Automated analysis of heart sound signals in screening for structural heart disease in children.

Our aim was to investigate the ability of an artificial intelligence (AI)-based algorithm to differentiate innocent murmurs from pathologic ones. An AI-based algorithm was developed using heart sound recordings collected from 1413 patients at the five university hospitals in Finland. The corresponding heart condition was verified using echocardiography. In the second phase of the study, patients referred to Helsinki New Children's Hospital due to a heart murmur were prospectively assessed with the algorithm, and then the results were compared with echocardiography findings. Ninety-eight children were included in this prospective study. The algorithm classified 72 (73%) of the heart sounds as normal and 26 (27%) as abnormal. Echocardiography was normal in 63 (64%) children and abnormal in 35 (36%). The algorithm recognized abnormal heart sounds in 24 of 35 children with abnormal echocardiography and normal heart sounds with normal echocardiography in 61 of 63 children. When the murmur was audible, the sensitivity and specificity of the algorithm were 83% (24/29) (confidence interval (CI) 64-94%) and 97% (59/61) (CI 89-100%), respectively. CONCLUSION: The algorithm was able to distinguish murmurs associated with structural cardiac anomalies from innocent murmurs with good sensitivity and specificity. The algorithm was unable to identify heart defects that did not cause a murmur. Further research is needed on the use of the algorithm in screening for heart murmurs in primary health care. WHAT IS KNOWN: • Innocent murmurs are common in children, while the incidence of moderate or severe congenital heart defects is low. Auscultation plays a significant role in assessing the need for further examinations of the murmur. The ability to differentiate innocent murmurs from those related to congenital heart defects requires clinical experience on the part of general practitioners. No AI-based auscultation algorithms have been systematically implemented in primary health care. WHAT IS NEW: • We developed an AI-based algorithm using a large dataset of sound samples validated by echocardiography. The algorithm performed well in recognizing pathological and innocent murmurs in children from different age groups.

Cardiac dysfunction in children with mulibrey nanism.

Mulibrey nanism is an autosomal recessive disease with severe growth failure and multiple organ involvement. Heart manifestations include constrictive pericarditis and restrictive cardiomyopathy. The purpose of this study was to evaluate left ventricular (LV) diastolic and systolic function in children with mulibrey nanism utilizing two- and three- dimensional (2-D and 3-D) echocardiography and measurement of serum levels of natriuretic peptides. Of the 30 children diagnosed with mulibrey nanism in Finland, 26 participated. The control group comprised 26 children. In 2-D echocardiography, the interventricular septum and LV posterior wall were thicker in patients. The left atrium/aorta ratio measured a median 1.8 (range, 1.4-2.5) in patients and 1.3 (range, 1.0-1.7) in controls (p < 0.001). Patients differed from controls in several indices of diastolic LV function. In 3-D echocardiography, LV end diastolic volume measured a median of 51.9 ml/m(2) (range, 33.3-73.4) in patients and 59.7 ml/m(2) (range, 37.6-87.6) in controls (p = 0.040), and serum levels of N-terminal proatriopeptide and N-terminal pro-brain natriuretic peptide measured, respectively, a median of 0.54 nmol/L (range, 0.04-4.7) and 289 ng/L (range, 18-9170) in patients and 0.28 nmol/L (range, 0.09-0.72; p < 0.001) and 54 ng/L (range, 26-139; p < 0.001) in controls. They correlated with several indices of diastolic LV function. In a significant proportion of children with mulibrey nanism, myocardial function is impaired. Significant correlations appeared between indices of LV function, size of the left atrium, and levels of natriuretic peptides, showing that measurement of serum levels of natriuretic peptides is a useful follow-up method despite its dependence on loading conditions.

From legacy and client/server systems to components in healthcare information systems in Finland.

A strategy and toolset (FixIT) for migrating a specific type of legacy systems--based on the FileMan DBMS of the U.S. Department of Veterans Affairs--to a two-tier client/server and web browser-based architecture was presented in MEDINFO'98. In the current paper we discuss the further migration to a multitier software component architecture. A literature survey and industry contacts were used to specify an open, component-based target architecture for healthcare information systems to be reached by the year 2005, as well as a phased migration strategy from the present FileMan/FixIT-based systems towards the target. The target architecture is based on large-grained business components and accommodates heterogeneous elements on the intra-component, intra-application, intra-organization and inter-organizational levels. Four logical tiers are identified within a business component. Three migration paths are specified for different cases: the tier-by-tier, piece-by-piece, and web-wrapping paths. It is argued that the architecture, supported by off-the-shelf toolsets, application frameworks and a new software development process, makes it possible to turn legacy systems into a valuable asset, split monolithic applications into reusable components, and ultimately replace the legacy parts at a feasible pace

Intervals for oral health examinations among Finnish children and adolescents: recommendations for the future.

AIM: To review the frequency of routine annual dental examinations for children in Finland and to make recommendations for appropriate examination intervals for children and adolescents. METHOD: The National Research and Development Centre for Welfare and Health in Finland appointed an expert group to prepare a review. RESULTS: According to the literature, examination intervals for individuals with low caries risk can be extended to 1.5-2.0 years without jeopardising their oral health. If implemented, this would lead to a saving of 15% in treatment and examination times for children. Although there is no accurate measure for identifying high-risk individuals, a considerable proportion of low-risk children can be identified fairly accurately. CONCLUSIONS: The expert group recommended prolonging the average examination intervals to 1.5-2.0 years, taking into account the risk of each individual, the local distribution of oral health problems and cost-effective use of resources. Part of the savings could be redirected to children with high levels of dental need and/or at risk of dropping out from the oral health services.

A high number of tumor-infiltrating lymphocytes are associated with a small tumor size, low tumor stage, and a favorable prognosis in operated small cell lung carcinoma.

Tumor-infiltrating lymphocytes, apoptosis, and angiogenesis have a pivotal role in tumor growth control. This study was undertaken to analyze the associations of these factors and their role in the prognosis, defined as survival time, of 56 patients operated on for small cell lung carcinoma (SCLC). Immunohistochemically detected T cells and macrophages were the most abundant tumor-infiltrating lymphocytes in SCLC, whereas the number of B cells was small. There was a trend in the number of intratumoral cytotoxic/suppressor CD8 cells that were associated with the extent of apoptotic bodies in SCLC, as measured by in situ 3'-end labeling of apoptotic DNA. A high number of intratumoral T cells and CD8 cells were associated significantly with a low tumor size (<3 cm) and low tumor stage (stages I-II). A high number of intratumoral macrophages were associated with a low tumor stage and angiogenesis, as measured by microvessel density. A high number of T cells, CD8 cells, and macrophages and a low tumor size (<3 cm) were prognostic markers predicting favorable survival time of the patients with SCLC.

Tumour infiltrating lymphocytes in relation to tumour angiogenesis, apoptosis and prognosis in patients with large cell lung carcinoma.

Immune escape of tumour infiltrating lymphocytes (TILs), angiogenesis and apoptosis are important factors that contribute to tumour growth. In the present study immunohistochemical methods were used to investigate the relationships of these factors and their role in the prognosis of 38 patients operated on for a large cell lung carcinoma (LCLC). T cells and macrophages were most commonly found TILs in LCLC while the number of intratumoural B cells was small. A high number of intratumoural macrophages associated with angiogenesis, as measured by microvessel density (MD). TILs were not associated with the extent of apoptosis in LCLC, as measured by in situ 3'-end labelling of apoptotic DNA. The high number of intratumoural macrophages and B cells was a prognostic marker showing a better survival time of the patients with LCLC. Furthermore, a high number of intratumoural macrophages was significantly associated with longer disease free survival and low tumour stage of the patients with LCLC. A high number of intratumoural B cells and macrophages was associated with a small tumour size suggesting that both B cells and macrophages are important TILs limiting the growth of LCLC. Instead, T cells were not associated with survival or with the size or stage of the tumour suggesting that cytotoxic T cells are less important mediators of tumour host interaction in LCLC than B cells and macrophages.

Accelerated apoptosis and low bcl-2 expression associated with neuroendocrine differentiation predict shortened survival in operated large cell carcinoma of the lung.

In order to test the hypothesis that increased apoptotic activity is connected with neuroendocrine differentiation and low differentiation degree in large cell carcinoma (LCLC) and is regulated by bcl-2 family proteins, we analysed the extent of apoptosis and tumor necrosis and their relation to the expression of bcl-2, bax, bak and mcl-1 in 35 LCLCs, of which 20 were classified as large cell neuroendocrine lung carcinomas (LCNEC) and 15 as large cell non-neuroendocrine lung carcinomas (LCNNEC). The extent of apoptosis was determined by detecting and counting the relative and absolute numbers of apoptotic cells and bodies using in situ 3 -end labelling of the apoptotic DNA. The extent and intensity of expression of the bcl-2, bax, bak and mcl-1 proteins were studied by immunohistochemistry. Also the relative volume density of necrosis was evaluated and correlated with the other parameters. Finally, all the parameters were evaluated as prognostic markers and correlated with data on the survival of the patients. Relatively high apoptotic indices were seen in both tumor types (average for both 2.53%, range 0.09 27.01%). Significantly higher bcl-2 and bak indices were detected more often in LCNECs than in LCNNECs. Immunohistochemically detected bax, bcl-2 and bak expression was independent of apoptotic index in both tumor types, while there was a statistically significant positive association between mcl-1 expression and apoptotic index in LCNNEC but not in LCNEC. There was a statistically significant association between high apoptotic index and shortened survival in LCLC. However, no association was found between tumor stage and apoptosis. The patients with LCNEC and low bcl-2 protein expression had a significantly shorter survival time than those with high bcl-2 indices. There was also a clear association between shortened survival and necrotic LCNNEC. LCLCs show relatively high apoptotic activity, which is associated with shortened survival. The expression of bcl-2, bak and mcl- 1 is associated with neuroendocrine differentiation in LCLC. Finally, our results support some previous reports suggesting that bcl-2 expression in combination with some other markers involved in apoptosis and/or proliferation may be of prognostic value in cases of lung carcinoma with neuroendocrine differentiation.

Design of the SGML-based electronic patient record system with the use of object-oriented analysis methods.

Since a patient record is typically a document updated by many users, required to be represented in many different layouts, and transferred from place to place, it is a good candidate to be represented structured and coded using the SGML document standard. The use of the SGML requires that the structure of the document is defined in advance by a Document Type Definition (DTD) and the document follows it. This paper represents a method which derives an SGML DTD by starting from the description of the usage of the patient record in medical care and nursing.

The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause Alzheimer's disease.

In early-onset familial Alzheimer's disease (AD) pathogenic mutations have been found in the amyloid precursor protein (APP) gene and in the presenilin (PS)-1 and PS-2 genes. We screened for mutations in these genes in 20 patients with familial AD from the Finnish population. In addition, we sampled 41 sporadic AD patients and 59 controls to test for mutations identified in our familial AD cases. We detected an A-to-G transition in the PS-1 gene, resulting in a glutamic acid (Glu)-to-glycine (Gly) substitution at codon 318 in 2 familial and 2 sporadic AD patients. The Glu318Gly mutation has previously been reported to cause AD. We also found the Glu318Gly mutation in 4 healthy aged controls (range, 74-87 years). We thus conclude that the mutation is most likely a rare polymorphism not related to AD.

Increased numbers of alveolar macrophages with apoptotic bodies predict lung carcinoma.

In our previous study on fixed tissue blocks, we reported a high apoptotic rate in patients with operated small cell lung carcinomas. In addition to tumour cells, numerous apoptotic bodies could also be found within alveolar macrophages within and close to tumour tissue. In order to test if such cells could be found in sputum smears and if their presence could be utilized as a marker in tumour diagnosis, we analyzed the occurrence of alveolar macrophages with apoptotic bodies (AMWABs) in a set of sputum smear and BAL samples from patients with and without a pulmonary malignancy. An increased amount of AMWABs in the cytoplasm could be found in sputum and BAL samples from patients with lung cancer. Interestingly, AMWABs could also be seen in patients with a histologically confirmed pulmonary malignancy, but with no detectable tumour cells in their sputum smear. Thus, the presence AMWABs in sputum smears could serve as a more sensitive marker of pulmonary malignancy than the presence of malignant cells per se. This is the first report describing apoptotic bodies in macrophages and the utility of their detection in cancer diagnosis.

Apoptosis in operated small cell lung carcinoma is inversely related to tumour necrosis and p53 immunoreactivity.

The present study was undertaken to analyse the extent of apoptosis in operated small cell lung carcinoma (SCLC) by using in situ labelling of the oligonucleosomal DNA fragments by terminal transferase. The extent of apoptosis was compared with the cell proliferation activity, as determined by Ki-67 immunohistochemistry; with the volume density of necrosis (per cent), as determined by the morphometric point counting method; and with the occurrence of immunohistochemically detectable p53 and bcl-2 proteins. By in situ labelling, remarkably high apoptotic indices (from 0.08 to 8.10 per cent) were seen in SCLC. A high percentage of SCLSs also showed an exceptionally high proliferation activity. Aberrant accumulation of p53 protein was seen in 37.5 per cent and bel-2 overexpression in 50 per cent of SCLCs. Necrosis was seen in 82.5 per cent of SCLCs. The extent of apoptosis was inversely related to the extent of tumour necrosis (P = 0.05) and to p53 protein accumulation (P = 0.008). A positive association was found between the extent of apoptosis and bel-2 immunoreactivity (P = 0.02). The apoptotic indices (per cent) correlated with the age (P < 0.05) and total smoking time of the patients (P = 0.06).

Enhanced apoptosis predicts shortened survival in non-small cell lung carcinoma.

This study was undertaken to determine the extent of apoptosis in lung carcinoma and to evaluate it as a prognostic marker. A series of 75 lung carcinomas (47 squamous cell carcinomas, 24 adenocarcinomas, 3 small cell carcinomas, and 1 large cell carcinoma) was analyzed for the extent of apoptosis by using the 3' end-labeling method of DNA in tissue sections. Apoptosis was correlated with the rate of cell proliferation, the immunohistochemically detectable p53 and bcl-2, the extent of tumor necrosis, and the survival data. The end-labeling method allowed a precise evaluation of the extent of apoptosis. In tumor tissue, the number of apoptotic bodies was roughly 2-fold greater than the number of apoptotic cells, whereas in nonneoplastic control tissues, the ratio was 1:1. The apoptotic indexes (percentages of apoptotic cells and bodies among tumor cells) were slightly higher in adenocarcinoma than in squamous cell carcinoma. There was no association between the extent of apoptosis and the expression of proliferating cell nuclear antigen or p53. On the other hand, tumor necrosis correlated significantly with proliferating cell nuclear antigen and p53 positivity (P = 0.00025 and 0.00087, respectively). Surprisingly, the extent of apoptosis was also found to be independent of the expression of bcl-2. Patients with apoptotic indexes greater than 1.5% had significantly shorter survival time than patients with apoptotic indexes equal to 1.50% or less (P < 0.01 by log rank). Aberrant p53 positivity also predicted a poor prognosis (P < 0.002 by log rank). By multivariate analysis, enhanced apoptosis showed a 1.9-fold risk (P = 0.04), and p53 positivity showed a 2.3-fold risk (P = 0.005) for a shortened survival. We conclude that both enhanced apoptosis and p53 positivity are independent prognostic markers in non-small cell lung carcinoma, predicting shortened survival time of the patients.

Cell-mediated and humoral immunity to mumps virus antigen.

In the present study, cell-mediated and humoral immunity to mumps virus was investigated. The study population consisted of 25 subjects of whom 17 were initially seropositive for mumps. Serum antibody levels and lymphocyte blast transformation activity were measured before and after vaccination with inactivated vaccine. In addition, the subjects were skin tested and HLA-typed. Significant antibody responses, measured by enzyme-linked immunosorbent assay (ELISA), were observed after vaccination in all immunoglobulin classes. However, the elevation in antibody levels was usually transient in both seronegative and seropositive subjects. The IgA response was significantly higher in the seropositive than in the seronegative group, but no such difference was found in IgM or IgG antibodies. Vaccination also caused a significant but transient rise in lymphocyte blast transformation activity. Transformation results parallelled skin-test results and seropositivity, but not antibody levels, in the seropositive group. Pronounced IgA reactivity was significantly associated with Dw3 and Dw4 (DR3 and DR4) antigens. No HLA association was observed in IgG or IgM levels or in transformation activity.