- Email: [email protected]
Enterohaemorrhagic Escherichia coli in Ngoïla (Cameroon) during an outbreak of bloody diarrhoea
RESEARCH LETTERS
5
systemic hypertension in Marfan’s syndrome. Br J Ophthalmol 1960; 44: 123–27. Gallagher PM, Ward P, Tan S, et al. High frequency of cystathione beta synthase mutation G 307 S in Irish homocystinuria patients. Hum Mut 1995; 6: 177–80.
Sir George E Clark Metabolic Unit, Royal Victoria Hospital, Belfast BT12 6BA, UK (D R Hadden)
the fourth patient reported worsening voiding. He was also depressed and required fluoxetine. He was re-treated with 50 U of botulinum toxin and the urinary symptoms improved. Uroflowmetric study showed a decrease in TQ and TQmax values at 1, 4, and 8 weeks compared with baseline values (table). Other variables were not changed. 1
Relief by botulinum toxin of voiding dysfunction due to prostatitis
2 3
Giorgio Maria, Antonio Destito, Sergio Lacquaniti, Anna Rita Bentivoglio, Giuseppe Brisinda, Alberto Albanese
4
5
Obstructive urinary symptoms due to chronic non-bacterial prostatitis are due to incomplete relaxation of the bladder neck or inappropriate contraction of the external urethral sphincter during voiding.1 Patients may respond to ␣adrenergic blocking drugs; if effective, treatment may need to be continued indefinitely. Botulinum toxin has been used and smooth 4 muscles. to weaken striated 2,3 Toxin injections into the external urethral sphincter to relieve urethral obstruction were described by Dykstra and Sidi.5 Apart from treatment of detrusor-sphincter dyssynergia, we have found no reports in the literature on the treatment of voiding dysfunction in non-bacterial prostatitis. Four consecutive men (mean age 30·7 [SD 5·7] years) with chronic non-bacterial prostatitis and poor bladder emptying because of spastic external urethral sphincter (mean duration of symptoms 18 [3] months), who failed to respond to tamsulosin 0·4 mg once daily for more than 4 months were enrolled. All the patients were examined, had uroflowmetric studies to assess times of urinary flow (TQ) and maximum urinary flow (TQmax), maximum flow (Qmax), average flow (Qave), and total urinary volume (Vcomp), and had anorectal manometry at rest (RT) and after maximum contraction (MC). An increased value of TQ and TQmax with a normal value of Qmax was taken to be indicative of incomplete relaxation of bladder neck. 1, 4, and 8 weeks after treatment, patients underwent the same assessments. With the patient lying on his left side, a 26-gauge monopolar needle electrode was inserted in the perineum in the anterior midline, about 1·5–2·0 cm from the anus and directed toward the prostatic apex, without sedation or local anaesthesia. 30 U of type A botulinum toxin were injected. No local complications or systemic side-effects were seen. Within 1 week of injection all patients had a striking improvement in their voiding; none complained of urinary incontinence. At 4 weeks, three patients showed a continuing improvement. At 8 weeks, the same three patients were satisfied with the therapy and none of them complained of urinary incontinence. The patients were followed up for a mean of 12 months. No relapse occurred in the three patients who improved. 6 weeks after treatment,
TQ (s) TQmax (s) Qmax (mL/s) Qave (mL/s) Vcomp (mL) RT (mm Hg) MC (mm Hg)
Baseline
1 week
4 weeks
8 weeks
49·3 (8·7) 20·7 (7·5) 16·7 (6·4) 11·0 (5·1) 353·5 (220·1) 70·0 (8·2) 90·0 (29·4)
23·2 (15·3)* 8·0 (1·8)* 15·2 (6·8)† 9·9 (4·5)† 200·7 (86·4)† 65·0 (10·0)† 66·0 (11·4)†
22·2 (17·5)* 9·7 (5·9)* 15·0 (3·4)† 8·7 (1·5)† 215·0 (97·4)† 59·2 (8·3)† 56·2 (15·9)†
26·5 (8·5)* 13·2 (4·4)* 21·6 (10·2)† 12·3 (5·4)† 405·2 (66·7)† 60·7 (16·2)† 72·7 (37·5)†
t test for paired samples. *p<0·05 vs baseline value. †p>0·05 vs baseline value.
Uroflowmetric and anorectal manometric values in four patients
THE LANCET • Vol 352 • August 22, 1998
Holtgrewe HL. Current trends in management of men with lower urinary tract symptoms and benign prostatic hyperplasia. Urology 1998; 51: 1–7. Jankovic J, Hallett M. Therapy with botulinum toxin. New York: Marcel Dekker, 1994. Albanese A, Maria G, Bentivoglio AR, Brisinda G, Cassetta E, Tonali P. Severe constipation in Parkinson’s disease relieved by botulinum toxin. Mov Disor 1997; 12: 764–66. Maria G, Cassetta E, Gui D, Brisinda G, Bentivoglio AR, Albanese A. A comparison of botulinum toxin and saline injection for treatment of chronic anal fissure. N Engl J Med 1998; 338: 217–20. Dykstra DD, Sidi AA. Treatment of detrusor-sphincter dyssynergia with botulinum A toxin: a double-blind study. Arch Phys Med Rehab 1990; 71: 24–28.
Departments of Surgery (Giorgio Maria; e-mail [email protected]), Urology and Neurology, Catholic University of Rome, I 00168 Rome, Italy
Enterohaemorrhagic Escherichia coli in Ngoïla (Cameroon) during an outbreak of bloody diarrhoea Yves Germani, Patrick Cunin, Etienne Tedjouka, Choua bou Ncharre, Jacques Morvan, Paul Martin
Ngoïla (2o37’ N, 14o1’ E, population 400) is in a rain-forest region of Cameroon. In November, 1997, there was an outbreak of red diarrhoea. After investigations by the District Health Authorities, metronidazole and cotrimoxazole were suggested to control the epidemic. By March, 1998, the Ministry of Health had reports of 237 cases and 44 deaths. The illness evolved slowly and deaths were not reported before day 7. Viral haemorrhagic fever was suspected and epidemiological investigations were started. We identified 22 patients, between March 25 and March 28 who presented with bloody diarrhoea or dysentery, duration of illness 3–58 days (median 7). Cramping abdominal pain, fever, and dehydration were noted in 96%, 43%, and 37%. Available antiparasitic and antibacterial agents were not effective against the illness. Stools and blood samples were collected from 22 patients either with dysentery or bloody diarrhoea, aged 2–60 years. Stool samples and serum samples were frozen in liquid nitrogen. Stool samples stored in merthiolate-iodineformaldehyde solution were screened for parasites. Stool cultures set up in the field were screened 2 days later for enteropathogenic bacteria. Serum samples were investigated at the Institut Pasteur de Bangui for Ebola Virus (sequence detection by RT PCR, ELISA IgM capture assay, ELISA antigen detection with IgM capture), Marburg virus (IgG and IgM), Rift Valley fever virus (ELISA antigen detection, FI ISA-IgM capture assay, viral isolation on Vero E6 cells), yellow fever virus (IgM), Rift Valley fever virus (IgG), CCHF virus (IgG) and hanta viruses (Hantaan, Seoul, Pumala). All were negative. Serum samples were negative for Ebola virus in the Institut Pasteur, Paris. Non-polio enterovirus was detected in 12 (54·5%) patients; parasites, including flagellates, amoebae, and helminths in 17 (77·3%); Entamoeba histolytica histolytica in seven. Stool cultures identified 11 (50%) patients infected with Escherichia coli 0157:H7; nine (41%) with Shigella dysenteriae type 1; and two (9%) with S boydii. Two patients were infected with both S dysenteriae type 1 and E coli
625
RESEARCH LETTERS
0157:H7, and one with both S dysenteriae type 1 and S boydii. PCR1–3 on E coli 0157:H7 showed DNA fragments of 130 and 494 nucleotides corresponding to amplified Shiga-like toxin 1 and to the attaching and effacing gene eaeA. Eight of nine S dysenteriae type 1 had similar patterns of resistance to amoxicillin and ticarcillin alone or in combination with clavulanic acid, tetracyclines, chromaphenicol, and cotrimoxazole. One was resistant to amoxicillin and ticarcillin only; they were all sensitive to nalidixic acid, ciprofloxacin, and other new quinolones. Both S boydii were resistant to tetracyclines only. All E coli 0157:H7 tested were resistant to amoxicillin and chloramphenicol. Before 1998, infections or outbreaks of enterohaemorrhagic E coli had not been reported in Cameroon as a cause of bloody diarrhoea. Similar observations were made in two central African Republic’s at Bangui and at Zémio.4 Enterohaemorrhagic E coli emerged there in 1997 and the major contributing factor was consumption of pies (kanda) prepared with smoked zebu meat. In some cases of bloody diarrhoea at Ngoïla, food history pointed to the consumption of smoked game meat. Epidemic S dysenteriae type 1 infection has re-emerged in Central Africa.5 At Ngoïla transmission was via person-toperson contact because of lack of personal and collective hygiene, and the high mortality rate during this outbreak was probably linked to the coexistence of three major enteropathogens, enterohaemorrhagic E coli, S dysenteriae type 1, and Entamoeba histolytica histolytica, and a lack of treatment at the begining of the epidemic, which is still in progress in villages along the road to Lomié (2051’N, 13052’E), the main city of the district. 1
2
3
4
5
Germani Y, Bégaud E, Le Bouguénec C. Detection of Escherichia coli attaching and effacing gene (eaeA) in enteropathogenic strains by polymerase chain reaction. Res Microbiol 1997; 148: 177–81. Pollard DR, Johnson WM, Lior H, Tyser SD, Rozee R. Rapid and specific detection of verotoxin genes in Escherichia coli by the polymerase reaction. J Clin Microbiol 1990; 28: 540–45. Tyler SD, Johnson WM, Lior H, Rozee R. Identification of verotoxin type 2 variant B subunit genes in Escherichia coli by the polymerase chain reaction and restriction fragment length polymorphism analysis. J Clin Microbiol 1991; 29: 1339–43. Germani Y, Soro B, Vohito M, Morel O, Morvan J. Enterohaemorrhagic Escherichia coli in Central African Republic; Lancet 1997; 349: 1670. Keush GT, Bennish ML. Shigellosis: recent progress, persisting problems and research issues. Pediatr Infect Dis J 1989; 8: 713–19.
Institut Pasteur de Bangui, BP 923, Bangui, République Centrafricaine (Y Germani); Centre Pasteur du Cameroun, Yaoundé, Cameroun; District de Lomié, Ministère de la Santé, Cameroun; World Health Organization, Yaoundé.
Breast cancer in female flight attendants
irritability, memory difficulties, loss of concentration, and gastrointestinal disturbances. Eastward travel is associated with worse disturbances than westward, perhaps because getting to sleep at bedtime at the destination is more difficult than premature wakening. Several days may be needed for full recovery.3 Severity of symptoms is related to the menstrual cycle, disruptions of which are also common in flight attendants.2 Jetlag disrupts the function of the pineal gland, which secretes melatonin in response to darkness and inhibits secretion during daylight. Melatonin is the chief hormone secreted by the pineal gland, and has a robust secretion cycle, starting at about 2100 h and ending at about 0800 h. Disruption of pineal-gland activity as a result of being awake during normal sleep time and attempting to sleep during normal waking time would, therefore, be expected to decrease secretion. Melatonin production is decreased by exposure to bright light during normal sleep time, whereas supplementary melatonin prevents the symptoms and is thought to be the best available pharmacological treatment for jetlag.3,4 Breast cancer is associated with decreased melatonin production, and supplementary melatonin has a protective effect against breast cancer in animals. A tumour sizedependent decline in the circadian amplitude of serum melatonin occurs in unoperated patients with primary breast cancer. Melatonin inhibits the growth of human breast-cancer cells, seemingly by down-regulating oestrogen receptor expression; at physiological concentrations (about 1 nmol/L) melatonin also augments the inhibitory actions of tamoxifen on human breast-cancer-cell growth. A significant difference in the luteal heat cycle has been reported between normal and precancerous breasts; the latter were persistently hotter, had an earlier rise in temperature, and showed a smaller increase during the luteal phase. Circadian rhythms in tissue proliferation and drug handling are also well documented. Melatonin is antiproliferative in oestrogen-responsive breast cancer (which accounts for about two-thirds of all breast cancers) and shows menstrual-cycle variation, with the highest values near menstruation and the lowest at ovulation.4,5 These data suggest that work-associated disturbances in biological rhythms in general and melatonin production in particular are involved in breast cancer, and may contribute to the increase of about two-fold in risk of breast cancer among female flight attendants. If this hypothesis is correct, female flight attendants as a group, and especially those with more disturbed sleep patterns, would be expected to have lower circulating melatonin than controls; duration of employment as a flight attendant should correlate positively with breast cancer risk and inversely with serum melatonin; and flight attendants with breast cancer should have more work-associated exposure to jetlag, and lower melatonin than those without breast cancer. 1
Anthony R Mawson 2
A high rate of breast cancer is present among Finnish female flight attendants after a mean of 13·9 years at work (standard incidence ratio 1·87 [95% CI 1·15–2·23]). The risk is most prominent 15 years after recruitment.1 This increase may be due to melatonin deficiency, resulting from work-associated interruptions in sleep-waking cycles (jetlag). Chronic disturbances in circadian rhythm are thought to lead to many of the health problems reported by shift workers, and because flight attendants commonly work at night and travel across many time zones, they are exposed to chronic interruptions in circadian rhythms.2 Jetlag is characterised by fatigue, headache, weakness,
626
3 4 5
Pukkala E, Auvinen H, Wahlberg G. Incidence of cancer among Finnish airline cabin attendants, 1967–1992. BMJ 1995; 311: 649–52. Suvanto S, Harma M, Ilmarinen J, Partinen M. Effects of 10 h time zone changes on female flight attendants’ circadian rhythms of body temperature, alertness and visual search. Ergonomics 1993; 36: 613–25. Waterhouse J, Reilly T, Atkinson G. Jet-lag. Lancet 1997; 350: 1611–16. Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336: 186–95. Bartsch C, Bartsch H, Karenovics A, et al. Nocturnal urinary 6-sulphatoxymelatonin excretion is decreased in primary breast cancer patients compared to age-matched controls and shows negative correlation with tumor-size. J Pineal Res 1997; 23: 53–81.
Research Planning and Evaluation, Carolinas Health Care System, Charlotte, NC 28232, USA (A R Mawson; e-mail [email protected])
THE LANCET • Vol 352 • August 22, 1998
5
systemic hypertension in Marfan’s syndrome. Br J Ophthalmol 1960; 44: 123–27. Gallagher PM, Ward P, Tan S, et al. High frequency of cystathione beta synthase mutation G 307 S in Irish homocystinuria patients. Hum Mut 1995; 6: 177–80.
Sir George E Clark Metabolic Unit, Royal Victoria Hospital, Belfast BT12 6BA, UK (D R Hadden)
the fourth patient reported worsening voiding. He was also depressed and required fluoxetine. He was re-treated with 50 U of botulinum toxin and the urinary symptoms improved. Uroflowmetric study showed a decrease in TQ and TQmax values at 1, 4, and 8 weeks compared with baseline values (table). Other variables were not changed. 1
Relief by botulinum toxin of voiding dysfunction due to prostatitis
2 3
Giorgio Maria, Antonio Destito, Sergio Lacquaniti, Anna Rita Bentivoglio, Giuseppe Brisinda, Alberto Albanese
4
5
Obstructive urinary symptoms due to chronic non-bacterial prostatitis are due to incomplete relaxation of the bladder neck or inappropriate contraction of the external urethral sphincter during voiding.1 Patients may respond to ␣adrenergic blocking drugs; if effective, treatment may need to be continued indefinitely. Botulinum toxin has been used and smooth 4 muscles. to weaken striated 2,3 Toxin injections into the external urethral sphincter to relieve urethral obstruction were described by Dykstra and Sidi.5 Apart from treatment of detrusor-sphincter dyssynergia, we have found no reports in the literature on the treatment of voiding dysfunction in non-bacterial prostatitis. Four consecutive men (mean age 30·7 [SD 5·7] years) with chronic non-bacterial prostatitis and poor bladder emptying because of spastic external urethral sphincter (mean duration of symptoms 18 [3] months), who failed to respond to tamsulosin 0·4 mg once daily for more than 4 months were enrolled. All the patients were examined, had uroflowmetric studies to assess times of urinary flow (TQ) and maximum urinary flow (TQmax), maximum flow (Qmax), average flow (Qave), and total urinary volume (Vcomp), and had anorectal manometry at rest (RT) and after maximum contraction (MC). An increased value of TQ and TQmax with a normal value of Qmax was taken to be indicative of incomplete relaxation of bladder neck. 1, 4, and 8 weeks after treatment, patients underwent the same assessments. With the patient lying on his left side, a 26-gauge monopolar needle electrode was inserted in the perineum in the anterior midline, about 1·5–2·0 cm from the anus and directed toward the prostatic apex, without sedation or local anaesthesia. 30 U of type A botulinum toxin were injected. No local complications or systemic side-effects were seen. Within 1 week of injection all patients had a striking improvement in their voiding; none complained of urinary incontinence. At 4 weeks, three patients showed a continuing improvement. At 8 weeks, the same three patients were satisfied with the therapy and none of them complained of urinary incontinence. The patients were followed up for a mean of 12 months. No relapse occurred in the three patients who improved. 6 weeks after treatment,
TQ (s) TQmax (s) Qmax (mL/s) Qave (mL/s) Vcomp (mL) RT (mm Hg) MC (mm Hg)
Baseline
1 week
4 weeks
8 weeks
49·3 (8·7) 20·7 (7·5) 16·7 (6·4) 11·0 (5·1) 353·5 (220·1) 70·0 (8·2) 90·0 (29·4)
23·2 (15·3)* 8·0 (1·8)* 15·2 (6·8)† 9·9 (4·5)† 200·7 (86·4)† 65·0 (10·0)† 66·0 (11·4)†
22·2 (17·5)* 9·7 (5·9)* 15·0 (3·4)† 8·7 (1·5)† 215·0 (97·4)† 59·2 (8·3)† 56·2 (15·9)†
26·5 (8·5)* 13·2 (4·4)* 21·6 (10·2)† 12·3 (5·4)† 405·2 (66·7)† 60·7 (16·2)† 72·7 (37·5)†
t test for paired samples. *p<0·05 vs baseline value. †p>0·05 vs baseline value.
Uroflowmetric and anorectal manometric values in four patients
THE LANCET • Vol 352 • August 22, 1998
Holtgrewe HL. Current trends in management of men with lower urinary tract symptoms and benign prostatic hyperplasia. Urology 1998; 51: 1–7. Jankovic J, Hallett M. Therapy with botulinum toxin. New York: Marcel Dekker, 1994. Albanese A, Maria G, Bentivoglio AR, Brisinda G, Cassetta E, Tonali P. Severe constipation in Parkinson’s disease relieved by botulinum toxin. Mov Disor 1997; 12: 764–66. Maria G, Cassetta E, Gui D, Brisinda G, Bentivoglio AR, Albanese A. A comparison of botulinum toxin and saline injection for treatment of chronic anal fissure. N Engl J Med 1998; 338: 217–20. Dykstra DD, Sidi AA. Treatment of detrusor-sphincter dyssynergia with botulinum A toxin: a double-blind study. Arch Phys Med Rehab 1990; 71: 24–28.
Departments of Surgery (Giorgio Maria; e-mail [email protected]), Urology and Neurology, Catholic University of Rome, I 00168 Rome, Italy
Enterohaemorrhagic Escherichia coli in Ngoïla (Cameroon) during an outbreak of bloody diarrhoea Yves Germani, Patrick Cunin, Etienne Tedjouka, Choua bou Ncharre, Jacques Morvan, Paul Martin
Ngoïla (2o37’ N, 14o1’ E, population 400) is in a rain-forest region of Cameroon. In November, 1997, there was an outbreak of red diarrhoea. After investigations by the District Health Authorities, metronidazole and cotrimoxazole were suggested to control the epidemic. By March, 1998, the Ministry of Health had reports of 237 cases and 44 deaths. The illness evolved slowly and deaths were not reported before day 7. Viral haemorrhagic fever was suspected and epidemiological investigations were started. We identified 22 patients, between March 25 and March 28 who presented with bloody diarrhoea or dysentery, duration of illness 3–58 days (median 7). Cramping abdominal pain, fever, and dehydration were noted in 96%, 43%, and 37%. Available antiparasitic and antibacterial agents were not effective against the illness. Stools and blood samples were collected from 22 patients either with dysentery or bloody diarrhoea, aged 2–60 years. Stool samples and serum samples were frozen in liquid nitrogen. Stool samples stored in merthiolate-iodineformaldehyde solution were screened for parasites. Stool cultures set up in the field were screened 2 days later for enteropathogenic bacteria. Serum samples were investigated at the Institut Pasteur de Bangui for Ebola Virus (sequence detection by RT PCR, ELISA IgM capture assay, ELISA antigen detection with IgM capture), Marburg virus (IgG and IgM), Rift Valley fever virus (ELISA antigen detection, FI ISA-IgM capture assay, viral isolation on Vero E6 cells), yellow fever virus (IgM), Rift Valley fever virus (IgG), CCHF virus (IgG) and hanta viruses (Hantaan, Seoul, Pumala). All were negative. Serum samples were negative for Ebola virus in the Institut Pasteur, Paris. Non-polio enterovirus was detected in 12 (54·5%) patients; parasites, including flagellates, amoebae, and helminths in 17 (77·3%); Entamoeba histolytica histolytica in seven. Stool cultures identified 11 (50%) patients infected with Escherichia coli 0157:H7; nine (41%) with Shigella dysenteriae type 1; and two (9%) with S boydii. Two patients were infected with both S dysenteriae type 1 and E coli
625
RESEARCH LETTERS
0157:H7, and one with both S dysenteriae type 1 and S boydii. PCR1–3 on E coli 0157:H7 showed DNA fragments of 130 and 494 nucleotides corresponding to amplified Shiga-like toxin 1 and to the attaching and effacing gene eaeA. Eight of nine S dysenteriae type 1 had similar patterns of resistance to amoxicillin and ticarcillin alone or in combination with clavulanic acid, tetracyclines, chromaphenicol, and cotrimoxazole. One was resistant to amoxicillin and ticarcillin only; they were all sensitive to nalidixic acid, ciprofloxacin, and other new quinolones. Both S boydii were resistant to tetracyclines only. All E coli 0157:H7 tested were resistant to amoxicillin and chloramphenicol. Before 1998, infections or outbreaks of enterohaemorrhagic E coli had not been reported in Cameroon as a cause of bloody diarrhoea. Similar observations were made in two central African Republic’s at Bangui and at Zémio.4 Enterohaemorrhagic E coli emerged there in 1997 and the major contributing factor was consumption of pies (kanda) prepared with smoked zebu meat. In some cases of bloody diarrhoea at Ngoïla, food history pointed to the consumption of smoked game meat. Epidemic S dysenteriae type 1 infection has re-emerged in Central Africa.5 At Ngoïla transmission was via person-toperson contact because of lack of personal and collective hygiene, and the high mortality rate during this outbreak was probably linked to the coexistence of three major enteropathogens, enterohaemorrhagic E coli, S dysenteriae type 1, and Entamoeba histolytica histolytica, and a lack of treatment at the begining of the epidemic, which is still in progress in villages along the road to Lomié (2051’N, 13052’E), the main city of the district. 1
2
3
4
5
Germani Y, Bégaud E, Le Bouguénec C. Detection of Escherichia coli attaching and effacing gene (eaeA) in enteropathogenic strains by polymerase chain reaction. Res Microbiol 1997; 148: 177–81. Pollard DR, Johnson WM, Lior H, Tyser SD, Rozee R. Rapid and specific detection of verotoxin genes in Escherichia coli by the polymerase reaction. J Clin Microbiol 1990; 28: 540–45. Tyler SD, Johnson WM, Lior H, Rozee R. Identification of verotoxin type 2 variant B subunit genes in Escherichia coli by the polymerase chain reaction and restriction fragment length polymorphism analysis. J Clin Microbiol 1991; 29: 1339–43. Germani Y, Soro B, Vohito M, Morel O, Morvan J. Enterohaemorrhagic Escherichia coli in Central African Republic; Lancet 1997; 349: 1670. Keush GT, Bennish ML. Shigellosis: recent progress, persisting problems and research issues. Pediatr Infect Dis J 1989; 8: 713–19.
Institut Pasteur de Bangui, BP 923, Bangui, République Centrafricaine (Y Germani); Centre Pasteur du Cameroun, Yaoundé, Cameroun; District de Lomié, Ministère de la Santé, Cameroun; World Health Organization, Yaoundé.
Breast cancer in female flight attendants
irritability, memory difficulties, loss of concentration, and gastrointestinal disturbances. Eastward travel is associated with worse disturbances than westward, perhaps because getting to sleep at bedtime at the destination is more difficult than premature wakening. Several days may be needed for full recovery.3 Severity of symptoms is related to the menstrual cycle, disruptions of which are also common in flight attendants.2 Jetlag disrupts the function of the pineal gland, which secretes melatonin in response to darkness and inhibits secretion during daylight. Melatonin is the chief hormone secreted by the pineal gland, and has a robust secretion cycle, starting at about 2100 h and ending at about 0800 h. Disruption of pineal-gland activity as a result of being awake during normal sleep time and attempting to sleep during normal waking time would, therefore, be expected to decrease secretion. Melatonin production is decreased by exposure to bright light during normal sleep time, whereas supplementary melatonin prevents the symptoms and is thought to be the best available pharmacological treatment for jetlag.3,4 Breast cancer is associated with decreased melatonin production, and supplementary melatonin has a protective effect against breast cancer in animals. A tumour sizedependent decline in the circadian amplitude of serum melatonin occurs in unoperated patients with primary breast cancer. Melatonin inhibits the growth of human breast-cancer cells, seemingly by down-regulating oestrogen receptor expression; at physiological concentrations (about 1 nmol/L) melatonin also augments the inhibitory actions of tamoxifen on human breast-cancer-cell growth. A significant difference in the luteal heat cycle has been reported between normal and precancerous breasts; the latter were persistently hotter, had an earlier rise in temperature, and showed a smaller increase during the luteal phase. Circadian rhythms in tissue proliferation and drug handling are also well documented. Melatonin is antiproliferative in oestrogen-responsive breast cancer (which accounts for about two-thirds of all breast cancers) and shows menstrual-cycle variation, with the highest values near menstruation and the lowest at ovulation.4,5 These data suggest that work-associated disturbances in biological rhythms in general and melatonin production in particular are involved in breast cancer, and may contribute to the increase of about two-fold in risk of breast cancer among female flight attendants. If this hypothesis is correct, female flight attendants as a group, and especially those with more disturbed sleep patterns, would be expected to have lower circulating melatonin than controls; duration of employment as a flight attendant should correlate positively with breast cancer risk and inversely with serum melatonin; and flight attendants with breast cancer should have more work-associated exposure to jetlag, and lower melatonin than those without breast cancer. 1
Anthony R Mawson 2
A high rate of breast cancer is present among Finnish female flight attendants after a mean of 13·9 years at work (standard incidence ratio 1·87 [95% CI 1·15–2·23]). The risk is most prominent 15 years after recruitment.1 This increase may be due to melatonin deficiency, resulting from work-associated interruptions in sleep-waking cycles (jetlag). Chronic disturbances in circadian rhythm are thought to lead to many of the health problems reported by shift workers, and because flight attendants commonly work at night and travel across many time zones, they are exposed to chronic interruptions in circadian rhythms.2 Jetlag is characterised by fatigue, headache, weakness,
626
3 4 5
Pukkala E, Auvinen H, Wahlberg G. Incidence of cancer among Finnish airline cabin attendants, 1967–1992. BMJ 1995; 311: 649–52. Suvanto S, Harma M, Ilmarinen J, Partinen M. Effects of 10 h time zone changes on female flight attendants’ circadian rhythms of body temperature, alertness and visual search. Ergonomics 1993; 36: 613–25. Waterhouse J, Reilly T, Atkinson G. Jet-lag. Lancet 1997; 350: 1611–16. Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336: 186–95. Bartsch C, Bartsch H, Karenovics A, et al. Nocturnal urinary 6-sulphatoxymelatonin excretion is decreased in primary breast cancer patients compared to age-matched controls and shows negative correlation with tumor-size. J Pineal Res 1997; 23: 53–81.
Research Planning and Evaluation, Carolinas Health Care System, Charlotte, NC 28232, USA (A R Mawson; e-mail [email protected])
THE LANCET • Vol 352 • August 22, 1998