Ulcerative cheilitis in a rhesus macaque.

A 2-year-old, female, simian immunodeficiency virus E543-infected rhesus macaque (Macaca mulatta) was presented for necropsy following euthanasia due to a history of diarrhea, weight loss, and a small, round ulcer along the left labial commissure. Histopathologic examination of the ulcer revealed infiltration by large numbers of degenerate and nondegenerate neutrophils and macrophages admixed with syncytial epithelial cells. Rare epithelial cells contained herpetic inclusion bodies. These cells stained positive for Human herpesvirus 1 via immunohistochemistry, and DNA sequencing confirmed the presence of closely related Macacine herpesvirus 1 (B virus).

Ovarian pathology in rhesus macaques: a 12-year retrospective.

BACKGROUND: Ovarian pathology is an important cause of decreased fertility and reproductive capability and may impact multiple systems, particularly in aging rhesus macaques. METHODS: Retrospective histopathologic and immunohistochemical analysis of 458 female rhesus macaque necropsies over 12 years at the New England Primate Research Center in Southborough, MA. RESULTS: Degenerative and inflammatory changes in the ovaries included mineralization, infiltration by lymphocytes, macrophages and multinucleated giant cells, endometriosis, and arteriopathy. Cystic changes included follicular cysts, cystic rete, and mesonephric duct cysts with cystic rete the most common. Neoplasms included granulosa cell tumors, cystadenoma, cystadenocarcinoma, and teratoma. CONCLUSIONS: Ovarian lesions of the rhesus macaque are similar to those of cynomolgus macaques and humans. These lesions are frequently incidental findings but may impact metabolic and neurocognitive studies.

MRC UKALL X. The UK protocol for childhood ALL: 1985-1990. The Medical Research Council Working Party on Childhood Leukaemia.

MRC UKALL X, the successor of UKALL VIII ran from 1985 to 1990 and accrued 1614 patients aged 0-15 years. After standard induction all children except those with initial white cell count greater than 100 x 10(9)/1 were randomised to one of four regimens; +/- early intensification +/- late intensification. CNS protection for all comprised cranial irradiation and intrathecal methotrexate with continuing treatment for two years. At a median follow up of four years the overall event free survival for all children is 66% (SE 1.5). This is a significant improvement over the previous MRC UKALL VIII trial. Age, sex and leucocyte count were highly significant prognostic factors. Analysis of the results indicates that the regimen containing both intensifications is superior. The strategy of early and late intensification has been adopted in the successor protocol MRC UKALL XI in which patients are additionally randomised to receive high dose methotrexate.

Acute lymphoblastic leukaemia in infancy: experience in MRC UKALL trials. Report from the Medical Research Council Working Party on Childhood Leukaemia.

Acute lymphoblastic leukaemia (ALL) is rare under 1 year and has a poor prognosis. Only 14 of 48 infants treated on two consecutive MRC UKALL trials remain alive in first remission. Forty infants have subsequently been treated on a protocol incorporating further intensification with an option for high-dose chemotherapy and autologous or allogeneic bone marrow transplantation. The results show no improvement over previous trials largely due to the number of remission deaths; four of nine being associated with toxicity of 5 days of etoposide and cytarabine. Only three of 11 children treated by high-dose chemotherapy and transplantation remain alive in remission. Multivariate analysis of the factors influencing prognosis in all 88 infants showed that only age was significant. Event-free survival was 40% at 5 years for children over 26 weeks but under 10% for younger children. These results show the susceptibility of infants to the toxicity of intensive chemotherapy and do not support the use of short term high-dose chemotherapy alone in the management of infant leukaemia. Despite the unique biological features of infant ALL it appears that these patients also may benefit from longer courses of treatment with a maintenance (continuing) phase.

The impact of age on outcome in lymphoblastic leukaemia; MRC UKALL X and XA compared: a report from the MRC Paediatric and Adult Working Parties.

The purpose of the study was to examine the influence of age on outcome in a large cohort of children and adults with lymphoblastic leukaemia who were treated on two similar trials. Factors influencing outcome were examined in 2204 patients aged over 1 year treated between 1985 and 1992 on the parallel Medical Research Council Trials UKALL X and XA, for children and adults, respectively. There was a progressive worsening in survival with increasing age from 85% (95% CI 83-87) at 5 years for children aged 1-9 to 24% (CI 17-31) for patients over 40. Induction failures, deaths in remission and bone marrow relapses increased significantly with age. Analysis of clinical and biological features showed dominance of early B-ALL in childhood and increasing incidence of the Ph' chromosome with age. Over 80% of eligible children, but a much lower proportion of adults especially those over 40, was entered. Compliance was stricter in the paediatric trial but most deviations in adults involved giving more treatment. Analysis of results in a proportional hazards model confirmed the overwhelming independent influence of age; with all other factors equal a 10 year old had half the risk of treatment failure of a 20 year old and a 44 year old double the risk. Selective entry to therapeutic trials and increased treatment-related toxicity are features of adult ALL but age itself remains a dominant prognostic factor. While improved supportive care and refinements of conventional therapy may have some effect on prognosis, new understandings and treatment approaches to adult ALL are needed.

Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukaemia, 1980-1997. Medical Research Council Childhood Leukaemia Working Party.

Results of three consecutive completed UK trials (1980-1997) for childhood lymphoblastic leukaemia are presented. National accrual has progressively increased so that over 90% of all the country's ALL cases were treated on the latest trial reported, UKALLXI. From 1980 to 1990, event-free and overall survival progressively improved, following adoption of an American therapy template and use of two post-remission intensification modules. Since 1990 despite demonstration of the benefit of a third intensification module overall event-free survival (EFS) has not improved further. Survival remains high due to a good retrieval rate especially for those relapsing off treatment after receipt of two intensification pulses. Possible reasons for the plateau in event-free survival (including type and dose of induction steroid, dropping of induction anthracycline, type and dose of asparaginase, gaps early in therapy following intensification, and overall lack of compliance in maintenance) are being explored in the latest protocol ALL '97. Cranial irradiation had been successfully replaced by a long course of intrathecal methotrexate injections for the majority of patients. Age (<1 year >10 years) sex (male) and white count >50 x 10(9)/l plus slow initial bone marrow clearance were consistently the most important independent prognostic indicators during this time period. Rome/NCI criteria accurately predict standard and high-risk groups for B cell lineage, but not consistently for T cell disease. This international collaborative venture might help us to define those truly at highest risk, and how we can optimise therapy for specific subgroups including T-ALL and those with unfavourable cytogenetics.

Characterization of genes encoding topoisomerase IV of Mycoplasma genitalium.

A type-II toposiomerase (Topo-IV) encoded by the parC and parE genes in Escherichia coli and Salmonella typhimurium is thought to be involved in cell septation and in the decatenation of newly replicated chromosomes. We have identified parC and parE homologs in the pleomorphic, wall-less organism Mycoplasma genitalium. Since the mechanics of cell septation in conventional eubacterial species is believed to be mediated by cell-wall constituents, there is no clear understanding of what coordinates that process in wall-less species. The presence of par genes in this bacterium, which has the smallest genome of any free-living organism, suggests that Topo-IV has been evolutionarily conserved because of an essential role in mediating cell division.

Survival from childhood cancer in Yorkshire, U.K.: effect of ethnicity and socio-economic status.

The effect of ethnicity and socio-economic status on the survival of a population-based cohort of 1979 children diagnosed with cancer between 1974 and 1995 was investigated. Ethnicity was assigned by computer algorithms and visual inspection as south Asian (or not) for each child, based on their full name. Socio-economic status was measured using the Carstairs index, based on census areas of case residence at diagnosis. 15 children (0.8%) were lost to follow-up. Log-rank tests showed survival from all cancers did not differ between south Asians and other children and no increased risk was observed for south Asians in any diagnostic category, although numbers were small. Increasing levels of deprivation were associated with significant trends of poorer survival from all cancers, leukaemias and brain tumours. Risk of death was typically higher for children from the most deprived areas although differences were not statistically significant after accounting for other factors including ethnicity. Taking all children with malignant disease together, neither ethnicity nor socio-economic status appear to influence survival after taking other factors into consideration.

Developmental responses to opioids reveals a lack of effect on stress-induced corticosterone levels in neonatal rats.

The neonate has an unusual capacity for survival and the possibility exists that mechanisms for controlling stress responses may differ in the developing animal. In adults both endogenous and exogenous opioids can modulate the corticosterone responses to stress. We have studied this effect in neonatal rats and found that opioid modulation is absent in early postnatal development. Neonatal rats of either sex were injected with morphine (5-50 mg kg-1), fentanyl (10-100 micrograms kg-1), buprenorphine (0.1-30 mg kg-1) or naloxone (0.1-10 mg kg-1) and plasma corticosterone measured fluorimetrically 15 or 20 min later. In addition naloxone reversibility studies (1 mg kg-1, co-administered) were carried out for the opioid agonists. In adult rats, elevations in plasma corticosterone caused by injection stress were potentiated by morphine, fentanyl and buprenorphine. In neonates, though injection stress-induced rises in plasma corticosterone were absent at 10 days, elevations were observed at 21 days and later. However, significant potentiation of this corticosterone response by fentanyl was absent at 21 days and at later ages (30 and 40 days) for morphine and buprenorphine. The potentiating effect of all three agonists did not become fully effective until day 45. In addition, in animals acclimatized to injection stress by 7 day injection pretreatment, fentanyl did not significantly alter corticosterone levels in 30 day old neonates. High doses of naloxone (10 mg kg-1) significantly increased the corticosterone response to injection stress in adult rats but this effect was absent in 30 day old animals. A dose of naloxone (I mg kg-') which had no significant effect on the corticosterone response inhibited the effects of morphine, fentanyl and buprenorphine in 45 day old and adult rats. 5 This late development of opioid action is unusual in comparison with the maturation of endogenous peptides, receptors and antinociceptive responses and suggests that alternative mechanisms may be involved in stress-control in the neonate.

Childhood lymphoma in Yorkshire.

AIMS: A histopathological review of 43 cases of childhood non-Hodgkin's lymphoma (NHL) in an attempt to identify histological variables of prognostic importance. METHOD: Each case was reclassified according to the Working Formulation and an attempt made to allocate an immunophenotype using a panel of monoclonal antibodies. Results were correlated with clinical data on site and survival. RESULTS: Of the 43 cases, 30 were males and 13 females. There were 17 cases of lymphoblastic lymphoma, 15 cases of small non-cleaved cell lymphoma (SNCC), and four cases of large cell lymphoma. The SNCC group was subdivided into 10 cases of Burkitt's lymphoma and five cases of non-Burkitt's lymphoma. An immunophenotype was allocated in 65.1% of cases (23 B, 5 T). The SNCC cases were spread throughout the 0-16 year age range while the lymphoblastic lymphoma cases tended to occur in older children. Most mediastinal tumours were lymphoblastic lymphoma and most abdominal tumours were SNCC. Statistical analysis failed to show a significant difference in survival among histological subgroups or immunophenotypes. CONCLUSION: No histological variables of prognostic importance were identified partly due to the great variation in treatment regimens, standard of supportive care, and prognosis over the period of the study (1972 to 1988).

Periodic acid Schiff reaction in childhood lymphoblastic leukaemia. The Medical Research Council Working Party on Childhood Leukaemia.

AIMS: To assess the prevalence and degree of periodic acid Schiff (PAS) positivity in blast cells from children with lymphoblastic leukaemia (ALL); its association with other disease characteristics; and its clinical importance in predicting the outcome of treatment. METHODS: Marrow slides from entrants to a large United Kingdom multicentre ALL trial (UKALL X) were batch processed and assessed blind for PAS positivity by one morphologist. Patients were classified into groups A, B, and C, corresponding to less than 1% PAS positive cells, 1-10%, and over 10%, respectively. Their PAS pattern was then compared with other clinical and pathological features of ALL and with treatment outcome. RESULTS: Slides from 921 children were examined of which 371 (40%) were categorised as group A, 324 (35%) as group B, and 226 (25%) as group C. There was a clear association between the presence of blast cell vacuoles on Romanowsky staining and PAS positivity. Group A (PAS negative) patients included a disproportionate excess of those with L2 morphology, those under 2 or over 6 years of age, those with an initial white cell count over 50 x 10(9)/l, those with a T or null cell immunophenotype, and those with chromosomal abnormalities other than "high hyperdiploidy". Four years from diagnosis, group C patients had an 8% disease free survival advantage over those in group A (2p = 0.01). This was irrespective of initial white cell count, but not of immunophenotype or the presence of vacuoles. CONCLUSIONS: Strong PAS positivity is a feature of "common" ALL and is particularly associated with blast cell vacuoles. It does occasionally occur in other disease subtypes with or without vacuoles. It predicts a better response to current treatment, but not independently of other cell characteristics.

12q13 abnormality in rhabdomyosarcoma. A nonrandom occurrence?

We describe two cases of rhabdomyosarcoma with a translocation involving 12q13 as the primary cytogenetic abnormality. Literature review of 35 cases has identified 3 other cases with this abnormality, and we speculate that this may be another nonrandom rearrangement in rhabdomyosarcoma.

Accidental actinomycin D overdosage in man, a case report.

Although actinomycin D is a relatively old cytotoxic agent, relatively little is known about its toxicity in man in comparison with some of the newer cytotoxic agents that have been extensively investigated. We wish to describe a case where an overdose of actinomycin D was inadvertently administered.

Dental parameters in the long-term survivors of childhood cancer compared with siblings.

There have been a number of reports on the dental health of long-term survivors (LTS) of childhood malignancy as compared with normal controls. However, it is usually difficult to identify a meaningful control population as most of these patients are from widely differing geographical areas and socio-economic status. The aim of this investigation was, therefore, to study the dental health of LTS compared with siblings. 46 LTS who had siblings of a similar age were identified for the study. Both groups were examined for dental caries, gingivitis and enamel defects. There was no statistically significant difference in the mean DMFS of the test and control groups. However, the LTS had a significantly (P = 0.006) higher number of decayed surfaces (1.50 +/- 0.30) as compared with their siblings (0.50 +/- 0.20). The LTS also had a significantly higher prevalence of severe gingivitis (1.11 +/- 0.33) compared with controls (0.02 +/- 0.02). There was a significantly higher prevalence of all types of enamel defects in the LTS and fewer teeth with no enamel defect as compared with their siblings, with the mean values being 15.7 +/- 0.9 and 25.3 +/- 0.3, respectively. It was concluded that there was a higher prevalence of untreated dental disease and developmental defects in long-term survivors.

Thalidomide in the treatment of graft-versus-host disease.

The success of allogeneic bone marrow transplantation has been restricted by the occurrence of graft-versus-host disease (GVHD). Attempts at prevention and treatment of GVHD have resulted in only a limited improvement and the morbidity and mortality rate remains high. Thalidomide has been known to have immunosuppressive properties for over 20 years, but it has only recently been used in GVHD. Evidence is now accumulating as to its value both in animal models, and in humans where most benefit has been seen in chronic GVHD. We report our experience using thalidomide in GVHD following allogeneic bone marrow transplantation and review the literature.

Ontogeny of catecholamine and GABA levels in rat brain: lack of effect of perinatal lead exposure.

In this study we report the ontogeny of noradrenaline, adrenaline, dopamine, and gamma-aminobutyric acid (GABA) in the rat striatum and the effect of perinatal exposure to low levels of lead. Lead administered in the maternal drinking water (100, 300 and 1000 ppm) from conception to weaning had no effect on the ontogeny of catecholamines. There was a 50% decrease in the levels of GABA at 10 days in rats exposed to the highest dose of lead, but no other changes were observed in lead-exposed rats at 21 and 30 days of age. These results contrast with our previously reported decrease in the levels of striatal proenkephalin products in lead-exposed rats, and suggest that this inhibitory effect of lead does not represent a generalised neurochemical toxicity.

Maternal performance of Hereford, Brangus, and reciprocal crossbred cows under semidesert conditions.

Maternal performance of 134 Hereford (H), Brangus (B), and reciprocal crossbred (H x B and B x H) cows from 2 to 7 yr of age was evaluated under semidesert conditions in this study. Calves produced by 2- and 3-yr-old cows were sired by Brangus and Hereford bulls. Calves produced by 4- to 7-yr-old cows were sired by Charolais bulls. Breed of sire and breed of dam of cow affected kilograms of weaning weight, 205-d weight, weaning weight as a percentage of cow weight, and 205-d weight as a percentage of cow weight produced annually. Brangus (either as sire or dam of cow) was superior to Hereford in all cases. Observed maternal heterosis on 2- to 3-yr-old cows was 23.0, 20.1, 30.0, 29.1, 23.9, and 23.0% for calf birth date, weaning percentage, weaning weight per year, 205-d weight per year, weaning weight as a percentage of cow weight per year, and 205-d weight as a percentage of cow weight per year, respectively (P less than .01). Observed maternal heterosis from mature cows was 19.8, 12.8, 21.0, 18.7, 17.4, and 15.4% for calf birth date, weaning percentage, weaning weight per year, 205-d weight per year, weaning weight as a percentage of cow weight per year, and 205-d weight as a percentage of cow weight per year, respectively (P less than .01). Results indicate large heterotic effects on annual cow productivity and an adaptive advantage for cows with Brangus sires and(or) dams under semidesert conditions.

Evaluation of biological efficiency of free-grazing beef cows under semidesert conditions.

Effects of cow BW, hip height, and estimated genetic potentials (EBV) for weaning weight direct and milk on cow productivity, fecal OM output, OM intake, and efficiency (kilograms of calf BW/kilogram of OM intake by the cow) were evaluated with 44 free-grazing crossbred cows under semidesert conditions. Calf BW were measured during early, mid-, and late lactation. Data were collected in four periods: Period 1 = late spring (early lactation), Period 2 = late summer (mid-lactation), Period 3 = mid-autumn (late lactation), and Period 4 = mid-winter (nonlactation). Calf BW increased linearly with cow BW (P < .01) in Periods 1, 2, and 3. Fecal OM output and OM intake increased with cow BW in Periods 2 (P < .01) and 4 (P < .01), and on average (P < .02). Overall efficiency decreased with increasing cow BW (P < .04). Taller cows excreted more fecal OM and had greater OM intake throughout the study (P < .02 to P < .11). Overall efficiency decreased with increasing cow hip height (P < .05). Weaning weight direct EBV of cows was related linearly to cow BW (P < .01 to P < .07) and to calf BW (P < .01 to P < .07). Calf weight in all periods increased linearly with milk EBV (P < .001). Overall, fecal OM output, OM intake, and efficiency were not affected by milk EBV.

Surgical management of thoracic malignancy in childhood: eight years' experience in Leeds.

During the period 1978 to 1986, 13 children aged 2-15 years underwent surgical resection of malignant thoracic tumours. Five children with neuroblastomas presented with chest pain and infections, pleural effusions, dysphagia, lymphadenopathy and paraplegia. Chemo- and radiotherapy were given preoperatively to previously diagnosed cases and postoperatively to all survivors. At operation, complete tumour clearance was possible in only two cases. Two children remain alive with no sign of recurrence at 6 and 7 1/2 years. Eight children with pulmonary metastases had undergone resection of the primary tumour and systemic chemotherapy. All were asymptomatic and were detected by chest radiographs. Wedge resection or lobectomy was performed. Two required contralateral resections at 4 months. Two children remain alive with no evidence of recurrence at 2 and 6 1/2 years. We conclude that aggressive surgical resection of childhood thoracic malignancy is worthwhile, but cooperation with a paediatric oncology team is essential.

Excess benign melanocytic naevi after chemotherapy for malignancy in childhood.

OBJECTIVE: To see whether children who have had chemotherapy develop increased numbers of moles. DESIGN: Blind assessment of patients having chemotherapy and subsequent comparison with the first suitable patients matched for age and sex who were attending the clinic during the same period after having completed treatment. Controls were obtained the following year by taking the first suitable patients attending a routine dermatology outpatient clinic who matched the study groups for age and sex. SETTING: Referrals to a paediatric oncology clinic and a dermatology clinic at two city hospitals. PATIENTS: The group receiving chemotherapy comprised all 32 patients with acute lymphatic leukaemia, lymphoma, and rhabdomyosarcoma who were attending the paediatric oncology clinic on two mornings a week during October 1987 to March 1988. The group who had completed treatment comprised 32 patients who were attending for follow up during the same period and who matched the first group for age and sex. Thirty two other patients attending the dermatology outpatient clinic with unrelated skin conditions served as controls. END POINT: Definite increase in numbers of moles on children after a course of chemotherapy. MEASUREMENTS AND MAIN RESULTS: Moles were counted by one observer on defined areas of the body and divided into those less than 3 mm and greater than or equal to 3 mm diameter. Patients receiving chemotherapy had a similar number of moles to the control group. By contrast patients who had completed chemotherapy had significant increases both in moles less than 3 mm and greater than or equal to 3 mm and in the total number of moles. These patients were more likely to have moles on acral sites. CONCLUSIONS: Children with substantially increased numbers of moles (benign melanocytic naevi) after successful chemotherapy for malignancy may have an increased risk of melanoma. They should be offered prolonged surveillance and cautioned about exposure to ultraviolet light.