Cardiovascular risk factors and incident giant cell arteritis: a population-based cohort study.

OBJECTIVE: To assess the strength of the effect of cardiovascular risk factors on the incidence of giant cell arteritis (GCA) in a general population context. METHOD: Data from the Reykjavik Study (RS), a population-based cohort study focusing on cardiovascular disease, were used. Everyone born in 1907-1935 living in Reykjavik, Iceland, or adjacent communities on 1 December 1967 were invited to participate. Subjects attended a study visit in 1967-1996 and information on cardiovascular risk factors [smoking habits, blood pressure, diabetes, body mass index (BMI), and serum cholesterol] was obtained. All temporal artery biopsies obtained from members of the RS cohort were re-examined by a single pathologist with expertise in vascular pathology. Effects of risk factors on GCA occurrence are expressed as incidence rate ratios (IRRs) with 95% confidence intervals (CIs). RESULTS: Altogether, 19 241 subjects contributed a median of 23.1 (interquartile range 17.6-29.4) years after the age of 50 to this analysis. During 444 126 person-years of follow-up, 194 subjects developed GCA, corresponding to an incidence rate of 43.6 (95% CI 37.8-50.2) per 100 000 person-years. Being overweight or obese  were inversely associated with GCA, especially in women [IRRs 0.70 (0.48-1.02) and 0.31 (0.14-0.71), respectively]. There was a weaker association between BMI and incident GCA in men. Smoking was inversely associated with GCA in men [IRR 0.47 (0.27-0.81)], but not in women. CONCLUSIONS: The incidence of GCA in Iceland is very high. High BMI protects against the occurrence of GCA, and smoking may protect against GCA in men.

Longitudinal study of TP53 mutations in eight patients with potentially malignant oral mucosal disorders.

OBJECTIVES: In a previous cross-sectional study, the authors found a higher rate of TP53 mutation in oral lichen planus (OLP) than in hyperkeratosis. By analysing for TP53 mutations in serial samples from patients on long-term follow-up of their oral lesions, it was hoped to determine if these mutations were related to disease progression. METHODS: Eight patients presenting with lesions diagnosed clinically as oral leukoplakia or lichen planus were followed from 2 to 12 years. Two to five samples of archival biopsy tissue were analysed from each patient by constant denaturant gradient gel electrophoresis for hotspots A, B, C, D and exon 6. RESULTS: Four patients were diagnosed clinically as OLP: two of these were confirmed histopathologically, one was diagnosed as non-specific hyperkeratosis and one as cancer. Four patients had leukoplakia only, with a histopathological diagnosis of hyperkeratosis. Seven patients had TP53 mutations, three of them on repeated occasions. All five patients who developed squamous-cell carcinoma had mutations. Two of them had mutated pre-malignant lesions, and one of these previously had a non-mutated cancer. Three patients had two different primary cancers, only one of them mutated. One patient developed a mutated cancer 5 years after the last mutation-free biopsy. Of the cancer-free patients, a lesion regarded clinically as cancer-suspicious in one case was mutated, in another patient two OLP lesions were mutated, the third had five biopsies taken during 8 years, all non-mutated. CONCLUSIONS: TP53 mutations may occur early or late in the development of oral squamous-cell carcinoma.

Role of TP53 in the progression of pre-malignant and malignant oral mucosal lesions. A follow-up study of 144 patients.

BACKGROUND: Prediction of progression from pre-malignant oral mucosal lesions to malignancy, or recurrence of an existing oral squamous cell carcinoma (OSCC), is an important clinical problem in oral medicine. METHODS: This study presents a follow-up of a study published in 2002. Samples from 54 patients with OSCC, 45 with oral lichen planus (OLP) and 45 with hyperkeratosis (clinically leukoplakia), diagnosed between 1987 and 1996, were analysed for TP53 protein expression and TP53 mutation. Follow-up was 11-17 years for OSCC (mean 13.3), 12-22 years for OLP (mean 15.9) and 12-17 years for hyperkeratosis (mean 14.5). RESULTS: Of the 54 OSCC patients, 28 experienced recurrent disease, 21 died of OSCC, 22 died of other causes. Of the 14 OSCC patients with mutated TP53 (n = 11), the cancer recurred in eight (57%) and in 20/39 (51%) without mutation. Expression of TP53 protein was significantly associated with reduced overall survival. Among OLP patients, nine were TP53-mutated out of 31 tested. One TP53-mutated OLP patient developed OSCC in a different site. Of the hyperkeratosis patients, three were mutated of 22 tested. One hyperkeratosis patient (non-mutated) developed OSCC in the same site. CONCLUSION: TP53 mutations can exist in benign oral mucosal lesions for many years without progression to malignancy. No association was found between TP53 protein expression or TP53 mutation and recurrence of OSCC or disease-related survival. Overall survival was reduced in patients with positive TP53 protein expression.

Orthotopic liver transplantation for hereditary fibrinogen amyloidosis.

Systemic amyloidosis results from the deposition of insoluble protein fibrils in various organs and tissues. To date, several different proteins have been associated with amyloid fibril formation, including immunoglobulin light chain, serum amyloid A protein, and transthyretin. Recent reports have shown that variant fibrinogen chains can form amyloid in certain kindreds. Hepatic transplantation has previously been reported in the treatment of hereditary amyloidosis associated with variant transthyretin proteins, which are mainly synthesized in the liver. This article reports the first use and long-term follow-up of combined hepatic and renal transplantation in the successful treatment of two patients with hereditary fibrinogen amyloidosis. Both patients experienced sustained improvement in renal function and nutritional status at 61/2 years and 28 months of follow-up, respectively. Orthotopic liver transplantation is effective and potentially curative treatment of hereditary fibrinogen amyloidosis.

Sleep and sleep habits from childhood to young adulthood over a 10-year period.

The aim of this epidemiological study was to utilise a cross-sectional as well as a longitudinal approach to examine sleep habits and how they develop in young people in Iceland. The 668 subjects (1-20 years) who responded to a postal survey in 1985 were followed up 5 and 10 years later. The majority of the variance in bedtime and sleep duration was explained by age, but also to a considerable degree by other factors such as residence, season, and year of survey or interaction of these factors. Natural phenomena, such as the diminution of total sleep duration in the first years of life and the tendency for longer sleep on weekends compared to weekdays were confirmed. The lengthening of sleep on weekends was first significant at the age of 9 and was greater among adolescents than young adults. The incidence of daytime sleepiness increased in adolescence, as did napping, at which time their nocturnal sleep time significantly decreased. Over a period of 10 years, a significant shift to earlier wake-up times occurred in children up to 15 years of age, which resulted in a shortened total sleep time. The idea that individual sleep duration is an inherent parameter is supported by the high positive correlation of total sleep time across a 10-year period (r=.73). The present data confirm that Icelandic adolescents (aged 11, 13, and 15) have delayed bedtimes and shorter nocturnal sleep compared to European peers.

Proliferation of primitive myeloid progenitors can be reversibly induced by HOXA10.

Recent studies show that several Hox transcription factors are important for regulation of proliferation and differentiation in hematopoiesis. Among these is H0XA10, which is selectively expressed at high levels in the most primitive subpopulation of human CD34(+) bone marrow cells. When overexpressed, H0XA10 increases the proliferation of early progenitor cells and can lead to the development of myeloid leukemia. To study the effects of H0XA10 on primitive hematopoietic progenitors in more detail, transgenic mice were generated with regulatable H0XA10 expression. The transgenic mouse model, referred to as tetO-HOXA10, contains the H0XA10 gene controlled by a tetracycline-responsive element and a minimal promoter. Thus, the expression of H0XA10 is inducible and reversible depending on the absence or presence of tetracycline or its analog, doxycycline. A retroviral vector containing the tetracycline transactivator gene (tTA) was used to induce expression of the H0XA10 gene in bone marrow cells from the transgenic mice. Reverse transcription-polymerase chain reaction analysis confirmed regulatable H0XA10 expression in several transgenic lines. H0XA10 induction led to the formation of hematopoietic colonies containing blastlike cells and megakaryocytes. Moreover, the induction of H0XA10 resulted in significant proliferative advantage of primitive hematopoietic progenitors (spleen colony-forming units [CFU-S(12)]), which was reversible on withdrawal of induction. Activation of H0XA10 expression in tet0-H0XA10 mice will therefore govern proliferation of primitive myeloid progenitors in a regulated fashion. This novel animal model can be used to identify the target genes of HOXA10 and better clarify the specific role of HOXA10 in normal and malignant hematopoiesis.

Gestational attenuation of Lyme arthritis is mediated by progesterone and IL-4.

Infection of different strains of laboratory mice with the agent of Lyme disease, Borrelia burgdorferi, results in arthritis, the severity of which has been correlated with the dominance of Th1 cytokines. In this study, we demonstrate that changes in B. burgdorferi-specific immunologic responses associated with pregnancy can alter the outcome of Lyme arthritis in mice. Whereas nonpregnant female C3H mice consistently developed severe Lyme arthritis, pregnant mice had a marked reduction in arthritis severity that was associated with a slight reduction in IFN-gamma and markedly increased levels of IL-4 production by B. burgdorferi-specific T cells. Similar reductions in arthritis severity and patterns of cytokine production were observed in nonpregnant, progesterone-implanted mice. Ab neutralization of IL-4 in progesterone-implanted mice resulted in severe arthritis. Our results are consistent with the known shift toward Th2 cytokine expression at the maternal-fetal interface, and are the first to show a pregnancy-related therapeutic effect in an infectious model.

Malignant neoplasms: discordance between clinical diagnoses and autopsy findings in 3,118 cases.

BACKGROUND: During the past few decades, hospital autopsy rates have steadily declined throughout the Western world. This decline is mainly attributed to the introduction of advanced diagnostic techniques. Despite technological developments, discrepancy rates between clinical diagnoses and autopsy findings remain high. Few studies have addressed discrepancy rates exclusively with regard to malignant neoplasms. In the present study, we reviewed the records of 3,118 autopsies performed at Mayo Clinic during a 6-year period (1994-1999) and identified clinically undiagnosed malignancies found at autopsy and clinically diagnosed cancers not confirmed at postmortem examination. MATERIALS AND METHODS: Autopsy protocols, provisional and final anatomic diagnoses, and data from the Mayo Autopsy Pathology Quality Assurance program were reviewed in an attempt to identify discrepancies between clinical diagnoses and autopsy findings regarding malignant neoplasms. RESULTS: In 3,118 autopsies performed at Mayo Clinic between 1994 and 1999, a malignant tumor was identified in 768 cases (25%). In 128 of 3,118 cases (4.1%), the malignancy was not diagnosed clinically. In 14 of 3,118 cases (0.45%), autopsy failed to confirm a clinically diagnosed cancer. A review of the literature is presented. CONCLUSIONS: Autopsy remains an effective tool for the confirmation and refutation of clinical diagnostic findings regarding malignant neoplasms.

Factor V leiden and morbid obesity in fatal postoperative pulmonary embolism.

HYPOTHESIS: Currently, the risk for postoperative acute pulmonary embolism (APE) is assessed clinically. We hypothesize that the expensive screening for the most common genetic thrombophilic clotting defect (factor V Leiden; R(506)Q) after exclusion of established clinical risk factors does not offer additional benefit to surgical patients. DESIGN: We reviewed protocols and histories from 8249 consecutive autopsies performed at the Mayo Clinic, Rochester, Minn. All patients who died of APE after routine surgery and who lacked any other clinical risk factors for APE were included and compared with matched controls. Genomic DNA was extracted from archival tissues and examined for R(506)Q by polymerase chain reaction amplification, restriction enzyme digestion, and direct sequencing. RESULTS: Acute pulmonary embolism was the immediate cause of death in 454 patients (5.5%). Of those, 32 (7.0%) had undergone routine surgery. These patients represent less than 0.07% of all case-adjusted surgical procedures in the same period. The rate of postoperative death from APE was higher after neurosurgical procedures (0.3%) than all other procedures (0.04%). Sixteen patients (50.0%) were morbidly obese. Only 1 patient was heterozygous and none were homozygous for R(506)Q. CONCLUSIONS: (1) Fatal APE is uncommon in surgical patients lacking clinically apparent risk factors for venous thromboembolism. (2) Neurosurgical patients are at increased risk for postoperative APE. (3) Morbid obesity is a major independent risk factor in cases of sudden death from APE postoperatively. (4) Routine preoperative screening for R(506)Q in the factor V gene does not appear to offer additional benefit in surgical patients without clinically recognizable thromboembolic risk factor(s).

Fatal pulmonary toxicity related to the administration of granulocyte colony-stimulating factor in amyloidosis: a report and review of growth factor-induced pulmonary toxicity.

We report on a 59-year-old man with renal amyloidosis who died after three doses of granulocyte colony-stimulating factor were administered. Noncardiac pulmonary edema was precipitated by the growth factor. Autopsy revealed amyloid in the lung not visible by plain chest radiograph. Patients with amyloidosis who are candidates for stem cell transplantation and are mobilized with growth factors must be monitored for unexpected pulmonary toxicity. We review the in vitro experimental evidence as well as the clinical data on the pulmonary toxicity of growth factors.

Formation of new vasa vasorum in vasculitis. Production of angiogenic cytokines by multinucleated giant cells.

Inflammation of the arterial wall in giant cell arteritis induces a series of structural changes, including the formation of new vasa vasorum. To study the regulation of neoangiogenesis in giant cell arteritis, temporal arteries were examined for the extent and localization of microvessel generation and for the production of angiogenic factors. In normal arteries, vasa vasorum were restricted to the adventitia, but in inflamed arteries, capillaries emerged in the media and the intima. These capillaries displayed a distinct topography with a circumferential arrangement in the external one-third of the intima. Neovascularization was closely correlated with the formation of lumen-obstructing intima, the fragmentation of the internal elastic lamina, and the presence of multinucleated giant cells. Comparison of tissue cytokine transcription in temporal arteries of giant cell arteritis patients with and without up-regulated neoangiogenesis identified interferon-gamma and vascular endothelial growth factor but not fibroblast growth factor-2 as mediators associated with vasa vasorum proliferation. Giant cells and CD68-positive macrophages at the media-intima junction were found to be the major cellular sources of vascular endothelial growth factor. These data demonstrate that formation of new vasa vasorum in vasculitis is regulated by inflammatory cells and not by arterial wall cells, raising the possibility that it represents a primary disease mechanism and not a secondary hypoxia-induced event. Increased neovascularization in interferon-gamma-rich arteries suggests that the formation of new vasa vasorum is determined by the nature of the immune response in the arterial wall, possibly resulting from the generation and functional activity of multinucleated giant cells.

Death from pulmonary thromboembolism in severe obesity: lack of association with established genetic and clinical risk factors.

Several clinical and environmental conditions are causally related to sudden death from acute pulmonary thromboembolism (APT). Morbid obesity, despite its frequency and association with adverse health effects, is usually considered at most only an additive risk factor for APT. We reviewed protocols and histories from 7227 consecutive autopsies performed between 1985 and 1996 at the Mayo Clinic, including all deaths from APT where no clinical or environmental risk factor could be identified in the study. Body mass indices (BMI) were calculated and compared with those of age- and sex-matched controls who had died suddenly and naturally without evidence of APT. Resistance to activated protein C is the most common molecular clotting defect predisposing to APT, and it is caused by a point mutation in the factor V gene (R506Q). Genomic DNA was extracted from archival tissues of all cases and controls, and the R506Q status was determined by polymerase chain reaction amplification, restriction endonuclease digestion, and direct sequencing. APT was found as the immediate cause of death in 433 patients, with 36 (8%) having no previously established risk factors. Twenty-four of these persons (67%) were morbidly obese (BMI >30 kg/m2). compared with only five controls (14%, P<0.0001). Four patients in both groups, each with a BMI <30 kg/m2. had at least one allele positive for R506Q. Morbid obesity is an independent risk factor in cases of sudden death from APT after the exclusion of previously established clinical, environmental, and molecular risk factors.

The role of parvovirus B19 in the pathogenesis of giant cell arteritis: a preliminary evaluation.

OBJECTIVE: To determine whether parvovirus B19 DNA is more likely to be present in the temporal arteries of patients with giant cell arteritis (GCA) than in the temporal arteries of control subjects. METHODS: We prospectively examined temporal artery biopsy (TAB) tissue from 50 consecutive patients presenting for TAB for the presence of B19 DNA using the polymerase chain reaction (PCR). Clinical and demographic information was obtained from the patients' medical records. A separate PCR analysis of 30 original tissue specimens was conducted at the Centers for Disease Control and Prevention (CDC) using primers directed toward another target sequence in the nonstructural coding area of B19. RESULTS: The 50 patients had an average age of 70.8 years; 27 (54%) were female. Amplicons for human beta-globulin, but not for cytomegalovirus, were produced for all tissue samples. The PCR results for B19 agreed in 29 of 30 samples tested by our institution and by the CDC (97% agreement; kappa = 0.9). A comparison of the B19 DNA analysis and the results of TAB indicated a statistically significant association between histologic evidence of GCA and the presence of B19 DNA in TAB tissue (chi2 = 10.38, P = 0.0013). CONCLUSION: These findings suggest that B19 may play a role in the pathogenesis of GCA.

Inherited renal neoplasms.

The application of positional cloning to the study of families with inherited renal neoplasms has allowed the identification of genes which are also important in the pathogenesis of sporadic tumors and has advanced the understanding of the mechanisms underlying renal carcinogenesis. This review provides a discussion of these mechanisms as well as the diagnosis and management of the inherited renal neoplasms.

Primary chondrosarcoma of long bones and limb girdles.

BACKGROUND: Chondrosarcomas are common solid malignant tumors of bone, second in incidence only to osteosarcomas. The biologic evolution of chondrosarcomas is slow, requiring long follow-up intervals for meaningful survival analysis. METHODS: This study describes the clinicopathologic profiles of 344 patients, 194 male and 150 female (M:F, 1.3:1.0), with primary chondrosarcoma of long bones and limb girdles seen at 1 institution over a period of 80 years. RESULTS: The average age at presentation was 46 years (range, 5-82 years). The pelvis was the most common location (1.7% of all patients). Local pain was the most frequently reported initial symptom (81.4%). Survival analysis was limited to 233 patients whose primary treatment was given at the Mayo Clinic. All 233 patients had potential follow-up of at least 5 years. The overall 5-year survival rate was 77% (the expected rate was 96%). Local recurrence developed in 19.7% of patients and metastatic lesions in 13.7%. The recurrence rate was higher for tumors of the shoulder and pelvis than for tumors of long bones. Radiographically, chondrosarcomas had a characteristic appearance, including a combination of bone expansion and cortical thickening. Entering the tumor at surgery increased the risk of local recurrence. Histologic tumor grade was an important predictor of local recurrence and metastasis. CONCLUSIONS: With adequate initial surgical intervention, chondrosarcoma is primarily a local disease with a low metastatic rate.

Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex.

BACKGROUND: The tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by seizures, mental retardation, and benign tumors of the brain, heart, skin, and kidney. Malignant tumors also can occur in patients with tuberous sclerosis, particularly in the kidney, although they occur less frequently than benign tumors. The types of malignancy that occur in TSC have not been characterized fully. METHODS: Clinical and pathologic features of 8 malignant tumors from 6 TSC patients ranging in age from 22 months to 21 years are reviewed. Six tumors were renal, one was from the inguinal region, and one was from the brain. The tumors were analyzed for loss of heterozygosity (LOH) in the chromosomal regions of the TSC1, TSC2, and VHL genes. RESULTS: Three patients (ages 7, 8, and 20 years) had renal cell carcinomas (RCCs). Two of these patients had multifocal RCCs. All three patients with RCC also had prominent multifocal dysplasia of renal cyst epithelium. Two patients (ages 20 and 21 years) had malignant angiomyolipomas (1 renal and 1 inguinal). One patient (age 22 months) had a Grade 4 giant cell astrocytoma (glioblastoma multiforme). LOH in the region of the TSC2 gene was found, either in the malignant tumor or in benign tumors, in all five patients whose DNA could be analyzed. CONCLUSIONS: Children with TSC, as well as adults with the disease, are at risk for developing malignant tumors. Two types of renal malignancy occur in TSC: RCC, which appears to arise from dysplastic renal cyst epithelial cells, and malignant angiomyolipoma. Tumors cytologically similar to malignant angiomyolipomas also may occur at extrarenal sites. LOH analyses suggest that the majority of patients with TSC who develop malignant tumors have germline TSC2, rather than TSC1, gene mutations.