Particle size and pathogenicity in the respiratory tract

Figures & data

Table 1. Sources of bioaerosol

Bioaerosol source	Mechanisms	Particle size distribution^a,b	Reference(s)
Healthcare	Surgical or dental procedures	Up to 50 µm^e	1 and 2
	Hospital air	<2 µm (22%), 2 to 6 µm (30%), >5 µm (48%)	3
	Mechanical ventilators, bed making, and resuspension on dust or skin squamae	0.3 to >5 µm	4 and 5
Water industry	Cooling towers	<5 up to >100 µm (bimodal peaks at <5 µm and 20–40 µm)	6
	Wastewater irrigation sites	1.0 to 5.9 µm	7
Agricultural/forestry industries	Grain harvesting, food processing, dust, and/or feces from animal housing and farming activities	0.9 to 18.9 µm 0.5 to >5 µm (increase in 2 to >5 µm range)	8 and 9
	Insecticidal crop spraying	4.6 to 39 µm^d	10 and 11
		12.3 to 37.1 µm^c	12
		15 to 45 µm^c	13
		60 to 100 µm (kromecote card); 5.3 to 7.3 µm (Anderson cascade impactor)	14
	Genetic dispersion	Pollen grains: 10 to 100 µm^e	15
		Fungal spores: 1 to 50 µm^e	16
Postal and shopping industry	Mail sorting and opening	0.3 to >5 µm; 19.6-fold increase in particles >5 µm	17
	Mist machine	“between 40 and 70 µm”	18
Leisure activities	Marine activities, e.g., surfing	24 to 44 µm, median 34 µm	19
	Whirlpools	<1 to 15 µm dependent on turbulence	20
Human activity	Breathing	<0.8 to 2 µm	21
	Speaking	16 to 125 µm	22 and 23
		<0.8 to 7 µm	21
	Shouting	0.5 to 10 µm (mean = 1.0 µm)	24
	Coughing	0.62 to 15.9 µm	21, 22, and 25–27
		40 to 125 µm	23 and 28
	Sneezing	7 to 125 µm	28 and 29
	Vuvuzela playing	0.5 to >10 µm (mean = 1.3 µm)	24
	Showering	Hot water (5.2 to 7.5 µm)	30
		Cold water (2.5 to 3.1 µm)
Miscellaneous	Pulp waste water treatment plant	2.4 to 3.5 µm (median); 99.9% of particles were below 15 µm	31
	Building tower (sweeping dust containing pigeon feces)	1.1 to 11.0 µm	32

^a Aerodynamic diameter; ^bdistributions should be viewed with caution as often experiments used samplers with cut off limits less than 15 µm and therefore were preferentially selective for particles smaller than this size; ^cspray-dried Bacillus thuringiensis produced at different homogenization speeds; ^dnon-biological aerosols for vector control; ^eprocedure- or species-dependent.

Table 2. Tissues that may represent the primary site of deposition, clearance and infection during exposure to a bioaerosol

Anatomical region	Tissue(s)	Function	Epithelium
Nasopharyngeal/Oropharyngeal	Nares to nasopharynx	Inhalation, filtration, and mucociliary clearance of foreign particles; warming/humidification of air	Ciliated
	Paranasal sinuses	Humidification of air; mucociliary clearance of foreign particles	Ciliated
	Olfactory epithelium	Detection of odors	Sensory
	Mouth to oropharynx	Mastication and ingestion; inhalation	Non-ciliated
	Tonsils, adenoids^a	Defense against inhaled/ingested pathogens; URT mucosal immunity	Lymphoepithelial
Tracheobronchial	Larynx	Sound generation; mucociliary clearance	Ciliated/non-cilated
	Trachea	Air conduction; mucociliary clearance	Ciliated
	Bronchi to bronchioles	Air conduction and particulate filtration; mucociliary clearance	Ciliated
Pulmonary	Respiratory bronchioles to alveoli	Air conduction; gaseous exchange; pulmonary clearance and immunity	Non-ciliated
Ocular	Ocular conjunctiva	Lubrication of ocular region	Non-ciliated
	Nasolacrimal duct	Drainage of excess tear fluid	Non-ciliated
Gastrointestinal	Esophageal, stomach and intestinal epithelium	Digestion and absorption of ingested material, including inhaled particles trapped in the mucociliary escalator	Non-ciliated
	Peyer patches	Defense against ingested pathogens	Lymphoepithelial

^a Nasal-associated lymphoid tissue (NALT) represents the rodent equivalent.

Figure 1. Schematic of the interplay between deposition sites and clearance mechanisms in the respiratory tract. BALT, bronchial-associated lymphoid tissue; LALT, lung-associated lymphoid tissue; LNs, lymph nodes; NALT, nasal-associated lymphoid tissue.

Table 3. Influence of aerosol particle size on the respiratory lethal dose values for respiratory pathogens

Particle size (μm)	Bacillus anthracis (cfu)		Yersinia pestis (cfu)		Francisella tularensis (cfu)		Brucella suis (cfu)	Burkholderia pseudomallei (cfu)	Coxiella burnetii (cfu)	VEEV (pfu)	EEEV^a (pfu)		Ricin^b (μg kg^−1)
Animal species	Guinea pig	Mouse (A/Jola)	Guinea pig	Mouse (Balb/c)	Guinea pig	Rhesus macaque	Guinea pig	Mouse (Balb/c)	Guinea pig	Guinea pig	Guinea pig	Mouse (Balb/c)	Mouse (Balb/c)
1.0–3.0	0.23–3.4 × 10^5	2.43 × 10^3	0.3–1.0 × 10^5	6.01 × 10^2	2.5	14–17.3	ANNEX A 1.3–1.9 × 10^2	4.0–5.0	1.9 × 10^6	20	0.52–1.1 × 10^4	4.6–6.2 × 10^2	12.2
4.0–6.5	2.21 × 10^5	ND	ND	ND	6.5 × 10^3	2.4 × 10^2	ND	ND	5.27 × 10^7	1.9 × 10^4	ND	ND	ND
8.5–13.0	0.7–5.7 × 10^6	7.65 × 10^3	0.7–2.1 × 10^5	2.95 × 10^3	1.95 × 10^4	5.5–8.72 × 10^2	ANNEX B 0.88–1.6 × 10^6	12.0	> 2.4 × 10^9	2.8 × 10^5	3.0 × 10^4	2.9 × 10^5	No lethality
20.0–25.0	ND	ND	ND	ND	ND	3.75–4.45 × 10^3	ND	ND	ND	ND	ND	ND	ND
Method 1–3 μm	COLL	COLL	COLL	COLL	NK	Atomizer	COLL	NK	NK	NK	COLL	COLL	COLL
Method >4 μm	STAG	FFAG	STAG	FFAG	NK	STAG	STAG	NK	NK	NK	STAG	STAG	STAG
References	70 and 73	76	71	75	73	69 and 73	72	77	73	73	74	74	78

cfu, colony forming unit; COLL, Collison nebulizer; EEEV, eastern equine encephalitis virus; FFAG, flow-focusing aerosol generator; ND, not determined; NK, not known; pfu, plaque forming unit; STAG, spinning top aerosol generator; VEEV, Venezuelan Equine Encephalitis virus. a, values represent LD₅₀ values from two virus strains (ArgM and NJ1959); b, no lethality using 45 µg kg⁻¹

Table 4. Effect of aerosol particle size and deposition site on infection kinetics and pathology for selected pathogens in animal models of infection

Pathogen	Yersinia pestis (murine)		Bacillus anthracis (murine)		Burkholderia pseudomallei (murine)		Francisella tularensis (Rhesus macaque)
Particle size	1	12	1	12	1	12	1	12
Deposition site	Lungs	Nasal mucosa	Lungs	Nasal mucosa	Lungs	Nasal mucosa	Lungs	Nasal mucosa
MLD (cfu)	6.01 × 10^2	2.95 × 10^3	2.43 × 10^3	7.65 × 10^3	4	12	17	8.72 × 10^2
MTTD (h)	72 ± 0	90 ± 11.5	101.6 ± 10.4	161.0 ± 16.1	73.8 ± 11.3	174.7 ± 14.9	138.9 ± 8.8	224.5 ± 9.6
Mortality^a (%)	100	80	78	56	100	90	100	83
Pathogenesis	1° pneumonia	Nasal ulceration	BALT infection	Nasal ulceration	1° pneumonia	Nasal ulceration	1° pneumonia	Nasal ulceration
	Splenitis	NALT infection	Mediastinal LN	NALT infection	Splenitis	NALT infection	Splenitis	Tonsillitis
	Septicemia	Cervical adenitis	Splenitis	Cervical adenitis	Septicemia	Cervical adenitis	Septicemia	Cervical adenitis
		Splenitis	Septicemia	Splenitis		Splenitis		Splenitis
		Septicemia				Septicemia		Septicemia
				Primary gastritis
		2° pneumonia		Peyer patches		Olfactory neuritis		Conjunctivitis
				Mesenteric LN		Brain abscess

^a Mortality indicated for retained dose of 10³ cfu in the lungs or nasal cavity; cfu, colony-forming unit. Data from references 69 and 75–77.

Table 5. Upper respiratory tract symptoms in bacterial select agents

Symptoms	Percentage of patients with symptom (%)
	Plague^a (Pharyngeal)	Tularemia (Oropharyngeal)	Anthrax (Nasopharynx)	Anthrax (Oropharyngeal)	Anthrax (Laryngeal)	Melioidosis (Pharyngocervical)
Fever	92	96	83	97	50	60
Tonsillitis	75	-	-	63	-	15
Pharyngitis	92	81	33	72	-	30
Nasal/sinus complaints	-	-	83	3	0	10
Malaise/fatigue	92	54	33	-	25	-
Headache	92	62	17	6	0	-
Cervical/submandibular lymphadenitis	83	92	50	100	-	85
Arthralgia/myalgia	83	35	-	-	-	5
Abdominal pain	50	-	17		25	-
Vomiting/nausea	50	-	0	3	25	5
Cough	42	-	0	6	0	5
Dysphagia	17	-	17	-	0	-
Diarrhea	17	-	-	3	-	-
Hemoptysis/dyspnea	8	-	17	39	75	-
Anorexia	-	46	17	-	-	-
Depression	-	50	17	-	0	-
Concentration	-	42	-	-	-	-
Sleep disturbance	-	46	-	-	-	-
Mortality	40%	< 10%	50%	40%	50%	< 10%
Treatable	+	+	+	+	+	+

^a Also known as tonsillar plague. Data taken from references 107–113, 117, 118, 121, and 124–128.

Jewett DL, Heinsohn P, Bennett C, Rosen A, Neuilly C. Blood-containing aerosols generated by surgical techniques: a possible infectious hazard. Am Ind Hyg Assoc J 1992; 53:228 - 31; http://dx.doi.org/10.1080/15298669291359564; PMID: 1529914

 PubMed Web of Science ®Google Scholar

Szymańska J. Dental bioaerosol as an occupational hazard in a dentist’s workplace. Ann Agric Environ Med 2007; 14:203 - 7; PMID: 18247451

 PubMed Web of Science ®Google Scholar

Greene VW, Vesley D, Bond RG, Michaelsen GS. Microbiological contamination of hospital air. I. Quantitative studies. Appl Microbiol 1962; 10:561 - 6; PMID: 13950172

 PubMedGoogle Scholar

Tang JW, Li Y, Eames I, Chan PKS, Ridgway GL. Factors involved in the aerosol transmission of infection and control of ventilation in healthcare premises. J Hosp Infect 2006; 64:100 - 14; http://dx.doi.org/10.1016/j.jhin.2006.05.022; PMID: 16916564

 PubMed Web of Science ®Google Scholar

Roberts K, Hathway A, Fletcher LA, Beggs CB, Elliott MW, Sleigh PA. Bioaerosol production on a respiratory ward. Indoor Built Environ 2006; 15:35 - 40; http://dx.doi.org/10.1177/1420326X06062562

 Web of Science ®Google Scholar

Rothman T, Ledbetter JO. Droplet size of cooling tower fog. Environ Lett 1975; 10:191 - 203; http://dx.doi.org/10.1080/00139307509435821; PMID: 1240052

 PubMed Web of Science ®Google Scholar

Bausum HT, Schaub SA, Kenyon KF, Small MJ. Comparison of coliphage and bacterial aerosols at a wastewater spray irrigation site. Appl Environ Microbiol 1982; 43:28 - 38; PMID: 7055376

 PubMed Web of Science ®Google Scholar

Lee S-A, Adhikari A, Grinshpun SA, McKay R, Shukla R, Reponen T. Personal exposure to airborne dust and microorganisms in agricultural environments. J Occup Environ Hyg 2006; 3:118 - 30; http://dx.doi.org/10.1080/15459620500524607; PMID: 16484176

 PubMed Web of Science ®Google Scholar

Olsen KN, Lund M, Skov J, Christensen LS, Hoorfar J. Detection of Campylobacter bacteria in air samples for continuous real-time monitoring of Campylobacter colonization in broiler flocks. Appl Environ Microbiol 2009; 75:2074 - 8; http://dx.doi.org/10.1128/AEM.02182-08; PMID: 19201953

 PubMed Web of Science ®Google Scholar

Rathburn CB Jr., Dukes JC. A comparison of the mortality of caged adult mosquitoes to the size, number and volume of ULV spray droplets sampled in an open and a vegetated area. J Am Mosq Control Assoc 1989; 5:173 - 5; PMID: 2746204

 PubMed Web of Science ®Google Scholar

Mount GA. A critical review of ultralow-volume aerosols of insecticide applied with vehicle-mounted generators for adult mosquito control. J Am Mosq Control Assoc 1998; 14:305 - 34; PMID: 9813829

 PubMed Web of Science ®Google Scholar

Kim JS, Je YH. Milling effect on the control efficacy of spray-dried Bacillus thuringiensis technical powder against diamondback moths. Pest Manag Sci 2012; 68:321 - 3; http://dx.doi.org/10.1002/ps.2330; PMID: 22413132

 PubMed Web of Science ®Google Scholar

Rosas-García NM. Laboratory and field tests of spray-dried and granular formulations of a Bacillus thuringiensis strain with insecticidal activity against the sugarcane borer. Pest Manag Sci 2006; 62:855 - 61; http://dx.doi.org/10.1002/ps.1245; PMID: 16786544

 PubMed Web of Science ®Google Scholar

Teschke K, Chow Y, Bartlett K, Ross A, van Netten C. Spatial and temporal distribution of airborne Bacillus thuringiensis var. kurstaki during an aerial spray program for gypsy moth eradication. Environ Health Perspect 2001; 109:47 - 54; http://dx.doi.org/10.1289/ehp.0110947; PMID: 11171524

 PubMed Web of Science ®Google Scholar

DiGiovanni F, Kevan PG. Factors affecting pollen dynamics and its importance to pollen contamination: a review. Can J Res 1991; 21:1155 - 70; http://dx.doi.org/10.1139/x91-163

 Web of Science ®Google Scholar

Brown JKM, Hovmøller MS. Aerial dispersal of pathogens on the global and continental scales and its impact on plant disease. Science 2002; 297:537 - 41; http://dx.doi.org/10.1126/science.1072678; PMID: 12142520

 PubMed Web of Science ®Google Scholar

Brandl H, Bachofen R, Bischoff M. Generation of bioaerosols during manual mail unpacking and sorting. J Appl Microbiol 2005; 99:1099 - 107; http://dx.doi.org/10.1111/j.1365-2672.2005.02700.x; PMID: 16238740

 PubMed Web of Science ®Google Scholar

Barrabeig I, Rovira A, Garcia M, Oliva JM, Vilamala A, Ferrer MD, Sabrià M, Domínguez A. Outbreak of Legionnaires’ disease associated with a supermarket mist machine. Epidemiol Infect 2010; 138:1823 - 8; http://dx.doi.org/10.1017/S0950268810000841; PMID: 20392306

 PubMed Web of Science ®Google Scholar

Baylor ER, Peters V, Baylor MB. Water-to-air transfer of virus. Science 1977; 197:763 - 4; http://dx.doi.org/10.1126/science.329413; PMID: 329413

 PubMed Web of Science ®Google Scholar

Baron PA, Willeke K. Respirable droplets from whirlpools: measurements of size distribution and estimation of disease potential. Environ Res 1986; 39:8 - 18; http://dx.doi.org/10.1016/S0013-9351(86)80003-2; PMID: 3943512

 PubMed Web of Science ®Google Scholar

Morawska L, Johnson GR, Ristovski ZD, Hargreaves M, Mengersen K, Corbett S, et al. Size distribution and sites of origin of droplets expelled from the human respiratory tract during expiratory activities. Aero Sci 2009; 40:256 - 69; http://dx.doi.org/10.1016/j.jaerosci.2008.11.002

 Web of Science ®Google Scholar

Chao CYH, Wan MP, Morawska L, Johnson GR, Ritovski ZD, Hargreaves M, et al. Characterization of expiration air jets and droplet size distributions immediately at the mouth opening. Aerosol Sci 2009; 40:122 - 33; http://dx.doi.org/10.1016/j.jaerosci.2008.10.003

 PubMed Web of Science ®Google Scholar

Xie X, Li Y, Sun H, Liu L. Exhaled droplets due to talking and coughing. J R Soc Interface 2009; 6:Suppl 6 S703 - 14; http://dx.doi.org/10.1098/rsif.2009.0388.focus; PMID: 19812073

 PubMed Web of Science ®Google Scholar

Lai KM, Bottomley C, McNerney R. Propagation of respiratory aerosols by the vuvuzela. PLoS One 2011; 6:e20086; http://dx.doi.org/10.1371/journal.pone.0020086; PMID: 21629778

 PubMedGoogle Scholar

Yang S, Lee GWM, Chen C-M, Wu C-C, Yu K-P. The size and concentration of droplets generated by coughing in human subjects. J Aerosol Med 2007; 20:484 - 94; http://dx.doi.org/10.1089/jam.2007.0610; PMID: 18158720

 PubMedGoogle Scholar

Lindsley WG, Blachere FM, Thewlis RE, Vishnu A, Davis KA, Cao G, Palmer JE, Clark KE, Fisher MA, Khakoo R, et al. Measurements of airborne influenza virus in aerosol particles from human coughs. PLoS One 2010; 5:e15100; http://dx.doi.org/10.1371/journal.pone.0015100; PMID: 21152051

 PubMed Web of Science ®Google Scholar

Duguid JP. The numbers and the sites of origin of the droplets expelled during expiratory activities. Edinb Med J 1945; 52:385 - 401; PMID: 21009905

 PubMedGoogle Scholar

Jennison MW. Atomizing of mouth and nose secretions into the air as revealed by high-speed photography. Aerobiol 1942; 17:106 - 28

 Google Scholar

Zhou Y, Benson JM, Irvin C, Irshad H, Cheng Y-S. Particle size distribution and inhalation dose of shower water under selected operating conditions. Inhal Toxicol 2007; 19:333 - 42; http://dx.doi.org/10.1080/08958370601144241; PMID: 17365038

 PubMed Web of Science ®Google Scholar

Blatny JM, Fossum H, Ho J, Tutkun M, Skogan G, Andreassen O, Fykse EM, Waagen V, Reif BA. Dispersion of Legionella-containing aerosols from a biological treatment plant, Norway. Front Biosci (Elite Ed) 2011; 3:1300 - 9; PMID: 21622136

 PubMedGoogle Scholar

Ruiz A, Bulmer GS. Particle size of airborn Cryptococcus neoformans in a tower. Appl Environ Microbiol 1981; 41:1225 - 9; PMID: 7020595

 PubMed Web of Science ®Google Scholar

Druett HA, Henderson DW, Packman LP, Peacock S. Studies on respiratory infection. I. The influence of particle size on respiratory infection with anthrax spores. J Hyg (Lond) 1953; 51:359 - 71; http://dx.doi.org/10.1017/S0022172400015795; PMID: 13096744

 PubMedGoogle Scholar

Fothergill LD. Biological warfare – Nature and consequences. Tex Med 1964; 60:8 - 14; PMID: 14115387

 PubMedGoogle Scholar

Thomas RJ, Davies C, Nunez A, Hibbs S, Flick-Smith H, Eastaugh L, Smither S, Gates A, Oyston P, Atkins T, et al. Influence of particle size on the pathology and efficacy of vaccination in a murine model of inhalational anthrax. J Med Microbiol 2010; 59:1415 - 27; http://dx.doi.org/10.1099/jmm.0.024117-0; PMID: 20798216

 PubMed Web of Science ®Google Scholar

Druett HA, Robinson JM, Henderson DW, Packman L, Peacock S. Studies on respiratory infection. II. The influence of aerosol particle size on infection of the guinea-pig with Pasteurella pestis.. J Hyg (Lond) 1956; 54:37 - 48; http://dx.doi.org/10.1017/S0022172400044284; PMID: 13319689

 PubMedGoogle Scholar

Thomas RJ, Webber D, Collinge A, Stagg AJ, Bailey SC, Nunez A, Gates A, Jayasekera PN, Taylor RR, Eley S, et al. Different pathologies but equal levels of responsiveness to the recombinant F1 and V antigen vaccine and ciprofloxacin in a murine model of plague caused by small- and large-particle aerosols. Infect Immun 2009; 77:1315 - 23; http://dx.doi.org/10.1128/IAI.01473-08; PMID: 19188359

 PubMed Web of Science ®Google Scholar

Day WC, Berendt RF. Experimental tularemia in Macaca mulatta: relationship of aerosol particle size to the infectivity of airborne Pasteurella tularensis. Infect Immun 1972; 5:77 - 82; PMID: 4632469

 PubMed Web of Science ®Google Scholar

Druett HA, Henderson DW, Peacock S. Studies on respiratory infection. III. Experiments with Brucella suis.. J Hyg (Lond) 1956; 54:49 - 57; http://dx.doi.org/10.1017/S0022172400044296; PMID: 13319690

 PubMedGoogle Scholar

Thomas RJ, Davies C, Nunez A, Hibbs S, Eastaugh L, Harding S, et al. Particle-size dependent effects in the Balb/c murine model of inhalational melioidosis. Front Cell Infect Microbiol 2012; 2:1 - 12; http://dx.doi.org/10.3389/fcimb.2012.00101; PMID: 22919593

 PubMed Web of Science ®Google Scholar

Roy CJ, Reed DS, Wilhelmsen CL, Hartings J, Norris S, Steele KE. Pathogenesis of aerosolized Eastern Equine Encephalitis virus infection in guinea pigs. Virol J 2009; 6:170 - 83; http://dx.doi.org/10.1186/1743-422X-6-170; PMID: 19852817

 PubMed Web of Science ®Google Scholar

Roy CJ, Hale M, Hartings JM, Pitt L, Duniho S. Impact of inhalation exposure modality and particle size on the respiratory deposition of ricin in BALB/c mice. Inhal Toxicol 2003; 15:619 - 38; PMID: 12692733

 PubMed Web of Science ®Google Scholar

Conrad FG, LeCocq FR, Krain R. A recent epidemic of plague in Vietnam. Arch Intern Med 1968; 122:193 - 8; http://dx.doi.org/10.1001/archinte.1968.00300080001001; PMID: 5691443

 PubMed Web of Science ®Google Scholar

Navacharoen N, Sirisanthana T, Navacharoen W, Ruckphaopunt K. Oropharyngeal anthrax. J Laryngol Otol 1985; 99:1293 - 5; http://dx.doi.org/10.1017/S002221510009856X; PMID: 3934300

 PubMed Web of Science ®Google Scholar

Holty JE, Kim RY, Bravata DM. Anthrax: a systematic review of atypical presentations. Ann Emerg Med 2006; 48:200 - 11; http://dx.doi.org/10.1016/j.annemergmed.2005.11.035; PMID: 16857469

 PubMed Web of Science ®Google Scholar

Ozdemir H, Demirdag K, Ozturk T, Kocakoc E. Anthrax of the gastrointestinal tract and oropharynx: CT findings. Emerg Radiol 2010; 17:161 - 4; http://dx.doi.org/10.1007/s10140-009-0821-y; PMID: 19499256

 PubMedGoogle Scholar

Chitadze N, Kuchuloria T, Clark DV, Tsertsvadze E, Chokheli M, Tsertsvadze N, Trapaidze N, Lane A, Bakanidze L, Tsanava S, et al. Water-borne outbreak of oropharyngeal and glandular tularemia in Georgia: investigation and follow-up. Infection 2009; 37:514 - 21; http://dx.doi.org/10.1007/s15010-009-8193-5; PMID: 19826763

 PubMed Web of Science ®Google Scholar

Pongrithsukda V, Simakachorn N, Pimda J. Childhood melioidosis in northeastern Thailand. Southeast Asian J Trop Med Public Health 1988; 19:309 - 16; PMID: 3227408

 PubMedGoogle Scholar

How H-S, Ng K-H, Yeo H-B, Tee H-P, Shah A. Pediatric melioidosis in Pahang, Malaysia. J Microbiol Immunol Infect 2005; 38:314 - 9; PMID: 16211138

 PubMedGoogle Scholar