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Hemophagoytic lymphohistiocytosis (HLH) is a rare life-threatening disorder caused by overactivation of the immune system, associated with infections, autoimmune disorders, and malignancies. The pathological hallmark of HLH is phagocytosis of blood cells and platelets by activated macrophages and histiocytes. In this report, we describe the onset of HLH in three children, aged 2, 5 and 7 years old, during the treatment of acute focal bacterial nephritis (AFBN) with an antibiotic, piperacillin-tazobactam (PIPC-TAZ). AFBN is acute localized bacterial infection of the kidney without abscess formation. PIPC-TAZ was chosen for the treatment of AFBN, because it not only has indications for complicated urinary tract infections, but also covers most of the causative bacteria of urinary tract infections, including β-lactamase-producing Escherichia coli. The clinical courses of the three patients were similar, and they were treated with PIPC-TAZ and amikacin (AMK) for AFBN. Fever went down 2 to 5 days later, and AMK was discontinued by day 6. However, fever recurred on 13 to 15 days after introduction of PIPC-TAZ therapy, even though all of the patients had no signs of recurrence of AFBN. The clinical features and laboratory tests of two patients fulfilled the criteria of HLH, whereas the other patient had initiated therapy before fulfilling the criteria. Cessation of PIPC-TAZ combined with corticosteroid therapy improved clinical symptoms. HLH of our patients was probably induced by PIPC-TAZ, as judged by the timing of the onset of HLH and the positivity of the drug-lymphocyte stimulation test. In conclusion, prolonged antibiotic therapy with PIPC-TAZ could be a cause of HLH.

Arterial stiffness is widely used in assessing arteriosclerosis in the background of increased cardiovascular events. Arteriosclerosis also causes reduction in exercise capacity, which is a most important prognostic factor in patients with cardiovascular disease; however, data on the association between arterial stiffness and exercise capacity are limited. Therefore, a simple and noninvasive measurement of arterial stiffness that reflects the central circulation and exercise capacity is needed. The arterial velocity pulse index (AVI) is a parameter of arterial stiffness measurable with the cuff oscillometric method; however, the clinical utility of this method is unclear. We aimed to evaluate the trend of AVI in patients with coronary artery disease (CAD), and the association between AVI and exercise capacity. A cross-sectional study of 116 patients with cardiac disease (34 CAD and 82 non-CAD patients) was performed. Non-CAD patients were those with any cardiac diseases who did not have proven CAD. The results showed that the AVI was significantly higher in CAD patients than non-CAD patients (P < 0.05, analysis of covariance). The AVI was inversely correlated with peakVO2 (r = -0.239, P < 0.05) and was a significant explanatory variable for peakVO2 in stepwise regression analysis (β = -14.62, t = -2.5, P < 0.05). These results indicate that the AVI is strongly associated with CAD and predictive of the exercise capacity in patients with cardiac diseases. We, therefore, propose that the cuff oscillometric method is clinically useful in evaluating arterial stiffness in patients with cardiac diseases, especially CAD.

We report a preterm infant who was prescribed an MCT formula and subsequently developed carnitine deficiency with liver dysfunction and an elevation of serum CK level. A male infant who had been born at 24 weeks' gestation with birth weight 799 g, was fed with an MCT formula containing 76.8% of all kinds of lipids, because of his steatorrhea after the 30th day. On the 100th day, he was noted hepatomegaly and elevation of serum levels of AST, ALT and CK. The needle biopsy of the liver indicated the existence of the liver damage. He showed low serum carnitine with high urinary loss of acylcarnitine and dicarboxylic aciduria. Administration of L-carnitine was an effective treatment. The carnitine deficiency might be exaggerated by an increased urinary loss of acylcarnitine. We should be cautious of the risk of carnitine deficiency in preterm infants during prolonged use of MCT formula.

This study discusses four children of hepatocellular carcinoma (HCC) who were asymptomatic HBsAg carriers or had HBsAg-positive chronic hepatitis for 3 to 11 years before the occurrence of the carcinoma. Three of these four patients were positive for anti-HBe at 3 to 5 years before the diagnosis of hepatocellular carcinoma. Autopsy findings disclosed liver cirrhosis in all the four patients. To the best of our knowledge few reports have documented children in HBsAg carrier status or with HBsAg-positive hepatitis prior to the development of hepatocellular carcinoma. It is emphasized that HBsAg-positive children, with or without detectable hepatic lesions in routine examinations, have a possibility of developing HCC, and should be carefully monitored for long periods.

To clarify features of late vitamin K deficiency hemorrhagic disease in Japanese infants, seventeen of 1,687 infants screened by normotests were examined for signs and symptoms suggesting hepatobiliary diseases. Clinical observations disclosed findings suggesting hepatobiliary diseases in 7 of the 17 selected infants with normotest values of less than 40%, and 11 infants had abnormal results in one or more liver function tests. Taken together, 14 of the 17 infants had findings suggesting hepatobiliary diseases. Upon vitamin K supplementation normotest values improved in various degrees in all infants, whether or not they had signs or symptoms of hepatobiliary diseases. Late vitamin K deficiency hemorrhagic disease of infancy may be related to subclinical hepatobiliary diseases.

A 15-month-old girl with propionic acidemia presented a failure to thrive and muscular hypotonia, who had been treated with diets low in leucine, valine, isoleucine, threonine and methionine. Supplementation with leucine gave her a catch up growth and brought about an improvement in muscular hypotonia in parallel with restoration of plasma leucine which had been below normal range during the treatment with the above diets. Oral loading test of leucine produced no ketoacidosis. These findings indicate that the restriction of leucine is not necessary in the dietary management of propionic acidemia.

An accurate and sensitive method by high-performance liquid chromatography connected with 3 alpha-hydroxysteroid dehydrogenase immobilized column for the measurement of urinary bile acids of noncholestatic and cholestatic infants was performed in this study. The purification and group separation of urinary bile acids were done through a piperidinohydroxypropyl Sephadex LH-20 column. By ultraviolet spectromonitor, non 3 alpha-hydroxy bile acids such as 3 beta-hydroxy-5-cholenate were determined, and 3 alpha-hydroxy bile acids by fluorescence spectromonitor. Urinary bile acids in the specimens obtained from noncholestatic and cholestatic infants were determined by this procedure. Major bile acids were cholate, chenodeoxycholate conjugates and cholate unconjugate in healthy infants. In cholestatic infants, total and individual bile acids were extremely increased, and 3 beta-hydroxy-5-cholenate conjugates appeared in the sulfated fraction.

To determine a participation of cytomegalovirus (CMV) infection in acute respiratory tract disease (ARTD) of low-birth-weight (LBW) infants, specific antibodies against CMV antigens, IgG antibodies against early antigens of CMV (IgG EA) and IgM antibodies against membrane antigens of CMV (IgG MA) were analyzed. The frequency of IgG EA in patients with ARTD was higher than that in controls (46% vs. 32%), and the geometrical mean titer (GMT) of IgG EA in the patients was also higher than that in controls (50.2 vs. 20.1). Five of 15 ARTD patients had IgM MA, and the frequency was significantly higher than that of controls (33% vs. 1.3%, p less than 0.01). Eleven of 15 LBW patients with ARTD had a history of blood transfusions during the neonatal period, and 5 of them had significant IgM MA indicating active CMV infection. All 4 LBW patients without blood transfusion were negative for IgM MA. These results suggest a close relationship of CMV infection to ARTD of LBW infants, but it remains for further studies whether blood transfusion is a primary source of CMV infection in LBW infants.

The skeletal muscle from a patient with familial intrahepatic cholestasis associated with vitamin E deficiency was studied by electron microscopy. The muscle fibers showed a variety of pathologic features including degenerative, necrotic and regenerative changes. Granule-like inclusions found in our biopsy specimens were similar in structure to those observed in vitamin E deficient animals. These inclusions were noted not only in the skeletal muscle fibers but also in endothelial cells of the intramuscular capillaries, Schwann cells and perineural cells. Disruption and disappearance of the plasma membrane, separation, disruption and pleats formation of the external lamina, and multilayered external laminae were observed in muscle fibers most frequently. The nerves among muscle fibers also showed degenerative features. These severely degenerative alterations of the muscle fiber have not so far been reported in vitamin E deficient patients. We discuss the process of cell damages caused by vitamin E deficiency.

We investigated the effects of long-term oral and intramuscular vitamin E repletion in children with chronic cholestasis. Clinical improvement or suppression of neuromuscular involvement after adequate vitamin E repletion was demonstrated. Light and electron microscopic abnormalities of the skeletal muscle, however, did not completely disappeared despite the correction of the biochemical abnormalities for more than 3 years. The muscle fibers showed less variety of pathologic features than before vitamin E repletion. Inclusions observed in the skeletal muscle fibers before vitamin E treatment were still observed in subsarcolemmal cytoplasm and the perinuclear regions. They were more irregularly curved and consisted of various substances. Similar inclusions were also observed in Schwann cells, perineural cells, fibroblasts, pericytes, endothelial cells and smooth muscle cells of intramuscular vessels. Although the external lamina was not disrupted, separation of the external lamina from the plasma membrane and multilayered external lamina were often observed. The nerves among muscle fibers still showed degenerative features. Morphological changes of the skeletal muscle during vitamin E therapy have not so far been reported in cases of chronic cholestasis. We discuss the relationship of these findings to vitamin E replacement in children with chronic cholestasis.

Two siblings with progressive intrahepatic cholestasis were reported. The brother died at 4 years of age because of hepatic failure followed by persistent obstructive jaundice starting at 4 months of age. The sister had unique clinical features, including recurrent obstructive jaundice since early infancy, radiopaque gallstone and neurological abnormalities which were cerebellar ataxia, bilateral ptosis, hyporeflexia and visual disturbance involving retinal degeneration and optic atrophy. She had a coarse facial appearance, camptodactyly and sclerotic skin with many scratch marks. Persistent high levels of serum bile acids were found while the patient was icteric and even anicteric, though serum cholesterol levels were approximately within normal limits. The serum lipoprotein-X was negative whenever examined. Cholestyramine treatment gave incomplete relief from pruritus but resulted in no improvement in her clinical course.

To elucidate relationship between acute respiratory tract diseases (ARTD) accompanying hepatitis and cytomegalovirus (CMV) infection in infancy, 74 full-term inpatients with ARTD and 34 control patients without ARTD or hepatitis were subjected to this study. By determining specific antibodies to CMV, IgG early antigen (IgG EA) and IgM membrane antibody (IgM MA) which are markers of active CMV replication, the following results were obtained. Thirty-one (41%) of the 74 patients with ARTD and 12 of the 34 control group (35%) had significant IgG EA (greater than or equal to 1:8). The geometric mean reciprocal titer in the group with ARTD (1:33.0) was higher than that in the control group (1:15.3). On the other hand, while 6 of the 74 patients with ARTD (8%) had significant IgM MA (greater than or equal to 1:8), none of the control group had positive IgM MA. Out of the 74 patients with ARTD, 8 (10%) patients, all except one being younger than 2-month-old, also had hepatitis. Of the 8 patients with hepatitis, 6 (75%) had significant IgG EA. The geometric mean reciprocal titer of the patients with hepatitis was higher than that of the patients without hepatitis, the titer being 1:42.6 and 1:30.7, respectively. On the other hand, 3 of the 8 patients with hepatitis (37%) had significant IgM MA while only 3 of the 66 patients without hepatitis (4.5%) had IgM MA. The frequencies of IgM MA between two groups were significantly different (p less than 0.05). CMV infection may be involved in some infants with ARTD, particularly in younger infants with both of ARTD and hepatitis.