John C. Partin

A clinicopathologic study of enterocyte-adherent Escherichia coli : a cause of protracted diarrhea in infants.

Fifteen infants (age 3-28 wk) suffered from severe diarrhea with acute dehydration and poor growth. Persistent watery stools and suboptimal nutrition necessitated central venous alimentation with prolonged hospitalization. Repeated stool and small intestinal fluid cultures yielded the classical enteropathogenic Escherichia coli serotype 0119:B14. In all patients, biopsy of the jejunum or rectal mucosa, or both, showed moderate to severe damage, irregular atrophy of surface epithelium, and subnuclear vacuolization of crypt epithelium. Ultrastructural studies revealed bacteria adherent to mucosal cells with flattening of microvilli, loss of the cellular terminal web, and cupping of the plasma membrane around individual bacteria. Heavily colonized cells had marked intracellular damage. Assays for heat-labile, heat-stable, and vero cell toxins were negative for these Escherichia coli isolates. Oral neomycin and nutritional support resulted in clearing of Escherichia coli 0119:B14 from stool and small bowel with improvement in histologic characteristics. Damage to enterocytes and villi by adherent nontoxigenic Escherichia coli 0119:B14 results in protracted diarrhea in infants.

An Ultrastructural Study of Enteropathogenic Escherichia Coli Infection in Human Infants

Over the past 2 years, we have studied and treated 18 infants with protracted diarrhea due to an enteropathogenic Escherichia coli serogroup 0119. All patients had persistent stool escretion and jejunal over-growth with this pathogenic E. coli. Jejunal biopsy revealed atrophy of villi with a chronic inflammatory cell infiltrate in the lamina propria. E. coli 0119 adhered to the luminal surface of enterocytes. Electron microscopy showed disappearance of glycocalyx and microvilli at the areas of bacterial adherence. Intracellular damage was indicated by dilatation of rough endoplasmic reticulum, mitochondrial changes, and cytoplasmic pallor. Similar changes in histology and ultrastructure occurred in ileal epithelial cells. Glandular crypt epithelium showed prominent subnuclear vacuolation and separation of lateral intercellular junctions throughout the small intestine. Rectal mucosal biopsy showed mucus depletion and irregular atrophy of the epithelium, with E. coli 0119 adherent to the luminal surface. Ultrastructural damage paralleled that in the small intestine. E. coli 0119 causes damage to epithelial cells throughout the infant intestinal tract. This damage leads to atrophy of villi and a marked reduction in absorptive surface area, resulting in protracted diarrhea.

Primary Bile Acid Malabsorption: Defective In Vitro Ileal Active Bile Acid Transport

Two boys with congenital diarrhea, steatorrhea, and growth failure were studied. Preliminary investigations indicated that the enterohepatic circulation of bile acids was interrupted. Radiographically, ileal structure was normal; ileal function was normal when assessed by vitamin B12 absorption. To confirm our clinical suspicion that the patients had an isolated defect of ileal active bile acid transport, peroral terminal ileal biopsies were performed. Ileal mucosa was incubated in vitro in oxygenated Krebs-Ringer bicarbonate buffer containing 10 mM glucose and 0.1, 1.0, or 10.0 mM taurocholic acid at 37 degrees C. Ileal uptake from the patients was 0.10 and 0.34 mumol/g dry wt . min in 0.1 mM taurocholic acid, 1.20 and 2.39 mumol/g dry wt . min in 1.0 mM taurocholic acid, and 21.19 and 11.14 mumol/g dry wt . min in 10.0 mM taurocholic acid. At every concentration, significant (p less than 0.05) reductions were present compared with ileum from 7 ileostomy controls, 0.5 to 27 yr old whose uptake was 1.40 +/- 0.28 mumol/g dry wt . min (mean +/- SEM) at 0.1 mM; 6.36 +/- 1.33 mumol/g dry wt . min at 1.0 mM, and 76.20 +/- 19.30 mumol/g dry wt . min at 10.0 mM taurocholic acid. Ultrastructural examination of the ileal mucosa failed to demonstrate a significant structural abnormality. Significant reduction in ileal uptake of taurocholic acid accompanying clinical and biochemical findings of interruption of the enterohepatic circulation in the absence of mucosal disease suggests that these children have a previously undescribed, congenital transport defect that includes absence of active ileal bile acid transport presenting as diarrhea in infancy.

Epidemic influenza myopathy in Cincinnati in 1977.

A distinctive myopathy was observed in 24 children following influenza B infection. The abrupt onset of severe muscle pain and difficulty in walking began as the respiratory symptoms were waning. The lower extremities, particularly the gastrocnemius and soleus muscles, were involved preferentially. Nasopharyngeal cultures were positive for influenza B Hong Kong in 18 of these patients. Serum creatine phosphokinase levels were significantly elevated (mean 55.2 units) when compared to controls and nine patients with Reye syndrome. The cardiac muscle isoenzyme was detected in the serum of 17 myopathy patients. Serum glutamic oxaloacetic transaminase, but not serum glutamic pyruvic transaminase, was elevated compared to controls (P less than 0.01) but less (P less than 0.001) than the patients with Reye syndrome. Twelve patients underwent muscle biopsy; segmental rhabdomyolysis without inflammation was detected in nine patients. Myopathy is a complication of influenza infection that can be diagnosed by clinical, biochemical, and virologic examination.

ASSOCIATION OF REYE'S SYNDROME WITH VIRAL INFECTION

Abstract From January to March, 1974, twenty-four cases of Reyes syndrome encephalopathy and fatty liver) were diagnosed in Cincinnati, Ohio. The epidemic coincided with an epidemic of influenza B, intermediate type. In eighteen of twenty-three cases (78%) in which viral studies were done, an acute viral infection was found in either the patient or a close contact with similar prodromal symptoms. Influenza-B infection was confirmed in twelve patients and twelve contacts, although influenza A, parainfluenza 1, adenovirus, and varicella-zoster virus infections also occurred. In four cases there was evidence of two different viruses infecting the patients or their contacts. Cellular immunity was studied in six cases and responses to phytohaemagglutinin and specific viral antigen were normal. This is the first epidemic of Reyes syndrome in which the association with viral infection has been confirmed in most patients by virological techniques. Impaired cellular immunity could not be implicated as the cause of the unusual reponse to infection.

Brain Ultrastructure in Reye's Disease. II.Acute Injury and Recovery Processes in Three Children

Acute and recovery biopsies of three patients with Reyes Disease are described. Pleomorphic changes of neuronal mitochondria were identified in all of the acute biopsies, similar in appearance to the characteristic alterations of hepatic mitochondria. Distinctive myelin bleb formation may be directly attributable to the mitochondrial injury. The mitochondrial lesion is reversible. There is morphologic evidence for regeneration and repair of myelin; but the presence of myelin ovoids at long intervals after recovery indicates a loss of some myelinated fibers. The neuronal mitochondrial changes, pleomorphism with matrix expansion, and myelin bleb formation, reflect a specific biochemical injury be attributable to ischemic injury secondary to brain edema.

Grade I Reye's Syndrome — Outcome and Predictors of Progression to Deeper Coma Grades

Abstract We studied 83 biopsy-proved cases of Grade I Reyes syndrome to determine the outcome, possible clinical or laboratory predictors of progression to deeper coma grades, and hepatic ultrastructural findings. Seventy-eight patients had no change in coma grade during hospitalization, whereas five (6 per cent) had progression to deeper coma grades. All the patients survived without sequelae except one who sustained severe brain damage. The mean (±S.E.) level of serum ammonia on admission was significantly higher (P = 0.005) in patients whose disease progressed to deeper neurologic grades (291±42 μg per deciliter) than in those whose disease did not so progress (53±5 μg per deciliter), and the corrected prothrombin time was significantly more prolonged (P = 0.005) in patients with progressing coma (3.9±0.5 seconds) than in those whose coma grade did not change (1.6±0.2 seconds). The combination of a prothrombin time 3 seconds or longer than that of the control and a serum level of ammonia on admission ...

Refractory infantile diarrhea due to primary bile acid malabsorption

A boy is described who had severe, refractory diarrhea beginning soon after birth. Prolonged parenteral alimentation was required to support life. Investigations of bile acid metabolism showed impaired intestinal absorption of bile acids. Contracted bile acid pool sizes resulted, with low intraluminal bile acid concentrations and severe, malabsorption of water and fat. Bile acid malabsorption is a cause of refractory infantile diarrhea.

Hypocalcemia and steatorrhea—Clues to etiology

Two boys with idiopathic hypoparathyroidism had extensive studies of gastrointestinal function during hypocalcemia accompanied by steatorrhea. No evidence of generalized gastrointestinal moniliasis or abnormal mucosal structure or function was observed. Studies of pancreatic function and bile salt metabolism during hypocalcemia demonstrated deficient meal-stimulated intraluminal pancreatic enzyme concentrations in both subjects and reduced bile salt concentrations in one subject. However, following stimulation with exogenous octapeptide of cholecystokinin, intraluminal pancreatic enzyme and bile salt concentrations were normal in both. Cholic acid pool sizes were markedly increased in both subjects during hypocalcemia (9 and 12 times larger than during normocalcemia) and cholic acid turnover was reduced during hypocalcemia in one subject. Our findings suggest that during hypocalcemia, insufficient endogenous cholecystokinin is released by the duodenal mucosa during a meal stimulus to stimulate normal gallbladder contraction and pancreatic enzyme secretion.

Morphology of Acute Myopathy Associated with Influenza B Infection

Calf muscle samples were obtained from 12 children with transient incapacitating myalgia and proved infection of the upper respiratory tract with influenza virus, type B. In all except one, light microscopy revealed isolated segmental muscle fiber degeneration and necrosis without frank myositis. Ultrastructural studies revealed that in zones of segmental necrosis, the sarcolemma was lysed but the basement membrane was intact. Focal degenerative changes included myofibrillar disarray with disruption/loss of the sarcoplasmic reticulum, glycogen depletion accompanied by mitochondriopathy, subsarcolemmal mitochondrial aggregates, activation of satellite cells, and focal filopodial transformation of the sarcolemma. The primary event in the pathogenesis of focal muscle fiber necrosis is likely to be biochemical and was not elucidated, but the focal sarcolemmal and T-tubule changes and mitochondriopathy suggest that destabilization of cell membranes may play a critical role. Sarcolemmal filopodia may be a marker for a specific type of membrane injury, but we were unable to establish that influenza virus has a direct role in its genesis.