Scattering and absorption in dense discrete random media of irregular particles.

We present an approximate numerical solution for the multiple scattering problem involving densely packed arbitrarily shaped small particles. We define incoherent volume elements that describe the statistics of the random medium and formulate an order-of-scattering solution for the entire random medium. We apply the T-matrix formalism to compute the incoherent interactions of irregular particles in the sequence of scattering events in the Monte Carlo radiative transfer algorithm. The T-matrices for the volume elements of arbitrarily shaped particles are computed by the volume-integral-equation (VIE)-based T-matrix method. We show that the approximate solution is in agreement with the numerically exact VIE solution for a small spherical random medium. Finally, we demonstrate the importance of applying irregular particle shape models in the analysis of multiple scattering by a large random medium of non-spherical particles.

Automated image analysis detects aging in clinical-grade mesenchymal stromal cell cultures.

BACKGROUND: Senescent cells are undesirable in cell therapy products due to reduced therapeutic activity and risk of aberrant cellular effects, and methods for assessing senescence are needed. Early-passage mesenchymal stromal cells (MSCs) are known to be small and spindle-shaped but become enlarged upon cell aging. Indeed, cell morphology is routinely evaluated during MSC production using subjective methods. We have therefore explored the possibility of utilizing automated imaging-based analysis of cell morphology in clinical cell manufacturing. METHODS: An imaging system was adopted for analyzing changes in cell morphology of bone marrow-derived MSCs during long-term culture. Cells taken from the cultures at the desired passages were plated at low density for imaging, representing morphological changes observed in the clinical-grade cultures. The manifestations of aging and onset of senescence were monitored by population doubling numbers, expression of p16INK4a and p21Cip1/Waf1, ß-galactosidase activity, and telomeric terminal restriction fragment analysis. RESULTS: Cell area was the most statistically significant and practical parameter for describing morphological changes, correlating with biochemical senescence markers. MSCs from passages 1 (p1) and 3 (p3) were remarkably uniform in size, with cell areas between 1800 and 2500 µm2. At p5 the cells began to enlarge resulting in a 4.8-fold increase at p6-9 as compared to p1. The expression of p16INK4a and activity of ß-galactosidase had a strong correlation with the increase in cell area, whereas the expression of p21Cip1/Waf1 reached its maximum at the onset of growth arrest and subsequently decreased. Mean telomere length shortened at an apparently constant rate during culture, from 8.2 ± 0.3 kbp at p1, reaching 6.08 ± 0.6 kbp at senescence. CONCLUSIONS: Imaging analysis of cell morphology is a useful tool for evaluating aging in cell cultures throughout the lifespan of MSCs. Our findings suggest that imaging analysis can reproducibly detect aging-related changes in cell morphology in MSC cultures. These findings suggest that cell morphology is still a supreme measure of cell quality and may be utilized to develop new noninvasive imaging-based methods to screen and quantitate aging in clinical-grade cell cultures.

Signalling Profiles of Blood Leucocytes in Sepsis and in Acute Pancreatitis in Relation to Disease Severity.

Intracellular signalling in blood leucocytes shows multiple aberrations in acute pancreatitis (AP) complicated by organ dysfunction (OD). We studied whether the aberrations associate with severity of AP and occur in sepsis complicated by OD. The study comprises 14 sepsis patients (11 with shock), 18 AP patients (nine mild; six moderately severe; three severe) and 28 healthy volunteers. Within 48 h after admission to hospital, phosphorylation of nuclear factor-ĸB (NF-ĸB), signal transducers and activators of transcription (STATs) 1,3, and extracellular signal-regulated kinases 1/2 were measured from stimulated or non-stimulated leucocytes using phosphospecific whole blood flow cytometry. In sepsis, as compared with healthy subjects, phosphorylated NF-ĸB levels of monocytes promoted by bacterial lipopolysaccharides, tumour necrosis factor or Escherichia coli cells were lower (P < 0.001 for all), pSTAT1 levels of monocytes promoted by IL-6 were lower (P < 0.05 for all), and STAT3 was constitutively phosphorylated in monocytes, neutrophils and lymphocytes (P < 0.001 for all). In AP, severity was associated with proportions of pSTAT1-positive monocytes and lymphocytes promoted by IL-6 (P < 0.01 for both), constitutive STAT3 phosphorylation in neutrophils (P < 0.05), but not with any of the pNF-ĸB levels. Monocyte pSTAT3 fluorescence intensity, promoted by IL-6, was lower in sepsis and AP patients with OD than in AP patients without OD (P < 0.001). Collectively, signalling aberrations in sepsis with OD mimic those described previously in AP with OD. Possibility that aberrations in STAT1 and STAT3 pathways provide novel markers predicting evolution of OD warrants studies including patients presenting without OD but developing it during follow-up.

Profile of a drunk driver and risk factors for drunk driving. Findings in roadside testing in the province of Uusimaa in Finland 1990-2008.

The aim of the present study was to define the profile of a drunk driver and to determine risk factors for drunk driving by analyzing data on both sober and drunk drivers. Systematic roadside surveys have been carried out in Southern Finland for over 18 years, with 20,000-30,000 drivers breath tested annually. During the study period, 1241 drunk drivers were caught (legal blood alcohol limit 0.50‰). The comparison material consisted of 3407 sober drivers. The surveys were designed to further investigate demographic features and driving habits of drivers. The prevalence of drunk driving has been 0.2% over the time period, with only random variations. According to the data, a typical drunk driver is a man aged 40-49 who has a valid driving license and drives his own car, usually alone, with a blood alcohol concentration (BAC) of 1.0‰. He has a job and is married or cohabiting. The profile remained consistent throughout the study period. The risk of drunk driving was found to be five times higher for men than for women. Divorcees and widow(er)s had a substantially higher risk factor for being caught drunk driving than married drivers. Drunk drivers are most likely to be caught by roadside testing on Saturday mornings. During the study period the blood alcohol limit for aggravated drunk driving was lowered in 1994 from 1.5 to 1.2‰. In 2004 the taxation of alcohol beverages was reduced by 30%. Neither of these measures affected the prevalence of drunk driving or the mean BAC of drunk drivers (p=0.63).

Predicting DUI recidivism of male drunken driving: a prospective study of the impact of alcohol markers and previous drunken driving.

The aim of the present study was to determine whether the alcohol biomarkers CDT, GGT, the biomarker gamma-CDT index and previous drunken driving contributed significantly to the prediction of DUI recidivism. The subjects consisted of two different samples of drivers, viz. drivers who were found to have a positive breath alcohol concentration during random breath testing surveys (n=237), and drunken drivers who were apprehended during ordinary police work (n=193). The drunken driving events were monitored using a data-base both retrospectively and prospectively. It was found that the biomarker index, gamma-CDT, emerged as a notable predictor of recidivism in the group of random breath tested drivers. Measurement of gamma-CDT and its impact on DUI recidivism has not to our knowledge been applied to random breath tested drivers before. The apprehended drunken drivers, on the other hand, did not show a significant relationship between gamma-CDT and DUI recidivism. However, in both groups of drivers it was found that a previous conviction for drunken driving strongly predicted DUI recidivism. More attention should be paid by both physicians and the police to the high risk of recidivism among those convicted of drunken driving.

Radiographic assessment of dental health in middle-aged men following sudden cardiac death.

Poor oral health has been suggested to be a risk factor for myocardial infarction. To study if dental pathology might predispose to pre-hospital sudden cardiac death, and using a sum index of panoramic tomography findings, we compared the oral health of middle-aged (33-69 yrs) male victims (Helsinki Sudden Death Study) of sudden cardiac death (n = 117) with that of controls, who died of non-cardiac diseases (n = 63) or suffered unnatural sudden death (n = 120). The mean number of teeth was 15.2, and 17.4% of the men were edentulous. Frequent age-associated findings in dentate victims were fillings (79.9%), horizontal bone loss (72.1%), periapical lesions (45.6%), residual roots (38.2%), and vertical pockets (30.9%). In multivariate analysis with coronary heart disease risk factors and number of teeth as covariates, poor oral health was associated (p = 0.053) with the risk of sudden cardiac death along with age, smoking, and body mass index. This association was especially strong (p = 0.009) among victims < 50 yrs.

Sudden death associated with a multifocal type II hemangioendothelioma of the liver in a 3-month-old infant.

Sudden unexpected death in an infant caused by or associated with neoplasm is rare. We describe a case of a sudden death in an apparently healthy 3-month-old female, in which the autopsy revealed a multiple type II infantile hepatic hemangioendothelioma (IHE). This uncommon tumor has, untreated, a relatively high mortality rate, mainly due cardiac failure resulting from massive arteriovenous shunts, but the association with sudden infant death is very rare.

A functional variant of the iNOS gene flanking region is associated with LAD coronary artery disease: an autopsy study.

BACKGROUND: Recent studies using reporter gene constructs have indicated significant differences in the promoter activity of inducible nitric oxide synthase (iNOS) gene variants. Although the exact role of iNOS in atherogenesis is unclear, it is possible that this variation site may influence the extent of coronary artery disease (CAD). METHODS: We amplified these (AAAT) repeat variants from the NOS2A gene (denoted iNOS R4 and iNOS R5) from 325 Finnish men included in the Helsinki Sudden Death Study, and studied their association with indices of stenosis and atherosclerosis of the left anterior descending artery (LAD), right coronary artery (RCA) and left circumflex artery (LCX). In order to understand the effect of iNOS genotype on different stages of CAD, our study population was divided into age groups. RESULTS: In the LAD, the progression of atherosclerosis seemed to be more pronounced in the 4/5 genotype carriers than in those with the 4/4 genotype when the different age groups were compared. More specifically, statistically significant differences between the genotypes were found in the subgroup of men aged > 55 years. In this group, men carrying the rare R4/5 genotype presented higher mean values of stenosis percentages (55% vs. 42%, P = 0.008), larger areas of fatty streaks (10.4% vs. 5.9%; P = 0.01) and complicated lesions (3.5% vs. 1.3%; P = 0.001) compared with the R4/4 carriers. No significant association of iNOS genotypes with stenosis and atherosclerosis of RCA and LCX was found. CONCLUSIONS: It appears unlikely the R4/5 genotype plays a major role in the pathogenesis of CAD, as it was not associated with stenosis and atherosclerosis in RCA and LCX. However this genotype may have some role in more pronounced CAD, as seen in the LAD.

International collaboration in mass disasters involving foreign nationals within the EU: medico-legal investigation of Finnish victims of the Milan Linate airport SAS SK 686 aircraft accident on 8 October 2001.

Identification of and investigation into the cause of death of foreign nationals in mass disasters are generally conducted according to the jurisdiction of the country in which the disaster occurs. However, such identification can be achieved only through co-operation with the authorities of the victims' countries of residence. On October 8th 2001 at Linate airport in Milan, Italy, an MD87 SAS airplane with 110 crew members and passengers on board collided on the ground with a Cessna Citation II jet with 2 pilots and 2 passengers. The plane then caught fire after having crashed into an airport baggage hangar causing the death of 4 other victims among the groundstaff. The accident claimed a total of 118 victims of 9 nationalities. Based on our experience from investigation of the Finnish victims, we explore how current national legislations of the EU member states and varying compliance with existing recommendations may influence the medico-legal investigation of a mass disaster. Legislative measures and further harmonisation of medico-legal procedures in connection with mass disasters within the EU are needed.

Cause-of-death query in validation of death certification by expert panel; effects on mortality statistics in Finland, 1995.

The correctness of selection, coding and registration of underlying cause-of-death is important for the quality of mortality statistics. One measure to improve quality is the query to the certifier for verification of the underlying cause-of-death. In Finland, 3478 death certificates, 7.1% of total 49074 certifications in 1995, were considered questionable by statisticians. The expert panel at Statistics Finland was able to resolve 2813 (80.9%) of them. However, 665 (19.1%) certificates needed to be further queried from the certifier. Of these, 318 (47.8%) were re-assigned to another ICD-9 category or to the applicable three-digit category within the main category of heart and vascular diseases, resulting in changes from a 17.00-fold increase in rheumatic heart diseases (ICD-9 codes 390-398) to a decrease of about one-half (0.45-fold change) in unspecified neoplasms (codes 235-239). However, a statistically significant impact on national mortality statistics was not observed in any of applied ICD categories. Among all questionable death certificates, most prone to query of the certifier, and with a statistical significance of P<0.05, were those with no cause-of-death specified, those stating underlying cause-of-death as non-specified neoplasms (with a observed/expected ratio, O/E, of 1.69), and heart and vascular diseases (1.45), with its subcategories of ischaemic heart diseases (1.33) and other heart diseases (2.92). Death certificate validation, by expert panel consultations and query to the certifiers, and the importance of estimation of the validity of cause-of-death information on death certificates are strongly pointed out in a continuous strive for correct and reliable mortality statistics.

Death in bathtub revisited with molecular genetics: a victim with suicidal traits and a LQTS gene mutation.

A 44-year-old woman with a medical history of mental disorders and previous suicidal behaviour was found in a bathtub and pronounced death few minutes later despite of resuscitation attempts. After police investigation and on the basis of autopsy findings, the death was classified as suicide drowning. Retrospective examination of clinical data revealed, a prolonged rate-corrected QT-interval (QTc: 468 ms) 3 months before death. Post-mortem (PM) DNA analysis disclosed KCNH2(FIN) mutation for the long-QT syndrome (LQTS). The value of PM molecular screening for LQTS is emphasised, especially for victims of putative drowning.

Drowning in Finland: "external cause" and "injury" codes.

BACKGROUND: The International Classification of Diseases (ICD) external codes (E codes) for drowning assist in determining the primary event leading to drowning, but do not alone allow the precise determination of the overall drowning rates. AIMS: To analyze the sensitivity of the ICD E codes for drowning. To describe the pattern and trend of drowning deaths that are classified with E codes other than for drowning. SETTING: Finland, 1969-2000. METHODS: Mortality files of Statistics Finland were searched electronically using the injury codes (I codes) and E codes for drowning. Cross analysis of I and E coded drownings was performed to determine the rate and pattern of drowning cases classified with E codes other than for drowning. Time trends were calculated using the Poisson regression model. RESULTS: Of 13 705 drowning deaths, 644 (4.7%) were not identified with the E codes for drowning. The great majority (n=547, 84.9%) of these cases were traffic accidents resulting in drowning. No significant time trends were found even after the introduction, in 1996, of the ICD 10th revision. CONCLUSIONS: In Finland, underestimation of overall drowning rates using the E code alone is less pronounced than in countries where similar studies have been performed. The relatively high rate of transport accidents resulting in drowning indicates a specific target for preventive countermeasures.

Fatal isolated ruptures of bladder following minor blunt trauma.

Traumatic bladder ruptures are generally secondary to severe trauma and associated with pelvic fractures. Conversely, isolated bladder ruptures following minor blunt trauma are rare and seldom fatal. We describe six fatal cases (five males, one female, 39-82 years old) of isolated bladder rupture subsequent to minor blunt trauma. Three cases were out-of-hospital deaths and among the three hospital cases, only one was diagnosed as bladder rupture ante-mortem. All victims had a history of chronic alcohol abuse. The differentiation between spontaneous and traumatic (accidental or purposely inflicted) bladder ruptures is crucial but may be difficult to assess, especially in cases involving alcohol abuse and occurring in a domestic setting.

Sudden death due to rupture of the arteria pancreatica magna: a complication of an immature pseudocyst in chronic pancreatitis.

Massive haemorrhage due to rupture of single pancreatic or peripancreatic vessels is a very rare but potentially lethal complication of acute and chronic pancreatitis. The splenic, gastroduodenal, and pancreatoduodenal arteries are the more commonly involved vessels, and rupture occurs mostly as a complication of large mature pseudocysts. We report a sudden death due to massive bleeding caused by rupture of the great pancreatic artery (arteria pancreatica magna), a complication of a small immature pseudocyst, in a 49-year-old male alcoholic with inactive chronic pancreatitis.

The role of alcohol in accident and violent deaths in Finland.

BACKGROUND: In Finland, the high rates of forensic autopsy and postmortem toxicology furnish a reliable base for nation-wide studies on alcohol-related violent deaths. MATERIAL AND METHODS: National mortality and population data within Finland, from 1987 to 1996, were used to analyze sex- and age-specific rates, proportions, and trends of violent deaths associated with alcohol. Deaths were defined as alcohol-related when alcohol was certified as a contributing factor to death. RESULTS: During the study period, 10,360 (23.3%) of the 45,544 violent deaths that occurred were alcohol-related. Among 15- to 64-year-olds, 28.6% of accidents, 30.5% of suicides, and 55.3% of homicides were associated with alcohol (alcohol-positive). Differences in epidemiologic patterns and trends for different types of violent death were observed between sexes and age groups. For instance, alcohol-positive accidents significantly decreased in males (-2.3%/year; CL95: -3.3, -1.2; p < 0.001), but not in females (+0.5%/year; CL95: -2.7, +3.7; p = 0.772), and alcohol-positive suicides increased slightly in females (+3.9%/year; CL95: +0.0, +7.9; p = 0.047), but not in males (-0.2%/year, CL95: -1.4, +1.0; p = 0.704). CONCLUSIONS: The victims of violent deaths have often consumed or abused alcohol before the fatal events. Especially in young adults, consumption of alcohol is likely one of the most serious risk factors in accidents and may decrease the threshold for suicide ideation and impulsive behaviors. Studies that explore the effects of sociodemographic and health factors on random populations with relevant control data will increase the understanding of the causal connection between alcohol and violent deaths.

Testing genetic susceptibility loci for alcoholic heart muscle disease.

BACKGROUND: Although many heavy alcohol users have subclinical alcoholic heart muscle disease, only a very few develop severe dilated cardiomyopathy. Therefore, and because cardiac abnormalities correlate only weakly with the duration or quantity of drinking, individual susceptibility differences may exist. In this work we examined whether common gene variants previously associated with cardiac hypertrophy or altered alcohol metabolism could modify the effects of alcohol on the heart. METHODS: We studied 700 middle-aged male victims of sudden death who underwent a medicolegal autopsy. In addition to routine postmortem examination, the weights and the cavity and wall dimensions of the left and right ventricle were measured. Coronary artery stenoses were determined from a silicone rubber cast of the arteries. Alcohol consumption and cardiovascular risk factors were assessed by a structured interview of the spouse. The following gene polymorphisms were determined by using polymerase chain reaction restriction fragment length polymorphism and solid-phase minisequencing techniques: angiotensin converting enzyme I/D, angiotensin II type 1 receptor 1166A/C, aldosterone synthase -344C/T, alcohol dehydrogenases 2 and 3, acetaldehyde dehydrogenase 2, and cytochrome P-450 2E1 DraI, PstI, RsaI, and MspI. RESULTS: The most consistent effects of alcohol (p < 0.05) were a higher total heart weight and a larger right ventricle size with increasing daily drinking. However, these and other effects of alcohol were statistically fully independent of the studied genotypes. CONCLUSIONS: The gene polymorphisms selected for and analyzed in our study are unlikely to modify the effects of alcohol on the heart. Other unknown factors determine the individual susceptibility to alcoholic heart muscle disease.

Coronary artery complicated lesion area is related to functional polymorphism of matrix metalloproteinase 9 gene: an autopsy study.

Matrix metalloproteinase 9 (MMP9) is expressed in human atherosclerotic plaques, and the protein is localized in human coronary atherosclerotic lesions. The MMP9 gene has a C-to-T promoter polymorphism at position -1562, which affects transcription and leads to promoter low-activity (C/C) and high-activity (C/T, T/T) genotypes. To determine whether these genotypes exert an influence on the atherosclerotic lesion area, we investigated their association with different types of coronary lesions in an autopsy cohort of 276 men aged 33 to 69 years. Areas of the coronary wall covered with fatty streaks and fibrotic, calcified, and complicated lesions were measured, and the percentage of coronary narrowing was determined. MMP9 genotypes were determined by polymerase chain reaction and restriction enzyme digestion. In men aged >/=53 years, the mean area of complicated lesions in 3 coronaries was significantly associated with the MMP9 genotype (P=0.008). Subjects with high promoter activity genotypes had, on average, larger complicated lesion areas than did those with the low-activity genotype. The MMP9 genotype persisted as an independent predictor of complicated lesion area after adjustment for age, body mass index, hypertension, diabetes, and smoking (P=0.012). These data provide evidence that the proposed effect of MMP9 in the process of atherosclerotic lesion development may be modified by the MMP9 genotype.

Forensic osteological investigations in Kosovo.

A team of Finnish forensic experts performed investigations of alleged mass graves in Kosovo under the mandate of the European Union (EU). Human skeletal remains from two locations were examined. The remains contained three almost complete skeletons, and individual bones and bone fragments, part of which were burned. Injuries, pathological changes, and findings for identification purposes were examined and documented using standard methods of forensic pathology and osteology. Gunshot injuries were found in some cases, but reliable determination of the cause and manner of death was not possible. A discrepancy arose between the number of victims reported in information received from the presiding district court, and results of the investigations. The estimation of the minimum number of victims was mostly acquired by DNA analysis.

Dose dependent but non-linear effects of alcohol on the left and right ventricle.

OBJECTIVE: To assess how left (LV) and right ventricular (RV) size, wall thickness, and mass depend on daily alcohol consumption. Among alcoholics, most common findings have been LV hypertrophy and mild systolic or diastolic dysfunction, accompanied occasionally by ventricular dilatation resembling dilated cardiomyopathy. Although it is commonly agreed that chronic heavy alcohol use is injurious to the heart, the dose-injury relation remains a matter of dispute. DESIGN: Prospective series of 700 Finnish men aged 33-70 years who died out of hospital and underwent a medicolegal necropsy. METHODS AND RESULTS: Data on alcohol use and other risk factors were obtained from the spouse. At necropsy, a transversal slice of the heart was traced on a transparent sheet and analysed later for LV and RV cavity areas and wall thicknesses. Coronary artery stenoses were measured from silicone casts of the arteries. In analyses of all men, daily alcohol dose predicted heart weight (beta = 0.17, p < 0.001) and RV cavity area (beta = 0.14, p = 0.007) independent of body size, age, coronary artery disease, hypertension, diabetes, and smoking. In the subgroup of men free of significant coronary artery disease, LV area averaged (SEM) 11.0 (1.0) cm(2) in men drinking < 12 g/day, 7.7 (0.7) cm(2) in those drinking 72-180 g/day, and 10.0 (0.9) cm(2) in those drinking > 180 g/day (p = 0.054). Very heavy drinking (> 180 g/day) was associated with an increase in RV cavity area (p = 0.005). CONCLUSIONS: The effects of alcohol on the heart in middle aged men are dose dependent but partly non-linear. In the absence of coronary artery disease, LV size shows a U shaped reduction with increasing daily alcohol use accompanied by an increase in RV size with very heavy drinking. These findings question the idea of progressive LV dilatation with increasing alcohol consumption among male victims of sudden death.

Platelet glycoprotein Ibalpha HPA-2 Met/VNTR B haplotype as a genetic predictor of myocardial infarction and sudden cardiac death.

BACKGROUND: Sudden cardiac death (SCD) is one of the leading manifestations of coronary heart disease in early middle age. Platelet glycoprotein (GP) Ib-IX-V receptor complexes play a key role in the initial adhesion of platelets to collagen during the formation of a coronary thrombus. The HPA-2 (Thr145 Met) and VNTR polymorphisms of the gene for GP Ibalpha have been studied previously in hospitalized patients with acute coronary syndromes. The significance of these polymorphisms in victims of sudden cardiac death is not known. METHODS AND RESULTS: The association of these 2 polymorphisms with coronary atherosclerosis, coronary artery stenosis, coronary thrombosis, myocardial infarction (MI), and SCD was studied in the Helsinki Sudden Death Study, which comprised 2 large autopsy series, collected 10 years apart during 1981 to 1982 and 1991 to 1992, of 700 middle-aged white Finnish men who suffered sudden or violent out-of-hospital death. The 2 polymorphisms showed an almost complete linkage disequilibrium. Men with acute MI (n=80) and coronary thrombosis (n=65) were more likely to be carriers of the HPA-2 Met allele (OR 2.0 and 2.6, respectively, P<0.005 for both) than were control subjects who died of noncardiac causes (n=367). In men <55 years old, the Met allele was overrepresented (OR 2.2) among victims of SCD (n=98) compared with control subjects (n=249). In men <55 years old, 17 of 29 men with acute MI (58.6%) and 16 of 23 men with coronary thrombosis (69.6%) were carriers of the HPA-2 Met allele compared with the 49 of 249 (19.7%) who had died of noncardiac causes (ORs 5.6 and 9.2, respectively). Similar associations were observed in the separate analyses of both autopsy series. CONCLUSIONS: Our results suggest that the HPA-2 Met/VNTR B haplotype of the platelet von Willebrand factor and thrombin receptor protein GP Ib-V-IX may be considered to be a major risk factor of coronary thrombosis, fatal MI, and SCD in early middle age.