Computed tomography (CT) angiography for confirmation of the clinical diagnosis of brain death.

BACKGROUND: The diagnosis of death using neurological criteria (brain death) has profound social, legal and ethical implications. The diagnosis can be made using standard clinical tests examining for brain function, but in some patient populations and in some countries additional tests may be required. Computed tomography (CT) angiography, which is currently in wide clinical use, has been identified as one such test. OBJECTIVES: To assess from the current literature the sensitivity of CT cerebral angiography as an additional confirmatory test for diagnosing death using neurological criteria, following satisfaction of clinical neurological criteria for brain death. SEARCH METHODS: We performed comprehensive literature searches to identify studies that would assess the diagnostic accuracy of CT angiography (the index test) in cohorts of adult patients, using the diagnosis of brain death according to neurological criteria as the target condition. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5) and the following databases from January 1992 to August 2012: MEDLINE; EMBASE; BNI; CINAHL; ISI Web of Science; BioMed Central. We also conducted searches in regional electronic bibliographic databases and subject-specific databases (MEDION; IndMed; African Index Medicus). A search was also conducted in Google Scholar where we reviewed the first 100 results only. We handsearched reference lists and conference proceedings to identify primary studies and review articles. Abstracts were identified by two authors. Methodological assessment of studies using the QUADAS-2 tool and further data extraction for re-analysis were performed by three authors. SELECTION CRITERIA: We included in this review all large case series and cohort studies that compared the results of CT angiography with the diagnosis of brain death according to neurological criteria. Uniquely, the reference standard was the same as the target condition in this review. DATA COLLECTION AND ANALYSIS: We reviewed all included studies for methodological quality according to the QUADAS-2 criteria. We encountered significant heterogeneity in methods used to interpret CT angiography studies and therefore, where possible, we re-analysed the published data to conform to a standard radiological interpretation model. The majority of studies (with one exception) were not designed to include patients who were not brain dead, and therefore overall specificity was not estimable as part of a meta-analysis. Sensitivity, confidence and prediction intervals were calculated for both as-published data and as re-analysed to a standardized interpretation model. MAIN RESULTS: Ten studies were found including 366 patients in total. We included eight studies in the as-published data analysis, comprising 337 patients . The methodological quality of the studies was overall satisfactory, however there was potential for introduction of significant bias in several specific areas relating to performance of the index test and to the timing of index versus reference tests. Results demonstrated a sensitivity estimate of 0.84 (95% confidence interval (CI) 0.69 to 0.93). The 95% approximate prediction interval was very wide (0.34 to 0.98). Data in three studies were available as a four-vessel interpretation model and the data could be re-analysed to a four-vessel interpretation model in a further five studies, comprising 314 patient events. Results demonstrated a similar sensitivity estimate of 0.85 (95% CI 0.77 to 0.91) but with an improved 95% approximate prediction interval (0.56 to 0.96). AUTHORS' CONCLUSIONS: The available evidence cannot support the use of CT angiography as a mandatory test, or as a complete replacement for neurological testing, in the management pathway of patients who are suspected to be clinically brain dead. CT angiography may be useful as a confirmatory or add-on test following a clinical diagnosis of death, assuming that clinicians are aware of the relatively low overall sensitivity. Consensus on a standard radiological interpretation protocol for future published studies would facilitate further meta-analysis.

The pathology of visible blood vessels on the nasal septum in children with epistaxis.

OBJECTIVE: Epistaxis is common in children, but its cause remains unknown. About half the children who present with epistaxis have prominent vessels on the nasal septum. The aim of this study was to determine the pathological nature of the prominent septal vessels in children with recurrent epistaxis. METHODS: 4mm punch biopsies of the nasal septal mucosa were taken from 5 children undergoing nasal cautery under general anaesthesia. RESULTS: Histology showed that the prominent vessels were thin-walled arterioles and capillaries with a surrounding inflammatory infiltrate. There was no evidence of venous varicosities or arterial microaneurysms. CONCLUSION: We postulate a mechanism for septal neovascularisation due to chronic low-grade inflammation as a cause for recurrent epistaxis in children.

Focal segmental glomerulosclerosis, Coats'-like retinopathy, sensorineural deafness and chromosome 4 duplication: a new association.

We describe the novel association in a girl of nephrotic syndrome due to focal segmental glomerulosclerosis, bilateral sensorineural deafness, basal ganglia calcification, bilateral retinopathy similar to that seen in Coats' disease, with de novo duplication of a subtelomeric region of chromosome 4q35. The chromosomal duplication was identified during investigation of a possible association with features of fascio-scapulo-humeral dystrophy (FSHD). This duplication has not previously been reported with FSGS and adds to the expanding number of genetic associations with steroid-resistant nephrotic syndrome.

Multifocal multi-organ ischaemia and infarction in a preterm baby due to maternal intravenous cocaine use: a case report.

INTRODUCTION: Although the adverse effects of cocaine use in pregnancy are well recognised, we believe this case highlights the importance of considering the route of administration, and suggests the possibility of multifocal damage relating to intravenous use. CASE PRESENTATION: A Caucasian female baby of 29-weeks' gestation was spontaneously delivered and subsequently developed multi-organ failure considered unrelated to simple prematurity. Intensive care was re-orientated following the development of massive intraventricular haemorrhage. CONCLUSION: This case illustrates the need for regular cranial ultrasound in babies of pregnancies at risk due to intravenous cocaine use and also the necessity of counselling women who misuse cocaine in the antenatal period. As such, this article will be of most interest to paediatric and obstetric staff.

Multifocal multi-organ ischaemia and infarction in a preterm baby due to maternal intravenous cocaine use: a case report.

INTRODUCTION: Although the adverse effects of cocaine use in pregnancy are well recognised, we believe this case highlights the importance of considering the route of administration, and suggests the possibility of multifocal damage relating to intravenous use. CASE PRESENTATION: A Caucasian female baby of 29-weeks' gestation was spontaneously delivered and subsequently developed multi-organ failure considered unrelated to simple prematurity. Intensive care was re-orientated following the development of massive intraventricular haemorrhage. CONCLUSION: This case illustrates the need for regular cranial ultrasound in babies of pregnancies at risk due to intravenous cocaine use and also the necessity of counselling women who misuse cocaine in the antenatal period. As such, this article will be of most interest to paediatric and obstetric staff.

Clinicopathological study of bilateral developmental cataracts diagnosed in utero.

BACKGROUND: We report a case of unusual, bilateral developmental cataracts in a fetus with a supernumerary chromosome. METHODS: A 42-year-old woman presented during her 6th pregnancy for assessment of fetal karyotype. This showed a supernumerary chromosome derived from chromosome 21. Subsequently fetal ultrasound suggested the presence of bilateral cataracts and the pregnancy was terminated at 19 weeks and 3 days' gestation. Both eyes were submitted for histopathological and electron microscopical examination. RESULTS: Histopathological examination revealed unusual bilateral developmental cataracts with abnormal bladder-type cells lining the posterior aspect of the lens vesicle, a poorly formed nuclear bow and a central mass of fibrillar material associated with macrophages lying within an area of liquefaction. Transmission electron microscopy revealed the presence of peg and socket joints in both central and posterior regions and degenerate crystallins in the posterior region. CONCLUSIONS: We described an unusual case of developmental cataract diagnosed in utero by ultrasound. The morphological appearances suggest that the defect occurred during or after formation of the secondary lens fibres. Detailed descriptions of cases such as this one may contribute to our understanding of lens development and cataract formation.

Renal transplant biopsy specimen adequacy in a paediatric population.

Updated guidelines on the diagnosis of acute allograft rejection including criteria for biopsy specimen adequacy were published in 1999. We sought to determine the adequacy of specimens in paediatric transplant patients and identify factors influencing adequacy. All renal transplant biopsies performed between 1998 and 2003 were classified as adequate (n =25), minimal (n =19) or inadequate (n =27) in accordance with the Banff 97 criteria, and the histological diagnoses were documented. The effect on specimen adequacy of grade of operator, method of sedation, age of child, needle gauge, number of cores and total core length was then investigated. Overall, a minimal or adequate specimen was obtained in 62% of cases. No histological diagnosis could be made in 30% of all specimens, just over half of which were inadequate. Higher rates of rejection were found in adequate (52%) than inadequate (33%) samples. The grade of operator (p =0.498), the age of the child at the time of biopsy (p =0.815) and type of sedation (p =0.188) did not affect adequacy. More than one core was obtained in 38 (54%) cases, and this was significantly associated with specimen adequacy (p <0.0005) as was longer total core length (p =0.002). Clinical features in isolation are not sufficient for the diagnosis of acute allograft rejection. Renal biopsy remains the gold standard and relies on adequate specimen collection. Our data shows that specimen adequacy according to the Banff 97 guidelines is achievable in children and that more than one core at the time of sampling significantly improves this achievement. Adequate sampling reduces the risk of an inconclusive histological diagnosis.

Identification of novel polymorphisms in the glucokinase and glucose-6-phosphatase genes in infants who died suddenly and unexpectedly.

Sudden and unexpected infant deaths can be unexplained [sudden infant death syndrome (SIDS)] or explained (non-SIDS) but risk factors including lower birthweight are similar in both groups. Mutations in the glucokinase (GK) gene result in Maturity Onset Diabetes of the Young type 2 (MODY 2) and are associated with lower birthweight. Low hepatic glucose-6-phosphatase (G6PC1) expression occurs in both low birthweight and SIDS infants. We investigated whether polymorphisms are prevalent in the GK and G6PC1 genes in infants who died suddenly and unexpectedly. Mutation analysis was performed by polymerase chain reaction (PCR) and denaturing high-performance liquid chromatography (DHPLC) in samples from 126 infants who died suddenly and unexpectedly (78 SIDS, 48 non-SIDS) and from 70 healthy, living infants. G6PC1 promoter polymorphism significance was investigated by transfection of reporter gene constructs into a H4IIE cell line. Heterozygous GK polymorphisms were identified in 17.9% of SIDS and 20.8% of non-SIDS infants: two rare silent polymorphisms, Y215Y and S263S, in the coding region; a third rare polymorphism, -45G>A, in the hepatic promoter and the most prevalent polymorphism, c.484-29G>C, in a non-coding region upstream from the intron 4-exon 5 junction. A novel heterozygous polymorphism -77G>A in the G6PC1 promoter in 6.3% of non-SIDS and 2.9% of control infants decreased basal G6PC1 promoter activity (p<0.001). We describe three novel polymorphisms in the GK gene, S263S, -45G>A, and a common (14.3%) intronic substitution, c.484-29G>C, in infants who died suddenly and unexpectedly. We identified the first G6PC1 promoter polymorphism, which lowers expression, potentially increasing risk of hypoglycaemia and hence risk of sudden and unexpected death.

Iodothyronine levels in the human developing brain: major regulatory roles of iodothyronine deiodinases in different areas.

Thyroid hormones are required for human brain development, but data on local regulation are limited. We describe the ontogenic changes in T(4), T(3), and rT(3) and in the activities of the types I, II, and III iodothyronine deiodinases (D1, D2, and D3) in different brain regions in normal fetuses (13-20 wk postmenstrual age) and premature infants (24-42 wk postmenstrual age). D1 activity was undetectable. The developmental changes in the concentrations of the iodothyronines and D2 and D3 activities showed spatial and temporal specificity but with divergence in the cerebral cortex and cerebellum. T(3) increased in the cortex between 13 and 20 wk to levels higher than adults, unexpected given the low circulating T(3). Considerable D2 activity was found in the cortex, which correlated positively with T(4) (r = 0.65). Cortex D3 activity was very low, as was D3 activity in germinal eminence and choroid plexus. In contrast, cerebellar T(3) was very low and increased only after midgestation. Cerebellum D3 activities were the highest (64 fmol/min.mg) of the regions studied, decreasing after midgestation. Other regions with high D3 activities (midbrain, basal ganglia, brain stem, spinal cord, hippocampus) also had low T(3) until D3 started decreasing after midgestation. D3 was correlated with T(3) (r = -0.682) and rT(3)/T(3) (r = 0.812) and rT(3)/T(4) (r = 0.889). Our data support the hypothesis that T(3) is required by the human cerebral cortex before midgestation, when mother is the only source of T(4). D2 and D3 play important roles in the local bioavailability of T(3). T(3) is produced from T(4) by D2, and D3 protects brain regions from excessive T(3) until differentiation is required.

Unadjusted and customised weight centiles in the identification of growth restriction among stillborn infants.

The study aims to compare the utility of unadjusted with customised weight standards in the identification of intrauterine growth restriction (IUGR) among unexplained stillborn infants undergoing postmortem examination. Unadjusted and customised birthweight centiles were determined for 51 unexplained stillborn infants undergoing perinatal autopsy. Unadjusted centiles were calculated from an ultrasonically derived fetal weight standard. Customised centiles were calculated from an online calculator which adjusts the standard to account for important physiological variables. IUGR was defined as moderate or severe according to brain/liver ratios of > 3 and > 5, respectively. The relationship between the weight centiles and abnormal brain/liver weight ratios was explored. Neither unadjusted nor customised standards identify stillborn infants with brain/liver ratios > 3:1. Both unadjusted and customised weight standards identify stillborn infants with brain/liver ratios > 5 equally well with high sensitivity (95%) but low specificities (63% and 66%, respectively). Customising weight standards to account for physiological variables does not identify growth restricted stillborn infants more usefully than an unadjusted fetal weight standard.

Glomerular basement membrane thickness in children: a stereologic assessment.

BACKGROUND: Stereologic methods have emerged as the technique of choice in assessing glomerular basement membrane (GBM) thickness, following conceptual modeling comparing the stereologic technique of harmonic mean of the orthogonal intercept estimation (Th) with the model based method of arithmetic mean estimation (ATH), with no direct comparison undertaken. We undertook to establish the gold standard for GBM estimation and use this technique to establish a range for GBM thickness in children. METHODS: Intra-observer and inter-glomerular variation was estimated in 34 cases with (presumed) normal GBM thickness, using Th, ATH and a rapid direct measurement technique, with intra-observer variation measured in 35 cases with GBM attenuation. A total of 34,011 measurements were undertaken to establish a range for Th in children on 212 biopsies from 199 patients (127 male) demonstrating minimal change nephropathy (N = 153), focal segmental glomerulosclerosis (24), no abnormality (24), and acute tubular necrosis (8), which were used as surrogates for normals. RESULTS: Th demonstrated less variation than ATH in both the normal and attenuated groups. GBM thickness increased throughout childhood, from 194 +/- 6.5 nm (mean +/- SE) at one year to 297 +/- 6.0 nm at 11 years, with a reduced rate of increase after age 11 years. CONCLUSION: Stereologic methods are superior to model based techniques in estimating GBM thickness and should be regarded as the technique of choice in this area. GBM thickness was observed to increase during childhood with no gender effect demonstrable as a main effect or interaction.