662

for the reference method, done in 79 non-diabetic subjects and 21 diabetics. Glycaemia varied between 2-7 and 14-8 mmol/1. The results obtained by these methods did not differ significantly. The coefficient of correlation was 0 993 and the linear regression

equation was y = 0-871 + 1’005x. Thus tropical climatic conditions did not affect the reliability of the reflectometers tested. As shown in temperate climatesthis simple, sensitive, and reproducible method does seem to be suitable for use in epidemiological investigation of diabetes mellitus in Africa. Institut Santé et Développement, 15-21 rue de l’Ecole de Médecine, 75006 Paris, France

Hôpital National

A. FISCH

du Point G,

E. PICHARD

Bamako, Mali Institut Santé et Paris

T. PRAZUCK H. LEBLANC

Developpement,

Hôpital National du Point G, Bamako

H. CISSE

1. McLarty DG, Swai AB, Kitange HM, et al. Prevalence of diabetes and impaired glucose tolerance in rural Tanzania. Lancet 1989; i: 871-75. 2. King H. Diabetes mellitus in Africans. Lancet 1989; ii: 42. 3. Rolph M. Diabetes mellitus in Africans. Lancet 1989; ii: 453 4. National Diabetes Data Group. Report of an expert committee on diabetes Bethesda: National Institute of Health (administrative document), 1985.

Slot-blot analysis of cachectin mRNA levels in mononuclear cells.

Samples from patients on pentoxifylline (PTX) were tested in three independent experiments (A, B, C), positive (HL-60) and negative (normal volunteer) controls being included.

improvement in the quality of life in a patient off all chemotherapy.

Pentoxifylline and wellbeing with

in

patients

cancer

SIR,-The cytokine tumour necrosis factor (TNF)/cachectin is a double-edged sword with both benefits (tumour necrosis activity) and negative attributes (cachectin activity). Pentoxifylline (oxpentifylline) modulates cachectin activity in laboratory tests. At concentrations easily achieved in ’patients this drug blocks production of cachectin in lipopolysaccharide-induced macrophagesand it protects cachectin-treated guineapigs from adult respiratory distress syndrome.3 We report our experience with this drug in two cancer patients. A 47-year-old woman with refractory metastatic lung cancer was treated with thiotepa/pentoxifylline in a pilot study of pentoxifylline’s ability to potentiate alkylating agent therapy. During all six monthly cycles the patient reported great improvement in her sense of wellbeing and in her appetite and energy level even though there was no tumour shrinkage. This experience, and the drug’s anti-cachectin activity in preclinical studies, prompted us to try pentoxifylline alone. We gave her two 1-week courses of oral pentoxifylline 400 mg thrice daily separated by 2 weeks of no treatment. During these 4 weeks the patient received no chemotherapy. During both courses the patient reported increased wellbeing, appetite, and ability to perform the activities of daily living. This improvement in symptoms began 4 days after the start of treatment and lasted for several days after the final dose in each course. The patient had previously received five different regimens of chemotherapy and assured us that her sense of wellbeing was not a placebo effect. 1

Blood was collected before and after each course of treatment from this patient and from a 36-year-old patient with breast cancer who was on combination thiotepa/pentoxifylline in the same phase I trial. The second patient was on pentoxifylline 1600 mg thrice daily for 5 days. However, she remained on thiotepa, confounding any evaluation of wellbeing. We assayed cachectin in blood samples by measuring cachectin mRNA in mononuclear cells rather than by protein assay, which seems to be insensitive.4,5 Full details of the method may be had from B. J. D. Cachectin mRNA was assayed by filter hybridisation with a radioactively labelled 400 base-pair cachectin probe (Cetus) with RNA from HL-60 cells pretreated with a phorbol ester as positive control and mononuclear RNA from a healthy volunteer as negative control. On three independent occasions pentoxifylline decreased the steady-state level of cachectin mRNA in mononuclear cells isolated from cancer patients (figure) and this was accompanied by a striking

This suggests, but does not prove, an inverse relation between cachectin and wellbeing. The mechanism by which this drug decreases cachectin mRNA may involve increased cyclic AMP.’6 These observations do not warrant the use of pentoxifylline in the cachexia of cancer (or AIDS); that would be premature. A well-designed study is underway. We thank Jean Gudas for technical advice; William Novick, Jr for encouragement; Emil Frei, III I for comments; and Ruth Sager and the Cetus Corporation for probes. Supported by grants from Aid for Cancer Research, Boston, Massachusetts, and American Cancer Society PRTF-95 and RD-303. Division of Cell Growth and Regulation, Department of Biological Chemistry and Molecular Pharmacology, and Department of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA, and Division of Medical Oncology, Department of Medicine, Beth Israel Hospital, Boston

BRUCE

J. DEZUBE JUDITH L. FRIDOVICH-KEIL ISABELLE BOUVARD ROGER F. LANGE ARTHUR B. PARDEE

B, Cerami A. Cachectm: more than a tumor necrosis factor. N Engl J Med 1987; 316: 379-85. 2 Stneter RM, Remick DG, Ward PA, et al Cellular and molecular regulation of tumor necrosis factor alpha production by pentoxifylline. Biochem Biophys Res Comm 1988; 155: 1230-36. 3. Lilly CM, Sandhu JS, Ishizaka A, et al. Pentoxifylline prevents tumor necrosis factor-induced lung injury. Am Rev Respir Dis 1989; 139: 1361-68. 4. Balkwill F, Burke F, Talbot D, et al. Evidence for tumor necrosis factor/cachectin production in cancer. Lancet 1987; ii 1229-32. 5. Bauer K, ten Carte H, Barzegar S, Spriggs DR, Sherman ML, Rosenberg RD Tumor 1. Beutler

factor infusions have a procoagulant effect on the hemostatic mechanism of humans. Blood 1989; 74: 165-72. 6. Ward A, Clissold SP. Pentoxifylline: a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs 1987; 34: necrosis

50-97.

Thyroid hormone receptor expression in "sick euthyroid" syndrome SIR,-Dr Williams and colleagues (Dec 23/30, p 1477) show that in with liver disease or chronic renal failure, and to a much lesser extent in critically ill patients in intensive care units (ICUs), tri-iodothyronine (T3) receptor expression is increased in the "sick euthyroid" syndrome. We suggest that the critically ill patients might not be euthyroid. The sick euthyroid syndrome is usually diagnosed on the basis of clinical euthyroidism, reciprocal changes in T and reverse T 3 CrT), normal thyroid stimulating hormone, and variable changes in thyroxine (TB). However, the clinical assessment of thyroid activity, including electrocardiographic analysis, in the complex ICU

patients

663

organ failure is often too crude and usually confounded by medication. The suggestion that these patients are

patient with multiple

euthyroid implies

that the sick euthyroid syndrome is a benign condition, which seems not to be the case. We have lately completed a study in critically ill patients with septicaemia in which we have shown a significant relation between severity of the sick euthyroid syndrome and that of delivery-

Other workers have shown that the severity of the syndrome or the administration of rT3 adversely affect outcome.2-5 In our study we could not establish whether the dysfunction in tissue oxygen autoregulation was a result of the critical illness, as was the sick euthyroid syndrome, or whether the syndrome had a causative role in the oxygen uptake disturbance. It is therefore noteworthy that Williams and colleagues found little or no increase in T3 receptor mRNA concentrations in ICU patients with multiple organ failure, suggesting that these patients were possibly not euthyroid. This may support our suspicion that critically ill patients with severe sick euthyroid syndrome may have some degree of hypothyroidism.

dependent oxygen consumption.1

Department of Anaesthesia, St Bartholomew’s Hospital, London EC1A 7BE, UK

remisssion. We believe that pamidronate could be an alternative treatment in MM patients with refractory bone pain. Furthermore, in some patients with a good response to chemotherapy this treatment can heal osteolytic bone lesions. We thank Laboratorio Gador for financial support.

Tinogasta 3153 (1417), Buenos Aires,

Argentina, and Division of Haematology, de Clinicas "Jose de San Martin", University of Buenos Aires

Hospital

1.

M. G. PALAZZO

Intensive Care,

Surgical University Hospital,

Geneva, Switzerland

Eight patients had a substantial decrease in urinary hydroxyproline. Prompt relief of bone pain was achieved within two or three weeks, with improvement in physical performance. Osteolytic lesions improved in five patiens; healing was observed radiographically in four after 3 months of therapy. During treatment no new osteolytic lesions or fractures appeared while MM remained in

P. M. SUTER

MGA, Suter PM, Lopez J. The relationship between thyroid function and oxygen consumption autoregulation in the septic patient. Br J Hosp Med 1989; 42: A139. 2.Kaptein EM,, Weiner JM, Robinson WS, Wheeler WS, Nicoloff JT. Relationship of altered thyroid hormone indices to survival in nonthyroidal illnesses. Clin Endocrinol 1982; 16: 565-74. 3. Slag MF, Morley JE, Elson MK, Crowson TW, Nuttal FD, Shaffer RB. Hypothyroxinaemia m critically ill patients as a predictor of high mortality. JAMA 1. Palazzo

1981; 245: 43-45. 4. Silberman H, Eisenberg D, Ryan J, et al. The relationship of thyroid indices m the critically ill patient to prognosis and nutritional factors. Surg Gynecol Obstet 1988; 166: 223-28. 5 Shigematsu H, Smith R, Shatney C. Detrimental effect of reverse haemorrhagic shock. Crit Care Med 1987; 15: 933-38.

Use of pamidronate for multiple osteolytic lesions

triodothyronine in

myeloma

SIR,-Bone pain is present in 70% of multiple myeloma (MM) patients at the time of diagnosis, and is caused by osteoporosis, osteolytic lesions, or pathological fractures. Several therapeutic approaches have been used to treat these bone lesions-namely, sodium and fluoride, chemotherapy, radiotherapy, biphosphonates. Rodriguez et all showed radiographical evidence of healing in osteolytic skull lesions in 30% of their patients with a good response to melphalan chemotherapy. The use of sodium fluoride, either alone or in combination with calcium and vitamin D, was then widely investigated. Stimulation of osteoblastic bone formation occurs with fluoride alone, but in the absence of additional calcium bone is incompletely mineralised. The net result is osteomalacia and increased bone resorption. The use of fluoride plus calcium resulted in an increase in bone formation as measured by histomorphometry, but was not better than placebo when osteolytic lesions were evaluated radiographically. Biphosphonates have proved to be good inhibitors of bone resorption2 and they have been used in the treatment of hypercalcaemiaand osteolytic lesions in MM,’ mainly in short-course trials. We evaluated a biphosphonate pamidronate (’Aminomux’, Gador) in eleven MM patients with osteolytic bone lesions. Ten patients received melphalan-prednisone (in combination with alpha-interferon in two), and one had polychemotherapy. The therapeutic schedule consisted of pamidronate 300 mg daily, calcium 1 g/daily, and oral 1,25 (OH)2D3 0-25 ug daily for 6-24 months. Two patients died because of myeloma kidney: they had received pamidronate for 4-6 months before death. Hypercalcaemia developed in four patients and resolved after calcium and vitamin D suppression, hydration, and increase of pamidronate dose up to 600 mg daily. Parathormone level did not increase even after 24 months of treatment, except in the two patients who died in renal failure.

ZULEMA MAN ALCIRA BEATRIZ OTERO PABLO RENDO LUCIA BARAZZUTTI JULIO CÉSAR SANCHEZ AVALOS

Rodriguez LH, Finkelstein JB, Schullenberger CC, Alexanian R. Bone healing in multiple myeloma with melphalan chemotherapy. Ann Intern Med 1972; 76:

551-56. 2. Van Breukelen FJM, Bijvoet OLM, van Oosterom AT. Inhibition of osteolytic bone lesions by (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (A.P.D.). Lancet

1979; i: 803-05. AD, Kanis JA, Cameron EC, et al. The use of dichloromethylene diphosphonate for the management of hypercalcaemia in multiple myeloma. Br J Haematol 1983; 54: 121-32. 4. Radl J, Croese JW, Zurker C, et al. Influence of treatment with APD biphosphonate on the bone lesions in the mouse 5T2 multiple myeloma. Cancer 1985; 55: 3. Paterson

1030-40.

Diagnosis of Creutzfeldt-Jakob disease by electron microscopy SiR,—The infectious agent(s) responsible for slow transmissible neurological diseases such as Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler syndrome has not yet been clearly identified and definitive diagnosis of these progressive spongiform encephalopathies is based on histological examination or on transmission of disease to laboratory animal hosts. In scrapie, the related disease of sheep and goats, infectivity seems to be associated with scrapie-associated fibrils/protease resistant protein (SAF/ PrP).l This protein is coded for by the normal genome and expressed equally in normal and infected animals; however, it does aggregate to form SAF in normal tissue. SAF form the core of tubulofilamentous virus-like particles2,3which are unique to spongiform encephalopathies. These particles containing SAF can be demonstrated by electron microscopy (EM) in hamster brains as early as 21 days post-inoculation, with clinical disease developing 40-60 days later,2 but they are not present in normal brains or in non-spongiform encephalopathies,4 and we have confirmed this in ten control patients aged 42-84. These observations suggest that tubulofilamentous particles/SAF can be used as an identifying feature of the spongiform encephalopathies. With the touch technique of EM grid preparation we examined four clinically diagnosed cases of CJD aged 46-76 (two males). These patients died during a 12 month period in 1988-89 and they had been ill for between 2 and 12 months; all four patients died in hospital. Fresh cortical brain slices were taken and grids were prepared for EM by placing ten formvar-carbon coated grids moistened with distilled water on the cut surface for a minute and rinsing them with fresh drops of distilled water for a further minute to lyse cells. Five of these ten grids from each patient were soaked in 1 % sodium dodecylsulphate (SDS) for 1 min, rinsed with water five times, and then fixed and stained together with the five non-SDS treated grids.2 Grids were examined in a Jeol 1200EX II electron

not

microscope. Examination of grids from four cases of spongiform encephalopathy prepared without SDS treatment revealed 50 nm diameter tubulofilamentous particles, often over 1 pm long (figure, a). Their distribution was uneven but averaged two or three per grid square. Often a small clump of two to five tubulofilamentous particles was observed (figure, a). SDS disrupted the outer coat,