Kevin E. Bove

Observations on the Assessment of Cardiac Hypertrophy Utilizing a Chamber Partition Technique

Three hundred fifty-four adult human hearts were dissected utilizing a technique similar to those previously described by Müller1 and Lewis.2 A classification was synthesized on the basis of anatomic characteristics of 100 normal hearts. Presumptive evidence of either left or right ventricular overload, provided by clinical and autopsy observation, served as essential corollary data in establishing normal limits. The existence of hypertrophy was readily recognized in hearts in which one or both ventricles increased in mass sufficiently to surpass the defined upper limit. Isolated ventricular hypertrophy of mild degree was recognized as a consequence of an abnormal LV+S/RV ratio in 58 hearts in which ventricular weights were within the normal range. Factors which would be expected to result in left or right ventricular overload were demonstrable in 42 of these cases. Atrial hypertrophy correlated well with hypertrophy of the corresponding ventricle and served as an invaluable aid in recognition of mild degrees of combined ventricular hypertrophy. This classification constitutes the basis for a subsequent correlative electrocardiographic study.

DNA Fragmentation Factor 45-deficient Cells Are More Resistant to Apoptosis and Exhibit Different Dying Morphology than Wild-type Control Cells

The DNA fragmentation factor 45 (DFF45) is a subunit of a heterodimeric DNase complex critical for the induction of DNA fragmentation in vitro. To understand the in vivo role of DFF45 in programmed cell death, we measured the expression of DFF45 during mouse development and compared DNA fragmentation and viability of DFF45-deficient cells with wild-type control cells after activation of apoptosis. We found that DFF45 is ubiquitously expressed throughout mouse development. Moreover, DFF45-deficient thymocytes are resistant to DNA fragmentation within vivo dexamethasone treatment. Furthermore, primary thymocytes from DFF45 mutant mice are also more resistant to apoptosis than wild-type control cells on exposure to several apoptotic stimuli. Dying DFF45-deficient thymocytes exhibit different morphology than wild-type control cells in that they show reduced degree of chromatin condensation, absent nuclear fragmentation, intranuclear cytoplasmic invagination, and striking nuclear chromatin conglutination after release from disintegrating cells. These results indicate that DFF45 is essential during normal apoptosis.

Mechanisms of Disease: inborn errors of bile acid synthesis

Inborn errors of bile acid synthesis are rare genetic disorders that can present as neonatal cholestasis, neurologic disease or fat-soluble-vitamin deficiencies. There are nine known defects of bile acid synthesis, including oxysterol 7α-hydroxylase deficiency, Δ4-3-oxosteroid-5β-reductase deficiency, 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency, cerebrotendinous xanthomatosis (also known as sterol 27-hydroxylase deficiency), α-methylacyl-CoA racemase deficiency, and Zellweger syndrome (also known as cerebrohepatorenal syndrome). These diseases are characterized by a failure to produce normal bile acids and an accumulation of unusual bile acids and bile acid intermediaries. Individuals with inborn errors of bile acid synthesis generally present with the hallmark features of normal or low serum bile acid concentrations, normal γ-glutamyl transpeptidase concentrations and the absence of pruritus. Failure to diagnose any of these conditions can result in liver failure or progressive chronic liver disease. If recognized early, many patients can have a remarkable clinical response to oral bile acid therapy.

Pathological findings in gaucher disease type 2 patients following enzyme therapy

The pathological outcomes following intravenous acid beta-glucosidase (alglucerase) infusions were compared in two siblings with Gaucher disease type 2, the acute neuronopathic variant. In case 1 enzyme infusions (four doses at 7 months) had no effect when severe progressive visceral and neuronopathic disease were present. Death from progressive disease occurred at 9 months. Case 2 was prenatally diagnosed. Enzyme infusions were initiated presymptomatically at 4 days of age and continued until death at 15.2 months. Development progressed satisfactorily, albeit at a slower than normal rate until age 10 months when progressive brain stem involvement became evident. Death occurred after slowly progressive brain stem dysfunction, but gross motor and cognitive skills were nearly normal. Postmortem light and electron microscope (EM) studies in both cases showed typical central nervous system (CNS) findings and massive infiltration of the lungs and lymph nodes by Gaucher cells. The liver, spleen, and bone marrow, except that in the temporal bone, in case 2 were normal. These studies show that enzyme therapy may slow but does not prevent the development of lethal CNS disease in Gaucher disease type 2, even when initiated presymptomatically. These findings also indicate the nonuniformity of tissue responses to enzyme therapy implying the existence of therapeutically inaccessible compartments that, in less severe variants, may create unexpected long-term disease complications.

Bile Acid Synthetic Defects and Liver Disease

1Division of Pediatric Pathology, Children’s Hospital Medical Center, and the University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA 2Division of Pediatric Gastroenterology, Children’s Hospital Medical Center, and the University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA 3Division of Mass Spectrometry, Children’s Hospital Medical Center, and the University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA 4Department of Pathology, Denver Children’s Hospital, 1056 East 19th Avenue, Denver, CO 80218, USA

Vascular Dysplasia in a Child with Tuberous Sclerosis

Tuberous sclerosis is characterized by the development of hamartomas in many organs, particularly the brain, skin, heart, and kidney. We report a child with typical features of this disease who also had a severe generalized vascular dysplasia of both muscular arteries and veins and an abdominal aortic aneurysm in association with obliterative dysplasia of the aortic vasa vasorum. This is the first report of such a widespread vascular abnormality in association with tuberous sclerosis. This case along with several reports of more isolated vascular abnormalities in these patients indicates that vascular dysplasia represents another manifestation of the generalized tendency to hamartoma formation seen in this disorder.

Hypocomplementemic and normocomplementemic acute nephritis in children: A comparison with respect to etiology, clinical manifestations, and glomerular morphology

Of 182 patients with acute glomerulonephritis, 20 had normal C3 levels at onset. Normocomplementemic and hypocomplementemic patients were similar with respect to incidence and site of preceding streptococcal infection, elevation of ASO titer, distribution by age, sex, race, season, and year,\and glomerular morphology by light and electron microscopy. They differed in that the normocomplementemic patients tended to have normal serum C5 levels and, for reasons not clear, reduced serum albumin and elevated cholesterol levels. The consistent absence by immunofluorescence of IgG in the glomeruli of five hypocomplementemic patients and its presence in five normocomplementemic patients was considered a chance observation. The data suggest that in each group the nephritis was poststreptococcal and that the mechanism producing poststreptococcal glomerulonephritis is capable of acting independently of that activating circulating C3.

Hepatoblastoma in a child with trisomy 18: cytogenetics, liver anomalies, and literature review.

A 26-month-old female with trisomy 18 and repaired omphalocele died of metastatic disease after resection of hepatoblastoma (HB) at 21 months of age. Four other cases (three of them published) suggest that the association of trisomy 18 and HB may be nonrandom. Karyotype abnormalities of the tumor in our case included duplication of 2q and +20, reported previously in HB arising in patients with normal karyotype. Antecedent growth disturbance of liver, either intrinsic (abnormal lobation) or related to contiguous extrinsic anomalies such as omphalocele or local diaphragmatic hypoplasia and possibly augmented by unusual sensitivity to noxious environmental agents, may predispose to hepatoblastoma in trisomy 18. Longevity in trisomy 18 predisposes to both hepatoblastoma and Wilms tumor, possibly by a shared pathway.

Cholangitis Associated With Cryptococcus neoformans

A 15-yr-old girl presented with complaints of right upper quadrant pain and jaundice. Elevation of serum alkaline phosphatase, signs of protal hypertension, and computed tomographic scan findings suggested a diagnosis of primary sclerosing cholangitis. However, cultures of the bile and of the common bile duct specimen obtained during a surgical procedure grew Cryptococcus neoformans. Treatment with amphotericin B was begun. An episode of upper gastrointestinal bleeding, however, led to the hepatorenal syndrome, and the patient died before antifungal therapy was completed. At autopsy, active sclerosing cholangitis associated with cryptococci involved the common bile duct. We suggest that opportunistic infection of the biliary tree should be considered in pediatric patients with presumed primary sclerosing cholangitis.

Aortic valve perforation

Abstract This paper describes fifteen patients with aortic valve perforation, in fourteen of whom this complication developed during the course of bacterial endocarditis. Aortic cusp perforation should be suspected whenever moderately severe or severe aortic insufficiency appears during bacterial endocarditis. The murmur of aortic insufficiency caused by cusp perforation is of the common decrescendo blowing quality, and is only occasionally of musical quality. In patients with aortic cusp perforation and attendant severe aortic insufficiency, congestive heart failure often develops within a few days or weeks. In our series heart failure appeared within one week to four and a half months in eleven of the fifteen patients. Eight of these patients, who had not been treated by aortic valve surgery, died within one day to six months after the appearance of heart failure. Three of our patients with acute bacterial endocarditis apparently died of a cardiac arrhythmia resulting from infection of the atrioventricular node or bundle of His. In seven of our patients the aortic insufficiency was treated surgically. In two patients the perforation was small enough to be closed by direct suturing; in five the aortic valve was excised and replaced by a Starr-Edwards prosthesis. Five of these seven patients survived to be discharged from the hospital, but one of the five died suddenly three months postoperatively, and another died of Candida endocarditis four and a half months after insertion of the prosthesis.