Transaortic Transcatheter Aortic Valve Implantation as a Second Choice over the Transapical Access.

BACKGROUND AND AIMS: In this report, we present our experience with the transaortic transcatheter aortic valve implantation using the SAPIEN valve. The procedural success, 30-day outcome, and survival up to 2 years are compared with the transapical access performed in patients in our institution. MATERIAL AND METHODS: Of a total of 282 transcatheter aortic valve implantation patients, 100 consecutive patients had a non-transfemoral approach. The transaortic and transapical access routes were used in 36 and 64 patients, respectively. The transaortic group had a higher mean logistic EuroSCORE (32.6 vs 25.2, p = 0.021) and more patients with left ventricular ejection fraction less than 40% (33.3% vs 14.1%, p = 0.023). RESULTS: The respective technical success rates for the transaortic and transapical groups were 100% and 95.2% (p = NS). There were significantly more perioperative hemodynamic problems necessitating cardiopulmonary resuscitation or mechanical circulatory support in the transapical group (18.8% vs 2.8%, p = 0.023). The transaortic group had a slightly shorter hospital stay (7 vs 8 days, p = 0.018). The 30-day mortality was 8.6% and 10.9% in the transaortic and transapical group, respectively (p = NS). Combined safety outcome was similar in both groups at 30 days. The respective 1-year survival rates for the transaortic and transapical groups were 71.5% and 68.3%, respectively (p = NS). CONCLUSION: The trans transcatheter aortic valve implantation is a considerable choice to transapical approach. Despite a higher risk patient cohort, the clinical outcome is at least comparable to the transapical transcatheter aortic valve implantation, and it can be utilized as a second choice for patients with prohibitive iliac-femoral anatomy for transfemoral access.

Severe heart failure and rhabdomyolysis associated with propofol infusion in a burn patient.

The authors report a favorable outcome in an adult burn patient, who developed severe propofol-related infusion syndrome presenting with rhabdomyolysis, acute kidney injury, and right-sided heart failure after a low-dose propofol infusion. Other possible causes for late-onset rhabdomyolysis after burn trauma were ruled out by extensive differential diagnostics. The most distinctive abnormal finding was a Brugada-type ST-segment elevation, reported previously associating with imminent death. The patient survived because of cessation of propofol infusion and continuous renal replacement therapy. ECG recording is important in early detection of propofol-related infusion syndrome. ST elevations in the ECG should lead to the immediate discontinuation of propofol.

Glomerular sclerosis in kidneys with congenital nephrotic syndrome (NPHS1).

Congenital nephrotic syndrome of the Finnish type (NPHS1) is a rare genetic disease caused by mutations in the NPHS1 gene encoding a major podocyte slit-diaphragm protein, nephrin. Patients with NPHS1 have severe nephrotic syndrome from birth and develop renal fibrosis in early childhood. In this work, we studied the development of glomerular sclerosis in kidneys removed from 4- to 44-month-old NPHS1 patients. The pathological lesions and expression of glomerular cell markers were studied in nephrectomized NPHS1 and control kidneys using light and electron microscopy and immunohistochemistry. An analysis of 1528 glomeruli from 20 patients revealed progressive mesangial sclerosis and capillary obliteration. Although few inflammatory cells were detected in the mesangial area, paraglomerular inflammation and fibrosis was common. The podocytes showed severe ultrastructural changes and hypertrophy with the upregulation of cyclins A and D1. Podocyte proliferation, however, was rare. Apoptosis was hardly detected and the expression of antiapoptotic B-cell lymphoma-2 and proapoptotic p53 were comparable to controls. Moderate amounts of podocytes were secreted into the urine of NPHS1 patients. Shrinkage of the glomerular tuft was common, whereas occlusion of tubular opening or protrusion of the glomerular tuft into subepithelial space or through the Bowman's capsule were not detected. The results indicate that, in NPHS1 kidneys, the damaged podocytes induce progressive mesangial expansion and capillary obliteration. Podocyte depletion, glomerular tuft adhesion, and misdirected filtration, however, seem to play a minor role in the nephron destruction.

Hematopoietic stem cell transplantation in infantile neuronal ceroid lipofuscinosis.

OBJECTIVE: To study the effect of allogeneic hematopoietic stem cell transplantation (SCT) on the clinical course of infantile neuronal ceroid lipofuscinosis (INCL), a lysosomal storage disease. BACKGROUND: INCL is a progressive encephalopathy with severe neuronal loss, especially in the cerebral and cerebellar cortex and retina. Autofluorescent lipopigments constitute the typical storage material in INCL. The disease is caused by recessive mutations in the palmitoyl protein thioesterase 1 (PPT1) gene. PPT1 is a depalmitoylating enzyme, which is transported to lysosomes through the mannose-6-phosphate receptor-mediated pathway, and participates in the lysosomal degradation of fatty acylated proteins. METHODS: Three patients with INCL received transplants and were followed up after SCT at the Hospital for Children and Adolescents at the University of Helsinki. The first patient rejected the first graft at the age of 7 months and had mild symptoms of INCL at the second transplantation at 11 months. The two other patients were asymptomatic when they received their transplants at the age of 4 months. RESULTS: PPT1 enzyme activity was normalized in peripheral leukocytes, but remained low in the CSF and resulted only in a mild and transient amelioration of the classic INCL. All patients who received transplants developed INCL by the age of 2 or 3 years. CONCLUSIONS: More experimental animal and cell culture studies are needed to determine the in vivo function of PPT1. SCT currently cannot be recommended as therapy for INCL.

Congenital nephrotic syndrome (NPHS1): features resulting from different mutations in Finnish patients.

BACKGROUND: Congenital nephrotic syndrome (NPHS1) is a rare disease inherited as an autosomally recessive trait. The NPHS1 gene mutated in NPHS1 children has recently been identified. The gene codes for nephrin, a cell-surface protein of podocytes. Two mutations, named Fin-major and Fin-minor, have been found in over 90% of the Finnish patients. In this study, we correlated the NPHS1 gene mutations to the clinical features and renal findings in 46 Finnish NPHS1 children. METHODS: Clinical data were collected from patient files, and kidney histology and electron microscopy samples were re-evaluated. The expression of nephrin was studied using immunohistochemistry, Western blotting, and in situ hybridization. RESULTS: Nephrotic syndrome was detected in most patients within days after birth regardless of the genotype detected. No difference could be found in neonatal, renal, cardiac, or neurological features in patients with different mutations. Nephrin was not expressed in kidneys with Fin-major or Fin-minor mutations, while another slit diaphragm-associated protein, ZO-1, stained normally. In electron microscopy, podocyte fusion and podocyte filtration slits of various sizes were detected. The slit diaphragms, however, were missing. In contrast to this, a nephrotic infant with Fin-major/R743C genotype expressed nephrin in kidney had normal slit diaphragms and responded to therapy with an angiotensin-converting enzyme inhibitor and indomethacin. CONCLUSIONS: The most common NPHS1 gene mutations, Fin-major and Fin-minor, both lead to an absence of nephrin and podocyte slit diaphragms, as well as a clinically severe form of NPHS1, the Finnish type of congenital nephrotic syndrome.

Lymphocyte inclusions in Finnish-variant late infantile neuronal ceroid lipofuscinosis (CLN5).

Electron microscopic reinvestigation of archival samples of peripheral blood lymphocytes of four patients with Finnish-variant late infantile neuronal ceroid lipofuscinosis (CLN5) showed inclusions with dark globules and particles showing fingerprint profiles. Findings, in contrast to an earlier report, show that the lymphocytes in this disease carry pathognomonic cytosomes like all other forms of neuronal ceroid lipofuscinosis in childhood.

Muscle membrane-skeleton protein changes and histopathological characterization of muscle-eye-brain disease.

Muscle-eye-brain disease belongs to congenital muscular dystrophies with central nervous system abnormalities. The etiology of MEB is still unknown, but abnormal immunoreactivity for laminin-2 has been reported. To evaluate disease progression in muscle tissue, 32 biopsy specimens from 17 muscle-eye-brain patients were analysed. The samples of four patients were studied by immunohistochemical techniques and by quantitative Western blotting. The samples showed a great variation in the muscle pathology. Regenerative fibers and mild fiber size variation were present in over 60%. At infancy, necrotic and regenerative fibers were common, while fat infiltration was the most prominent finding in the age group over five years. In quantitative studies, the amount of laminin alpha 2 chain was clearly reduced to 10-20% of normal. In contrast, laminin beta 2 chain was overexpressed in the Western blotting studies. These findings may reflect a yet unidentified primary disturbance in the basement membrane composition and function.

Correction of peripheral lysosomal accumulation in mice with aspartylglucosaminuria by bone marrow transplantation.

OBJECTIVE: Bone marrow transplantation has been shown to alleviate symptoms outside the CNS in many lysosomal storage diseases depending on the type and stage of the disease, but the effect on neurological symptoms is variable or still unclear. Aspartylglucosaminuria (AGU) is a lysosomal storage disease characterized by mental retardation, recurrent infections in childhood, hepatosplenomegaly and coarse facial features. Vacuolized storage lysosomes are found in all tissues of patients and uncleaved enzyme substrate is excreted in the urine. The recently generated AGU mouse model closely mimicks the human disease and serves as a good model to study the efficiency of bone marrow transplantation in this disease. METHODS: Eight-week-old AGU mice were lethally irradiated and transplanted with bone marrow from normal donors. The AGA enzyme activity was measured in the liver and the brain and the degree of correction of tissue pathology was analyzed by light and electron microscopy. Reverse bone marrow transplantation (AGU bone marrow to wild-type mice) was also performed. RESULTS: Six months after transplantation the AGA enzyme activity was 13% of normal in the liver, but only 3% in the brain. Tissue pathology was reversed in the liver and the spleen, but not in the brain and the kidney. The urinary excretion of enzyme substrate was diminished but still detectable. No storage vacuoles were found in the tissues after reverse transplantation, but subtle excretion of uncleaved substrate was detected in the urine. CONCLUSION: Liver and spleen pathology of AGU was corrected by bone marrow transplantation, but there was no effect on lysosomal accumulation in the CNS and in the kidneys.

Cellular expression of xanthine oxidoreductase protein in normal human tissues.

Xanthine oxidoreductase is an important cytoplasmic source of reactive oxygen species, and has been implicated in the pathogenesis of ischemia-reperfusion damage. Because the cellular localization of this protein remains unclear, our aim was to study its distribution in fresh normal human tissue obtained at surgery. For immunohistochemical studies we purified the protein from human milk and raised a polyclonal antibody in rabbits. In the liver the protein was preferentially localized to the periportal hepatocytes and it was absent from the perivenous region. In the proximal intestine, the protein was expressed in epithelial cells and goblet cells. Lactating mammary gland acinar cells showed intense staining. Small vessel vascular endothelial cells of the intestine, mammary gland, and skeletal muscle showed immunoreactivity, but in the kidney, glomerular endothelial cells were negative. No cells in the heart, brain, or lung expressed the enzyme protein. The observed localization of the xanthine oxidoreductase protein is consistent with previously observed enzyme activities in the organs studied. The widely assumed exclusive localization to capillary endothelium obviously does not apply to humans.

Prenatal diagnosis of variant late infantile neuronal ceroid lipofuscinosis (vLINCL[Finnish]; CLN5).

The first prenatal diagnosis of variant late infantile neuronal ceroid lipofuscinosis (vLINCL[Finnish]; CLN5) is reported. The disease belongs to the group of progressive encephalopathies in children with psycho-motor deterioration, visual failure and premature death. Neurons and several extraneural cells harbour lysosomal inclusions showing accumulation of material with histochemical characteristics of ceroid and lipofuscin. A Finnish woman with a daughter with vLINCL came for genetic counselling for her current pregnancy. Electron microscopy of a chorionic villus sample (CVS) at the 11th week of gestation did not reveal inclusions characteristic for NCL. DNA analysis showed that the fetus had inherited the major mutation, a 2 bp deletion of the CLN5 gene from the mother, and the same paternal (and maternal) haplotypes for COLAC1 and AC224 as the affected daughter. The pregnancy was terminated. Electron microscopy of the CVS of the aborted fetus at the 14th week of pregnancy showed lysosomal electron dense inclusions with straight and curved lamellar profiles consistent with vLINCL. Prenatal diagnosis of NCL-disorders (CLN1, CLN2, CLN3) can be made from CVS by demonstrating the mutations of the affected genes or by haplotype analysis using the closely linked markers in most cases. In various clinical settings the DNA diagnostics may not be possible. Demonstration of the characteristic inclusions of the placenta and fetal tissues remains a helpful adjunct in such cases.

Nephronophthisis in Finland: epidemiology and comparison of genetically classified subgroups.

Nephronophthisis--medullary cystic kidney disease is a progressive chronic tubulointerstitial nephritis leading to terminal renal failure. About two thirds of the patients with familial juvenile nephronophthisis, an autosomal recessive disease, have a homozygous deletion at the gene locus on 2q13. Through a nationwide search, 59 patients were ascertained in Finland. The incidence was 1:61,800 live births when calculated over a 20-year period. Of the patients, 17 came from four families showing dominant inheritance and 37 patients from 28 apparently recessive families when classified by family history, clinical features or presence of a deletion on 2q13. Two were considered as new dominant mutations; three sporadic patients could not be classified. The most significant difference between the patients with deletions, patients without deletions but having recessive family history, and patients belonging to families with dominant inheritance was the age at first symptoms, at the start of dialysis and at transplantation. These facts will be of help in determining the mode of inheritance of a sporadic patient without a deletion.

Infection-associated intimal thickening in the coronary arteries of children.

OBJECTIVES: based on autopsy material from children this study investigated the possible relationship of clinically evident infection prior to death with intimal thickening of the coronary arteries. BACKGROUND: viral infections are suggested to be associated with intimal thickening in the coronary arteries both in animals and man. METHODS: the coronary arteries were examined in 175 autopsied children 0-15 years of age (median 7 days). Semi-serial cross sections of the coronary arteries were screened for maximal intimal thickening at 0.2 mm intervals. The length of the internal elastic lamina, the areas of arterial media and intima were measured from cross-sections. Irregular linings of the arteries were mathematically transformed to circles. The percentage of intimal and musculoelastic layer area to luminal area encircled by arterial media was calculated. RESULTS: intimal thickening increased with age but was also associated with the presence of infectious disease at death. Already in the newborn children, who died shortly after the birth, the percentage of intimal and musculoelastic layer area to luminal area encircled by arterial media was big, maximally 55%. In the left coronary artery the mean percentages were 32 and 21% in the groups with viral and bacterial infections, respectively as compared to 16% in the group with no evidence of infection. CONCLUSION: infections in general and viral infections in particular, seem to be associated with intimal thickening, which may predispose coronary arteries to atherosclerosis. Atherogenesis might have a rapid dynamic component.

Bone marrow transplantation in aspartylglucosaminuria--histopathological and MRI study.

This study comprised two patients with aspartylglucosaminuria (AGU), who were followed up for 4 and 7 years. The patients underwent allogeneic bone marrow transplantation (BMT) at the ages of 2 and 2.6 years. Both patients had abnormal speech development and gross motor clumsiness. At the time of the BMT, they were mentally retarded. We report on follow-up data of these patients obtained by MRI, in addition to the histopathological, biochemical and clinical investigations. MR images of six non-transplanted patients and seven healthy children served as controls. In the non-transplanted patients, MRI revealed evident delay of myelination in contrast to the two transplanted patients showing fair or evident grey- vs. white matter differentiation on T2-weighted images. The aspartylglucosaminidase (AGA) activity in blood leukocytes reached a heterozygous level. Urinary excretion of aspartylglucosamine and glycoasparagines slowly decreased but remained about a third of the pre-BMT level 5 years after BMT. Storage lysosomes in electron microscopic investigations were not decreased 6 months after BMT, but after 1.5-2 years, rectal mucosa samples showed a decrease in the storage vacuoles of different cells. Three years after BMT, no cells with storage vacuoles were present. Allogeneic BMT slowly normalises the pathological, biochemical and MRI findings in patients with AGU.

Effects of alpha tocopherol and beta carotene supplements on symptoms, progression, and prognosis of angina pectoris.

OBJECTIVE: To evaluate the effects of alpha tocopherol and beta carotene supplements on recurrence and progression of angina symptoms, and incidence of major coronary events in men with angina pectoris. DESIGN: Placebo controlled clinical trial. SETTING: The Finnish alpha tocopherol beta carotene cancer prevention study primarily undertaken to examine the effects of alpha tocopherol and beta carotene on cancer. SUBJECTS: Male smokers aged 50-69 years who had angina pectoris in the Rose chest pain questionnaire at baseline (n = 1795). INTERVENTIONS: alpha tocopherol (vitamin E) 50 mg/day, beta carotene 20 mg/day or both, or placebo in 2 x 2 factorial design. MAIN OUTCOME MEASURES: Recurrence of angina pectoris at annual follow up visits when the questionnaire was readministered; progression from mild to severe angina; incidence of major coronary events (non-fatal myocardial infarction and fatal coronary heart disease). RESULTS: There were 2513 recurrences of angina pectoris during follow up (median 4 years). Compared to placebo, the odds ratios for recurrence in the active treatment groups were: alpha tocopherol only 1.06 (95% confidence interval (CI) 0.85 to 1.33), alpha tocopherol and beta carotene 1.02 (0.82 to 1.27), beta carotene only 1.06 (0.84 to 1.33). There were no significant differences in progression to severe angina among the groups given supplements or placebo. Altogether 314 major coronary events were observed during follow up (median 5.5 years) and the risk for them did not differ significantly among the groups given supplements or placebo. CONCLUSIONS: There was no evidence of beneficial effects for alpha tocopherol or beta carotene supplements in male smokers with angina pectoris, indicating no basis for therapeutic or preventive use of these agents in such patients.

Chronic arthritis in patients with aspartylglucosaminuria.

OBJECTIVE: To study the frequency and clinical features of chronic inflammatory arthritis in aspartylglucosaminuria (AGU), a rare disorder of glycoprotein degradation inherited as an autosomal recessive trait and significantly more frequent in Finland than in other parts of the world. METHODS: Of the 164 patients with AGU identified in Finland, 121 were examined by one of the authors, and 43 by their own physicians. For this study, we clinically reexamined all patients with AGU who had arthritis, and relevant laboratory and radiographic studies were performed. RESULTS: Nine of 164 patients (5.5%) were found to have chronic inflammatory arthritis. In 5 patients, the symptoms had started in childhood. Five were seropositive for rheumatoid factor. Symmetric polyarthritis of both small and large joints was seen in 5 patients and erosions in 5. Seropositive rheumatoid arthritis was found in 3 first-degree relatives as well. CONCLUSION: Chronic inflammatory arthritis is a feature of AGU and is characterized by onset in childhood, seropositivity for rheumatoid factor, and a deforming course.

Atypical juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposit-like inclusions in the autonomic nerve cells of the gut wall.

In this 8-year-old boy, who had been exposed to alcohol and oxazepam during pregnancy, visual failure was the first symptom of a neuronal ceroid lipofuscinosis (NCL) disorder, noticed at the age of 5 years. Ophthalmological examinations revealed a cystic type of macular degeneration, which would be more likely to be found in variant late infantile NCL. However, vacuolated lymphocytes were found in peripheral blood films and a diagnosis of the juvenile form of NCL (JNCL) was made. Molecular genetic studies showed the patient to be homozygous for the major mutation of JNCL, a 1.02-kb deletion. In whole-night polysomnography, there was significantly more epileptiform activity than in other JNCL patients under 10 years of age. Using magnetic resonance imaging, the signal intensity of the white matter was increased, especially in the periventricular area. In addition, there were enlarged perivascular spaces in the watershead areas. The corpus callosum was thin. Finally, in the autonomic ganglion cells of the submucosal nerve plexus there were membrane-enclosed homogeneous and granular cytosomes resembling the granular osmiophilic deposits of infantile NCL. However, extraneural cells, including blood capillaries and smooth muscle, showed inclusions with fingerprint and curvilinear profiles. The features of the present case indicated a phenotypic variant of JNCL.

Retinal vascular changes following supplementation with alpha-tocopherol or beta-carotene.

PURPOSE: To examine if long-term supplementation with alpha-tocopherol (AT) or beta-carotene (BC) was associated with the prevalence of vascular changes in retinal arterioles. METHODS: An end-of-trial subsample from a double-blind, placebo-controlled clinical trial designed to study the effects of alpha-tocopherol and beta-carotene on lung cancer incidence (ATBC Study). SETTING: Source population of Helsinki and the surrounding province. PARTICIPANTS: 1072 men 50-69 years old and smoking at least 5 cigarettes per day at study entry. INTERVENTIONS: Random allocation to one of four supplementation regimens: 50 mg per day alpha-tocopherol, 20 mg per day beta-carotene, both alpha-tocopherol and beta-carotene, or placebo. Median follow-up time was 6.6 years (range 5.2-8.0 years). MAIN OUTCOME MEASURE: Presence of vascular changes in retinal arterioles as determined from end-of-trial retinal color photographs. RESULTS: Retinal vascular changes were most prevalent in the AT (161 men, 62%), and in the BC (163 men, 62%) groups. The prevalence rate was lowest in the AT plus BC group (161 men, 55%), and slightly higher in the placebo group (145 men, 57%). There was no statistically significant association of either AT (OR 0.9, 95% CI 0.7-1.2) or BC (OR 1.0, 95% CI 0.8-1.3) supplementation with the prevalence of retinal vascular changes after adjusting for major risk factors. CONCLUSIONS: Supplementation with alpha-tocopherol or beta-carotene for a median of 6.6 years does not protect against retinal vascular changes among smoking males.

Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease.

BACKGROUND: Oxidized low-density lipoprotein is involved in the pathogenesis of atherosclerosis. In epidemiological studies antioxidants have been inversely related with coronary heart disease. Findings from controlled trials are inconclusive. METHODS: We studied the primary preventive effect of vitamin E (alpha tocopherol) and beta carotene supplementation on major coronary events in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a controlled trial undertaken primarily to examine the effects of these agents on cancer. A total of 27 271 Finnish male smokers aged 50 to 69 years with no history of myocardial infarction were randomly assigned to receive vitamin E (50 mg), beta carotene (20 mg), both agents, or placebo daily for 5 to 8 years (median, 6.1 years). The end point was the first major coronary event, either nonfatal myocardial infarction (surviving at least 28 days; n = 1204) or fatal coronary heart disease (n = 907). RESULTS: The incidence of primary major coronary events decreased 4% (95% confidence interval, -12% to 4%) among recipients of vitamin E and increased 1% (95% confidence interval, -7% to 10%) among recipients of beta carotene compared with the respective nonrecipients. Neither agent affected the incidence of nonfatal myocardial infarction. Supplementation with vitamin E decreased the incidence of fatal coronary heart disease by 8% (95% confidence interval, -19% to 5%), but beta carotene had no effect on this end point. CONCLUSIONS: Supplementation with a small dose of vitamin E has only marginal effect on the incidence of fatal coronary heart disease in male smokers with no history of myocardial infarction, but no influence on nonfatal myocardial infarction. Supplementation with beta carotene has no primary preventive effect on major coronary events.