Decreased endothelin receptor B expression in large primary uveal melanomas is associated with early clinical metastasis and short survival

The most devastating aspect of cancer is the metastasis of tumour cells to organs distant from the original tumour site. The major problem facing oncologists treating uveal melanoma, the most common cancer of the eye, is metastatic disease. To lower mortality, it is necessary to increase our understanding of the molecular genetic alterations involved in this process. Using suppression subtractive hybridisation, we have analysed differential gene expression between four primary tumours from patients who have developed clinical metastasis and four primary tumours from patients with no evidence of metastasis to date. We have identified endothelin receptor type B as differentially expressed between these tumours and confirmed this observation using comparative multiplex RT-PCR. In a further 33 tumours, reduced endothelin receptor type B expression correlated with death from metastatic disease. Reduced expression also correlated with other known prognostic indicators, including the presence of epithelioid cells, chromosome 3 allelic imbalance and chromosome 8q allelic imbalance. Endothelin receptor type B expression was also reduced in four out of four primary small cell lung carcinomas compared to normal bronchial epithelium. We also show that the observed down-regulation of endothelin receptor type B in uveal melanoma was not due to gene deletion. Our findings suggest a role for endothelin receptor type B in the metastasis of uveal melanoma and, potentially, in the metastasis of other neural crest tumours.     

Novelty-related activation within the medial temporal lobes

Functional magnetic resonance imaging (fMRI) was used to examine whether (1) verbal associative encoding activates the medial temporal lobes (MTL) and related regions more than non-associative encoding, (2) verbal associative novelty is related to enhanced MTL activation, and (3) verbal item novelty is related to enhanced MTL activation and, if so, whether these activations are in different or overlapping sites. No increase in MTL activation was found during verbal associative encoding relative to non-associative encoding, although associative encoding was related to a relative increase in activation in the posterior cingulate cortex. In contrast, verbal associative novelty was found to activate the MTL and posterior cingulate cortex. Verbal item novelty did not significantly activate any brain region. The verbal associative novelty-related effect occurred despite subjects having little awareness of associative novelty. The verbal associative novelty-related activation in the MTL may be related either to unconscious novelty detection or to a priming effect at encoding. We argue that if the priming explanation is correct then this may account for our failure to observe an associative encoding MTL activation.     

Assessing emotional and behavioral problems in children with intellectual disability: revisiting the factor structure of the developmental behavior checklist

The objective of the reported study was to reassess the factor structure of the Developmental Behaviour Checklist (DBC) in a large cross-cultural sample representing all levels of intellectual disability. Parent and teacher DBC ratings on a combined sample of 1536 Dutch and Australian children and adolescents (ages 3–22) with mild to profound intellectual disability were used. Principal components analyses produced five subscales: Disruptive/Antisocial, Self-Absorbed, Communication Disturbance, Anxiety, and Social Relating, explaining 43.7% of the total variance. Internal consistencies of these subscales ranged from .66 to .91. The revised factor structure of the DBC appears to be an improved and useful tool for assessing emotional and behavioral problems in children with intellectual disabilities.     

Phase 1 study to identify tumour hypoxia in patients with head and neck cancer using technetium-99m BRU 59-21

The aim of this study was to assess the safety and biodistribution of technetium-99m BRU 59-21, a novel radioactively labelled 2-nitro-imidazole hypoxic marker, in head and neck cancer patients and to correlate uptake with pimonidazole staining. (99m)Tc-BRU 59-21 was administered intravenously (mean dose 824 MBq, range 780-857 MBq) to ten head and neck cancer patients scheduled for primary surgery, and whole-body images and SPET scans were then obtained. Uptake of radioactivity in the regions of interest was determined and tumour to normal tissue ratios were calculated after correlative evaluation with MRI/CT. Twelve to 16 h before surgery (up to 2 weeks after the scan), patients received pimonidazole intravenously. Tumour sections were stained immunohistochemically for pimonidazole binding. No serious adverse events were reported. In five patients there were ten adverse events, which were mild in intensity and resolved completely without intervention. Uptake of (99m)Tc-BRU 59-21 was observed in eight of the ten primary tumours. Tumour to normal tissue ratios on the SPET scans for primary tumour and lymph nodes increased from 1.8 (range 0.9-2.7) to 2.1 (range 0.8-3.7) between 30 min and 3 h post injection. Tumour to normal tissue ratios in the primary tumour were significantly correlated with pimonidazole staining for SPET scans performed 30 min and 3 h post injection ( P=0.016 and P=0.037, respectively). When primary tumour and involved lymph nodes were considered in conjunction, correlation between the tumour to normal tissue ratio and pimonidazole staining was observed for early ( P<0.001) but not for late SPET scans ( P=0.076). However, late scans showed better tumour delineation than early scans. Administration of (99m)Tc-BRU 59-21 in head and neck cancer patients appears to be safe and feasible. Uptake and retention in tumour tissue was observed, suggestive of tumour hypoxia, and this was supported by correlations with staining for the hypoxic marker pimonidazole.     

Diffusion-weighted magnetic resonance imaging detects early neuropathology following four vessel occlusion ischemia in the rat

Early neuropathology following a prolonged duration of four-vessel occlusion (4 VO) ischemia in the rat was charted using magnetic resonance imaging (MRI). Animals received either 30 minutes of 4 VO (N = 6) or sham operation (N = 6) prior to in vivo assessment. Proton density and T(2) and combined T(2)/diffusion-weighted (T(2)/DW) MRI were performed at 6, 24, and 72 hours postocclusion. T(2)/DW imaging was the most effective sequence for delineating between injured and intact tissues, indicating neuropathology in the dorsolateral striatum at 24 hours and in the CA1/CA2 subfields of the hippocampus at 72 hours following ischemia. Apparent diffusion coefficient values were significantly reduced in the striatum (P = 0.03) and hippocampus (P = 0.005) at 24 and 72 hours, respectively. This is the first report, to our knowledge, of T(2)/DW imaging detecting lesions following 4 VO in accord with the known temporal evolution of ischemic brain damage.     

Primary molar pulp therapy--histological evaluation of failure

Objectives. Qualitative comparison of the clinical, radiographic and histological outcomes in a small sample of cariously exposed primary molars, extracted after unsucessful pulp treatment by two vital pulpotomy methods. Subjects and methods. The primary molars were extracted, because of treatment failure, during a longitudinal clinical investigation of the relative efficacy of 20% Buckley’s Formocresol versus calcium hydroxide powder as pulp dressings in vital pulp therapy (in press). Fifty‐two child patients were sequentially enrolled in the longitudinal clinical investigation, 26 boys and 26 girls. Primary molar teeth requiring vital pulp therapy were randomly allocated to either the formocresol group (F) or the calcium hydroxide group (C). Coronal pulp amputation was prescribed only in teeth with vital, cariously‐exposed pulp tissue. All cases were reviewed using predefined clinical and radiological criteria. Seventy‐nine cariously‐exposed primary molars required vital pulp therapy. Forty‐four teeth were included in group F and 35 in group C. Five per cent (n = 2) of teeth in group F and 11 per cent of teeth (n = 4) in group C were terminated from the trial due to clinical and/or radiographic failure. Of the six teeth extracted, five were sufficiently intact to be retained for histological evaluation. Results. Post‐extraction radiographs taken before specimen preparation showed reactionary dentine barrier (bridge) formation in teeth treated with calcium hydroxide. However, the narrowing of root canals, indicative of appositional reactionary dentine deposition, was seen in both groups (F and C). Histological examination confirmed these findings and revealed that pus cells were evident in all specimens examined. There was also histological evidence of resorption of reactionary dentine within the root canal and that forming the calcified barrier (dentine bridge). Conclusion. The clinical and radiographic outcomes for the five teeth correlate well with the reported findings from decalcified histological section. Although numbers are small, the histological findings may indicate possible reasons for treatment failure. There are few reports of this sort in the literature of this under‐researched treatment modality.     

High mortality rates in tuberculosis patients in Zomba Hospital, Malawi, during 32 months of follow-up

There is little information about long-term follow-up in patients with smear-negative pulmonary tuberculosis (PTB) or extrapulmonary tuberculosis (EPTB) who have been treated under routine programme conditions in sub-Saharan Africa. A prospective study was carried out to determine outcome 32 months from start of treatment in an unselected cohort of 827 adults TB inpatients registered at Zomba Hospital, Malawi, in 1 July-31 December 1995. By 32 months, 351 (42%) patients had died. Death rates were 30% (95% confidence interval [95% CI] 25-35%) in 386 patients with smear-positive PTB, 60% (95% CI 53-67%) in 211 patients with smear-negative PTB and 47% (95% CI 40-54%) in 230 patients with EPTB. Of the 793 patients with concordant HIV test results 612 (77%) were HIV seropositive: 47% HIV-positive patients were dead by 32 months compared with 27% HIV-negative patients (adjusted hazard ratio [HR] 2.3; 95% CI 1.7-3.1, P < 0.001). Smear-negative PTB patients had the highest death rates during the 32-month follow-up (HR 2.7; 95% CI 2.1-3.5, P < 0.001 compared to smear-positive patients), followed by EPTB patients (HR 1.9; 95% CI 1.5-2.5, P < 0.001 compared to smear-positive patients). When analysis was restricted to after the treatment period had finished (i.e., months 12-32), the differences in mortality were maintained for HIV-serostatus and for types of TB. Low-cost, easy to implement strategies for reducing mortality in HIV-positive TB patients in sub-Saharan Africa (such as the use of trimethoprim-sulphamethoxazole prophylaxis) need to be tested urgently in programme settings.     

Height and weight achievement in cleft lip and palate.

Growth was studied in 83 children with cleft lip and/or palate aged 0-4 years attending a specialist regional centre. Information was collected by a personal interview, postal questionnaire, and record review. The group as a whole grew relatively poorly in early infancy but subsequently recovered, attaining both expected weight and height by last follow up at age 25.5 months (range 3 to 47). However, the group proved heterogeneous, with children with isolated clefts of the secondary palate showing the most abnormal growth. Children with underlying syndromes were significantly more likely to be short at follow up, while type or severity of cleft was not significantly related to follow up height. Therefore, while cleft palate was associated with significant growth faltering in early infancy, rapid recovery took place following surgical repair and appears to have resulted in no residual growth deficit.