Response to IFNα in myelogenous leukaemia

of food

under primitive conditions, inadequate garbage disposal, or the general breakdown of hygiene caused by water and power shortage may have resulted in a higher density of rodent. Increased contact between rodent and human beings may explain the higher number of cases of HFRS observed in this area. United Nations forces are also stationed in Bosnia. We have confirmed at least two cases of HFRS among the multinational UN forces. Unawareness of the disease, combined with lack of diagnostic capability in the absence of a coordinated reporting system have made it difficult to assess the true extent of the situation among the military personnel. The problem with HFRS may extend outside Bosnia and be of concern to the health authorities not only in the regions of the former Yugoslavia but also other countries that have troops stationed in them. amounts

stored

conclude that a new hantavirus was present, for which we propose the name Rio Mamore virus (RMV). RMV comprises a monophyletic lineage in phylogenetic trees, with geographic sequence variants from La Paz and Beni districts. These genotypes differed by a maximum of 17-9% and 2-3% from one another at the nucleotide and aminoacid level, respectively. Compared with Bayou hantavirus/ the nearest relative of RMV, genetic and aminoacid differences were 20-4-21-7% and 8-3-10-6%, respectively. RMV is the first described indigenous hantavirus of South America. Oryzomine rodents are widespread, occurring in all the regions in which HPS has been reported in South America. The molecular identification of a potential aetiological agent should facilitate elucidation of its role in human disease. we

*Brian

M Hukic, A Kurt, S Torstensson, *B Niklasson

Å Lundkvist,

D

Wiger,

University Clinical Center in Tuzla, Bosnia and Herzegovina, Skåne Wing no 10, S-262 82 Ångelholm, Sweden; *Swedish Institute for Infectious Disease Control, S-105 21 Stockholm, Sweden; National Institute of Public Health, Oslo, Norway; National Defense Research Establishment, Umeå, Sweden

1

Smadel JE. Epidemic haemorrhagic fever. Am J Publ Health 1951; 43:

1327-30. Stuhlfauth K. Bericht über ein neues schlammfieberähnliches krankenheitsbild bei Deutschen truppen in Lappland. Dtsch Med Wochenschr 1943; 69: 439-43. 3 Hortling H. En epidemi av fältfeber (?) i finska Lappland. Nord Med 2

3

4

1946; 30: 1001-04. 4

5

Niklasson B, Tkachenko E, Ivanov AP, et al. Haemorrhagic fever with renal syndrome: evaluation of ELISA for detection of Puumala virus specific IgG and IgM. Res Virol 1990; 141: 637-48. Avsic-Zupanc T, Likar M, Novakovic S, et al. Evidence of the presence of two hantaviruses in Slovenia, Yugoslavia. Arch Virol 1990; suppl 1: 87-94.

Hantavirus pulmonary syndrome-related virus from Bolivia SIR-Hantavirus pulmonary syndrome (HPS) has recently recognised in South America. In Sao Paulo State, Brazil, two fatalities occurred in an outbreak involving three brothers.’ In Argentina, 29 cases have been reported in disparate habitats from subtropical Salta Province to temperate areas in Patagonia and in islands of the Parana River.2 A cluster of cases in western Paraguay is currently under investigation. The rodent hosts for these hantaviruses have not been identified. However, sigmodontine rodents came to South America with the bridging of the Bolivar Trench during the Pliocene, and presumably carried hantaviruses with them. A high proportion of cases have occurred in riverine biomes where oryzomine rodents (especially Oligoryzomys spp) predominate. Several species achieve high densities and commonly enter human habitations. We studied supematan’ts of tissue samples of Bolivian specimens from the collections of the Museum of Southwestern Biology in Albuquerque. There were 35 0 microtis, four 0 chacoensis, nine 0 flavescens. Five of 35 0 microtis (14%) from three regions of Bolivia were positive for antibodies reactive with Sin Nombre Virus been

(SNV) nucleocapsid protein by

western

blot.3 The

from these specimens, collected in 1985, RNA.

The

were

kidneys used

Iversson LB, Rosa MD, et al. Investigation on caseof human disease caused by Hantavirus in Juquitiba, state of Sao Paulo, Brazil. Am J Trop Med Hyg 1995; 53 (suppl): abstr 439. Levis SC, Briggiler Am, Cacass M, et al. Emergence of hantavirus pulmonary syndrome in Argentina. Am J Trop Med Hyg 1995; 53 (suppl): abstr 441. Yamada T, Hjella B, Lanzi R, Morris C, Anderson B, Jenison S. Antibody responses to Four Comers hantavirus in the deer mouse (Peromyscus mamculatus): identification of an immunodominant region of the nucleocapsid protein. J Virol 1995; 69: 1939-43. Morzunov SP, Feldmann H, Spiropoulon CF, et al. A newly recognized virus associated with a fatal case of hantavirus pulmonary syndrome in Louisiana. J Virol 1995; 69: 1980-83.

Zaparoli MA, contacts

2 1

Hjelle, Norah Torrez-Martinez, Frederick T Koster

Departments of *Pathology, and Medicine, and Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, USA

to

RNA was subjected to reverse prepare transcription-PCR analysis with consensus hantavirus S segment primers. A 442-nt cDNA product was produced from all seropositive 0 microtis specimens. The nucleotide sequences of the amplification products were determined. Based upon the large nucleotide and aminoacid sequence differences from known hantaviruses,

Response to IFN&agr; in myelogenous leukaemia SIR In their commentary (Oct 14, p 984), Kumar and Gulati review the efficacy of recombinant alpha interferon (IFNa) in chronic myeloid leukaemia (CML) and discuss the results of various clinical trials. We have treated 81 patients with newly diagnosed chromosome Philadelphia (Ph)-positive CML very soon after diagnosis (median time 1

month;

0-7). patients were given IFNa (5X10" units/m2 per day, subcutaneously) for 6 months. For patients who achieved a complete haematological response (CHR, according to Houston’s criteria’), the IFNa dose was adjusted to range

Our

maintain the white blood cell count between 1500 and 5000/)iL and the platelet count between 50 000 and 150 000/gL. The median age of our 81 patients was 50-5 years (17-5-70 45 male, 36 female); by Sokal’s criteria, 46% were low risk, 36% intermediate risk, and 18% high risk. 66 achieved CHR, and the actuarial proportion of patients who achieved CHR at 6 months was 65±10% (95% CI), and at 12 months it was 84±8%. Among the 66 responders who had a cytogenetic evaluation, 31 achieved a complete

(CCR=100% Ph-negative metaphases); a major cytogenetic response (MCR) Ph-negative metaphases). The actuarial proportion

cytogenetic

response

five others achieved

(>65%

who achieved MCR at 6, 12, and 24 months was 7±5%, 31±11% and 56±13%, respectively. The 5-year transformation-free survival (TFS) of the 81 patients was 77±14% (figure); this was influenced by the CHR rate at 3 months (p=0008) and the achievement of MCR or CCR (p<0-0009 and p<00005, respectively). Our results are similar to those reported by the Houston group’ and somewhat better than those reported by other investigators. Differences in results may be due to differing proportions of patients with good prognostic factors, and also to differences in the dose of IFNa. In various multicentre studies the dose has been lower than in both our study and the Houston trial. We tried to maintain the dose 57

World distribution of factor V Leiden mutation

Figure:

Actuarial transformation free-survival

(TFS) of 81 IFNa

treated-CML patients Cumulative incidence analysed by Kaplan-Meier method and compared by log-rank test. 5-year TFS of 81 patients was 77% (95% CI ±14).

of IFNa to achieve myelosuppression as defined by white cell and platelet counts of less than 5000/L and less than 150 000/L, respectively. Our experience of adverse effects (requiring a decrease in IFNa dose) was no more frequent than that in multicentre studies. Recently another multicentre study2 reported results similar to those in previous multicentre analyses. The mean number of patients treated at each individual centre was lower in these trials than in both ours and the Houston trial. Thus, for CML patients treated with IFNa-as for treatments such as bone marrow transplantation3 and other surgical procedures4-the prognosis may also be influenced by the breadth of treatment experience gained by physicians and institutions.

François-Xavier Mahon,

Carole

Fabères, *Josy Reiffers

Service des maladies du sang, CHU Bordeaux, Hôpital 33604 PESSAC, France

Haut-Levêque,

SiR-Rees and colleagues (Oct 28, p 1133-34) report the distribution of factor V (Argso6-7Glu) Leiden in 24 different populations. Their results suggest a high prevalence of heterozygotes in Europeans, whereas the point mutation is absent in ethnic groups from African countries, the MiddleEast, Asia, Australasia, Asia Minor, and the Americas. They conclude that the factor V Leiden point mutation is rare in populations other than European caucasians. However, they report no data on Inuit (Greenland Eskimos), another population with a low incidence of acute ischaemic heart disease and venous thromboembolism.’1 We have studied the Factor V Leiden point mutation in a group of 133 unrelated Greenland Inuit (62 men, 71 women), aged 30-34 years.2 To dilute a possible effect of migration we studied exclusively those individuals born in Greenland by Inuit mothers who were also born in Greenland. We determined factor V Leiden by amplification of the factor V gene by PCR and digestion of the fragment with Mnll.’ None of the subjects in our Inuit population had a history of cardiovascular diseases and none was heterozygous or homozygous for the factor V Leiden point mutation. Thus, our data further support the view that the factor V Leiden point mutation has its origin in the European caucasian population, as suggested by Rees and colleagues. *Moniek P M de Maat, Cornelis Kluft, Jørgen Jespersen,

Jørgen

1

2 1

2

3

4

Kantarjian HM, Smith TL, O’Brien S, et al. Prolonged survival in chronic myelogenous leukemia following cytogenetic response to alpha interferon therapy. Ann Intern Med 1995; 122: 254-61. Ohnishi K, Ohno R, Tomonoga M, et al. A randomized trial comparing Interferon-&agr; with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase. Blood 1995; 86: 906-16. Horovitz MM, Przepiorka D, Champlin RE, et al. Should HLAidentical sibling bone marrow transplants for leukemia be restricted to large centers? Blood 1992; 79: 2771-74. Luft HS, Bunker JP, Enthoven AC. Should operations be regionalized? The empirical relations between surgical volume and mortality. N Engl J Med 1979; 301: 1364-69.

Exit linoleic acid too? SIR-Inoted Katan’s comment (Nov 11, p 1245) that the Dutch are to reduce the trans fatty acid content of margarines to no more than 5%, and will state the content on product labels, because of the association of trans fats with coronary heart disease (CHD). However, about 40% of all margarine high in polyunsaturates is cis-linoleic acid (CLA). In view of the vast amount of information on CLA’s association with CHD and non-insulin dependent diabetes’ with breast cancer in animals, and human breast cells in vitro3 and in vivo/ would not a warning about the CLA content be of greater value?

Barry A Groves Kohima.

1 2

3 4

58

Lyneham Road. Milton

under

Wychwood, Oxford 0X7 6LP, UK

Raheja BS. Obesity and coronary risk factors among South Asians. Lancet 1991; 337: 971. Kearney R. Promotion and prevention of tumour growth effects of endotoxin, inflammation and dietary lipids. Int Clin Nutr Rev 1987;

7: 157-68. France T, Brown P. Test tube cancers raise doubts over fats. New Scientist 1991; Dec 7: 12. Rose DP, Hatala MA. Dietary fatty acids and breast cancer invasion and metastasis. Nutr Cancer 1994; 21: 103-11.

Gram

*Institute for Thrombosis Research, South Jutland University Centre, Denmark; and Gaubius Laboratory TNO-PG, Leiden, Netherlands

3

Esbjerg,

Bjerregaard P, Dyerberg J. Mortality from ischaemic heart disease and cerebrovascular disease in Greenland. Int J Epidemiol 1988; 17: 514-19. de Knijff P,

Johansen LG, Rosseneu M, Frants RR, Jespersen J, Havekes LM. Lipoprotein profile of a Greenland Inuit population. Arterioscler Thrombos 1992; 12: 1371-79. Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated factor V. Nature 1994; 369: 64-67.

SIR-In about 95% of cases, activated protein C resistance is caused by a point mutation in factor V gene, known as factor V Leiden.’As initially shown in a Dutch population this mutation is, with a carrier rate of 2-9%, the most frequent genetic disposition for thrombophilia and deep vein thrombosis. 1,2 Rees and colleagues have shown that the allele occurs mutant predominantly in caucasian with an populations, average frequency of 4-4% in Europeans. The estimated allele frequencies in a small overall sample size of 618 individuals of five different European populations ranging from 0 to 7%. In an attempt to generate reliable criteria for morbidity estimates in a local population, a large scale epidemiological study has been done with a simple and fast method. Dried blood specimens were collected on filter paper test cards (Schleicher and Schull 2992) from 814 anonymous, apparently healthy individuals of a north-eastern German population. DNA was extracted from 3 mm filter paper discs and used to amplify a 267 base-pair fragment of the critical factor V gene region by PCR.’ The factor V Leiden allele was then detected by heteroduplex analysis.’ 58 mutant alleles (56 heterozygote, 2 homozygote) were found among the 1628 alleles tested, resulting in an allele frequency of 3-56% (carrier rate 7-12%). This allele frequency is significantly higher than those found in Italy* (1-45%; 1628 alleles tested; -test; p<0-001) and a Dutch5 population which provided a (1-48%; 948 alleles tested; p<0-001) sample size sufficient for statistical analysis. Our result provides the first reliable statistical evidence for unequal distribution of factor V mutant alleles in Europe.