Vol. 51, No. 2APPLIED AND ENVIRONMENTAL MICROBIOLOGY, Feb. 1986, p. 261-2670099-2240/86/020261-07$02.00/0Copyright © 1986, American Society for Microbiology

Pathogenicity of a Fungus Resembling Wangiella dermatitidisIsolated from Edible Mushrooms

NURIA KAZANAS

Division of Microbiology, Food and Drug Administration, Washington, D.C. 20204

Received 15 October 1985/Accepted 28 October 1985

A fungus resembling the human pathogen Wangiella dermatitidis (Kano) McGinnis, a dematiaceoushyphomycete, was recovered from imported desiccated "black fungus" mushrooms (Auricularia polytrichia(Mont.) Sacc.), a food item popular in Far Eastern cuisine. Except for its conidia, which are mostly reniformto allantoid rather than ovoid as is characteristic for W. dermatitidis, and the undecided mode of conidiogenesis,the isolate closely resembles W. dermatitidis in gross and microscopic morphology, thermotolerance, andgeneral and neurotrophic infectivity patterns in mice injected intraperitoneally. The foodborne isolate was alsoinfective for infant mice inoculated by oral intubation. The systematic position of the isolate is still underinvestigation. There has been no previous report of W. dermatitidis or of a fungus resembling it occurring in or

on foods or of the infectivity of a fungus for a mammalian host by oral intubation.

The genus Wangiella McGinnis was proposed (19, 20) toaccommodate the dematiaceous hyphomycete originally de-scribed as Hormiscium dermatitidis Kano and subsequentlyplaced in three other genera: Fonsecaea Negroni,Hormodendrum Bonorden, and Phialophora Medlar. How-ever, de Hoog (7) disagreed with previous classifications,and it was placed in the genus Exophiala Carmichael (8).Acceptance of this species as Exophiala dermatitidis (Kano)de Hoog (12, 23) was based on the evidence from scanningelectron microscopy that Kano's isolate (CBS 207.35) pos-sessed the annellidic mode of conidiogenesis. Yet, accordingto McGinnis (19), conidia in the genus Wangiella arise fromphialides without a collarette. Later, Hohl et al. (13) criti-cally studied 26 cultures of Wangiella dermatitidis, includingKano's type culture, and accepted this species into the genusWangiella McGinnis as W. dermatitidis. Matsumoto et al.(18) also agreed to the placing of the species into the genusWangiella. The American Type Culture Collection currentlyregisters W. dermatitidis McGinnis (1982) as Exophialadermatitidis (Kano) de Hoog (1984) (ATCC 28869 = CBS207.35).

Isolates of W. dermatitidis are difficult to identify. Theorganism grows slowly on primary isolation and it is difficultto see the conidiophores, particularly the feature that iscritical for classification, i.e., phialides without collarettes(19). It is never easy to determine the presence of collarettes,and unless conidiogenesis is well established, final genusidentification is usually delayed. Hence, for the present, werefer to this foodborne isolate as one "resembling W.dermatitidis."

W. dermatitidis is a polymorphic pathogen, dermatropicas well as neurotropic, that causes cutaneous and dissemi-nated "phaeohyphomycosis" (2, 3). This fungus, basically asaprophyte, normally grows in soil or on wood and organicdebris.

Reports (13, 18) of human infections and human isolates ofW. dermatitidis indicate that the majority of human infec-tions have occurred in Japan and Taiwan. Not until recentlywas a case reported in the United States (13). Hohl et al. (13)consider the fungus to be not merely an opportunisticpathogen but basically "invasive, capable of disseminationand very difficult to treat."

W. dermatitidis has not been previously isolated from

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foods. The isolation of a dematiaceous fungus that resemblesW. dermatitidis from edible desiccated mushrooms importedinto the United States from Taiwan follows the isolation ofanother pathogenic fungus, Sporothrix schenckii Hecktonand Perkins, from the same type of food (16). Experimen-tally, the S. schenckii isolate was pathogenic for mice byintraperitoneal (i.p.) or oral inoculation (N. Kazanas,Mycopathologia, in press).The present paper describes the pathogenicity in a mam-

malian host of the foodborne dematiaceous fungus resem-bling W. dermatitidis and the host's gastrointestinal tract asa potential portal of entry. Histological preparations weremade to determine if the host tissue (mouse) is susceptible toinfection and whether melanin synthesized by the fungus cellwall was deposited in that tissue.

MATERIALS AND METHODS

Isolation procedure. Desiccated mushrooms (Auriculariapolytrichia (Mont.) Sacc.) were purchased in a New YorkCity retail store specializing in East Asian foods. Themushrooms, which were packaged in sealed cellophane bags,had been imported from Taiwan and were prepared for fungalrecovery according to methods described for S. schenckii(16). Fungal colonies on plates were counted and represen-tative types were isolated in pure culture. The microanatomyof the fungus was examined on isolates grown in modifiedSabouraud dextrose agar (SDA) and potato dextrose agar; thesporulation pattern was identified and determined at roomtemperature with slide cultures on potato dextrose agar.Colonies suggestive of W. dermatitidis from SDA mediumwere inoculated onto the surface of SDA to test their abilityto grow at 40°C but not at 50°C (24).

Inoculation of experimental hosts. A representative isolatewas used to determine the pathogenicity of the fungus formice. The isolate was grown on SDA at room temperature(24 to 26°C) for 8 days. Growth (mostly yeast cells) from oneslant was harvested by suspending it in 5 ml of sterilephysiological saline. The number of organisms was esti-mated by counting in a hemacytometer and confirmed bycolony counts. A group of eight (four female and four male)adult ICR Swiss albino Webster (Harlan Sprague-DawleyInc., Indianapolis, Ind.) mice (20 to 30 g) were each given asingle 1.0-ml dose containing 3 x 107 fungal cells. Forty-six

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4-day-old CF1 mice (Harlan Sprague-Dawley) were given asingle 0.05-ml dose containing 2 x 107 fungal cells by gavagewith a 0.50-ml tuberculin syringe equipped with a blunt27.5-gauge needle tipped with flexible polyethylene tubing.The Bl-D Yale tuberculin syringe (Becton Dickinson and Co.,Rutherford, N.J.), calibrated in 0.01-ml divisions, was usedwith a holder in a calibrated syringe microburet (model SB2;Micrometric Instrument Co., Cleveland, Ohio). The properlength of tubing for a newborn mouse was equal to thedistance between its nose and the xiphoid of its externum.This distance was marked with tape on the tubing beforeintroduction to guard against rupture of the stomach by anexcessively long tube. The tip of the tubing was stretched tohairlike thinness to avoid sharp edges. Intragastric intuba-tion delivered a volume of 0.05 ml. The nostrils and mouth ofeach newborn mouse were examined for the presence of bluedye with a magnifying lens immediately following intubationand at 30 min. Mice showing blue dye were eliminated fromexperiments. The mice were housed in Nalgene plasticisolator cages with filter covers (Nalgene Co., Rochester,N.Y.) in a room maintained with suitable light and temper-ature. Purina mouse chokv and water were provided adlibitum.

Recovery of fungus from infected mice. Treated mice andcontrols were killed and necropsied on days 7, 11, and 26after i.p. injection and on days 3, 5, 8, 12, 16, 19, and 23 afterintubation. On the day of sacrifice, the brain and internalorgans were removed. A pool of organs (lungs, liver, spleen,kidney, and heart) was weighed and homogenized with amortar and pestle in 5 ml of sterile physiological saline.Appropriate dilutions were made and plated in duplicate onmycobiotic agar medium (Difco Laboratories, Detroit,Mich.) and incubated at 28°C until colonies were apparent(about 8 to 10 days).

Histopathologic examination. Two adult mice were killed, afemale on day 11 and a male on day 31 after i.p. injection; anintubated infant was killed on each of days 3, 5, 8, 12, 16, 19,23, and 39 for histopathologic examination. The brain, liver,spleen, pancreas, kidney, lungs, and heart of mice given ani.p. injection, plus the kidneys, thyroid, lymph nodes, stom-ach, intestines, and testes of intubated mice, were removedaseptically and fixed in 10% Formalin (intestines and stom-ach in separate containers), embedded in paraffin, and sec-tioned by conventional procedures. Tissues sections werestained with hematoxylin and eosin and Grocott-Gomorimethenamine silver nitrate. In addition, sections of thebrain, spleen, pancreas, and liver of mice given an i.p.injection were stained with Masson-Fontana stain for mela-nin deposits and with dopa-oxidase for melanin-formingcells. Both stains included melanin-bleaching preparations.

RESULTSFungal isolates from edible mushrooms. Fungal colonies on

mycobiotic agar plates were counted and isolated on day 15of incubation. One of two plates inoculated with a 1:500dilution of the mushroom homogenate contained six colo-nies; two were black, yeasty, and slow growing, with micro-scopic morphology suggestive of W. dermatitidis. The otherfour colonies were identified as Aspergillus versicolor. Fungirepresentative of several genera isolated from other dilutionplates were lyophilized in skim milk for subsequent charac-terization. Colonies resembling W. dermatitidis were notfound on plates with 10- to 100-fold dilutions of the blendedmushroom homogenate.The isolate grew well at 25, 37, and 40°C but not at 50°C.

At ambient temperatures of 22 to 26°C on SDA, the fungus

resembling W. dermatitidis (which grew slowly on routinemedia during primary isolation) produced smooth, black,mucoid, even stringy, yeastlike colonies (Fig. 1). After 20 ormore days, a dark, olive-gray, aerial mycelium, velvety inappearance and closely adherent in structure, could be seenat the periphery of the colonies. The microscopic morphol-ogy was consistent with the McGinnis (20) description of W.dermatitidis with one exception. Instead of being ovoid, theconidia were mostly reniform and allantoid. Conidia wereproduced from terminal (Fig. 2A) and intercalary (Fig. 2B)conidiogenous cells. The fungus was able to produceblastoconidia (Fig. 3) and conidia under identical culturalconditions on SDA medium. It is inconclusive whether thisfungus has an annellide mode of conidiogenous cell devel-opment as observed by scanning electron microscopy for thegenus Exophiala (12, 21); however, further studies are inprogress.

Recovery of fungus from i.p. injected mice. Six of eightmice given i.p. injection were killed for fungus recovery, andtwo were used for histopathologic preparations. The funguswas recovered from the brain and pool of visceral organs ofall three female mice but not from the three males. Culturalevidence of the fungus was obtained from the organ pool onday 7 after injection, when the first mouse was sacrificed. Ondays 11 and 26, multiplication of the fungus was alsoapparent in the brain, and numbers of CFU (5 x 107/100 mg)remained high in the organ pool. Macroscopic lesions werenot observed in mice killed on day 7; however, grosslyabnormal livers were seen in all female mice autopsied ondays 11 and 26 and in the fourth male mouse (used forhistopathologic studies) on day 31 after injection. The mostcommon abnormalities were darkening and enlargementwith numerous abscesses (Fig. 4). An abscess formed in theperitoneum at the injection site in all mice yielded abundantfungal colonies of the isolate. When killed, the female micewere hypomotive and runty and unusually irritable andvicious.

Histopathology of i.p. injected mice. Histopathologic find-ings in the internal organs of male mice (after 31 days) andfemale mice (after 10 days) are shown in Table 1. Yeast cellsand a few mycelial forms of the fungus, microabscesses, andwell-developed granulomas were observed in the livers ofboth male and female mice. In the male mouse, acutenecrotizing phaeohyphomycosis of retroperitoneal tissueswith multiple yeast cells and early hyphal formation with anadmixture of polymorphonuclear leukocytes and mononu-

FIG. 1. Colonies of the foodborne, pathogenic, dematiaceousfungus that resembles W. dermatitidis on SDA at 28°C for 10 days.x1.25.

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clear cells was observed. The male mouse showed an acuteand chronic inflammatory response in the blood vessel wallof what appeared to be the right atrium and inferior venacava (given juxtaposition of liver and myocardial tissue).Within the vessel was a recent septic thrombus with ratherearly organization; within the thrombus were pigmentedyeast cells and a few short hyphal elements. There was noinvasion of the endothelium of vascular wall by the fungus.Septic thromboembolus with no organization was present in

FIG. 3. Photomicrograph of blastoconidial cells of the de-matiaceous fungus resembling W. dermatitidis. Grown on potatodextrose agar at 28°C for 8 days. x 1,000.

the liver tissue; again there were multiple yeast cells withonly few small hyphal fragments.Although there was no apparent involvement of the pan-

creas, kidney, spleen, and brain of the male mouse, in thefemale mouse the fungus and lesions were present in thetissue of those organs. The female mouse also showed asevere necrotizing phaeohyphomycosis of perirenal adiposetissue at the renal hilum, as well as of the tail of the pancreasadjacent to the hilum of the spleen. Again there were yeastcells and a few nonbranching septated hyphae. Consistentwith the known neurotropism of pathogenic dematiaceoushyphomycetes was the focus of the infection in the brain. Anabscess was present in the region of the mesial temporal lobeadjacent to the hippocampus. This focus was notable for amore prolific formation of septate hyphae than appeared inany other organ. These hyphae were also longer and more

FIG. 2. Terminal (A) and intercalary (B) conidiogenous cells andconidia of the foodborne, pathogenic, dematiaceous fungus thatresembles W. dermatitidis. Grown on potato dextrose agar at 28°Cfor 8 days. x 1,000.

FIG. 4. Mouse injected i.p. with the foodborne, pathogtAic,dematiaceous fungus that resembles W. dermatitidis. Arrows pointto peritoneal abscesses. x1.25.

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TABLE 1. Histopathologic findings in adult mice 10 and 31 days after i.p. injection with a foodborne fungusresembling W. dermatitidis (3 x 107)

Organ Male mouse (31 days) Female mouse (10 days)

Liver Large granulomas with central caseation, necrosis, Small granulomas, acute microabscesses, focalnumerous microabscesses, microgranulomas, focal hemorrhages, focal consolidation; no fungusnecrosis-acute hepatitis; many fungal cells

Brain No specific reaction Acute inflammation, abscesses in the parenchyma,moderate number of yeast and mycelial forms ofthe fungus

Pancreas Edematous, no fungus Large granuloma with pus at center; massive numbersof yeast and mycelial forms of the fungus

Kidney No specific reaction Subcapsular granuloma; yeast and mycelial formsabundant at center

Spleen Reactive, congested Acute granuloma in the capsule; abundant yeast andmycelial forms of the fungus

Lungs No specific reaction Focal consolidation; no fungus

Peritoneum Well-developed granuloma with central necrosis andcaseation; abundant yeast and hyphal forms offungus at center of granuloma

Submaxillary pouch Granulomas, acute; abundant yeast and chain formsor areolar fat of the fungus

Heart, adrenal, No specific reactionssalivary glands

Blood vessel Thrombus; abundant yeast and few hyphal forms

plentiful than those in the extracerebral foci. The yeast formof the fungus in the host tissues (male and female) wassimilar to the budding form observed in microculture; formsshowing transverse septae and what appeared to be several

stages of binary fission were also observed (Fig. 5).Recovery of fungus from orally intubated mice. Table 2

summarizes the cultural and histopathologic findings in4-day-old CF1 mice inoculated by oral intubation with the

I

FIG. 5. Histopathologic sections of mouse liver tissue showing budding yeast (A, E), transverse septa (A, B), binary fission (C), andmycelial forms (D) of the fungus resembling W. dermatitidis. x 1,000.

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TABLE 2. Infections of neonatal mice intubated by the oral route with a foodborne dematiaceous fungusresembling W. dermatitidis (2 x 107)

Days post- Cultural recovery/no. of mice No. of mice No. of miceinoculation necropsied infected/no. Histological evidence infected/no.

necropsied necropsied

3 Organs, 1/5; intestines, 2/5 3/5 NRa 0/1S Organs,b 1/5; organs,c 1/5 2/5 NR 0/18 Organs, 1/5; as day 5, 1/5 2/5 NR 0/1

12 Organs, 2/5 2/5 NR 0/116 0/5 0/5 Yeast cells in lumen of stomach and intestines 1/119 0/5 0/5 NR 0/123 0/2 0/2 Yeast cells in lumen of stomach and intestines, 1/1

on surface of epithelial lining of intestines30 0/4 0/4 Same as day 23 1/139 0/4 0/4

a NR, No reaction.b Intestines.c Intestines, stomach, brain; higher numbers recovered, especially in brain.

foodborne fungus resembling W. dermatitidis. Of the 46 miceintubated, 38 were sacrificed for fungus recovery; the restwere used for histopathologic preparations. Nine of thosekilled for fungal recovery showed cultural evidence of thefungus. The fungus was recovered from the visceral organsof animals sacrificed on days 3, 5, 8, and 12 but wasrecovered from the intestines only on days 3 and 8 afterinoculation. Evidence of fungus multiplication in the internalorgans and brain was obtained in two of the five micesacrificed on day 8. Less fungus was obtained from theinternal organs of two of the five mice sacrificed on days 8and 12; fungus was not recovered from mice sacrificed ondays 16, 19, 20, 23, and 30. After 26 days of incubation atambient temperature, colonies typical for this fungus wereisolated from the internal organs. However, colonies iso-lated from the intestines, stomach, and brain remained in thevery mucoid yeast form; mycelium was not observed. Thisphenomenon was observed following day 5 after inoculation.No death or cannibalism of the neonatal mice was notedduring the entire experimental period.

Histopathology of orally intubated mice. Histopathologicpreparations showed the presence of Wangiella-like speciesof fungus only in the lumen of the stomach of the mousesacrificed on day 16, with increased numbers of fungalelements observed in the lumen of the stomach and on thesurface of the epithelial lining of the mice sacrificed on days23 and 30 after inoculation. Fungal elements existed only inyeast cell form; mycelial forms were not observed. Nolesions of the cellular or pyogenic response types were seenwith or without fungal elements in these mice.

DISCUSSIONAlthough W. dermatitidis appears to be ubiquitous, it has

not been previously isolated from foods. This paper de-scribes a fungus closely resembling W. dermatitidis, isolatedfrom imported desiccated edible mushrooms, and its infec-tivity in mice. Compared with studies of foodborne toxigenicfungi, little work has been done on the occurrence orselective growth of human pathogenic fungi in or on foods.Furthermore, only two investigations (1; Kazanas, in press)have demonstrated the infectivity of the isolates in an animalmodel.

In its microscopic and gross morphology, thermotoler-ance, and general and neurotropic pathogenicity for micegiven i.p. injections, the fungus recovered from mushroomsis very similar to W. dermatitidis. Whether it is a newgenus/species or identical to W. dermatitidis will depend on

results of current studies on conidiogenesis. The fission cellsobserved in tissue are unknown in W. dermatitidis, althoughtransverse septa in tissue is typical in this fungus. Trans-verse septae and the vegetative cells subsequently separatedby splitting transversally through the thickened septal wallsare commonly known as fission cells. Inasmuch as asexualreproduction in yeasts sometimes involves the process offission or budding, the presence of fission cells in W.dermatitidis is noteworthy.A new species of the genus Exophiala, recently described

by Iwatsu et al. (14) as E. castellanii (= CBS 158.58 = ATCC18657 = NCMH 254), was compared with the foodbornedematiaceous isolate and found to differ in colonial morphol-ogy, conidial shape, and thermotolerance at 40°C. Animalpathogenicity was not reported for E. castellanii. Thethermotolerance of the foodborne isolate was consistentwith the thermotolerance of W. dermatitidis (18, 24, 25).Only one strain of W. dermatitidis, which does not grow at40°C, has been described (25).

Cultural evidence of infection of the brain and the pool ofvisceral organs of adult mice inoculated i.p. with thedematiaceous foodborne fungus was obtained in females butnot in males after 31 days. However, histopathologic find-ings in a male sacrificed on day 31 after injection showedmicroabscesses, well-developed granulomas, and the pres-ence of yeast and mycelial forms of the fungus in the liverand retroperitoneal tissues, as well as a septic thrombo-embolus. The pathogenesis of these lesions may have beenrelated to the introduction of a venous branch during theinitial i.p. injection; alternatively, the organism may haveinvaded the small retroperitoneal veins and propagated thethrombus from these sites. Given the acuteness of inflam-matory response and the minimal amount of organization ofthe thrombus, the latter seems more probable. The excellentstate of preservation of the intestinal tract in this specimenprecluded a long postmortem interval of fungal proliferation.Females also showed lesions in the brain, pancreas, kidney,and spleen in addition to the liver on day 11. The pool of thevisceral organs of infant mice orally intubated showed cul-tural evidence of the fungus from day 3 to 12, but the funguswas recovered from the intestines only to day 8; culturalevidence of the fungus persisted in the brain of intubatedinfant mice from days 8 through 12. After day 12, the funguswas no longer recovered from the infants, but yeast formswere observed in the lumen of the stomach and intestines inhistopathologic preparations on day 16 and at termination ofthe experiment on day 23. Thus, up to day 12 the fungus was

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recovered from 45% of the infant mice intubated with theisolate.

Fungal multiplication was considerable in the brain ofmice inoculated by either i.p. injection or oral gavage. W.dermatitidis has been recognized as neurotropic, and itsneurotropism has been confirmed by injection in experimen-tal animals (15, 22, 25). Nishimura and Miyaji (21) reportedon a strain of W. dermatitidis (as E. dermatitidis), isolatedfrom a room humidifier, that caused allergic reactions in apatient; the strain's favorite target in the injected experimen-tal mouse was the brain, followed by the kidney and liver.With the foodborne isolate, however, the liver appears to bethe primary target organ.

Like other dematiaceous fungi, W. dermatitidis is termeda black yeast because it has a black yeast form that producesa dark pigment. Melanin synthesis within the cell wall of W.dermatitidis is responsible for this dark pigment (11). Al-though our fungus produced large amounts of a black sub-stance which precipitated in broth during incubation, tissuesof mice infected with the fungus and prepared with melaninstains and bleach showed no melanin deposits.Confirmed human infections with W. dermatitidis have

been reported in 21 cases: 18 in Japan, 2 in Taiwan (sistersliving together), and 1 in North America. Mortality was 48%(18); females 10 to 30 years old constituted 67% of the cases.In seven cases, the brain was involved, and in one case theoropharynx was the initial site of involvement; female micein this experiment were more susceptible to the dematiace-ous isolate resembling W. dermatitidis than were males. Theincidence of infection with S. schenckii in Japan is alsohigher in females (10). In Latin America, on the other hand,females are less susceptible to another fungus, Paracoc-cidioides brasilienses (26, 27), perhaps because of the estro-gen inhibition of mycelium-to-yeast transformation (28)necessary to establish infection in this fungus. The onewell-documented case of W. dermatitidis infection in NorthAmerica was a subcutaneous cystic ulcerous knee in adiabetic man with impaired T-cell function and cutaneousanergy; the individual died suddenly from fulminant pneu-monia (13).

S. schenckii, the etiologic agent of human and animalsporotrichosis, has also been isolated from edible mush-rooms (16). It is pathogenic for adult mice by i.p. injectionand for infant mice by oral intubation (Kazanas, in press). Inhumans, only two cases of S. schenckii involvement of thegastrointestinal tract have been reported (5, 6). Other fungihave been involved in gastrointestinal infections (1, 4, 9, 17,30) and in one death (2). W. dermatitidis (18) and otherdematiaceous fungi, S. schenckii and Exophiala jeanselmei(29), have also been associated with human esophagealpathology. However, the sources of human digestive tractinfections with fungi remain to be documented.The dematiaceous fungal isolate under study here closely

resembles W. dermatitidis in its gross and microscopicmorphology, thermotolerance, and general and neurotropicinfectivity for mice. This foodborne isolate appears to bemore virulent in female than in male mice and can infectinfant mice by the oral/gastric route, bypassing the lungs.This is the first report of experimental animal phaeohypho-mycosis by the oral/gastric route.Inasmuch as W. dermatitidis is not considered to be

merely an opportunistic pathogen and the portal of entry ofthe infections reported in some patients remains obscure(13), the recovery of an identical or similar fungus fromedible mushrooms that can infect an experimental mammalby the oral/gastric route is of public health interest.

ACKNOWLEDGMENTS

I thank George J. Jackson, Food and Drug Administration, fortechnical advice and assistance; Khurshed A. Chowdhury, Food andDrug Administration, and Thomas J. Walsh, University of MarylandCancer Center, for confirming the pathological findings; Michael R.McGinnis, Memorial Hospital and University of North Carolina, forreviewing the manuscript; Lois A. Tomlinson for editorial assistance;Mary L. Chaney for secretarial services; and Sheryl Norcome forfinal typing of the manuscript.

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