742
much the same for the three groups (about 19 months). The median age for women whose smears lacked or contained endocervical cells was the same (33 years). Thus 36 % of smears classified as sampling false negatives had no endocervical cells whereas only 13% of those regarded as screening errors had none. The proportion of smears lacking endocervical cells in our practice as a whole was 15 % for the same period. Only 4 of the 117 (3-4%) diagnostic CIN III smears lacked endocervical cells. Our data point to an increased chance of sampling false-negative results in smears lacking endocervical cells. Therefore we believe that earlier rescreening might be advisable for most of the 10% or so of women in our practice whose smears lack endocervical cells. Such smear reports carry the comment "elective repeat smear should be considered at say 2-3 months taking into account the patient’s age, clinical and cytological history". Whether the absence of endocervical cells results from poor sampling technique or inaccessibility of the upper transformation zone and lower endocervical canal cannot be differentiated in smear reports. We feel that many smears lacking endocervical cells do so because of poor sampling skill-as shown by the wide range (2%-53%) of endocervical cell absence for smear-takers in our practice, in which the same implement is used in a similar population of women. However, preoccupation with obtaining endocervical cells (and use of the endocervical brush alone by some smear-takers) may lead to an inadequate squamous cell component. Such smears are just as deficient with respect to sample reliability as those that lack endocervical cells. 18 Glen Street, Eastwood, NSW 2122, Australia
nerve
stimulation
SIR,-In your Feb 23 editorial you make several points that are to reconcile. First, you state that the mechanism by which
hard
transcutaneous electrical nerve stimulation (TENS) works is unclear. You then say that there is considerable debate about whether TENS has any value other than that of placebo, and that the equipment represents a significant expense. Finally, you conclude that it is a sensible course of treatment to offer patients with chronic low-back pain, and that it "may well be irrelevant to subject TENS to further trials". The first two points are related. Only when a clear mechanism of action is proposed can a rational programme of experimental testing be devised. Otherwise, since the placebo effect in patients is so strong and the interrelationship between physician and patient is so complex, to establish that an effect even exists is very difficult. This is especially true in conditions such as chronic low-back pain, which in most cases is both episodic and difficult to ascribe to a clear organic cause. If TENS operates only as a placebo, then surely a cheaper placebo would be preferable? Your conclusion ought to have been that further testing is indeed required, and that proponents of TENS as a treatment of clinical value should be required to produce a testable hypothesis about how it works. Otherwise, TENS retreats into the twilight world of medical myth in which organic conditions are allowed to go untreated for as long as the placebo effects mask the patient’s perception of the symptoms.
Department of Biology and Preclinical Medicine, University of St Andrews, St Andrews, Fife KY16 9TS, UK
JOHN C. MCLACHLAN
COLIN LAVERTY JULIA THURLOE
Raised
luteinising hormone and spontaneous miscarriage
SIR,-Medical investigation after early spontaneous miscarriage is usually only recommended for patients with a history of recurrent miscarriage. Dr Regan and her colleagues (Nov 10, p 1141) show that patients with a high prepregnancy concentration of luteinising hormone (LH) have a higher frequency of spontaneous miscarriage than do those with normal values. In 1989 a miscarriage clinic was introduced in Dublin for the support and counselling of all patients one month after a spontaneous miscarriage.l 48 patients were followed for a year in whom LH and follicle stimulating hormone (FSH) concentration was measured on day 8 of the first complete cycle after miscarriage. None of the patients had a history of recurrent miscarriage. As in Regan and colleagues’ investigation, a high serum LH concentration was defmed as 10 IU/1 or more. Of the 48 patients, 6 (13%) had a post-pregnancy serum LH concentration greater than 10 IU/1.2 of these 6 were nulliparous, 2 were multiparous and had had one previous miscarriage, and 2 were multiparous but had had no previous miscarriage. In 5 of the 6 patients, an empty gestational sac was confirmed histologically and in the 6th a macerated fetus was identified at 19 weeks’ gestation. All 6 patients also had an LH/FSH ratio of over 3-0. These findings raise the possibility that screening for polycystic ovarian syndrome may be worthwhile even after one spontaneous miscarriage. Pituitary suppression before induction of ovulation significantly reduces the risk of spontaneous miscarriage in women with polycystic ovarian disease and primary recurrent spontaneous miscarriages.2 However, a randomised controlled trial of patients with a raised LH concentration after miscarriage is essential to show whether further investigations and treatment improve the outcome of the next pregnancy. Coombe Lying-In Dublin 8, Ireland
Transcutaneous electrical
Hospital,
MICHAEL J. TURNER
1. Turner MJ, Flannelly GM, Wingfield M, et al. The miscarriage clinic: an audit of the first year. Br J Obstet Gynaecol (in press). 2. Johnson P, Pearce JM. Recurrent spontaneous abortion and polycystic ovarian disease: comparison of two regimens to induce ovulation. Br MedJ 1990; 300: 154-56.
Growth of Plasmodium falciparum inhibited by HbD-Ouled-Rabah SIR,-Several variant haemoglobins have been associated with resistance to infection with Plasmodium falciparum. In-vitro cultures with variant red cells have revealed enhanced parasite resistance in the presence of Hb S, C, E, and H, for example.1 We now report that HbD-Ouled-Rabah (&bgr;19 Asn->Lys) in the homozygous form decreases parasite growth in vitro. A blood sample was obtained from a known homozygote for HbD Ouled-Rabah in Mali and sent to Paris where, together with a shipment control, it was forwarded to New York for processing. The presence of HbD (and absence of any other major Hb component such as HbA or HbS) was confirmed by cellulose acetate and citrate agar electrophoresis and a solubility test for HbS. A quantitative assay for glucose-6-phosphate dehydrogenase was also normal. The red cells were placed in culture with the FCR-3 strain of Pfalciparum 2 The African donor’s plasma was discarded and the red cells were washed thoroughly in culture medium. Parasitaemia was evaluated by counting 1000 red cells for 4 days (two growth cycles) in triplicate with Giemsa-stained smears, and the uptake of 3H-hypoxanthine was measured at 48 h. Parasite growth in the HbD Ouled-Rabah sample was about 60% of the control rate (figure), which in turn was similar to growth in fresh normal A + red cells obtained locally. Hypoxanthine uptake at 48 h confirmed the Giemsa stain results with uptake of 44% of the control value. HbD Ouled-Rabah is polymorphic at a surprisingly high frequency among the Kel Kummer people, a highly inbred Tuareg tribe of north-east Mali in which men marry their matrilineal cross-cousin. This abnormal haemoglobin is considered a genetic marker for the Tuareg people, because it is also found in other areas inhabited by this ethnic group. A frequency of 21 % was found for this mutant haemoglobin in a 1982 survey among the upper caste of the Kel Kummer population.3 High frequency of a particular Hb (or other red cell polymorphism) in a malarious area generally raises the suspicion that resistance to plasmodium infection has served as a potent selective factor in the spread of the mutant gene. Our results could also be the consequence of an as yet unidentified genetic defect coexisting with HbD Ouled-Rabah in red cells, so in-vitro culture studies on heterozygotes for HbD Ouled Rabah and
much the same for the three groups (about 19 months). The median age for women whose smears lacked or contained endocervical cells was the same (33 years). Thus 36 % of smears classified as sampling false negatives had no endocervical cells whereas only 13% of those regarded as screening errors had none. The proportion of smears lacking endocervical cells in our practice as a whole was 15 % for the same period. Only 4 of the 117 (3-4%) diagnostic CIN III smears lacked endocervical cells. Our data point to an increased chance of sampling false-negative results in smears lacking endocervical cells. Therefore we believe that earlier rescreening might be advisable for most of the 10% or so of women in our practice whose smears lack endocervical cells. Such smear reports carry the comment "elective repeat smear should be considered at say 2-3 months taking into account the patient’s age, clinical and cytological history". Whether the absence of endocervical cells results from poor sampling technique or inaccessibility of the upper transformation zone and lower endocervical canal cannot be differentiated in smear reports. We feel that many smears lacking endocervical cells do so because of poor sampling skill-as shown by the wide range (2%-53%) of endocervical cell absence for smear-takers in our practice, in which the same implement is used in a similar population of women. However, preoccupation with obtaining endocervical cells (and use of the endocervical brush alone by some smear-takers) may lead to an inadequate squamous cell component. Such smears are just as deficient with respect to sample reliability as those that lack endocervical cells. 18 Glen Street, Eastwood, NSW 2122, Australia
nerve
stimulation
SIR,-In your Feb 23 editorial you make several points that are to reconcile. First, you state that the mechanism by which
hard
transcutaneous electrical nerve stimulation (TENS) works is unclear. You then say that there is considerable debate about whether TENS has any value other than that of placebo, and that the equipment represents a significant expense. Finally, you conclude that it is a sensible course of treatment to offer patients with chronic low-back pain, and that it "may well be irrelevant to subject TENS to further trials". The first two points are related. Only when a clear mechanism of action is proposed can a rational programme of experimental testing be devised. Otherwise, since the placebo effect in patients is so strong and the interrelationship between physician and patient is so complex, to establish that an effect even exists is very difficult. This is especially true in conditions such as chronic low-back pain, which in most cases is both episodic and difficult to ascribe to a clear organic cause. If TENS operates only as a placebo, then surely a cheaper placebo would be preferable? Your conclusion ought to have been that further testing is indeed required, and that proponents of TENS as a treatment of clinical value should be required to produce a testable hypothesis about how it works. Otherwise, TENS retreats into the twilight world of medical myth in which organic conditions are allowed to go untreated for as long as the placebo effects mask the patient’s perception of the symptoms.
Department of Biology and Preclinical Medicine, University of St Andrews, St Andrews, Fife KY16 9TS, UK
JOHN C. MCLACHLAN
COLIN LAVERTY JULIA THURLOE
Raised
luteinising hormone and spontaneous miscarriage
SIR,-Medical investigation after early spontaneous miscarriage is usually only recommended for patients with a history of recurrent miscarriage. Dr Regan and her colleagues (Nov 10, p 1141) show that patients with a high prepregnancy concentration of luteinising hormone (LH) have a higher frequency of spontaneous miscarriage than do those with normal values. In 1989 a miscarriage clinic was introduced in Dublin for the support and counselling of all patients one month after a spontaneous miscarriage.l 48 patients were followed for a year in whom LH and follicle stimulating hormone (FSH) concentration was measured on day 8 of the first complete cycle after miscarriage. None of the patients had a history of recurrent miscarriage. As in Regan and colleagues’ investigation, a high serum LH concentration was defmed as 10 IU/1 or more. Of the 48 patients, 6 (13%) had a post-pregnancy serum LH concentration greater than 10 IU/1.2 of these 6 were nulliparous, 2 were multiparous and had had one previous miscarriage, and 2 were multiparous but had had no previous miscarriage. In 5 of the 6 patients, an empty gestational sac was confirmed histologically and in the 6th a macerated fetus was identified at 19 weeks’ gestation. All 6 patients also had an LH/FSH ratio of over 3-0. These findings raise the possibility that screening for polycystic ovarian syndrome may be worthwhile even after one spontaneous miscarriage. Pituitary suppression before induction of ovulation significantly reduces the risk of spontaneous miscarriage in women with polycystic ovarian disease and primary recurrent spontaneous miscarriages.2 However, a randomised controlled trial of patients with a raised LH concentration after miscarriage is essential to show whether further investigations and treatment improve the outcome of the next pregnancy. Coombe Lying-In Dublin 8, Ireland
Transcutaneous electrical
Hospital,
MICHAEL J. TURNER
1. Turner MJ, Flannelly GM, Wingfield M, et al. The miscarriage clinic: an audit of the first year. Br J Obstet Gynaecol (in press). 2. Johnson P, Pearce JM. Recurrent spontaneous abortion and polycystic ovarian disease: comparison of two regimens to induce ovulation. Br MedJ 1990; 300: 154-56.
Growth of Plasmodium falciparum inhibited by HbD-Ouled-Rabah SIR,-Several variant haemoglobins have been associated with resistance to infection with Plasmodium falciparum. In-vitro cultures with variant red cells have revealed enhanced parasite resistance in the presence of Hb S, C, E, and H, for example.1 We now report that HbD-Ouled-Rabah (&bgr;19 Asn->Lys) in the homozygous form decreases parasite growth in vitro. A blood sample was obtained from a known homozygote for HbD Ouled-Rabah in Mali and sent to Paris where, together with a shipment control, it was forwarded to New York for processing. The presence of HbD (and absence of any other major Hb component such as HbA or HbS) was confirmed by cellulose acetate and citrate agar electrophoresis and a solubility test for HbS. A quantitative assay for glucose-6-phosphate dehydrogenase was also normal. The red cells were placed in culture with the FCR-3 strain of Pfalciparum 2 The African donor’s plasma was discarded and the red cells were washed thoroughly in culture medium. Parasitaemia was evaluated by counting 1000 red cells for 4 days (two growth cycles) in triplicate with Giemsa-stained smears, and the uptake of 3H-hypoxanthine was measured at 48 h. Parasite growth in the HbD Ouled-Rabah sample was about 60% of the control rate (figure), which in turn was similar to growth in fresh normal A + red cells obtained locally. Hypoxanthine uptake at 48 h confirmed the Giemsa stain results with uptake of 44% of the control value. HbD Ouled-Rabah is polymorphic at a surprisingly high frequency among the Kel Kummer people, a highly inbred Tuareg tribe of north-east Mali in which men marry their matrilineal cross-cousin. This abnormal haemoglobin is considered a genetic marker for the Tuareg people, because it is also found in other areas inhabited by this ethnic group. A frequency of 21 % was found for this mutant haemoglobin in a 1982 survey among the upper caste of the Kel Kummer population.3 High frequency of a particular Hb (or other red cell polymorphism) in a malarious area generally raises the suspicion that resistance to plasmodium infection has served as a potent selective factor in the spread of the mutant gene. Our results could also be the consequence of an as yet unidentified genetic defect coexisting with HbD Ouled-Rabah in red cells, so in-vitro culture studies on heterozygotes for HbD Ouled Rabah and
