Diabetic ketoacidosis--a possible complicating factor in deaths associated with drug overdose: two case reports.

Two cases are described where diabetic ketoacidosis was found in conjunction with significant levels of prescription drugs. Case 1: A 45-year-old woman with a history of insulin-dependent diabetes mellitus was found to have Armanni-Ebstein nephropathy characteristic of hyperglycaemia with a vitreous humour glucose level of 63.1 mmol/L and a beta-hydroxybutyrate level of 14.25 mmol/L. Ancillary toxicological evaluation revealed a lethal level of sertraline (2.5 mg/L), with an elevated level of methadone (0.23mg/L). Death was due to diabetic ketoacidosis complicating mixed drug toxicity. Case 2: A 27-year-old man with a history of insulin-dependent diabetes mellitus was found to have Armanni-Ebstein nephropathy with a vitreous humour glucose level of 51.7 mmol/L and a beta-hydroxybutyrate level of 18.6mmol/L. Ancillary toxicological evaluation revealed a potentially lethal level of methadone of 0.39mg/L. Death was attributed to diabetic ketoacidosis complicating methadone toxicity. These cases demonstrate a situation where drug toxicity led to diabetic ketoacidosis resulting in death most likely from a combination of factors. Measuring vitreous humour glucose and beta-hydroxybutyrate levels is important in individuals with histories, or scene evidence, of insulin-dependent diabetes mellitus, in addition to toxicological screening when there is evidence of possible drug taking. It appears that drug intoxication in both cases had impaired the ability to administer insulin, resulting in the development over time of diabetic ketoacidotic states. Lethal mechanisms were, therefore, more complex than simple drug toxicity or diabetic ketoacidosis in isolation.

Fatty acid composition of brain, retina, and erythrocytes in breast- and formula-fed infants.

Breast-fed infants score better on visual and developmental tests than do formula-fed infants and this has been related to higher concentrations of erythrocyte docosahexaenoic acid (DHA, 22:6 omega 3). This prompted an investigation into the relationship between brain, retina, and erythrocyte fatty acids and diet in infancy. Total lipids of erythrocytes, retina, and brain cortex from 35 term infants were analyzed by capillary gas chromatography. Breast-fed infants had a greater proportion of DHA in their erythrocytes and brain cortex relative to those fed formula (P < 0.005) but differences were not observed in retina. Cortex DHA increased in breast-fed (but not formula-fed) infants with age (r2 = 0.72, P < 0.01, n = 15), largely an effect of length of feeding (r2 = 0.62, P < 0.01, n = 35). There was an association between age at death and erythrocyte DHA with cortex DHA (r2 = 0.50, P < 0.01). In contrast, accretion of cortex arachidonic acid was dependent on age but not diet. The higher concentration of DHA in brains of breast-fed infants may explain the improved neurodevelopment reported in breast-fed compared with formula-fed infants.

Quantitative histomorphometric analysis of the human growth plate from birth to adolescence.

Longitudinal bone growth occurs via the transformation of growth plate cartilage into bone through a series of cell and matrix changes, termed endochondral ossification. In this study, we characterize the development of trabecular bone from growth plate cartilage in the human rib from birth to adolescence. The height of the proliferative and hypertrophic zones within the growth plate and the primary bone spongiosa decreased with increasing age, with the greatest change observed in the first year of postnatal life. Within these zones, an internal rearrangement of tissue structure occurred. The matrix volume fraction (either cartilage or bone) increased with age in each of the zones. A concomitant increase in cartilage septae thickness and bone trabecular thickness was observed. A decrease in cartilage septae number was seen in the proliferative zone and a decrease in bone trabeculae number was also observed in the primary spongiosa. However, no difference in cartilage septae number was noted in the hypertrophic zone, the region at which cartilage is transformed into bone. Together the proliferative and hypertrophic regions of the growth plate and the bone primary spongiosa appear to constitute the active growth region, with concomitant changes observed that result in longitudinal growth. In contrast, bone mineral volume in the secondary spongiosa was stable over the ages examined; however, trabecular architecture underwent consolidation as trabecular number decreased and trabecular thickness increased. The integration of the structural transformation from cartilage to bone is crucial in achieving the dual purposes of longitudinal growth and peak bone mass. The structure developed during childhood will have an important bearing on the response to bone-altering disease in later life.

Clinicopathologic findings in congenital aneurysms of the great vessels.

We describe the clinical, histopathologic, and angiographic findings in four children with congenital abnormalities of the great vessels of unknown cause, comprising either single or multiple arterial aneurysms, aortic/arterial dilatation, vessel tortuosity, or combinations of these abnormalities. Two children had early and severe respiratory distress due to aneurysmal compression of the trachea. All children had diffuse dilatation of several arteries, and two children also had tortuosity of multiple arteries. Progression of these abnormalities was clearly evident in one child, in whom diffuse vessel irregularity and tortuosity affected intra-abdominal, and intra and extra-cranial arteries. One child died at 5 years, while the other three have undergone successful surgical repair in the first 3 months of life and are now well, between age 2.5 and 7 years. The phenotype of each child appears unique but all have in common the rare finding of aneurysms of the aorta and main pulmonary artery. Congenital aortic aneurysms did not occur as an isolated finding in any of these children.

Cytokine receptor expression in human lymphoid tissue: analysis by fluorescence microscopy.

A highly-sensitive flourescence method, capable of detecting cytokine receptors present at low concentrations (around 100 molecules per cell) by flow cytometry, was adapted for use on tissue sections. This method was used to examine the expression of several cytokine receptors in lymphoid tissues. IL-2 receptors were distributed broadly, with higher concentrations in T cell areas. IL-1 receptor Type 1 was detected in T cell areas and in the follicular mantle, and was strongly expressed on vascular endothelium. IL-6 receptor was found at very low concentration, both within and outside germinal centres. The gp 130 molecule, which is involved in the functional receptor complex for IL-6 and several other cytokines, was present at higher concentrations, particularly in the germinal centre. Analysis of receptor expression in secondary lymphoid tissue provides evidence bearing on the physiological roles of cytokines, as these tissues contain cells at various stages of physiological activation located in well-defined functional zones.

Pathologic features of the ureteroileal anastomosis in ileal conduits in childhood.

Ileal conduit urinary diversions are associated with a high incidence of late complications often requiring major revision surgery. Although the etiology of the late complications is not always clear, there may be unilateral or bilateral hydroureteronephrosis, with the conduits showing narrowing and stricture formation with villous atrophy, chronic inflammation, and fibrosis. Histologic review of 20 ureteroileal anastomoses from 12 patients showed variable degrees of chronic changes. In addition, cystically dilated intestinal glands were noted in six anastomoses, transitional epithelial-lined cysts were noted in nine, aggregated pools of mucus were noted in four, mixed transitional and intestinal epithelial-lined cysts were noted in two, and polypoid lesions with mucus pools or cysts projecting into the lumen were noted in five. Twelve cysts measured over 1 mm in diameter; six measured over 2 mm. These histologic features may result from overgrowth of intestinal glands by transitional epithelium, with subsequent gland dilatation, rupture, and mucus pooling. It is possible that the larger "cysts" and "polyps" may have contributed to the ureteroileal obstruction, a finding that may have bearing on other types of urinary tract reconstructions using bowel segments.

A study of the sequential morphologic changes after manual coronary endarterectomy.

Manual coronary endarterectomies heal in the long-term by a poorly understood process of myofibrointimal proliferation. A retrospective analysis of detailed cardiovascular pathologic examinations of 51 patients dying at varying intervals after endarterectomy provides insight into the sequence of this proliferative response. Twenty-one patients died within 7 days, 6 at 8 to 30 days, 3 at 31 days to 6 months, 4 at 6 months to 5 years, and 17 at more than 5 years after endarterectomy. The observations made suggest that the denuded arterial surface heals after the fibrin-platelet mural thrombus that covers it is organized and is replaced by fibrosis and myofibroblast proliferation. In unusual cases proliferation is exuberant, resulting in significant restenosis, an outcome in which recurrent atherosclerosis contributes to only a minor degree. This is the first series in which the sequential reparative changes at varying times after manual coronary endarterectomy have been studied.

Type IV Ehlers-Danlos syndrome presenting as sudden infant death.

A previously healthy 5-month-old female infant presented with sudden death due to spontaneous subarachnoid hemorrhage associated with minor multifocal visceral hemorrhages. The clinical diagnosis had been sudden infant death syndrome. Although the family history was noncontributory and other features of type IV Ehlers-Danlos syndrome (EDS) were absent, the pattern of hemorrhage was consistent with this type of connective tissue disorder. The diagnosis was confirmed after postmortem analysis of skin and aorta showed less than 5% type III collagen (normal greater than 15%). Extensive literature review failed to find any other reported cases of sudden death in infancy due to intracranial hemorrhage in patients with previously unsuspected type IV EDS. The authors suggest that collagen analysis should be performed in cases of unexplained multifocal spontaneous hemorrhage in infancy so that this rare diagnosis will not be missed.

Vascular causes of sudden death in infancy, childhood, and adolescence.

Vascular causes of sudden death in infancy, childhood, and adolescence range from primary disorders of the vasculature involving structural compromise, as in anomalous coronary arteries, to vascular problems that may arise as secondary phenomena, such as the infectious arteritides. The etiology of the underlying condition may be understood, as in fatal pulmonary thromboembolism, or it may be shrouded in mystery, as in idiopathic arterial calcinosis. The absence of a clinical history indicating an underlying vascular problem in a number of disorders that may cause sudden childhood death underlines the importance of a meticulous autopsy examination in such cases.

Immunohistochemical characterisation of the costochondral junction in SIDS.

AIM: To characterise the distribution of major growth plate proteoglycans in a group of infants who died of SIDS. METHODS: Nine such infants and eight age matched controls were selected from the necropsy files at the Adelaide Children's Hospital. Sections of rib and adjacent costal cartilage were stained for chondroitin-4-sulphate, chondroitin-6-sulphate, and keratan sulphate with antibodies 2-B-6, 3-B-3, and 5-D-4, respectively, using standard techniques. RESULTS: The distribution of proteoglycans within the extracellular matrix of the costochondral junction in the group of SIDS infants was identical with that found in control infants. CONCLUSION: Any changes present in the growth plate in cases of SIDS are most likely caused by secondary phenomena.

Observer reliability in assessing villitis of unknown aetiology.

AIMS: To evaluate observer variation in diagnosis of villitis of unknown aetiology. METHODS: Fifty haematoxylin and eosin stained sections were circulated to three pathologists who were asked to assess if villitis was present. These slides, with an additional 20, were recirculated and reassessed by the same pathologists. RESULTS: Intra-observer agreement was 84.7% (range 74--92%) and interobserver agreement was 81%. A conjoint review by the three pathologists revealed that sources of differences included the overlooking of isolated single or small numbers of affected villi, the difficulty in assessing stromal cellularity close to infarcted parenchyma, and apparent stromal hypercellularity in immature villi. CONCLUSIONS: Experienced pathologists can show a significant interobserver variation in assessing villitis of unknown aetiology. Future studies on villitis of unknown aetiology should address the problem of observer reproducibility of diagnosis.

Autoaugmentation omentocystoplasty in a sheep model.

OBJECTIVE: To develop a sheep model of autoaugmentation omentocystoplasty and study the histologic appearance, and to compare the urodynamic results with a control group. METHODS: Ten male lambs underwent a bladder autoaugmentation reinforced with an omental patch. Three were culled early, to study urothelial survival and inflammatory changes. One was sacrificed at six months to assess late histologic changes; five sheep had a urodynamic study at that stage and two died of unknown causes without further investigation. A group of seven six-month-old male sheep, of similar weights, formed the control urodynamic group. RESULTS: The urothelial lining remained viable under the omentum, but marked inflammation and heterotopic calcification were seen within the subepithelial tissues in most of the animals. The histologic changes were reflected in the bladder dynamic data, which were no better than the control group; the average compliance value was 9.2 +/- 6.4 mL/cm H2O, compared to the control group figure of 11.8 +/- 5.2 mL/cm H2O. CONCLUSIONS: It would appear that autoaugmentation alone does not usually produce bladder augmentation in the sheep.

Autoaugmentation gastrocystoplasty and demucosalized gastrocystoplasty in a sheep model.

OBJECTIVES: To compare the normal sheep bladder at 6 and 12 months with bladders subjected to either an autoaugmentation gastrocystoplasty or a clam demucosalized gastrocystoplasty. METHODS: Twenty male lambs aged between 8 and 10 weeks had an autoaugmentation gastrocystoplasty in which de-epithelialized stomach muscle was added to an intact urothelium. The functional, radiologic, and histologic outcomes were compared with 11 animals who underwent a clam demucosalized gastrocystoplasty and 14 control animals. A total of 18 operated animals had a urodynamic study at 6 months and 9 at 12 months. RESULTS: The average bladder volume for the autoaugmentation gastrocystoplasty group at 12 months was greater than that of the control group (401 +/- 120 mL versus 205 +/- 77 mL). The demucosalized clam bladders had been less effectively enlarged (286 +/- 77 mL). The compliance values for autoaugmentation gastrocystoplasty animals were 14.7 +/- 11.3 mL/cm water (H2O) compared with 9.0 +/- 4.8 mL/cm H2O in the demucosalized gastrocystoplasty group, and 9.1 +/- 3.7 mL/cm H2O for the control animals. CONCLUSIONS: The addition of the autoaugmentation procedure improves the prospect of enlarging the normal sheep bladder when using demucosalized gastric muscle.

Test and teach. Number seventy-three. Diagnosis: Alexander's disease.

Alexander's disease is a progressive degenerative neurological disorder developing in early childhood which is characterized by accumulation of Rosenthal fibres throughout the cerebral white matter. These fibres are composed of glial fibrillary acidic protein and ubiquinated alpha beta crystallin. The absence of atypia, increased cellularity, mitotic activity or necrosis in biopsy material allows differentiation from neoplasia glial processes. Clinical features suggestive of the diagnosis include progressive mental retardation with an increase in head circumference.

Peripheral nerve and vasculature involvement in myophosphorylase deficiency (McArdle's disease).

A 60 year old white male presented with atypical chest pain and exercise-induced myalgia. Physical examination revealed slight proximal limb muscle weakness and wasting. Serum creatine phosphokinase levels were persistently elevated and electromyography showed changes consistent with a mild myopathy. Light microscopic and ultrastructural study revealed excess free glycogen within skeletal muscle, and histochemical staining showed absence of myophosphorylase activity. Biochemical quantitation confirmed the diagnosis of McArdle's disease by demonstrating absent phosphorylase activity in skeletal muscle with increased glycogen. In addition, increased amounts of free and membrane-bound glycogen were found within axons, Schwann cells, fibroblasts and occasional vascular smooth muscle and endothelial cells that had been included within the skeletal muscle biopsy. This case demonstrates more widespread glycogen accumulation than has been previously reported in McArdle's disease.

DNA analysis and clinical outcome in pediatric adrenal cortical tumors.

Adrenal cortical neoplasms are uncommon and it is often difficult to separate benign tumors from those that are malignant. Histology does not provide a reliable guide, particularly in pediatric cases. It has been suggested that analysis of nuclear DNA content may complement conventional histopathologic methods in the diagnosis of malignancy. Six previously reported adrenal cortical tumors from children aged 6 mths to 6 yrs were analysed using a CAS 200 image analysis system which provided DNA histograms on each of the cases. In 5 cases a significant proportion of the tumors showed aneuploidy and in only one case did most of the tumor cells show a diploid pattern. All 6 cases were treated with surgery alone with long term survival and follow up of 2-15 yrs except in one child with a histologically benign aneuploid tumor who died post-operatively from measles pneumonia. No correlation between histological appearance, outcome and ploidy was seen. The aneuploid tumors included those classified by current histological methods as benign (1), indeterminant (2) and malignant (2). The one diploid tumor seen was a large tumor of indeterminant malignancy that did not recur. Although the series is quite small these observations suggest that abnormalities of DNA content may not provide an objective measure of the malignant potential of adrenal cortical tumors in children.

Adrenal cortical tumors in childhood--clinicopathological features of six cases.

Six cases of adrenal cortical tumors are presented with a discussion of the clinical features and histological findings. Five of the 6 children, aged between 6 mths and 6 yrs, presented with symptoms of hyperadrenalism, 4 with virilization and 1 with Cushingoid features. The remaining infant presented with an asymptomatic abdominal mass. In each case there was a unilateral tumor separated from the residual adrenal gland by a thin fibrous capsule. Surgical resection was the treatment employed and, in the 5 cases with functional tumors, perioperative hydrocortisone was given. None of the children received post-operative chemotherapy or radiotherapy. Bizarre cellular morphology, a high mitotic count and extensive necrosis were all seen in clinically benign disease, demonstrating not only the efficacy of local resection but also the difficulty in applying the usual histological criteria of malignancy to these pediatric adrenal tumors. At follow-up, 5 of the 6 patients are alive with no evidence of recurrent disease. The only death resulted from measles pneumonitis in the 1 child who presented with Cushing's syndrome.

Clinicopathological features of xanthogranulomatous pyelonephritis in infancy.

Xanthogranulomatous pyelonephritis (XGP) is an unusual chronic inflammatory condition which most often affects women in their 5th to 7th decades and is rare in infants. Predisposing factors include infection, calculi and obstructive uropathy. We have reviewed the surgical files of 4 cases seen over a 28 yr period from 1964-91. All of the 3 partial and one total nephrectomy specimens demonstrated typical features of XGP with renal parenchyma effaced by a mixed acute and chronic inflammatory infiltrate which included prominent aggregates of foamy histiocytes containing eosinophilic inclusions. No Michaelis-Gutmann bodies were seen. This study shows the association of XGP with chronic infection, anatomical malformation and reflux in infancy, and raises the possibility of a temporary altered immune response in its pathogenesis.

Metastatic osteogenic sarcoma to the heart presenting as bacterial endocarditis.

A patient with metastatic osteogenic sarcoma involving the left atrium is described who presented with features of bacterial endocarditis. The source of infection was the adjacent esophagus into which the tumor had eroded. This case demonstrates that sarcomas metastasizing to the heart may result in a clinical condition indistinguishable from infective endocarditis. At post-mortem, careful dissection of cardiac metastases should be undertaken to check for possible esophageal involvement.