Medical Research Council leukaemia trial--UKALL V: an attempt to reduce the immunosuppressive effects of therapy in childhood acute lymphoblastic leukemia. Report to the Council by the Working Party on Leukaemia in Childhood

The Medical Research Council UKALL V trial for children with standard-risk acute lymphoblastic leukemia (ALL) (aged 1 to 14 years, leucocyte count less than 20 X 10(9)/L) was designed to determine whether the immunosuppressive effects of treatment could be reduced without sacrifice of antileukemic effect by alterations in the type of continuing therapy or in fractionation of cranial irradiation. Remission was achieved in 496 children on standard induction therapy, and 309 children received 24 Gy of cranial irradiation in ten to 16 fractions over 21 days, and 174 received 21 Gy in five to nine fractions over 21 days. The type of radiotherapy administered had no influence on relapse at any site or rate of death in remission. All 496 children were randomized to receive chemotherapy for 2 or 3 years with 6-mercaptopurine and methotrexate either as a continuous (group C) or a semicontinuous (group G) regimen or as a five-day pulse every 3 weeks (group I). All groups also received vincristine and prednisolone every 6 weeks. With a minimum follow-up of almost 7 years, patients in group I had significantly fewer remission deaths (P = .025) but a much higher rate of bone marrow relapse than those in group C or G (P = .002). There was an overall benefit for 3 years of chemotherapy compared with 2 years, which in contrast to previous studies, was more apparent in girls and in patients in groups C and G. Testicular relapse occurred in 37 boys, including 19 patients off therapy, with a previously negative biopsy. The overall results confirmed the prognostic significance of initial leucocyte count, even among these standard-risk patients, while girls had a superior rate of disease-free survival, but not of hematologic remission. It is concluded that, even among standard-risk patients, the prognosis is influenced by the height of the initial leukocyte count. While alterations in the fractionation of cranial irradiation do not appear to have influenced disease-free survival, intermittent continuing chemotherapy, although less immunosuppressive, is less effective than conventional continuous therapy in the treatment of ALL. In this study, 3 years of chemotherapy appeared superior to 2 years.     

Gastrin: growth enhancing effects on human gastric and colonic tumour cells

Two colorectal (HT29, LoVo) and one gastric (MKN45) human tumour cell lines were examined for their in vitro trophic response to human gastrin-17. MKN45 and HT29 responded by increased 75Se selenomethionine uptake to exogenous gastrin (139 +/- 5.5% and 123 +/- 3% of control values respectively) whereas LoVo showed no significant response to this hormone. When these same cell lines were grown as xenografts in nude mice, similar responses were seen to exogenously administered human gastrin-17 (10 micrograms mouse-1 day-1, subcutaneous injection). MKN45 xenografts showed a greater response to continuously administered gastrin (osmotic mini-pumps, (10 micrograms mouse-1 day-1) when compared to the same dose given via a subcutaneous bolus injection. The hormone-treated xenografts had a two-fold increase in tumour cross-sectional area and growth rate when compared to saline-treated controls. Dose-response studies revealed that 0.4 micrograms gastrin mouse-1 day-1 appeared to be the minimally effective dose. As gastric and colorectal tumour cells show a trophic response to gastrin, antagonists of the gastrin receptor may prevent this effect causing tumour stasis. The gastric tumour cell line, MKN45, is gastrin-responsive and would be an ideal model for screening potent receptor antagonists.     

The effects of ice massage, ice massage with exercise, and exercise on the prevention and treatment of delayed onset muscle soreness

We investigated the effects of ice massage, ice massage with exercise, and exercise on the prevention and treatment of delayed onset muscle soreness (DOMS). Twenty-two subjects were randomly assigned to one of four groups. Preexercise measures were recorded for range of motion (ROM), strength, perceived soreness, and serum creatine kinase (CK) levels. Subjects performed up to 300 concentric/eccentric contractions of the elbow flexors with 90% of their 10 repetition maximum to induce muscle soreness. Dependent variables were assessed at 2, 4, 6, 24, 48, 72, 96, and 120 hours postexercise. Significant differences occurred in all variables with respect to time (ANOVA(p<.05)). However, no significant mode of treatment, or mode of treatment/assessment time interaction was present. Decreases in range of motion and flexion strength correspond with increases in perceived soreness. The nonsignificant mode of treatment/assessment time interaction suggests that the use of ice massage, ice massage with exercise, or exercise alone is not effective in significantly reducing the symptoms of delayed onset muscle soreness. In fact, though not statistically significant, the pattern of the data suggested the use of ice in the treatment of DOMS may be contraindicated. Further investigation is recommended.     

Simultaneous presentation of sarcoidosis and acute myeloid leukaemia: predisposition to pulmonary haemorrhage.

A case of coexistent acute myeloid leukaemia and sarcoidosis is reported. This was complicated by recurrent pulmonary haemorrhage during reinduction and consolidation chemotherapy. A review of published papers on malignancy and sarcoidosis, in particular acute leukaemia is given. The outcome of most cases of acute leukaemia and sarcoidosis is poor with respiratory complications a frequent cause of death in this group. It is proposed that modifications to treatment to avoid pulmonary toxicity and maintenance of platelet counts above 40 x 10(9)/l are warranted to reduce the risk of this complication.     

Hydrosalpinges adversely affect markers of endometrial receptivity

While in-vitro fertilization (IVF) was initially developed in women with tubal factor infertility, recent clinical studies have suggested that the presence of hydrosalpinges lowers implantation and pregnancy rates. We postulated that these hydrosalpinges cause impaired endometrial receptivity. A total of 103 women with hydrosalpinges were prospectively evaluated, and compared with 55 infertile and 44 fertile controls. All women had endometrial biopsies during the window of implantation, analysed by conventional histological criteria, and also stained for three integrin markers of endometrial receptivity (alpha1beta1, alpha4beta1 and alpha vbeta3). Women with hydrosalpinges (cases) expressed significantly less of the alpha vbeta3 integrin compared with controls. There was no difference in expression of alpha1beta1 or alpha4beta1 among groups. A significantly greater number of cases had out of phase histology and missing alpha vbeta3 (type I defects) and absent integrin expression despite normal histological maturation (type II) defects, compared with controls. Of 20 women with impaired endometrial receptivity who were also biopsied after hydrosalpinx surgery, 70% demonstrated increased alpha vbeta3 expression. Seventy-seven percent of type I and 57% of type II defects were corrected postoperatively. Using markers of endometrial receptivity, this study demonstrates that inflammatory hydrosalpinges have an adverse effect on endometrial receptivity, which in some cases may be overcome by surgical treatment of the hydrosalpinx.      

bcl-2 transgene expression promotes survival and reduces proliferation of CD3-CD4-CD8- T cell progenitors

Proliferative expansion and apoptotic cell death play prominent roles in T cell development. The molecular control of cell cycle progression and apoptosis appear to be inter-connected since the Bcl-2 protein can inhibit apoptosis and slow cell cycle progression in cortical thymocytes and mature T cells, particularly during the transition from the quiescent state into the cell cycle. Here the impact of bcl-2 transgene expression on CD3-CD4-CD8- T cell progenitors was assessed. Bcl-2 enhanced the survival of these progenitors at all of the four major differentiation stages, CD25- CD44+ (pro-T1), CD25 + CD44+ (pro- T2), CD25 + CD44- (pro-T3) and CD25-CD44- (pro-T4). However, it reduced cell cycling and slowed turnover only in the pro-T4 subset. From an analysis of bcl-2 transgenic mice expressing a TCR transgene or bearing a mutation in the scid or rag-1 gene we conclude that Bcl-2 inhibits proliferation only of T cell progenitors that are activated via the pre- TCR, not those stimulated via c-Kit and the IL-7 receptor.      

Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism

Parathyroid hormone secretion is negatively regulated by a 7- transmembrane domain, G-protein coupled Ca(2+)-sensing receptor. We hypothesized that activating mutations in this receptor might cause autosomal dominant hypoparathyroidism (ADHP). Consistent with this hypothesis, we identified, in two families with ADHP, heterozygous missense mutations in the Ca(2+)-sensing receptor gene that cosegregated with the disorder. None of 50 normal controls had either mutation. We also identified a de novo, missense Ca(2+)-sensing receptor mutation in a child with severe sporadic hypoparathyroidism. The amino acid substitution in one ADHP family affected the N-terminal, extracellular domain of the receptor. The other mutations involved the transmembrane region. Unlike patients with acquired hypoparathyroidism, patients with these mutations had hypercalciuria even at low serum calcium concentrations. Their greater hypercalciuria presumably reflected activation of Ca(2+)-sensing receptors in kidney cells, where the receptor negatively regulates calcium reabsorption. This augmented hypercalciuria increases the risk of renal complications and thus has implications for the choice of therapy.      

Symptomatic peripheral arterial disease: the value of a validated questionnaire and a clinical decision rule

BACKGROUND: If a validated questionnaire, when applied to patients reporting with symptoms of intermittent claudication, could adequately discriminate between those with and without peripheral arterial disease, GPs could avoid the diagnostic measurement of the ankle brachial index. AIM: To investigate the Edinburgh Claudication Questionnaire (ECQ) in general practice and to develop a clinical decision rule based on risk factors to enable GPs to easily assess the likelihood of peripheral arterial disease. DESIGN OF STUDY: An observational study. SETTING: General practice in The Netherlands. METHOD: This observational study included patients of > or =55 years visiting their GP for symptoms suggestive of intermittent claudication or with one risk factor. The ECQ and the ankle brachial index were performed. The prevalence of peripheral arterial disease, defined as an ankle brachial index <0.9, was related to risk factors using logistic regression analyses, on which a clinical decision rule was developed and related to the presence of peripheral arterial disease. RESULTS: Of the 4790 included patients visiting their GP with symptoms suggestive of intermittent claudication, 4527 were eligible for analyses. The prevalence of peripheral arterial disease in this group was 48.3%. The sensitivity of the ECQ was only 56.2%. The prevalence of peripheral arterial disease in a clinical decision rule that included age, male sex, smoking, hypertension, hypercholesterolemia, and a positive ECQ, increased from 14% in the lowest to 76% in the highest category. CONCLUSION: This study indicates that the ECQ alone has an inadequate diagnostic value in detecting patients with peripheral arterial disease. The ankle brachial index should be performed to diagnose peripheral arterial disease in patients with complaints suggestive of intermittent claudication, although our clinical decision rule could help to differentiate between extremely high and lower prevalence of peripheral arterial disease.     

An influenza A(H3) reassortant was epidemic in Australia and New Zealand in 2003

During 2003, Australia and New Zealand experienced substantial outbreaks of influenza. The strain responsible was an A(H3N2) influenza virus described as A/Fujian/411/2002-like, which had circulated as a minor variant in the previous Northern Hemisphere (NH) winter, mainly in Korea and Japan. Early in the year the isolates were very similar to those that had been previously isolated in the NH, however, a reassortant strain emerged early in the New Zealand winter, followed by the appearance of similar viruses in Australia and other regional areas. While the hemagglutinin HA1 sequence of these viruses demonstrated only minor differences from the A/Fujian/411/2002 reference strain, the neuraminidase gene was clearly different from that of other recently circulating H3 viruses and most closely matched an earlier reference strain A/Chile/6416/2001. Three internal genes (NS, NP, M) in the reassortant viruses were also more closely related to the A/Chile/6416/2001 lineage. This reassortant A(H3) virus predominated in Australia and New Zealand in 2003 was also seen in Brazil and Malaysia during 2003 and was widespread in the United States and Europe during their 2003-04 winter. Interestingly most of the strains of A(H3) that were isolated at the beginning of the 2004 winter in Australia, did not have this earlier A/Chile/6416/2001-like neuraminidase but had a neuraminidase that was similar to that of the reference strain A/Fujian/411/2002. This was suggestive of the re-introduction of influenza A(H3) from other countries, however, there was still low level circulation of the reassortant virus in 2004 with isolates detected in Australia and Singapore.