Victims of lethal hypothermia have decreased levels of thrombomodulin in myocardium and urine.

Severe cold stress has been shown to cause changes in the expression and secretion of thrombomodulin (TM), an endothelial protein regulating haemostasis and inflammation. To further evaluate TM as a cold stress indicator, relative TM mRNA and TM protein levels in the myocardium and the concentrations of TM in serum and urine were analysed in different causes of death (hypothermia main cause, n = 80; hypothermia contributory cause, n = 26; cardiovascular disease (CVD) main cause, n = 94; trauma main cause, n = 45; other main cause, n = 25). Urinary catecholamine concentrations and myocardial heat shock factor 1 (HSF1) transcript levels were also studied. The TM mRNA and the TM protein levels in myocardium and urine were significantly lower in hypothermia deaths than those in the controls. Post-mortem interval did not correlate with urinary TM concentration. The sensitivity and specificity of urinary TM assay to detect hypothermia deaths were 70.8 and 70.3 %, respectively. Catecholamine concentrations in urine correlated significantly with TM concentration in urine and TM mRNA levels in all groups excluding CVD deaths. There were no differences in the HSF1 transcript levels and no correlation to TM levels. These findings provide further evidence that cold stress and hypothermia affect TM expression and secretion and that they are possibly linked to catecholamine action. Thus, measuring post-mortem TM levels may provide additional support to diagnosing hypothermia in medico-legal examination. The results may also provide additional knowledge for the treatment of hypothermic patients and the use of hypothermia for medical purposes.

WFS1 variants in Finnish patients with diabetes mellitus, sensorineural hearing impairment or optic atrophy, and in suicide victims.

Mutations in the wolframin gene, WFS1, cause Wolfram syndrome, a rare recessive neurodegenerative disorder. The clinical features include early-onset bilateral optic atrophy (OA), diabetes mellitus (DM), diabetes insipidus, hearing impairment, urinary tract abnormalities and psychiatric illness, and, furthermore, WFS1 variants appear to be associated with non-syndromic DM and hearing impairment. Variation of WFS1 was investigated in Finnish subjects consisting 182 patients with DM, 117 patients with sensorineural hearing impairment (SNHI) and 44 patients with OA, and in 95 suicide victims. Twenty-two variants were found in the coding region of WFS1, including three novel nonsynonymous variants. The frequency of the p.[His456] allele was significantly higher in the patients with SNHI (11.5%; corrected P=0.00008), DM (6.6%; corrected P=0.036) or OA (9.1%; corrected P=0.043) than that in the 285 controls (3.3%). The frequency of the p.[His611] allele was 55.8% in the patients with DM being higher than that in the controls (47%; corrected P=0.039). The frequencies of p.[His456] and p.[His611] were similarly increased in an independent group of patients with DM (N=299). The results support previous findings that genetic variation of WFS1 contributes to the risk of DM and SNHI.

Stress-specific responses of p21 expression: implication of transcript variant p21 alt-a in long-term hypoxia.

p21 (CDKN1A, Cip1, Waf1) is a cyclin-dependent kinase inhibitor capable of causing cell cycle arrest or promoting cell cycle transit as well as acting as a regulator of apoptosis. In this study, we analyzed the effects of various antemortem conditions on p21 protein level and expression profiles of known p21 transcript variants in human heart tissue. The selected death cause groups were: non-cardiac, hypothermia, acute ischemia, and chronic hypoxia. Immunohistochemical staining of p21 in cardiac myocytes could be observed only in hypothermia death cases, in which the mRNA expression of the most abundant variant, p21V1, also exceeded that in other death cause groups. Cytoplasmic localization of p21 protein in vascular smooth muscle cells together with substantially increased expression of cardioprotective Pim-1 especially in chronic hypoxia, but in acute ischemia and hypothermia as well, indicate change of p21 function from cell cycle arrest to promotion of proliferation and cell survival in these cases. In chronic hypoxia deaths the expression of variant p21 alt-a was highly pronounced whereas the expression of variant p21B was low. In chronic hypoxia deaths the expression of p53 was substantially higher compared to the other groups, being a potential regulator of p21 alt-a expression. In acute ischemia deaths increased expression of variant p21B, suggested to be proapoptotic in several cell lines, was observed. Our results suggest a role for variant p21 alt-a in hypoxia and for variant p21B in acute myocardial ischemia. The known cardioprotective aspect of hypothermia might come from an increased p21 protein level.

Encephalopsin (OPN3) protein abundance in the adult mouse brain.

Encephalopsin belongs to the family of extraretinal opsins having a putative role in CNS tissue photosensitivity. Encephalopsin mRNA has earlier been localized in rodent brains, but expression and localization of the protein has not yet been reported. In this study, we aimed to define encephalopsin protein abundance and localization in the rodent brain. The distribution and localization of encephalopsin protein in a mouse brain and selected peripheral tissues were analysed in ten mice, using Western blotting and immunohistochemistry. The specificity of immunoreaction was validated by primary antibody omitting and immunizing peptide blocking experiment. We found encephalopsin protein abundant in the mouse brain, but not in the periphery. Encephalopsin protein was present in neurons of the mouse cerebral cortex, paraventricular area, and cerebellar cells. Our results show that encephalopsin is expressed at the protein level in different brain areas of the mouse. Therefore, the suggested idea that encephalopsin plays a role in non-visual photic processes seems to be applicable. Evidently, further investigations are needed to find out the signalling mechanisms, and the potential physiological role of encephalopsin in phototransduction due to the changes in ambient light.

Parkinson's disease and suicide: a profile of suicide victims with Parkinson's disease in a population-based study during the years 1988-2002 in Northern Finland.

OBJECTIVE: We studied the prevalence of hospital-treated Parkinson's disease (PD) among suicide victims and the profile of these persons, taking into account suicide attempts, timing of depression and comorbid somatic diseases. METHODS: The database of this study consisted of suicide victims aged 50 years of age or older (n = 555) during a fourteen-year period in the province of Oulu in Northern Finland. RESULTS: Hospital-treated Parkinson's disease occurred in 1.6% of the subjects, indicating a rather low prevalence of suicide in this group of patients. The persons with PD had attempted suicide earlier in 44% of the cases, while the corresponding percentage for other victims in older age was 9.9% (p = 0.009 Fischer exact test). CONCLUSIONS: Based on the case characteristics of our study the profile of PD person who completed suicide was as follows: male subject with recently diagnosed disease, living in rural area, having multiple physical illnesses, and having attempted suicide earlier. Psychiatric consultation is thus highly recommended for the PD patients with this disease profile.

Cardiac arrest and left ventricular fibrosis in a Finnish family with the lamin A/C mutation.

INTRODUCTION: We screened the candidate genes from a Finnish family in which the mother was resuscitated from ventricular fibrillation and the daughter died suddenly without any prior cardiac symptoms. METHODS AND RESULTS: In addition to screening of potential structural gene mutations, phenotyping of the proband and medico-legal autopsy of the victim of the sudden death, including histopathological examinations, were performed. Genetic screening revealed an R541C mutation in the lamin A/C gene both in the proband and her daughter. None of the 16 first- or second-degree relatives, or 96 unrelated healthy subjects, carried the same mutation. In the proband, the size and the global function of the left ventricle (LV) were normal, but a local hypokinesia and thinning of inferoposterior area of the LV were seen in 2D echocardiography and magnetic resonance imaging. Coronary angiogram and the results of the electrophysiological study were normal. Autopsy of the victim of sudden death showed localized thinning and fibrosis in the inferoposterior area of the LV, with only minimal fibrosis in the right ventricle and no abnormalities in the interventricular septum. CONCLUSION: These observations indicate that a fatal or near-fatal cardiac arrhythmia can be the first clinical manifestation of a "de novo" mutation R541C of the lamin A/C gene. Replacement of cardiac myocytes by fibrosis seems to be the predominant pathologic-anatomic finding.

Association between physical illnesses and depressive symptoms requiring hospitalization in suicide victims.

We examined an association between a history of hospital-treated depression and physical diseases in 1877 suicide victims from Northern Finland. Information on physical diseases and depression of victims was extracted from the Finnish Hospital Discharge Registers. Of suicide victims, 31% of female and 16% of male victims had a lifetime history of depression. When compared with victims without any lifetime hospital-treated physical illnesses, a history of depression was shown to associate with the diseases of the nervous, circulatory, respiratory, and musculoskeletal systems in the group of symptoms and signs, injuries and poisonings, and infectious diseases among male victims. Respectively, in female victims, an increased prevalence of depression was seen in endocrine, nutritional and metabolic diseases, diseases of the nervous, circulatory, genitourinary, skin and subcutaneous tissue, and musculoskeletal systems, and with injuries and poisonings, pregnancy-related problems and infectious diseases. This study is the first to evaluate comorbidity between physical illnesses and depression over the lifetime in suicide victims; earlier studies reported findings in living patients from epidemiological or clinical populations. Since depression can affect quality of life in severely ill patients, targeting depression in patients with chronic illness may assist in decreasing suicide rates.

The distribution of melanopsin (OPN4) protein in the human brain.

Until now, melanopsin (OPN4) - a specialized photopigment being responsive especially to blue light wavelengths - has not been found in the human brain at protein level outside the retina. More specifically, OPN4 has only been found in about 2% of retinal ganglion cells (i.e. in intrinsically photosensitive retinal ganglion cells), and in a subtype of retinal cone-cells. Given that Allen Institute for Brain Science has described a wide distribution of OPN4 mRNA in two human brains, we aimed to investigate whether OPN4 is present in the human brain also at protein level. Western blotting and immunohistochemistry, as well as immunoelectron microscopy, were used to analyse the existence and distribution of OPN4 protein in 18 investigated areas of the human brain in samples obtained in forensic autopsies from 10 male subjects (54 ± 3.5 years). OPN4 protein expression was found in all subjects, and, furthermore, in 5 out of 10 subjects in all investigated brain areas localized in membranous compartments and cytoplasmic vesicles of neurons. To our opinion, the wide distribution of OPN4 in central areas of the human brain evokes a question whether ambient light has important straight targets in the human brain outside the retinohypothalamic tract (RHT). Further studies are, however, needed to investigate the putative physiological phototransductive actions of inborn OPN4 protein outside the RHT in the human brain.

Collagen XVII is expressed in human CNS neurons.

Type XVII collagen (collagen XVII) is a component of hemidesmosomes, which connect epithelial cells to the underlying basement membrane. Previously, an association has been suggested between neurological disorders and the skin disease bullous pemphigoid, where autoimmunity is directed against collagen XVII. Furthermore, the lack of alpha6 integrin, a ligand of collagen XVII, has been implicated in defects of cortical organization in the mouse brain. In this study, we demonstrate for the first time the presence of collagen XVII in neurons of the human brain by in situ hybridisation, immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). We propose that collagen XVII may be involved in the pathogenesis of various disorders affecting neuronal migration or synaptic plasticity.

The role of the FTD-ALS associated C9orf72 expansion in suicide victims.

Impulsive and aggressive traits are not only common features displayed by patients with behavioural variant frontotemporal dementia (bvFTD), they may well be the first clinical manifestations of the disease. In addition, suicidal behaviour has been postulated to be a symptom of bvFTD. A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) is the major genetic cause for familial bvFTD. During recent years, several genetic factors predisposing to suicide have been identified, but there are no previous studies analysing the role of the C9orf72 expansion in suicides. In the present study, we aimed to analyse the prevalence of the C9orf72 expansion in unselected suicide victims. The prevalence of the C9orf72 expansion was analysed in a cohort of 109 Finnish victims of suicide (mean age at death 46.1 years; range 18-86 years). The C9orf72 expansion was analysed from the post mortem blood samples. Results showed that no abnormal length C9orf72 expansions were detected in the study cohort. In conclusion, even though suicidal behaviour may be encountered in bvFTD patients, the C9orf72 expansion is not a common genetic finding in unselected suicide victims.

Lifetime prevalences of physical diseases and mental disorders in young suicide victims.

OBJECTIVE: Evaluation was done of a possible link between psychiatric and physical illnesses in suicide victims 25 years of age or younger. METHODS: This was a follow-up study based on a 13-year database (n = 1,585) of all suicides committed during the years 1988 to 2000 in northern Finland with linkage to national hospital discharge registers. The setting for the study was the province of Oulu, located in northern Finland. Subjects comprised 202 male and 27 female suicide victims aged 25 years or less. RESULTS: Despite the young age of the suicide victims, lifetime prevalence of physical illness was about 70% in both males and females. In relation to mental disorders, female suicide victims were affected significantly more (45%) than their male counterparts (21%). About 27% of the subjects with physical illnesses had also suffered from mental disorders, but the respective proportion among those without any physical illness was only 7%. An increased prevalence of mental disorders was found in victims with diseases of the skin and subcutaneous tissues, musculoskeletal, respiratory, and digestive systems. Furthermore, increased incidences of mental disorders were also noticed in connection with injuries, poisonings, and symptoms or signs of infectious diseases. Prevalence of mental disorders in these physical disease categories varied from 25% to 44%. CONCLUSION: We recommend a greater attention to young people with physical illnesses and other symptoms in the hope that such screening may lead to an early recognition of psychiatric disorders and suicidal tendencies.

Hypophyseal hemorrhage and panhypopituitarism during Puumala Virus Infection: Magnetic Resonance Imaging and detection of viral antigen in the hypophysis.

We describe 3 cases of nephropathia epidemica (NE) that confirm that Puumala virus infection may cause hypophyseal injury. Autopsy revealed a hemorrhagic hypophysis positive for Puumala virus antigen in both neuroendocrine stromal and vascular endothelial cells in 1 patient, and 2 patients developed hypophyseal hemorrhage (diagnosed with magnetic resonance imaging) during or shortly after acute NE, both of whom developed panhypopituitarism.

Serotonin transporter distribution and density in the cerebral cortex of alcoholic and nonalcoholic comparison subjects: a whole-hemisphere autoradiography study.

OBJECTIVE: Lesions of the medial prefrontal cortex and dysfunctions in serotonin turnover are two well-established factors associated with impulsive and sociopathic behaviors, but no firm neuroanatomical data have linked these pathophysiological findings. The aims of this study were to identify putative areas in the human brain that are rich in serotonin transporter sites, particularly within the medial prefrontal cortex, and to determine whether serotonin transporter density in this area is altered among alcoholic subjects. METHOD: Serotonin transporter density was measured among 17 alcoholic and 10 nonalcoholic comparison subjects by postmortem whole-hemisphere autoradiography with [(3)H]citalopram. RESULTS: In the human cerebral cortex, serotonin transporter binding sites were concentrated in the perigenual anterior cingulate cortex. Substantially sparser serotonin transporter density (up to 35%) was observed in the perigenual anterior cingulate cortex of alcoholic subjects in relation to nonalcoholic comparison subjects. After adjustment for age and postmortem delay, this finding remained statistically significant. CONCLUSIONS: A lower serotonin transporter density among the alcoholic subjects was observed, specifically in the so-called "affect" region, suggesting an association between ethanol addiction and dysfunctional serotonergic neurotransmission in this area.

Is occupation relevant in suicide?

BACKGROUND: The seasonality of suicide rates and methods of suicide may be related to changes in weather and conditions of employment. Particularly the amount of occupational outdoor exposure could show differences in the distribution of suicides by season and the selection of suicide method, in addition to age at the time of death. METHODS: The data consisted of all death certificates (n=1359) of completed suicides in the province of Oulu, Finland, during the years 1988-1999. For male subjects included in this study, four occupational groups were identified according to decreasing occupational outdoor exposure. The mean ages, the distribution of suicide methods and the seasonal variation in suicides for each occupational group were analyzed. RESULTS: Farmers were significantly older at the time of suicide than construction or indoor workers, and farmers employed significantly more violent methods than the other occupational groups. In the spring, farmers had a significant peak in the rate of suicides. In the winter, forest workers had a significant trough in the rate of suicides. In the summer, indoor workers had a significant peak in the rate of suicides. LIMITATIONS: The analyses were restricted to males due to the low number of females in the study population. CONCLUSIONS: The novel finding in this study was that the seasonality of violent suicides was most strongly seen as a spring peak and a winter trough among outdoor workers. The recognition of typical risk factors of different occupations, such as outdoor exposure, and occupational-related susceptibility towards certain suicide methods could benefit in the prevention of suicides.

Cyclic time patterns of death from suicide in northern Finland.

BACKGROUND: Time patterns of suicide have been attributed not only to social and psychological factors but also to direct geophysical effects. Seasonal variations in day length and temperature seem likely to contribute to the timing of the suicide process. METHODS: We analysed all suicides (n=1658) committed in a northern province of Finland during a period of 153 months. Daily data on the number of suicides, local weather conditions and geomagnetic storms were compiled and modelled with Poisson regression using the province population as the denominator, and with the means of harmonic series for seasonal variation. Time series analysis of monthly numbers of suicides was carried out using the seasonal-trend decomposition procedure based on loess. RESULTS: Marked fluctuations in the number of suicides occurred during the study period (P=0.01). There was significant seasonal variation in death from suicide (P=0.01), but analysis of the meteorological data showed no evidence of effect on the risk of suicide. LIMITATIONS: Assessment of mental disorder or alcohol consumption was missing, since only data derived from death certificate was available for each case. CONCLUSIONS: The seasonal effect was significant, but remained modest compared to sex and age as risk factors for suicide. Preventive measures need to be tailored according to time of the year.

Is seasonality of suicides stronger in victims with hospital-treated atopic disorders?

The aim of the present study was to test whether the seasonal distribution of suicides differed between atopic and non-atopic suicide victims. A cross-sectional comparison of the semi-annual and seasonal distribution of suicides was made by using a 13-year database of all suicides (1296 males, 289 females) committed during the years 1988-2000 in the province of Oulu in Northern Finland. During the first half of the year, the proportion of suicides among atopic patients was significantly higher than that linked with non-atopic patients. Of all atopic patients, 72% committed suicide during the first and 28% during the second half of the year. Suicides among victims without any atopic disorders followed a uniform seasonal distribution throughout the year (50 vs. 50%). The exacerbation of an atopic disorder may increase the risk of suicide in spring; something that should be taken note of in clinical work.

Survival time after last hospitalization among suicide victims in northern Finland.

Psychiatric patients exhibit increased suicide risk shortly after hospitalization, but little is known about patients who are discharged after treatment for physical illness. Information on all suicides over a period of 13 years in northern Finland as well as information from hospital registers were used to examine the interval between the last hospitalization and the suicide. On the basis of discharge diagnoses of physical or psychiatric illnesses, three groups were distinguished. Among victims with psychiatric disorders, survival time was shorter than among those without such a history, even if the last admission was for a physical condition. Clinicians should note the putative suicide risk among somatic patients at discharge, especially among those with a psychiatric history.

Increased adrenaline to noradrenaline ratio is a superior indicator of antemortem hypothermia compared with separate catecholamine concentrations.

The significance of urinary catecholamines and small gastric mucosal bleedings, Wischnewsky's spots, in postmortem diagnosis of hypothermia deaths was evaluated. Autopsy cases (n=358) were divided into hypothermia, suspected hypothermia, and control groups. The catecholamine levels did not correlate with the length of the postmortem period. The adrenaline to noradrenaline ratio was most effective in detecting hypothermia (68.9% sensitivity, 78.1% specificity). The median adrenaline concentrations were significantly higher in hypothermia than in control groups. The control group containing mostly sudden cardiac deaths with no cold exposure had a noradrenaline level comparable to the hypothermia groups. The sensitivity and specificity of determining Wischnewsky's spots in hypothermia deaths were 63.9% and 88.3%, respectively. The adrenaline to noradrenaline ratio is more suitable in proving antemortem cold stress than either of these independently, and its diagnostic value is comparable to that of Wischnewsky's spots.

Human locus coeruleus neurons express the GABA(A) receptor gamma2 subunit gene and produce benzodiazepine binding.

Noradrenergic neurons of the locus coeruleus project throughout the cerebral cortex and multiple subcortical structures. Alterations in the locus coeruleus firing are associated with vigilance states and with fear and anxiety disorders. Brain ionotropic type A receptors for gamma-aminobutyric acid (GABA) serve as targets for anxiolytic and sedative drugs, and play an essential regulatory role in the locus coeruleus. GABA(A) receptors are composed of a variable array of subunits forming heteropentameric chloride channels with different pharmacological properties. The gamma2 subunit is essential for the formation of the binding site for benzodiazepines, allosteric modulators of GABA(A) receptors that are clinically often used as sedatives/hypnotics and anxiolytics. There are contradictory reports in regard to the gamma2 subunit's expression and participation in the functional GABA(A) receptors in the mammalian locus coeruleus. We report here that the gamma2 subunit is transcribed and participates in the assembly of functional GABA(A) receptors in the tyrosine hydroxylase-positive neuromelanin-containing neurons within postmortem human locus coeruleus as demonstrated by in situ hybridization with specific gamma2 subunit oligonucleotides and autoradiographic assay for flumazenil-sensitive [(3)H]Ro 15-4513 binding to benzodiazepine sites. These sites were also sensitive to the alpha1 subunit-preferring agonist zolpidem. Our data suggest a species difference in the expression profiles of the alpha1 and gamma2 subunits in the locus coeruleus, with the sedation-related benzodiazepine sites being more important in man than rodents. This may explain the repeated failures in the transition of novel drugs with a promising neuropharmacological profile in rodents to human clinical usage, due to intolerable sedative effects.

Suicide after hospitalization in the elderly: a population based study of suicides in Northern Finland between 1988-2003.

OBJECTIVE: Elderly people commit suicide more often than people under the age of 65. An elevated risk is also attached to depression and other axis I psychiatric disorders. However, little is known about the preferred suicide method, effect of primary psychiatric diagnosis, and length of time between discharge from psychiatric hospitalization and suicide. The lack of information is most apparent in the oldest old (individuals over 75 years). METHODS: On the basis of forensic examinations, data on suicide rates were separately examined for the 50-64, 65-74 and over 75 year-olds (Total n=564) with regard to suicide method, history of psychiatric hospitalization and primary diagnoses gathered from the Finnish Hospital Discharge Register. Study population consisted of all suicides committed between 1988 and 2003 in the province of Oulu in Northern Finland. RESULTS: Of the oldest old, females had more frequent hospitalizations than males in connection with psychiatric disorders (61% vs 23%), of which depression was the most common (39% vs 14%). In this age group, 42% committed suicide within 3 months after being discharged from hospital and 83% used a violent method. Both elderly males and females were less often under the influence of alcohol, but used more often violent methods than middle-aged persons. CONCLUSIONS: Suicide rates within the first 3 months following discharge from hospital in the 65-74 and the over 75 year olds were substantial and should influence post-hospitalization treatment strategies. To reduce the risk of suicides in elderly patients discharged from hospital, close post-hospitalization supervision combined with proper psychoactive medication and psychotherapy, are possible interventions.