-old boy developed an extremely altered metabolic profile after having been treated with valproate polytherapy for 3 months. The altered pattern included strongly elevated serum levels of the 4-ene as well as of the x-/x 1-metabolites, with the b-metabolites (2-ene; 2,3′-diene) being diminished. Two samples obtained previously had shown a common pattern. The infant died 3 weeks after the last sample had been taken. Two boys of the same age showed similar but less intense deviations in their metabolic profiles at the onset of valproate therapy. Within a few weeks they approached, in a step-wise fashion, the average pattern common for children under 3 years of age. The striking alterations were paralleled by the metabolic profiles of an adult patient who suffered from intrahepatic metastasis and renal insufficiency. From the close resemblance of the abnormal metabolic patterns it was concluded that liver dysfunction results in alteration of the whole metabolic system. Regular inspection of the entire profile of an individual might help to recognize conspicuous alterations in time to avoid severe side effects.
Effects of classical antiepileptics on thresholds for phenomena induced by cortical stimulation in rats
Authors: Haugvicová R , Bílková E , Kubová H , Mareš P
Published: October 2002

Our aim was to study the effects of phenobarbital, phenytoin and ethosuximide on epileptic afterdischarges induced by cortical stimulation in rats. Fifteen-second series of low-frequency (8 Hz) rhythmic stimulation of the sensorimotor cortex were applied in rats with chronically implanted electrodes. Intervals between the stimulation series were at least 10 min and intensity was increased in a step-wise manner. Threshold current intensities were estimated for movements directly induced by stimulation, epileptic afterdischarges of the spike-and-wave type, clonic seizures accompanying this type of afterdischarge and transition into the limbic type of afterdischarge. Phenobarbital, phenytoin and ethosuximide were administered intraperitoneally before the first stimulation series. Phenobarbital (20, 40 and 80 mg kg−1) significantly increased the thresholds for the first three phenomena in a dose-dependent manner. Transition into the limbic afterdischarge was influenced only by the highest dose. Phenytoin (60 mg kg−1) only increased the thresholds insignificantly and ethosuximide (125 mg kg−1) was ineffective. We concluded that our model is useful for testing anticonvulsant effects. Results with three antiepileptic drugs correspond with their efficacy against myoclonic seizures in man.
Optimal control of queueing networks: an approach via fluid models
Authors: Bäuerle Nicole
Published: October 2002

We consider a general control problem for networks with linear dynamics which includes the special cases of scheduling in multiclass queueing networks and routeing problems. The fluid approximation of the network is used to derive new results about the optimal control for the stochastic network. The main emphasis lies on the average-cost criterion; however, theβ-discounted as well as the finite-cost problems are also investigated. One of our main results states that the fluid problem provides a lower bound to the stochastic network problem. For scheduling problems in multiclass queueing networks we show the existence of an average-cost optimal decision rule, if the usual traffic conditions are satisfied. Moreover, we give under the same conditions a simple stabilizing scheduling policy. Another important issue that we address is the construction of simple asymptotically optimal decision rules. Asymptotic optimality is here seen with respect to fluid scaling. We show that every minimizer of the optimality equation is asymptotically optimal and, what is more important for practical purposes, we outline a general way to identify fluid optimal feedback rules as asymptotically optimal. Last, but not least, for routeing problems an asymptotically optimal decision rule is given explicitly, namely a so-called least-loaded-routeing rule.
Rates of convergence for products of random stochastic 2 × 2 matrices
Authors: Neininger Ralph
Published: October 2002

Products of independent identically distributed random stochastic 2 × 2 matrices are known to converge in distribution under a trivial condition. Rates for this convergence are estimated in terms of the minimal Lp-metrics and the Kolmogoroff metric and applications to convergence rates of related interval splitting procedures are discussed.
Approximate entropy for testing randomness
Authors: Rukhin Andrew L.
Published: October 2002

This paper arose from interest in assessing the quality of random number generators. The problem of testing randomness of a string of binary bits produced by such a generator gained importance with the wide use of public key cryptography and the need for secure encryption algorithms. All such algorithms are based on a generator of (pseudo) random numbers; the testing of such generators for randomness became crucial for the communications industry where digital signatures and key management are vital for information processing.

The concept of approximate entropy has been introduced in a series of papers by S. Pincus and co-authors. The corresponding statistic is designed to measure the degree of randomness of observed sequences. It is based on incremental contrasts of empirical entropies based on the frequencies of different patterns in the sequence. Sequences with large approximate entropy must have substantial fluctuation or irregularity. Alternatively, small values of this characteristic imply strong regularity, or lack of randomness, in a sequence. Pincus and Kalman (1997) evaluated approximate entropies for binary and decimal expansions of e, π, √2 and √3 with the surprising conclusion that the expansion of √3 demonstrated much less irregularity than that of π. Tractable small sample distributions are hardly available, and testing randomness is based, as a rule, on fairly long strings. Therefore, to have rigorous statistical tests of randomness based on this approximate entropy statistic, one needs the limiting distribution of this characteristic under the randomness assumption. Until now this distribution remained unknown and was thought to be difficult to obtain. To derive the limiting distribution of approximate entropy we modify its definition. It is shown that the approximate entropy as well as its modified version converges in distribution to a χ2-random variable. The P-values of approximate entropy test statistics for binary expansions of e, π and √3 are plotted. Although some of these values for √3 digits are small, they do not provide enough statistical significance against the randomness hypothesis.
The Galton-Watson process revisited: some martingale relationships and applications
Authors: Lynch James D.
Published: October 2002

A martingale is used to study extinction probabilities of the Galton-Watson process using a stopping time argument. This same martingale defines a martingale function in its argument s; consequently, its derivative is also a martingale. The argument s can be classified as regular or irregular and this classification dictates very different behavior of the Galton-Watson process. For example, it is shown that irregularity of a point s is equivalent to the derivative martingale sequence at s being closable, (i.e., it has limit which, when attached to the original sequence, the martingale structure is retained). It is also shown that for irregular points the limit of the derivative is the derivative of the limit, and two different types of norming constants for the asymptotics of the Galton-Watson process are asymptotically equivalent only for irregular points.
An investment model with entry and exit decisions
Authors: Duckworth J. Kate , Zervos Mihail
Published: October 2002

We consider an investment model which generalizes a number of models that have been studied in the literature. The model involves entry and exit decisions as well as decisions relating to production scheduling. We then address the problem of its valuation from the standpoint of the dynamic programming approach. Our analysis results in a closed form analytic solution that can take qualitatively different forms depending on parameter values.
New improved bounds for reliability of consecutive-k-out-of-n:F systems
Authors: Muselli Marco
Published: October 2002

New bounds are found for the reliability of consecutive-k-out-of-n:F systems with equal component failure probabilities. The expressions involved are simple, thus allowing a direct use in the derivation of theoretical properties.

These bounds can also be employed in numerical computations when the value ofnorkis so large that the exact calculation of the reliability is not achievable. Comparisons show that the approximation errors exhibited by these new formulas are lower than those of other widely used bounds.
Optimal stopping of a risk process: model with interest rates
Authors: Muciek Bogdan Krzysztof
Published: October 2002

The following problem in risk theory is considered. An insurance company, endowed with an initial capital a ≥ 0, receives premiums and pays out claims that occur according to a renewal process {N(t), t ≥ 0}. The times between consecutive claims are i.i.d. The sequence of successive claims is a sequence of i.i.d. random variables. The capital of the company is invested at interest rate α ∊ [0,1], claims increase at rate β ∊ [0,1]. The aim is to find the stopping time that maximizes the capital of the company. A dynamic programming method is used to find the optimal stopping time and to specify the expected capital at that time.
Stationary solution to the fluid queue fed by an M/M/1 queue
Authors: Barbot N. , Sericola B.
Published: October 2002

We consider an infinite-capacity buffer receiving fluid at a rate depending on the state of an M/M/1 queue. We obtain a new analytic expression for the joint stationary distribution of the buffer level and the state of the M/M/1 queue. This expression is obtained by the use of generating functions which are explicitly inverted. The case of a finite capacity fluid queue is also considered.
Branching processes with deteriorating random environments
Authors: Jagers Peter , Lu Zhunwei
Published: October 2002

We introduce Galton-Watson-style branching processes in random environments which are deteriorating rather than stationary or independent. Some primary results on process growth and extinction probability are shown, and two simple examples are given.
The busy cycle of the reflected superposition of Brownian motion and a compound Poisson process
Authors: Perry David , Stadje Wolfgang
Published: October 2002

We consider a reflected superposition of a Brownian motion and a compound Poisson process as a model for the workload process of a queueing system with two types of customers under heavy traffic. The distributions of the duration of a busy cycle and the maximum workload during a cycle are determined in closed form.
Signatures of indirect majority systems
Authors: Boland Philip J.
Published: October 2002

If τ is the lifetime of a coherent system, then the signature of the system is the vector of probabilities that the lifetime coincides with the ith order statistic of the component lifetimes. The signature can be useful in comparing different systems. In this treatment we give a characterization of the signature of a system with independent identically distributed components in terms of the number of path sets in the system as well as in terms of the number of what we call ordered cut sets. We consider, in particular, the signatures of indirect majority systems and compare them with the signatures of simple majority systems of the same size. We note that the signature of an indirect majority system of size r × s = n is symmetric around , and use this to show that the expected lifetime of an r × s = n indirect majority system exceeds that of a simple (direct) majority system of size n when the components are exponentially distributed with the same parameter.
Amish lethal microcephaly: A new metabolic disorder with severe congenital microcephaly and 2‐ketoglutaric aciduria
Authors: Kelley Richard I. , Robinson Donna , Puffenberger Erik G. , Strauss Kevin A. , Morton D. Holmes
Published: October 2002

A new metabolic disorder characterized by severe congenital microcephaly, death within the first year, and severe 2‐ketoglutaric aciduria has been found among the Old‐Order Amish of Lancaster County, Pennsylvania. Amish lethal microcephaly segregates as an autosomal recessive disorder and has an unusually high incidence of at least 1 in 500 births. When the infants are well, the urine organic acid profiles show isolated, extreme elevations of 2‐ketoglutaric acid. However, during otherwise simple viral illnesses, the infants often develop a metabolic acidosis, which may follow a lethal course. Cranial magnetic resonance imaging of a single patient showed a smooth, immature brain similar to that of a 20‐week fetus except for a moderate degree of cerebellar vermal hypoplasia. Assay of 2‐ketoglutarate dehydrogenase in cultured lymphoblasts of one patient showed normal activity. Amish lethal microcephaly maps to 17q25 and may be caused by a defect in a mitochondrial inner membrane protein functioning as a 2‐ketoglutarate transporter. © 2002 Wiley‐Liss, Inc.
Two cases of the caudal duplication anomaly including a discordant monozygotic twin
Authors: Kroes H.Y. , Takahashi M. , Zijlstra R.J. , Baert J.A.L.L. , Kooi K.A. , Hofstra R.M.W. , van Essen A.J.
Published: October 2002

We present two unrelated patients with various duplications in the caudal region. One patient presented with a duplication of the distal spine from L4, left double ureter, duplication of the vagina and cervix, and duplication of the distal colon. The second patient was diagnosed with a duplication of the colon, bladder, vagina and uterus. The first patient had an unaffected monozygotic twin sister. Dominguez et al. [1993: Am J Dis Child 147:1048–1052] presented six similar cases, and introduced the name “caudal duplication syndrome.” The pathogenesis of the caudal duplication anomaly is unclear. The possibility of a polytopic primary developmental field defect or a disruptive sequence are discussed. On the other hand, somatic or germline mutations in certain developmental genes could be involved, as illustrated by the mouse mutations disorganisation and fused. DNA‐analysis of the AXIN1 gene, the human homologue of the gene responsible for fused, performed in our first patient, did not show any apparent pathogenic mutation. © 2002 Wiley‐Liss, Inc.
Clinical and genetic heterogeneity of Seckel syndrome
Authors: Faivre L. , Le Merrer M. , Lyonnet S. , Plauchu H. , Dagoneau N. , Campos‐Xavier A.B. , Attia‐Sobol J. , Verloes A. , Munnich A. , Cormier‐Daire V.
Published: October 2002

Seckel syndrome is a rare autosomal recessive condition belonging to the group of osteodysplastic primordial “dwarfism” and characterized by the association of 1) severe pre‐ and postnatal growth retardation, 2) microcephaly with mental retardation, and 3) specific dysmorphic features. Recently, two disease loci have been mapped to chromosomes 3q22.1‐q24 and 18p11.31‐q11.2, respectively, by homozygosity mapping in consanguineous families. Here, we report on the exclusion of these loci in five consanguineous and one multiplex nonconsanguineous Seckel syndrome families and in two consanguineous families presenting type II osteodysplastic primordial dwarfism. These results support the view that Seckel syndrome is a clinically and genetically heterogeneous condition. © 2002 Wiley‐Liss, Inc.
Tibial/femoral hypoplasia with “hook” pelvis: A potentially unique dysostosis
Authors: Mégarbané André , Ghanem Ismat
Published: October 2002

We report a 2‐year‐5‐month‐old girl with malformed lower limbs. The radiographic skeletal survey revealed agenesis of the ilio‐pubic rami with pubic dehiscence, right hip dislocation, bilateral coxa vara, short femurs, femoro‐tibial synchondrosis, bilateral hypoplastic tibiae more severe on the left side, and hypoplastic left calcaneus and talus. To the best of our knowledge, this combination of multiple congenital skeletal abnormalities has not been reported before. © 2002 Wiley‐Liss, Inc.
Predictive factors for suicidal ideation in patients with unresectable lung carcinoma
Authors: Akechi Tatsuo , Okamura Hitoshi , Nishiwaki Yutaka , Uchitomi Yosuke
Published: October 2002

BACKGROUND

Despite serious concern over the suicidality of cancer patients in clinical oncology practice, few studies have addressed this issue. The purpose of the current study was to investigate the prevalence and predictive factors of suicidal ideation in patients with unresectable lung carcinoma in a follow‐up setting.

METHODS

Patients with newly diagnosed unresectable nonsmall cell lung carcinoma participated in this study. Their suicidal ideation was assessed 6 months after disclosure of the cancer diagnosis. Predictive factors for suicidal ideation were investigated by assessing a broad range of biomedical and psychosocial factors between the time of disclosure and start of cancer therapy (baseline) and 6 months after disclosure of the cancer diagnosis (follow‐up).

RESULTS

Although strong suicidal ideation was rare in this population, 13 (15%) of the 89 subjects who completed the baseline and follow‐up ratings had some degree of suicidal ideation 6 months after disclosure of the cancer diagnosis. Univariate analysis revealed that significant predictive factors for suicidal ideation were pain at baseline, declining physical function, and the development of a depressive disorder. Multivariate analysis indicated that pain at baseline (odds ratio [OR] = 3.72, 95% confidence interval [CI] = 1.12–14.69, P = 0.04) and the development of a depressive disorder (OR =27.97, 95% CI = 5.18–214.14, P = 0.0003) were the final significant predictive factors.

CONCLUSIONS

Suicidal ideation among unresectable lung carcinoma patients should not be neglected because it is not rare. Comprehensive care consisting of at least earlier pain management and appropriate psychiatric intervention is indispensable to prevent subsequent suicidal ideation. Cancer 2002;95:1085–93. © 2002 American Cancer Society.

DOI 10.1002/cncr.10769
Metastatic prostate carcinoma to bone
Authors: Cheville John C. , Tindall Donald , Boelter Christopher , Jenkins Robert , Lohse Christine M. , Pankratz V. Shane , Sebo Thomas J. , Davis Brian , Blute Michael L.
Published: October 2002

BACKGROUND

The objective of this study was to examine the clinical and pathologic features of metastatic prostate carcinoma to bone in a large cohort of men, and the associations of these features with outcome.

METHODS

Sixty‐eight men who underwent surgery for metastatic prostate carcinoma to bone for stabilization of a pathologic fracture or impending fracture were studied. Clinical characteristics included the type of treatment for the primary and metastatic prostate carcinoma, age and serum prostate specific antigen (PSA) at the diagnosis of the metastatic prostate carcinoma, radiographic findings of the metastasis (osteoblastic, osteolytic, or mixed), and the number of metastatic sites at the time of the surgery for the metastasis. Pathologic features examined included Gleason score of the metastatic prostate carcinoma. Immunohistochemical stains for MIB‐1, cytokeratin, PSA, synaptophysin, chromogranin A, serotonin, estrogen receptor, progesterone receptor, and androgen receptor were performed for all cases. The Kaplan–Meier method was used to estimate cancer‐specific survival. The duration of follow‐up was defined as the interval from the date of surgery for the metastasis to the date of death or last follow‐up. Univariate and multivariate Cox proportional hazards models were fit to assess the features that were associated with death from prostate carcinoma.

RESULTS

The average (standard deviation) time from the surgery for the metastasis to death from prostate carcinoma was 1.5 (1.9) years, ranging from 0 days to 10 years, with a median of 1 year. The estimated cancer‐specific survival rates at 1 year, 2 years, and 3 years were 54.3%, 28.8%, and 22.9%, respectively. Median cancer‐specific survival occurred at 1.1 years. After 4 years of follow‐up, there were only seven patients left at risk for death from prostate carcinoma. Features that were found to be significantly associated with death from prostate carcinoma univariately included the interval between the diagnosis of metastasis and the surgery for metastasis (P < 0.001), androgen deprivation therapy before surgery for the metastasis (P = 0.002), presentation with metastasis (P = 0.003), the number of metastatic sites (P = 0.034), Gleason score of the metastasis (P = 0.002), and tumor positivity for chromogranin A (P = 0.041). On multivariate analysis, the interval between the diagnosis of metastasis and the surgery for metastasis (P < 0.001), Gleason score of the metastasis (P < 0.001), and tumor positivity for chromogranin A (P = 0.009) were associated significantly with death from prostate carcinoma.

CONCLUSIONS

Although cancer‐specific survival for patients after surgery for prostate carcinoma metastatic to bone is poor, assessments of tumor differentiation of the metastasis and chromogranin A positivity provide prognostic information. Cancer 2002;95:1028–36. © 2002 American Cancer Society.

DOI 10.1002/cncr.10788
Telomerase activity and human telomerase reverse transcriptase mRNA expression are correlated with clinical aggressiveness in soft tissue tumors
Authors: Tomoda Ryota , Seto Masashi , Tsumuki Hideaki , Iida Koji , Yamazaki Takashi , Sonoda Jun , Matsumine Akihiko , Uchida Atsumasa
Published: October 2002

BACKGROUND

Telomerase is a ribonucleoprotein enzyme that extends telomere specific repeats on the ends of chromosomes. Telomerase activity has been detected frequently in various types of human tumors and has been associated with cell immortality and oncogenesis. Human telomerase reverse transcriptase (hTERT), a telomerase catalytic subunit, reportedly regulates telomerase activity. Little is known about telomerase activity and hTERT mRNA expression in soft tissue tumors. The objective of this study was to clarify the correlation between these two parameters and clinical aggressiveness in soft tissue tumors.

METHODS

In 41 surgically resected soft tissue tumors, telomerase activity was measured by the fluorescence‐based telomeric repeat‐amplification protocol and hTERT mRNA expression was determined by real‐time polymerase chain reaction.

RESULTS

Telomerase activity was detected in 52% of sarcomas and in none of the benign soft tissue tumors (P < 0.05). Telomerase activity was found in 77% of 13 locally recurrent sarcomas and in 89% of 9 sarcomas with distant metastasis. The frequency of the presence of telomerase activity in those tumors was significantly greater compared with the frequency of telomerase activity in the other sarcomas (P < 0.05 and P < 0.01, respectively). All telomerase positive sarcomas expressed hTERT mRNA. The mean level of hTERT mRNA expression in sarcomas was significantly greater compared with the mean hTERT mRNA expression level in benign tumors (P < 0.05) and in locally recurrent sarcomas compared with primary sarcomas (P < 0.001).

CONCLUSIONS

The results of the current study suggest that the detection of telomerase activity and the level of hTERT mRNA expression are useful markers for evaluating the clinical aggressiveness in soft tissue tumors. Cancer 2002;95:1127–33. © 2002 American Cancer Society.

DOI 10.1002/cncr.10793
Analysis of HIV‐1 variation in blood and semen during treatment and treatment interruption
Authors: Choudhury Bhudipa , Pillay Deenan , Taylor Stephen , Cane Patricia A.
Published: October 2002

The variability of populations of human immunodeficiency virus type 1 (HIV‐1) in blood and semen, with respect to envelope and polymerase gene sequences, was examined longitudinally in a patient experiencing treatment failure, interruption of treatment, and successful reintroduction of therapy. During treatment failure, there was little evidence of compartmentalisation between blood and semen, with virus with identical resistance‐associated mutations observed in both compartments and lack of clustering with respect to envelope gene sequences. After cessation of treatment, wild‐type virus became the predominant population, displaying distinct envelope gene populations, indicating that wild‐type virus had overgrown the resistant virus, rather than the resistant virus reverting to wild‐type. Once successful therapy had been recommenced, it was possible to distinguish distinct populations of virus in the two compartments. These data support the hypothesis that the male genital tract represents a distinct HIV‐1 reservoir. J. Med. Virol. 68:467–472, 2002. © 2002 Wiley‐Liss, Inc.
Platinum agents in the treatment of osteosarcoma: Efficacy of cisplatin vs. carboplatin in human osteosarcoma cell lines
Authors: Robson H. , Meyer S. , Shalet S.M. , Anderson E. , Roberts S. , Eden O.B.
Published: October 2002

Background

Cisplatin (cDDP), when used either alone or, more often, in combination with other agents, especially adriamycin, achieves a high response rate in osteosarcoma. Its use, however, is limited by severe nephro‐ and neuro‐toxicity. Second generation platinum compounds, most notably carboplatin (CBDCA), have been developed in order to attempt to reduce these dose‐limiting toxicities, and thus improve the therapeutic ratio. Studies evaluating the role of combination CT containing CBDCA vs. cDDP have demonstrated differing results depending on the tumor type tested and its role in the treatment of osteosarcoma has yet to be clarified.

Procedure

In this study, we compared the in vitro anti‐tumor activity of cDDP and CBDCA in a panel of three human osteosarcoma cell lines (HOS, MG63, and U2OS).

Results

cDDP and CBDCA (0–20 μmol) showed marked variation in cytotoxicity among the three cell lines. EC50 values for CBDCA in HOS and MG63 cells were approximately two‐fold higher than for cDDP and the ratio of AUCCBDCA to AUCcDDP varied from 1.8 in the HOS cell line to 2.3 in the MG63 cell line. Exposure of MG63 and HOS cells to either cDDP or CBDCA (1.67 and 13.5 μmol) caused a G2/M cell cycle arrest by 24 hr. Also evident was a sub G1 peak indicative of cell death by apoptosis. U2OS cells were relatively resistant to the cytotoxic effects of both drugs, although a cell cycle arrest in response to DNA damage was observed. This suggests that unlike MG63 and HOS cells, U2OS cells have either a more efficient repair pathway for platinum‐induced DNA damage or are able to evade apoptosis. Examination of apoptotic events and cellular recovery demonstrated that both an 8–16‐fold higher concentration and longer treatment period for CBDCA compared with cDDP was required to produce equivalent cell death and a loss of the ability of single cell clones to form colonies in both the HOS and MG63, but not the U2OS cell line.

Conclusions

Our findings suggest that CBDCA at a two‐ to four‐fold higher concentration than cDDP has potential therapeutic activity in platinum sensitive osteosarcomas, particularly when cDDP cytotoxicity compromises therapeutic efficacy. Med Pediatr Oncol 2002;39:573–580. © 2002 Wiley‐Liss, Inc.
Improving perishable product inventory management using goal programming
Authors: Kendall Kenneth E. , Lee Sang M.
Published: October 2002

The multiple objectives of perishable product inventory management are examined in this paper. These objectives include: (1) satisfying demand by carrying sufficient inventories, (2) holding down inventory carrying costs, (3) keeping the amount of product spoilage (outdating) at an acceptable level, and (4) maintaining quality by using the product while it is still fresh, and (5) keeping the cost of rotation low. Some of the above objectives are in conflict. Thus, certain redistribution policies may help attain one or more of these objectives to a greater extent. Redistribution involves the transfer of the product from outlets where demand is low to outlets where demand is high. A goal programming model for solving redistribution problems is presented. An example is provided and sensitivity analysis is performed in order to determine when redistribution is advantageous. Applicability of the model is discussed.
A heuristic method for aggregate planning: Production decision framework
Authors: Holt Jack A.
Published: October 2002

This paper presents an understandable and straight‐forward method for making work force level and inventory planning decisions, i.e., dynamic aggregate planning decisions.

The development phase utilizes a ratio, named RPCC, which represents the relative value of the cost of changing the production level to the cost of carrying inventory. This ratio is used to determine the length of an effective planning horizon. Two indicators are calculated to reflect the demand to current production rate over different time periods. Based on the joint values of these indicators, the planning problem is subdivided into one of nine mutually exclusive and exhaustive states. A set of action statements, representing logical responses to each of the sub‐problems, is formulated.

After completion of the development phase, the performance of the Production Decision Framework model is tested in several real case environments. Suggestions are made for further improvement.
Sequential facility location with distance dependent demand
Authors: Oded Berman , Celik Parkan
Published: October 2002

Systems providing identical service to many population centers frequently face the issue of where to locate the next retail outlet, branch, store, etc. In such systems the demand for the facilities' service depends mainly on the distance between facilities and customers. It is assumed that there are already m facilities located on a network to respond to the demand at the nodes. The paper addresses the problems of finding a location on the network for the (m + 1)st facility corresponding to a given total expected demand and of determining which demand points will be served by which facility. Also the range of the total expected demand values that can be realized along each link in the m + 1 facility system is determined. Examples and a discussion of the results are provided.
Capacity planning techniques for manufacturing control systems: Information requirements and operational features
Authors: Berry William L. , Schmitt CPIM Thomas G. , Vollmann Thomas E.
Published: October 2002

Substantial interest has been focused on techniques that determine the amount and timing of work center capacity to satisfy the master production schedule. Although several techniques have been developed for preparing work center capacity plans, very little analysis of the operational features and the application of these techniques has been reported. Four techniques, capacity planning using overall factors (CPOF), capacity bills, resource profiles, and capacity requirements planning (CRP), vary substantially in their complexity and the level of detail required to plan work center capacities. All four procedures require the use of the master production schedule to develop a capacity plan, but some have much more demanding data requirements. Important differences are the means by which capacity requirements are estimated by the techniques and the manner in which the bill of material, manufacturing lead time and inventory status information are incorporated into the capacity plan. The purpose of this paper is to describe the operational features of the four capacity planning techniques, the underlying data base requirements, and some key managerial issues in choosing among these techniques.