- Email: [email protected]
Pacemaker failure caused by traveller’s diarrhoea
Travel Medicine and Infectious Disease (2011) 9, 149e152
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/tmid
CASE REPORT
Pacemaker failure caused by traveller’s diarrhoea ¨der a, A. Lu ¨ffl c,d,e, U. Gieseler e,f, T. Ku ¨ckhoff b, V. Scho ¨pper a,e,* S. Schro a
Institute for Occupational and Social Medicine, Aachen Technical University, Aachen, Germany Institute of Physiology, Aachen Technical University, Aachen, Germany c Dept. of Sportorthopedics, Klinikum Bamberg, Germany d Dept. of Trauma Surgery, Friedrich Alexander University Erlangen-Nuremberg, Germany e Medical Commission of the Union Internationale des Associations d’Alpinisme (UIAA MedCom), Bern, Switzerland f Dept. of Internal Medicine, Diakonissenkrankenhaus Speyer, Germany b
Received 22 September 2010; received in revised form 24 March 2011; accepted 28 March 2011 Available online 29 April 2011
KEYWORDS Pacemaker; Electrolyte shift; Traveller’s diarrhoea
Summary A female patient with a VVI pacemaker suffered from traveller’s diarrhoea which she treated with tea and water. After the onset of arrhythmia a pacemaker failure and a sodium concentration of 117 mmol/l was found. After substitution of sodium chloride, there was a remission of symptoms, the pacemaker ECG was normal. ª 2011 Elsevier Ltd. All rights reserved.
Medical situation and later findings During a cruise in the eastern Mediterranean Sea, a 73-year old female fell ill with a massive gastroenterities, diarrhoea, and vomiting. Two years prior to the cruise the patient had been implanted with a VVI pacemaker (St. Jude Medical) as a result of recurring atrial fibrillation and associated bradyarrhythmia. The Norovirus was eventually identified as the causal agent to the patient’s symptoms during the cruise. During her Norovirus bout, the patient treated herself with plenty of water and tea; no electrolyte substitution was performed. Later she noticed
* Corresponding author. Institute for Occupational and Social Medicine, RWTH Aachen University, Pauwelstr. 30, D-52074 Aachen, Germany. Tel.: þ49 1520 1820256. E-mail address: [email protected] (T. Ku ¨pper).
bradyarrhythmia with frequencies below 60/min that was much like she had experienced prior to her pacemaker implantation. At the time of her hospitalisation, the diarrhoea had nearly ceased. The ECG showed a sensing defect and an exit block (Fig. 1), and the only other pathological finding was the extraordinary low plasma sodium level of 117 mmol/l (potassium was 3.8 mmol/l). The patient was treated with intravenous infusions of potassium-supplemented saline for four days. At day 4 the sodium level was within the low normal range and the ECG was as usual for this patient (Fig. 2). There was no other treatment except the electrolyte substitution.
Discussion Traveller’s diarrhoea is the disease of highest incidence while travelling (20e60%).1 The risk may vary among
1477-8939/$ - see front matter ª 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tmaid.2011.03.004
150
S. Schro ¨der et al.
Figure 1
ECG at the day of admission.
tourists and the region visited. Typically it is higher in trekkers in Asia or in South America, compared to travellers in central Europe or Northern America. The individual risk of getting ill with traveller’s diarrhoea is high (20e90%) within an 2-week-stay in most developing countries.2 In the low risk countries of Central and Northern Europe and Northern America the rate of the disease is lower than 8% within a 2-week-stay.2 Infectious diseases on board of cruise ships are special problem as the pathogens have a confined space to spread and people are in close contact to each other. Therefore, the passengers are at risk for any disease of high contagiosity. The phenomenon described in this case is comparable to exercise-associated hyponatremia (EAH). EAH is common in several sports disciplines such as marathons and triathlons that demand physical endurance. There is clear evidence that the primary cause of EAH is fluid consumption in excess of that required to replace insensible losses.3 Although there are some cases of EAH in cold and moderate climates,4 the condition is typically found in hot and humid conditions such as with hikers on strenuous trails in the Grand Canyon.5,6 Here the main symptoms are neurological such as seizures.3,7 The most serious symptoms and signs of EAH are reflective of pulmonary and cerebral manifestations of fluid overload and include noncardiogenic pulmonary edema and cerebral edema with encephalopathy. Early symptoms include nausea, vomiting, and headache, and later signs include confusion, disorientation, seizures, coma, and the crepitations of pulmonary edema. In the wilderness setting, plausible differential diagnosis includes heat stroke, hypothermia, hypernatremia, and high-altitude cerebral edema.3,8 The combination of hyponatremia and massive exertion seems to be another situation with specific risks: Bruso et al. reported
that more than 1% of the participants of the Western State Endurance Run 2009 had to be hospitalized with the combination of hyponatremia and rhabdomyolysis.9 Obviously the risk was even more pronounced when the patients had taken nonsteroidal anti-inflammatory drugs (NSAIDs) before. In contrast to a typical EAH in which sodium as well as potassium deficiency is present (review in Francesconi et al.10) our patient suffered exclusively from hyponatremia. Our patient suffered from comparable physiological alterations as EAH patients. However, in this case the fluid loss was caused by diarrhoea and vomiting instead of an athlete sweating. EAH is a dilutional hyponatremia favoured by excessive drinking of hypotonic fluids while loosing large amounts of body fluid.3 The athlete displays an increase in the total body water content11 without an parallel increase in the electrolyte content. The same effect was described by Severi et al. (2001) in patients undergoing haemodialysis.12 Haemodialysis may affect the cardiovascular function due to massive loss of body water; as a consequence, it modifies the characteristic composition of extracellular and intracellular fluids. Changes in potassium and calcium were prominent and affected the rhythm of the sine node pacemaker. Our patient suffered from comparable physiological alterations as EAH patients, although the fluid loss was not caused by sweating as in athletes but by diarrhoea and vomiting. Electrolyte imbalances were induced by substitution of fluids without electrolytes. Patients with cardiac pacemakers display a considerable variability in the threshold required for myocardial stimulation. This variability may be related to local tissue reactions at the electrodeemyocardium interface, to the choice of specific electrodes or to individual physiological variations during the day. There are many conditions that
Pacemaker failure
151
Figure 2
ECG after sodium substitution (day 4).
may increase the pacing threshold, especially metabolic and electrolyte abnormalities.13,14 A theoretical problem may be artefacts of a superficially (skin) performed ECG, but this should be excluded as the phenomenon was constant over a certain time. Some medications may cause failure of pacemakers, i.e. a combination of several antiarrhythmic substances. As our patient did not take any medications, this mechanism can be excluded. Another reason for the failure could be a microdislocation. Clinically this would become manifest if the pacemaker signal in the ECG appeared weaker. Frequently, a new sensor may be required in those cases. However, microdislocation is highly unlikely in our patient because of the ECG normalization after reconstitution of normal plasma sodium concentrations. We propose the importance of sodium currents as the main causing effect which caused a failure of the stimulation and sensing function of a pacemaker. As plausible explanation, we propose the importance of sodium currents through fast sodium channels for an adequate spreading of electrical signal within the myocardium. The amplitude of currents through these channels is nearly linearly related to the extracellular sodium concentrations in electrophysiological experiments.15e17 In turn, the conductance of depolarizing signals to neighbouring cells may become insufficient in the presence of sodium currents about 30% lower than normal. In the same line, sensing of the pacemaker may fail if the electrical field caused by sodium currents decreases below a threshold in the vicinity of the electrode. Certainly, particular local conditions may have contributed to the temporal failure of the pacemaker. For
example, partly scarred tissue in the region where the electrode was anchored may have precluded adequate conduction of electrical signals in hyponatremia, while the strength of the electrical field is sufficient for conduction when normal sodium currents are prevalent in the region. Another contribution would be if the intensity of the pacemaker’s pulse was only slightly above the myocardium’s threshold (normally it should be twice as high). Unfortunately we do not have any information about the intensity when the problem occurred. Our proposed pathogenesis could be verified clinically in the patient by artificial induction of hyponatremia and the application of impulses of variable strength through the pacemaker electrode. Such a procedure may be ethically disputable because the patient was not vitally threatened by her arrhythmia and the hyponatremia was a singular event that seems avoidable in future. On the other hand, when a vital thread existed, a relocation of the electrode may be a safer option. Even more simply, stronger electrical signals and lowering the threshold of sensing may be tried if similar problems may arise again in the patient. At any rate, the patient was reluctant to further investigations, leaving our explanation of the pacemaker failure hypothetical. In summary, the patient is potentially at risk for bradyarrhythmia during episodes of severe disorders of the electrolyte homeostasis. If this happens again, a thorough investigation of the various pacemaker functions should be performed and a relocation of the electrode considered. Only if pacemaker failure could definitively not be explained on the basis of diminished sodium currents in the presence of low sodium concentrations, along with borderline electrical
152 quality of the tissue adjacent to the electrode, further analysis including that of potential mutations in the patient’s cardiac sodium channel may be deliberated.
Conclusion To our knowledge this is the first case with a complete pacemaker failure which may be caused by an electrolyte shift. While travelling, an adequate supply of fluid and electrolytes may be of particular importance for persons with pacemakers. Drug history and electrolyte concentrations should be known before departure and the patient should be given specific advice on how to avoid dehydration and manage traveller’s diarrhoea.
Conflict of interest We declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere.
Acknowledgements The authors would like to thank Dr. Travis Heggie, University of North Dakota, Grand Forks ND (USA), for his careful proofreading.
References 1. Steffen R, Amitirigala I, Mutsch M. Health risks among travelers e need for regular updates. J Travel Med 2008;15(3):145e6. 2. Steffen R. Epidemiology of traveler’s diarrhea. Clin Infect Dis 2005;41(Suppl. 8):S536e40. 3. Rogers IR, Hew-Butler T. Exercise-associated hyponatremia: overzealous fluid consumption. Wilderness Environ Med 2009; 20(2):139e43.
S. Schro ¨der et al. 4. Zafren K. Hyponatremia in a cold environment. Wilderness Environ Med 1998;9(1):54e5. 5. Backer HD, Shopes E, Collins SL. Hyponatremia in recreational hikers in Grand Canyon National Park. J Wilderness Med 1993; 4(4):391e406. 6. Backer HD, Shopes E, Collins SL, Barkan H. Exertional heat illness and hyponatremia in hikers. Am J Emerg Med 1999; 17(6):532e9. 7. Basnyat B, Sleggs J, Spinger M. Seizures and delirium in a trekker: the consequences of excessive water drinking? Wilderness Environ Med 2000;11(1):69e70. 8. Ayus JC, Varon J, Arieff AI. Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners. Ann Intern Med 2000;132(9):711e4. 9. Bruso JR, Hoffman MD, Rogers IR, Lee L, Towle G, HewButler T. Rhabdomyolysis and hyponatremia: a cluster of five cases at the 161-km 2009 Western States Endurance Run. Wilderness Environ Med 2010;21(4):303e8. 10. Francesconi RP, Willis JS, Gaffin SL, Hubbard RW. On the trail of potassium in heat injury. Wilderness Environ Med 1997;8(2): 105e10. 11. Rothwell SP, Rosengren DJ. Severe exercise-associated hyponatremia on the Kokoda Trail, Papua New Guinea. Wilderness Environ Med 2008;19(1):42e4. 12. Severi S, Cavalcanti S, Mancini E, Santoro A. Heart rate response to hemodialysis-induced changes in potassium and calcium levels. J Nephrol 2001;14(6):488e96. 13. Hughes Jr JC, Tyers GF, Torman HA. Effects of acidebase imbalance on myocardial pacing thresholds. J Thorac Cardiovasc Surg 1975;69(5):743e6. 14. Dohrmann ML, Goldschlager NF. Myocardial stimulation threshold in patients with cardiac pacemakers: effect of physiologic variables, pharmacologic agents, and lead electrodes. Cardiol Clin 1985;3(4):527e37. 15. Hodgkin AL, Huxley AF. A quantitative description of membrane current and its application to induction and excitation in nerve. J Physiol 1952;117:500e44. 16. Sheets MF, Scanley BE, Hanck DA, Makielski JC, Fozzard HA. Open sodium channel properties of single canine cardiac Purkinje cells. Biophys J 1987;52(1):13e22. 17. Hille B. Ion channels of excitable membranes. Sunderland, MA: Sinauer Associates Inc; 2001.
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/tmid
CASE REPORT
Pacemaker failure caused by traveller’s diarrhoea ¨der a, A. Lu ¨ffl c,d,e, U. Gieseler e,f, T. Ku ¨ckhoff b, V. Scho ¨pper a,e,* S. Schro a
Institute for Occupational and Social Medicine, Aachen Technical University, Aachen, Germany Institute of Physiology, Aachen Technical University, Aachen, Germany c Dept. of Sportorthopedics, Klinikum Bamberg, Germany d Dept. of Trauma Surgery, Friedrich Alexander University Erlangen-Nuremberg, Germany e Medical Commission of the Union Internationale des Associations d’Alpinisme (UIAA MedCom), Bern, Switzerland f Dept. of Internal Medicine, Diakonissenkrankenhaus Speyer, Germany b
Received 22 September 2010; received in revised form 24 March 2011; accepted 28 March 2011 Available online 29 April 2011
KEYWORDS Pacemaker; Electrolyte shift; Traveller’s diarrhoea
Summary A female patient with a VVI pacemaker suffered from traveller’s diarrhoea which she treated with tea and water. After the onset of arrhythmia a pacemaker failure and a sodium concentration of 117 mmol/l was found. After substitution of sodium chloride, there was a remission of symptoms, the pacemaker ECG was normal. ª 2011 Elsevier Ltd. All rights reserved.
Medical situation and later findings During a cruise in the eastern Mediterranean Sea, a 73-year old female fell ill with a massive gastroenterities, diarrhoea, and vomiting. Two years prior to the cruise the patient had been implanted with a VVI pacemaker (St. Jude Medical) as a result of recurring atrial fibrillation and associated bradyarrhythmia. The Norovirus was eventually identified as the causal agent to the patient’s symptoms during the cruise. During her Norovirus bout, the patient treated herself with plenty of water and tea; no electrolyte substitution was performed. Later she noticed
* Corresponding author. Institute for Occupational and Social Medicine, RWTH Aachen University, Pauwelstr. 30, D-52074 Aachen, Germany. Tel.: þ49 1520 1820256. E-mail address: [email protected] (T. Ku ¨pper).
bradyarrhythmia with frequencies below 60/min that was much like she had experienced prior to her pacemaker implantation. At the time of her hospitalisation, the diarrhoea had nearly ceased. The ECG showed a sensing defect and an exit block (Fig. 1), and the only other pathological finding was the extraordinary low plasma sodium level of 117 mmol/l (potassium was 3.8 mmol/l). The patient was treated with intravenous infusions of potassium-supplemented saline for four days. At day 4 the sodium level was within the low normal range and the ECG was as usual for this patient (Fig. 2). There was no other treatment except the electrolyte substitution.
Discussion Traveller’s diarrhoea is the disease of highest incidence while travelling (20e60%).1 The risk may vary among
1477-8939/$ - see front matter ª 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tmaid.2011.03.004
150
S. Schro ¨der et al.
Figure 1
ECG at the day of admission.
tourists and the region visited. Typically it is higher in trekkers in Asia or in South America, compared to travellers in central Europe or Northern America. The individual risk of getting ill with traveller’s diarrhoea is high (20e90%) within an 2-week-stay in most developing countries.2 In the low risk countries of Central and Northern Europe and Northern America the rate of the disease is lower than 8% within a 2-week-stay.2 Infectious diseases on board of cruise ships are special problem as the pathogens have a confined space to spread and people are in close contact to each other. Therefore, the passengers are at risk for any disease of high contagiosity. The phenomenon described in this case is comparable to exercise-associated hyponatremia (EAH). EAH is common in several sports disciplines such as marathons and triathlons that demand physical endurance. There is clear evidence that the primary cause of EAH is fluid consumption in excess of that required to replace insensible losses.3 Although there are some cases of EAH in cold and moderate climates,4 the condition is typically found in hot and humid conditions such as with hikers on strenuous trails in the Grand Canyon.5,6 Here the main symptoms are neurological such as seizures.3,7 The most serious symptoms and signs of EAH are reflective of pulmonary and cerebral manifestations of fluid overload and include noncardiogenic pulmonary edema and cerebral edema with encephalopathy. Early symptoms include nausea, vomiting, and headache, and later signs include confusion, disorientation, seizures, coma, and the crepitations of pulmonary edema. In the wilderness setting, plausible differential diagnosis includes heat stroke, hypothermia, hypernatremia, and high-altitude cerebral edema.3,8 The combination of hyponatremia and massive exertion seems to be another situation with specific risks: Bruso et al. reported
that more than 1% of the participants of the Western State Endurance Run 2009 had to be hospitalized with the combination of hyponatremia and rhabdomyolysis.9 Obviously the risk was even more pronounced when the patients had taken nonsteroidal anti-inflammatory drugs (NSAIDs) before. In contrast to a typical EAH in which sodium as well as potassium deficiency is present (review in Francesconi et al.10) our patient suffered exclusively from hyponatremia. Our patient suffered from comparable physiological alterations as EAH patients. However, in this case the fluid loss was caused by diarrhoea and vomiting instead of an athlete sweating. EAH is a dilutional hyponatremia favoured by excessive drinking of hypotonic fluids while loosing large amounts of body fluid.3 The athlete displays an increase in the total body water content11 without an parallel increase in the electrolyte content. The same effect was described by Severi et al. (2001) in patients undergoing haemodialysis.12 Haemodialysis may affect the cardiovascular function due to massive loss of body water; as a consequence, it modifies the characteristic composition of extracellular and intracellular fluids. Changes in potassium and calcium were prominent and affected the rhythm of the sine node pacemaker. Our patient suffered from comparable physiological alterations as EAH patients, although the fluid loss was not caused by sweating as in athletes but by diarrhoea and vomiting. Electrolyte imbalances were induced by substitution of fluids without electrolytes. Patients with cardiac pacemakers display a considerable variability in the threshold required for myocardial stimulation. This variability may be related to local tissue reactions at the electrodeemyocardium interface, to the choice of specific electrodes or to individual physiological variations during the day. There are many conditions that
Pacemaker failure
151
Figure 2
ECG after sodium substitution (day 4).
may increase the pacing threshold, especially metabolic and electrolyte abnormalities.13,14 A theoretical problem may be artefacts of a superficially (skin) performed ECG, but this should be excluded as the phenomenon was constant over a certain time. Some medications may cause failure of pacemakers, i.e. a combination of several antiarrhythmic substances. As our patient did not take any medications, this mechanism can be excluded. Another reason for the failure could be a microdislocation. Clinically this would become manifest if the pacemaker signal in the ECG appeared weaker. Frequently, a new sensor may be required in those cases. However, microdislocation is highly unlikely in our patient because of the ECG normalization after reconstitution of normal plasma sodium concentrations. We propose the importance of sodium currents as the main causing effect which caused a failure of the stimulation and sensing function of a pacemaker. As plausible explanation, we propose the importance of sodium currents through fast sodium channels for an adequate spreading of electrical signal within the myocardium. The amplitude of currents through these channels is nearly linearly related to the extracellular sodium concentrations in electrophysiological experiments.15e17 In turn, the conductance of depolarizing signals to neighbouring cells may become insufficient in the presence of sodium currents about 30% lower than normal. In the same line, sensing of the pacemaker may fail if the electrical field caused by sodium currents decreases below a threshold in the vicinity of the electrode. Certainly, particular local conditions may have contributed to the temporal failure of the pacemaker. For
example, partly scarred tissue in the region where the electrode was anchored may have precluded adequate conduction of electrical signals in hyponatremia, while the strength of the electrical field is sufficient for conduction when normal sodium currents are prevalent in the region. Another contribution would be if the intensity of the pacemaker’s pulse was only slightly above the myocardium’s threshold (normally it should be twice as high). Unfortunately we do not have any information about the intensity when the problem occurred. Our proposed pathogenesis could be verified clinically in the patient by artificial induction of hyponatremia and the application of impulses of variable strength through the pacemaker electrode. Such a procedure may be ethically disputable because the patient was not vitally threatened by her arrhythmia and the hyponatremia was a singular event that seems avoidable in future. On the other hand, when a vital thread existed, a relocation of the electrode may be a safer option. Even more simply, stronger electrical signals and lowering the threshold of sensing may be tried if similar problems may arise again in the patient. At any rate, the patient was reluctant to further investigations, leaving our explanation of the pacemaker failure hypothetical. In summary, the patient is potentially at risk for bradyarrhythmia during episodes of severe disorders of the electrolyte homeostasis. If this happens again, a thorough investigation of the various pacemaker functions should be performed and a relocation of the electrode considered. Only if pacemaker failure could definitively not be explained on the basis of diminished sodium currents in the presence of low sodium concentrations, along with borderline electrical
152 quality of the tissue adjacent to the electrode, further analysis including that of potential mutations in the patient’s cardiac sodium channel may be deliberated.
Conclusion To our knowledge this is the first case with a complete pacemaker failure which may be caused by an electrolyte shift. While travelling, an adequate supply of fluid and electrolytes may be of particular importance for persons with pacemakers. Drug history and electrolyte concentrations should be known before departure and the patient should be given specific advice on how to avoid dehydration and manage traveller’s diarrhoea.
Conflict of interest We declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere.
Acknowledgements The authors would like to thank Dr. Travis Heggie, University of North Dakota, Grand Forks ND (USA), for his careful proofreading.
References 1. Steffen R, Amitirigala I, Mutsch M. Health risks among travelers e need for regular updates. J Travel Med 2008;15(3):145e6. 2. Steffen R. Epidemiology of traveler’s diarrhea. Clin Infect Dis 2005;41(Suppl. 8):S536e40. 3. Rogers IR, Hew-Butler T. Exercise-associated hyponatremia: overzealous fluid consumption. Wilderness Environ Med 2009; 20(2):139e43.
S. Schro ¨der et al. 4. Zafren K. Hyponatremia in a cold environment. Wilderness Environ Med 1998;9(1):54e5. 5. Backer HD, Shopes E, Collins SL. Hyponatremia in recreational hikers in Grand Canyon National Park. J Wilderness Med 1993; 4(4):391e406. 6. Backer HD, Shopes E, Collins SL, Barkan H. Exertional heat illness and hyponatremia in hikers. Am J Emerg Med 1999; 17(6):532e9. 7. Basnyat B, Sleggs J, Spinger M. Seizures and delirium in a trekker: the consequences of excessive water drinking? Wilderness Environ Med 2000;11(1):69e70. 8. Ayus JC, Varon J, Arieff AI. Hyponatremia, cerebral edema, and noncardiogenic pulmonary edema in marathon runners. Ann Intern Med 2000;132(9):711e4. 9. Bruso JR, Hoffman MD, Rogers IR, Lee L, Towle G, HewButler T. Rhabdomyolysis and hyponatremia: a cluster of five cases at the 161-km 2009 Western States Endurance Run. Wilderness Environ Med 2010;21(4):303e8. 10. Francesconi RP, Willis JS, Gaffin SL, Hubbard RW. On the trail of potassium in heat injury. Wilderness Environ Med 1997;8(2): 105e10. 11. Rothwell SP, Rosengren DJ. Severe exercise-associated hyponatremia on the Kokoda Trail, Papua New Guinea. Wilderness Environ Med 2008;19(1):42e4. 12. Severi S, Cavalcanti S, Mancini E, Santoro A. Heart rate response to hemodialysis-induced changes in potassium and calcium levels. J Nephrol 2001;14(6):488e96. 13. Hughes Jr JC, Tyers GF, Torman HA. Effects of acidebase imbalance on myocardial pacing thresholds. J Thorac Cardiovasc Surg 1975;69(5):743e6. 14. Dohrmann ML, Goldschlager NF. Myocardial stimulation threshold in patients with cardiac pacemakers: effect of physiologic variables, pharmacologic agents, and lead electrodes. Cardiol Clin 1985;3(4):527e37. 15. Hodgkin AL, Huxley AF. A quantitative description of membrane current and its application to induction and excitation in nerve. J Physiol 1952;117:500e44. 16. Sheets MF, Scanley BE, Hanck DA, Makielski JC, Fozzard HA. Open sodium channel properties of single canine cardiac Purkinje cells. Biophys J 1987;52(1):13e22. 17. Hille B. Ion channels of excitable membranes. Sunderland, MA: Sinauer Associates Inc; 2001.