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brief communications

Wireless capsule endoscopy

The discomfort of internal gastrointestinal examination may soon be a thing of the past.

e have developed a new type of was initially associated with CMOS image
endoscopy, which for the first time sensors and has allowed CMOS chips to
allows painless endoscopic imaging achieve an image quality comparable to
of the whole of the small bowel. This proce- those of charge-coupled device image sen-
dure involves a wireless capsule endoscope sors5, but using much less power.
and we describe here its successful testing in Advances in ASIC design allowed the
humans. integration of a very small video transmitter
The invention of fibre-optic endoscopy 1 of sufficient power output, efficiency and
made visualization of the whole stomach, bandwidth into the capsule. Synchronous
upper small bowel and colon possible. switching of the LEDs, the CMOS sensor
The procedures used to examine these and the ASIC transmitter minimize power
(gastroscopy, small-bowel endoscopy and consumption. By careful design of the
colonoscopy, respectively) cause discomfort optics, we were able to eliminate internal
because they require flexible, relatively wide reflections which are a common problem
cables to be pushed into the bowel — these when the illumination and imager are
cables carry light by fibre-optic bundles, incorporated under the same dome.
power and video signals. Small-bowel With ethical committee approval, the
endoscopy in particular is constrained by first studies were performed on ten normal
problems of discomfort and limitations of human volunteers. The capsule was easily
how far enteroscopes can be advanced into swallowed and caused no discomfort. Pro-
the small bowel. There is a clinical need for pelled by peristalsis (see Supplementary
improved methods of examining the small Information), it successfully transmitted
bowel and colon, especially in patients with video images (Fig. 1) from the stomach,
recurrent gastrointestinal bleeding. small bowel and caecum (mean gastric
The invention of the transistor made it transit time was 80 min, range 17–280 min;
possible to design swallowable electronic mean small-bowel transit time was 90 min,
radio-telemetry capsules for the study of range 45–140 min; mouth-to-evacuation
gastrointestinal physiological parameters. time was 24 h, range 10–48 h). High-quality
These capsules were first reported in the images were received throughout the video
1950s and were used to measure tempera- Figure 1 Samples of images of the small bowel acquired by the transmissions, lasting up to 6 hours.
ture2, pressure2,3 and pH3,4. We have devel- capsule endoscope during human in vivo studies. a,b, Gastric Gavriel Iddan*, Gavriel Meron*,
oped and tested a new type of video- folds in the body of the stomach; c,d, villous pattern of the small Arkady Glukhovsky*, Paul Swain†
telemetry capsule endoscope that is small bowel enhanced by the presence of a little water and an air bub- *Given Imaging Ltd, Building 7, New Industrial
enough to be swallowed (11230 mm) and ble in the lumen; e,f, airless images of normal jejunum, viewed Park, Yoqneam 20692, Israel
has no external wires, fibre-optic bundles or with the lumen closed in front of the optical dome of the capsule; †Royal London Hospital, Whitechapel,
cables. By using a lens of short focal length, g,h, views of the terminal ileum. London E1 1BB, UK
images are obtained as the optical window 1. Hopkins, H. H. & Kapany, N. S. Nature 173, 39–41 (1954).
of the capsule sweeps past the gut wall, emitting diode (LED) illumination. Novel 2. Zworkin, V. K. Nature 179, 898 (1957).
3. Mackay, R. S. & Jacobson, B. Nature 179, 1239–1240 (1957).
without requiring air inflation of the gut optical design, better energy management 4. Noller, H. G. Deutsche Med. Wsch. 85, 1707 (1960).
lumen. The capsule endoscope is propelled and overall system design were also impor- 5. Fossum, E. R. Proc. SPIE 1900, 2–14 (1993).
by peristalsis through the gastrointestinal tant in creating the capsule. Supplementary information is available on Nature’s World-Wide
tract and does not require a pushing force The addition of a buffer amplifier on Web site ( or as paper copy from the
to propel it through the bowel. each pixel reduced the output noise that London editorial office of Nature.
The video images are transmitted using
UHF-band radio-telemetry to aerials taped
to the body which allow image capture, and
the signal strength is used to calculate the Cell biology for microwave equipment may need to be
position of the capsule in the body (see reconsidered.
Supplementary Information); the images Non-thermal heat-shock Heat-shock proteins (HSPs) are in-
are stored on a portable recorder. This sys-
tem allows more than 5 hours of continu-
response to microwaves duced in most organisms by adverse
conditions (such as heat or toxicants) that
ous recording. The patient need not be cause damage to cellular proteins, acting as

xposure limits set for microwave radia-
confined to a hospital environment during tion assume that any biological effects molecular chaperones to rescue damaged
the examination and is free to continue his result from tissue heating1: non- proteins2. To detect HSP responses, we have
or her daily routine. thermal effects have been reported but pioneered the use of transgenic C. elegans
The design of the video capsule was remain controversial. We show here that strains carrying reporter-gene constructs
made possible by progress in the perfor- prolonged exposure to low-intensity micro- (encoding b-galactosidase in strain PC72
mance of three technologies: complemen- wave fields can induce heat-shock responses or green fluorescent protein (GFP) in
tary metal oxide silicon (CMOS) image in the soil nematode Caenorhabditis elegans. strain PC161) regulated by homologous
sensors, application-specific integrated This effect appears to be non-thermal, hsp16 heat-shock promoters3. When
circuit (ASIC) devices, and white-light- suggesting that current exposure limits set exposed to diverse stressors at 20–25 °C,
NATURE | VOL 405 | 25 MAY 2000 | © 2000 Macmillan Magazines Ltd 417
brief communications
these worms express readily detectable
reporter products, whereas controls show
minimal expression4.
Worms were exposed overnight to
continuous-wave microwave radiation at
750 MHz and 0.5 W in the transverse
electromagnetic (TEM) cell described previ-
ously5. Figure 1 shows temperature profiles
for reporter expression in both irradiated
and control (foil-shielded) worm cultures.
In microwave-exposed cultures, expression
is comparable to that of controls at 24.0 °C
(P¤0.05), but then rises steeply through
24.5 and 25.0 to 25.5 °C (P*0.001). In non- Figure 2 PC72 and PC161 (similar to PC72, but carrying an additional GFP reporter under hsp16 control) worms were either exposed for
exposed controls, heat-induced reporter 18 h at 25 °C to microwaves (750 MHz, 0.5 W) or kept as 25 °C controls, then reporter expression was localized in situ by staining with
expression follows the pattern for HSP16 X-gal (PC72) or viewing under ultraviolet light on a fluorescence microscope (PC161). a, Exposed PC72 worm, showing nuclear staining
(ref. 6), increasing sharply only above 27 °C for b-galactosidase throughout the gut; b, typical PC72 worm under control conditions: no observable staining; c, exposed PC161 worm,
(to a maximum at 30 °C). There is thus a showing GFP fluorescence throughout ovoid embryos; d, typical control PC161 worm, showing yellowish gut autofluorescence (also in c)
disparity of 3 °C between exposed and con- but no GFP fluorescence in embryos. Note that many worms in a and c show little reporter expression. Scale bars, 50 mm.
trol induction profiles.
A thermal explanation for this disparity 1 °C warmer than the saline) would have ‡Medical Countermeasures, CBD Porton Down,
would require that the exposed worms been easily detectable in this experiment. Salisbury, Wiltshire SP4 0JQ, UK
become 3 °C warmer than controls — or Second, in situ detection of reporter §Department of Biochemistry and Molecular
more if only a minority of worms/tissues is products shows that lacZ is expressed Biology, University of British Columbia,
affected. We reject this thermal explanation throughout the gut in PC72 worms (Fig. 2146 Health Sciences Mall, Vancouver V6T 1Z3,
on several grounds, not least the diffusion 2a,b), and also that GFP is expressed in Canada
of heat over 18 hours. many embryos within adult PC161 worms 1. ANSI/IEEE C95.1-1992 American National Standard-Safety
First, no temperature difference is (Fig. 2c,d). These expression sites together Levels with Respect to Exposure to Radio Frequency
Electromagnetic Fields, 3 kHz to 300 GHz (IEEE, New York,
detectable between control and exposed constitute about half of worm tissues. 1992).
cultures after irradiation5. This is also true Third, the field at the centre of our TEM 2. Parsell, D. & Lindquist, S. Annu. Rev. Genet. 27, 437–496
for concentrated (50% w/v) worm suspen- cell is 45 V m11, and the measured permit- (1993).
sions incubated for 18 h at 25 °C alongside a tivity of concentrated worm suspensions (at 3. Dennis, J., Mutawakil, M., Lowe, K. & de Pomerai, D.
Aquatic Toxicol. 40, 37–50 (1997).
saline solution alone, under exposed versus 615 MHz) gives a conductivity of about 4. Candido, E. & Jones, D. Trends Biotechnol. 40, 125–129
control conditions (24.6850.116 °C s.d., 0.48 V11 m11. The calculated specific (1996).
P40.28, for all 16 measurements under absorption rate (SAR) is only 0.001 W kg11, 5. Daniells, C. et al. Mutat. Res. 399, 55–64 (1998).
four conditions using a sensitive copper– which is much less than published values7 6. Snutch, T. & Baillie, D. Can. J. Biochem. Cell Biol. 61, 480–487
constantan microthermocouple). Tempera- for mobile phones (0.02–1.0 W kg11). 7. Gandhi, O., Lazzi, G. & Furse, C. IEEE Trans. Microwave Theor.
ture differences of 0.5 °C (that is, worms Mobile-phone manufacturers claim that Tech. 44, 1884–1897 (1996).
SARs in this range are insufficient to cause 8. Nishizawa, J. et al. Circulation 99, 934–941 (1999).
9. Williams, P. & Dusenbery, D. Environ. Toxicol. Chem. 9,
measurable tissue heating within the 1285–1290 (1990).
human head, and we are not disputing this.
Per cent β-galactosidase activity
relative to 15°C controls (100%)

10. Jewitt, N., Anthony, P., Lowe, K. & de Pomerai, D.

We suggest instead that the induction of Enzyme Microb. Technol. 25, 349–356 (1999).
2500 heat-shock proteins described here could
2000 involve non-thermal mechanisms. These
could include microwave disruption of the
weak bonds that maintain the active folded Structural biology
forms of proteins; enhanced production of
500 reactive oxygen species (known to be induc- Proton-powered turbine
0 ers of HSPs8); or interference with cell- of a plant motor
20 22 24 26 28 30
signalling pathways that affect HSP induc-
Temperature (°C) tion (by heat-shock-factor activation). All

TP synthases are enzymes that can
these mechanisms are testable using the work in two directions to catalyse
Figure 1 Saline9 suspensions of young adult PC72 worms grown functional genomic tools that are available either the synthesis or breakdown of
synchronously at 15 °C (ref. 10) were split between three condi- in C. elegans. Because of the universality of ATP, and they constitute the smallest rotary
tions for a total of 18 h: (1) exposed to microwaves (in TEM cell at the heat-shock response2, a similar non- motors in biology. The flow of protons pro-
750 MHz and 0.5 W; ref. 5) within a Leec LT3 incubator; (2) tem- thermal induction might also occur in pels the rotation1 of a membrane-spanning
perature controls shielded with aluminium foil in the same incuba- human tissues exposed to microwaves, a complex of identical protein subunits, the
tor; (3) baseline controls at 15 °C. Incubator temperatures of possibility that needs investigation. number of which determines the efficiency
24.0, 24.5, 25.0 and 25.5 °C were tested using 12 replicates for David de Pomerai*, Clare Daniells*, of energy conversion. This proton-powered
each condition; controls only (6 replicates of condition 2) were Helen David*, Joanna Allan*, Ian Duce*, turbine is predicted to consist of 12 sub-
also run at 22, 26, 27 and 28 °C. All worm samples were Mohammed Mutwakil*, David Thomas†, units2–4, based on data for Escherichia coli 5.
assayed fluorometrically4,5 for b-galactosidase activity. Enzyme Phillip Sewell†, John Tattersall‡, The yeast mitochondrial enzyme, however,
activities were normalized against 15 °C baseline controls (100%) Don Jones§, Peter Candido§ has only 10 subunits6. We have imaged the
within each batch to allow comparison of reporter induction at dif- *Molecular Toxicology Division, School of Biological ATP synthase from leaf chloroplasts by
ferent temperatures. Squares, blue solid line; reporter activities Sciences and †School of Electrical and Electronic using atomic force microscopy and, surpris-
(5s.e.m.) in microwave-exposed cultures. Circles, red dashed Engineering, University of Nottingham, ingly, find that its turbine has 14 subunits,
line; control reporter activities (5s.e.m.) at each temperature. Nottingham NG7 2RD, UK arranged in a cylindrical ring.
418 © 2000 Macmillan Magazines Ltd NATURE | VOL 405 | 25 MAY 2000 |


Smoking gun: an image at 1-km resolution from the Terra satellite in August 2002 shows forest fires (red polygons) with white smoke plumes.

(inside intact forests) and the combined resulting subset of 17 intact areas totals 25% of Danilo Mollicone, Hugh D. Eva, Frédéric Achard
impact of humans and climate change (outside the total intact area. Institute for Environment and Sustainability,
intact forests). During seasons of climatic anomalies (2002 Joint Research Centre of the European
We combined an atlas of Russia’s intact forest and 2003), fire-event densities in the most- Commission, TP 440, 21020 Ispra, Italy
landscapes4 with a land-cover map9 drawn up intact forests were twice the normal density e-mail:
for 1999–2000 to delineate intact and non- (Table 1). But, more surprisingly, density ratios
intact forests (see supplementary information). of forest-fire events outside and inside most- 1. Thompson, D. W. J. & Wallace, J. M. Science 293, 85–89
The total area covered by the atlas4 is 1,118 mil- intact forests are at least 7.9 and as high as 14.4 2. Dale, V. H. et al. BioScience 51, 723–734 (2001).
lion ha, including 205 million ha of intact during the four-year study period. These 3. Schiermeier, Q. Nature 435, 732–733 (2005).
forests. Active fires detected by the Terra satel- results show that human impact had a con- 4. Aksenov, D. et al. Atlas of Russia’s Intact Forest Landscapes
(Global Forest Watch Russia, Moscow, 2002); available at
lite10 were used to derive our fire database for stant ‘multiplication’ effect on the fire events,
the period 2002 to 2005 (Fig. 1). These active and that a maximum of 13% of fire ignition in 5. Sukhinin, A. et al. Remote Sens. Environ. 93, 546–564
fires were separated into those that fell inside or the non-intact forests is explained by natural (2004).
6. Goldammer, J. G., Sukhinin, A. & Csiszar, I. Int. Forest Fire
outside intact forests. Active fires that were spa- disturbance, with the rest being directly News [online] 29, <
tially and temporally concurrent were then induced by humans. iffn_online.htm> (2003).
grouped together to identify individual fire Forest regions of boreal Eurasia, and partic- 7. International Research Institute for Climate Prediction IRI
events. Finally, fire events were attributed to the ularly Siberia, have seen a reduction in popu- Map Room (2005); available at
zone in which they started. lation following the creation of the Russian 8. Mouillot, F. & Field, C. B. Global Change Biol. 11, 398–420
We found that 85% of the 23,818 active fires Federation. But the human impact on the (2005).
in intact forests in 2002 were located within a forests through fires is higher owing to lack 9. Bartalev, S., Belward, A. S., Erchov, D. & Isaev, A. S.
Int. J. Remote Sens. 24, 1977–1982 (2003).
10-km-wide buffer zone inside the perimeter of control, ineffectual fire-management poli- 10. Justice, C. O. et al. Remote Sens. Environ. 83, 244–262
of the intact forests, indicating that the borders cies and new socioeconomic conditions in (2002).
of these areas could have been affected by fires the region7,11,12. It is also a consequence of the 11. Achard, F., Stibig, H.-J., Laestadius, L., Yaroshenko, A. &
Aksenov, D. Identification of “Hot Spot Areas” of Forest Cover
starting on the outside. We therefore selected oil boom in Siberia13. The fact that recent Changes in Boreal Eurasia (European Commission,
a new subset of ‘most-intact’ forests to repre- increases in ‘wild’ fires in Eurasian boreal Luxembourg, 2005); available at
sent more strictly the concept of intact forest forests are primarily a result of human behav-
12. Karpachevskiy, M. Forest Fires in the Russian Taiga: Natural
— these comprised the largest individual iour on the ground has implications for the Disaster or Poor Management? (Taiga Rescue Network
intact areas and the individual intact areas global carbon budget3 and should be taken Factsheet, Jokkmokk, Sweden, 2004).
with the smallest perimeter-to-area ratio. The into account in future mitigation policies. 13. Dienes, L. Eurasian Geogr. Econ. 45, 319–345 (2004).

Supplementary information accompanies this

Table 1 | Number and density of fire events in forests of the Russian Federation communication on Nature’s website.
Received 11 November 2005; accepted 2 March 2006.
2002 2003 2004 2005 Competing financial interests: declared none.
Forest type* Number of fire events doi:10.1038/440436a

All forests in study region 5,929 6,461 4,627 3,796

Non-intact forests 5,420 5,967 4,417 3,477 RETRACTION
Intact forests 509 494 210 319 Cell biology: Non-thermal heat-shock response to
Most-intact forests 109 96 49 119† microwaves
Density of fire events (103 per km2) D. de Pomerai, C. Daniells, H. David, J. Allan, I. Duce,
M. Mutwakil, D. Thomas, P. Sewell, J. Tattersall,
All forests in study region 1.09 1.19 0.85 0.70 D. Jones, P. Candido
Non-intact forests 1.60 1.77 1.31 1.03 Nature 405, 417–418 (2000)
Intact forests 0.248 0.241 0.102 0.128
Our claim that weak microwave fields induce a heat-
Most-intact forests 0.202 0.178 0.091 0.115
shock response in Caenorhabditis elegans by a non-
Density ratio of fire events thermal mechanism is invalidated by new findings
Ratio non-intact/intact 6.5 7.3 12.8 8.1 showing that there is a small heating effect under
Ratio non-intact/most-intact 7.9 9.9 14.4 9.0 these conditions (A. Dawe et al. Bioelectromagnetics
*The area of all forests in the study zone is 543 million ha, of which 338 million ha is non-intact forest and 205 million ha is intact 27, 88–97; 2006). This temperature rise (about
forest. The total area of ‘most-intact’ forest (a subset of intact forest; see text) is 54 million ha. The fire season is considered to 0.2 C) causes heat-shock induction comparable to
last until 21 September. that noted in our communication.
†From these 119 fire events in most-intact forests, 57 are located in two large intact forest areas in the basin of the Taz River,
where oil was being prospected (as revealed by fine spatial resolution imagery) in 2005. Intact areas were delineated using
C.D., J.A., M.M., D.J. and P.C. were not available to
satellite imagery from the year 2000; some areas may no longer have been intact in 2005, in particular as a result of the oil boom sign this retraction.
in Siberia13. Fire-event densities are estimated without these 57 fires. doi:10.1038/440437a

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