The involvement of the GPR39-Zn(2+)-sensing receptor in the pathophysiology of depression. Studies in rodent models and suicide victims.

Zinc is one of the most important trace elements in our body. Patients suffering from depression show lower serum zinc levels compared to healthy controls. Zincs antagonism to the glutamatergic system seems to be responsible for mood recovery. Recent years have shown that zinc may regulate neurotransmission via the metabotropic GPR39 receptor. Activation of the GPR39-Zn(2+)-sensing receptor (GPR39) triggers diverse neuronal pathways leading to a cAMP-responsive element binding the protein (CREB) expression, which then induces synthesis of the brain-derived neurotrophic factor and, in turn, activation of the Tropomyosin receptor kinase B (TrkB) receptor. In the present study, we investigated the alteration of the GPR39 in different models of depression, such as zinc deficiency and olfactory bulbectomy and in suicide victims. Additionaly, we focused on CREB-BDNF/TrkB under zinc deficient conditions in mice. To demonstrate depressive-like behaviour, a standard and modified forced swim test (FST) was performed. To evaluate expression of GPR39, CREB, BDNF and TrkB, Western Blot analysis was used. Zinc deficient mice and rats showed decreased GPR39 expression in the hippocampus and frontal cortex. A decreased level of hippocampal and cortical GPR39 was also observed in suicide victims. In contrast, increased GPR39 in the hippocampus of olfactory bulbectomized rats was observed. Additionally, we found a decreased expression of CREB, BDNF and TrkB only in the hippocampus of zinc-deficient mice. Our present study demonstrates the associacion of the GPR39 Zn(2+)-sensing receptor in the pathomechanism of depression. Down-regulation of CREB, BDNF, TrkB and GPR39 receptor found under zinc-deficient conditions in the hippocampus, may play an important role in the pathophysiology of mood disorders, since most of patients suffering from depression show lower serum zinc.

Zinc, magnesium and NMDA receptor alterations in the hippocampus of suicide victims.

BACKGROUND: There is evidence for an association between suicidal behavior and depression. Accumulating data suggests that depression is related to a dysfunction of the brain's glutamatergic system, and that the N-methyl-d-aspartate (NMDA) receptor plays an important role in antidepressant activity. Zinc and magnesium, the potent antagonists of the NMDA receptor complex, are involved in the pathophysiology of depression and exhibit antidepressant activity. METHODS: The present study investigated the potency of Zn(2+) and Mg(2+) to [(3)H] MK-801, which binds to the NMDA receptor channel in the hippocampus of suicide victims (n=17) and sudden death controls (n=6). Moreover, the concentrations of zinc and magnesium (by flame atomic absorption spectrometry) and levels of NMDA subunits (NR2A and NR2B) and PSD-95 protein (by Western blotting) were determined. RESULTS: Our results revealed that there was a statistically significant decrease (by 29% and 40%) in the potency of zinc and magnesium (respectively) to inhibit [(3)H] MK-801 binding to NMDA receptors in the hippocampus in suicide tissue relative to the controls. These alterations were associated with increased NR2A (+68%) and decreases in both the NR2B (-46%) and PSD-95 (-35%) levels. Furthermore, lower concentrations (-9%) of magnesium (although not of zinc) were demonstrated in suicide tissue. CONCLUSIONS: Our findings indicate that alterations in the zinc, magnesium and NMDA receptor complex in the hippocampus are potentially involved in the pathophysiology of suicide-related disorders (depression), which may lead to functional NMDA receptor hyperactivity.

Microvessel density and area in pituitary microadenomas.

Microvessel density (MVD) and area (MVA) were assessed in 53 clinically silent pituitary microadenomas and in surrounding normal pituitary tissue using CD34 immunostaining and digital image analysis system. Twenty-one microadenomas (40%) were avascular; in the others, both MVD and MVA were significantly lower than in the normal pituitary tissue. No significant differences in MVD and MVA were found between hormonally immunonegative and immunopositive tumors or between different hormonal subtypes of immunopositive microadenomas. In microadenomas and in normal pituitary tissue, MVD and MVA were not significantly influenced by age or sex. These results suggest that pituitary adenomas at early developmental stage are either avascular or significantly less vascular than normal pituitary tissue and that differences in vascularity of pituitary adenomas associated with the variables of sex, age, clinical presentation and immunohistochemical phenotype reported in the literature can evolve with tumor growth and possibly acquire statistical significance in large macroadenomas.

Incidence of pituitary necrotic lesions in autopsy material.

Pituitary necrosis is mostly a result of pituitary haemorrhage or infarct. The frequency of pituitary necrosis in the Polish population has not yet been investigated. Hence, the aim of this study was to estimate the incidence of pituitary necrotic lesions in forensic autopsy material and to assess possible correlations of pituitary necrosis with sex, age, other pituitary pathologies, endocrine disorders and atherosclerosis. Serial sections of 100 human pituitary glands stained with hematoxylin-eosin were examined microscopically. Pituitary necrosis was found in 19 cases (19%), all of them in persons aged > 40 years. The majority of the lesions had relatively large size, occupying 10-50% of the gland. According to family interviews, none of the subjects manifested any clinical symptoms related to pituitary insufficiency, hence al the detected cases can be regarded as subclinical. There was no association of pituitary necrosis occurrence with sex, other pituitary pathologies found upon autopsy, endocrine diseases or cause of death. Only correlations with age and atherosclerosis were statistically significant. This study has shown that subclinical pituitary necrosis is a relatively frequent phenomenon in elderly persons, probably resulting from age-related deterioration in the vascular status.

Increased incidence of pituitary microadenomas in suicide victims.

BACKGROUND: Current data suggest an influence of the hypothalamic-pituitary-adrenal axis on suicidal behavior. The frequency of pituitary adenomas in suicide victims has not yet been investigated. OBJECTIVES: The aim of this study was to assess whether the incidence of pituitary adenomas is correlated with suicide. METHODS: Serial sections of 151 human pituitary glands obtained upon autopsy were examined microscopically. The glands were collected from 70 suicide victims and 81 subjects whose deaths were classified as unexpected or accidental (nonsuicidal group). The sections were stained with hematoxylin-eosin and the presence of adenoma was confirmed by immunostaining for collagen III. RESULTS: In the suicidal group, pituitary microadenomas were found in 32 cases (47.7%), while in the nonsuicidal group microadenomas were detected in 15 cases (18.3%). The observed difference was statistically significant (p = 0.0003). The relative risk ratio of suicide in persons with pituitary adenomas was estimated at 1.9. Logistic regression analysis in a model controlled for age and sex showed that microadenomas constituted a unique risk factor in this model. The immunohistochemical phenotyping revealed a higher percentage of immunopositive (secreting) microadenomas in the nonsuicidal group as compared to the suicidal group (80.0 vs. 59.38%) and a predominance of growth hormone-secreting microadenomas in both groups. However, these differences as well as differences in the hormonal profiles of microadenomas between the groups were not significant. CONCLUSIONS: These results suggest that pituitary adenomas belong to suicide risk factors.

[Completed suicide in outline--on basis of Cracow's Institute of Forensic Medicine data in 1991-2000 years]. / Samobójstwo dokonane--zarys zjawiska na podstawie materialu krakowskiego zakladu medycyny sadowej z lat 1991-2000.

The study presents the results of research into completed suicide. The authors have analyzed cases of completed suicide committed in Cracow and it's environs in the years 1991-2000. The aim of the research is to describe some features of this phenomenon with it's transformations in the last periods. The presented material bases on archival data of postmortem examinations made in Cracow's Institute of Forensic Medicine. Analyses' were executed in reference of victims' sex, age and place of residence, number and frequency of suicides in Cracow population, methods, predictors and possible motives. The authors also present a sketch of the bibliography regarding the topic, and the comparison between the results of the present study and the results of earlier studies from Cracow environs of the phenomenon of suicide. 1933 cases of completed suicides were analysed, from what over a half concerned occupants of our city. The average coefficient for 100 000 occupants carried out 13.2. There were 1485 men and 448 women among victims, in age from 13 to 95 years. Male to female avarage ratio carried out 3.3:1 in the described period.. Average age carried out 45.5 years, for men 44.5, and for women 48.8 years. The superiority of men is strongly visible in groups of young persons and in "middle age". Results from archival data show that, hanging was the the most frequent way of suicide. In studied material there were more then 63% cases of suicidal hanging. Falls from height, poisonings and drownings were next in line. In very considerable number of cases (almost 60%) the presence of mental disorder in anamnesis was affirmed. This concerned particularly women where the most frequent were depression disorders. For men, first of all factors was dependence from acohol. Over one third of the victims were pensioners and unemployeds. The level of ethanol in blood in 718 cases was crossed 0.5 promille.

Suicide and suicide attempts in adolescents and young adults in Kraków in the years 2002-2003.

The aim of the study was to present the increasingly alarming phenomenon of completed suicide in adolescents and young adults. The material analysed had been drawn from the records of post-mortem examinations conducted by the Institute of Forensic Medicine in Kraków. The analysis covered cases of completed suicide committed by 15-30 years old inhabitants of Kraków or its environs between the September 2002 and the September 2003. The group of subjects analysed comprised 47 individuals (9 females and 38 males); 57.4% of these had resided in a big city (Kraków), and the remaining 42.6%--in villages or little towns near Kraków. The data regarding cases of completed suicide were compared with the data regarding suicide attempts by self-intoxication in the period under consideration, extracted from the documentation of the Department of Clinical Toxicology in Kraków. The latter data encompassed 233 cases of suicide attempts by individuals ranging in age from 15 to 29 years, with females constituting 62.2% of these, and males--37.8%. 65% of the attempters had been residents of Kraków. The analysis of the data from the Institute of Forensic Medicine revealed that nearly half of the suicide victims concerned had been treated for mental disorders, mainly depression and addictive disorders. The occurrence of suicide attempts prior to the fatal act was established in the case of 17 subjects (18.5%). Over half of the subjects (48.9%) committed suicide by hanging themselves, 17%--by falling from a height, 8.6%--by drowning, and 19.1%--by self-intoxication with medicaments. 77.2% of the subjects committed suicide at home. In the case of 23 subjects (48.9%), the post-mortem examination revealed the presence of alcohol. The analysis of the cases of suicide attempts by self-intoxication revealed a significant percentage of depressive disorders (26%)--of high occurrence especially in the case of females, whereas alcohol addiction was the predominant diagnosis in the case of males. Furthermore, the majority of the attempters exhibited situational reactions or personality disorders. Suicide attempts constitute an essential part of the issue of suicide in adolescents and young adults and require further research. What attracts notice, is a high percentage of males among suicide victims, and a high percentage of suicide victims with earlier suicide attempts. The results of the study should be taken into consideration in suicide prevention in groups especially endangered by the risk of completed suicide, such as adolescents and young adults after suicide attempts.

Massive acute arsenic poisonings.

Arsenic poisonings are still important in the field of toxicology, though they are not as frequent as about 20-30 years ago. In this paper, the arsenic concentrations in ante- and post-mortem materials, and also forensic and anatomo-pathological aspects in three cases of massive acute poisoning with arsenic(III) oxide (two of them with unexplained criminalistic background, in which arsenic was taken for amphetamine and one suicide), are presented. Ante-mortem blood and urine arsenic concentrations ranged from 2.3 to 6.7 microg/ml, respectively. Post-mortem tissue total arsenic concentrations were also detected in large concentrations. In case 3, the contents of the duodenum contained as much as 30.1% arsenic(III) oxide. The high concentrations of arsenic detected in blood and tissues in all presented cases are particularly noteworthy in that they are very rarely detected at these concentrations in fatal arsenic poisonings.

[Influence of weather factors on suicidal hangings]. / Wplyw warunków meteorologicznych na wypadki samobójstw przez powieszenie.

The paper presents a certain biometeorological problem. The evaluation of influence of weather factors on frequency of suicidal cases by hanging in the area of Cracow City during 1991-2002 was examined. Rapid changes of air pressure, air temperature, hot, sweltering and sultry days, very frosty days, days with strong or foehn wind, days with thunderstorms, fog and haze were selected as unfavourable weather factors. They give an occasion for strong psychical stress. The results of detailed investigations are next: more frequency of cases of suicide during the advance of cold fronts, rapid decreases of air pressure during hot, sweltering and sultry days, days with thunderstorms and foehn winds in the Tatra Mountains.

[Application of HPLC/MS for evaluation of fatal poisoning with digoxin in the aspect of medico-legal evidence]. / Zastosowanie techniki HPLC/MS w ocenie zatrucia smiertelnego digoksyna w aspekcie orzecznictwa sadowo-lekarskiego.

This paper presents a case of suicidal poisoning of a woman with digoxin administered by injection. The autopsy of the subject was performed in the Institute of Forensic Medicine CMUJ. Body fluids (blood, urine, perylimph) and tissues (kidney, liver, brain) were collected for toxicological investigation. Digoxin determination was carried out by means of high performance liquid chromatography with mass spectrometry (HPLC/MS) which revealed digoxin in extremely high concentrations in specimens examined. The method is especially useful for analysis of cardiac glycosides in fatal poisonings for medicolegal purposes.

[Cardiomyocyte apoptosis in immunohistochemical diagnosis of sudden cardiac death]. / Apoptoza kardiomiocytów w diagnostyce immunohistochemicznej naglych zgonów sercowych.

In a considerable number of cases of sudden death "routine" diagnosis is insufficient to prove myocardial ischaemia especially in early myocardial infarction. One of the additional methods of postmortem diagnosis is detection of cardiomyocyte DNA fragmentation related to apoptosis. The authors presented research on 34 cases. All postmortem examination were conducted in the Chair of Forensic Medicine of the Jagiellonian University in Kraków. The data from history were taken into account as well as the results of gross macroscopic and microscopic examination (hematoxylin et eosin staining). In 19 cases the result of TUNEL assay was positive, in 5 apoptotic cell count was 80-90%. "Positive" cases showed focal or diffuse apoptotic myocytes. In 15 cases apoptotic reaction was negative including 3 cases of fatal ethanol intoxication and 1 aminotryptyline intoxication. In 22 cases the acid fuchsin technique (Nielsen's) was applied. The authors confronted their results with the data from literature and presented principles of qualification and practical interpretation of immunohistochemical apoptosis reaction.

Reduced potency of zinc to interact with NMDA receptors in hippocampal tissue of suicide victims.

Zinc is involved in both psychopathology and treatment of depression. Since a considerable percentage of suicide victims had suffered from depression, we hypothesized that alteration in zinc homeostasis might occur in their brain tissue. We now report that zinc content is not altered in the hippocampal or cortical tissue of suicide victims (n = 10) compared to age-matched controls (n = 10). However, there is a statistically significant 26% decrease in the potency (increase in the IC(50) value) of zinc to inhibit [(3)H]MK-801 binding to NMDA receptors in the hippocampal but not cortical tissue of suicide subjects. The data represent the first demonstration that the alteration in zinc interaction with NMDA receptors may be involved in psychopathology underlying suicidal attempts.

[Male and female suicides in the material of Department of Forensic Medicine in Krakow--comparative analysis]. / Samobójstwa kobiet i mezczyzn w materiale krakowskiego Zakladu Medycyny Sadowej--analiza porównawcza.

The study presents the results of research into completed suicide obtained by cooperation between the Department of Forensic Medicine and the University Psychiatry Department in Kraków. The aim of the research is to determine similarities and differences among the cases of completed suicide depending on the sex of the subjects. The authors analyzed cases of completed suicide committed in Kraków and its environs in the years 1991-2000. The groups of females and males have been compared from the point of view of medical-forensic and psychosocial aspects. The authors also present a sketch of the bibliography regarding the topic, and the comparison between the results of the present study and the results of earlier studies from Kraków environs on the phenomenon of suicide.

[Completed suicide and depression in the elderly]. / Samobójstwa dokonane i depresja u osób w wieku podeszlym.

The aim of the study was to present problems of completed suicide and depression in the elderly. Postmortem examinations were conducted in the Institute of Forensic Medicine of the Jagiellonian University. The analysis included cases of completed suicide in adults, from which all the cases of individuals aged over 65 who in the years 1998, 1999, and 2000 committed suicide within the area of Kraków the City were selected for the present study. The examined group consisted of 92 individuals ranging in age from 65 to 89 years, including 34 females and 58 males. The mean age was 72.5 for the entire group. 44.5% of the subjects had resided in a big city (Kraków); the remainder of the group had resided in villages and towns around Kraków. 57.6% of the subjects committed suicide by hanging, 16.3%--by falling from a height, and 13%--by drowning. In the majority of cases (77.2%), the suicide was committed at home. In 17 cases (18.5%), the post mortem revealed the presence of alcohol. As regards somatic diseases in the examined population, the data from the anamnesis (often incomplete) indicate frequent occurrence of cardiovascular diseases. 43.5% of the subjects, who committed suicide, had been treated for mental disorders, mainly for depression, organic brain disorders, and alcohol addiction. 17 of the subjects (18.5%) had previously attempted to commit suicide. The above results indicate that a typical representative of the elderly committing suicide is a septuagenarian residing in the country or in a small town, and most typically committing suicide by hanging at home. The attention must be paid to the high number of mental disorders, especially depression, detected among both male and female subjects. The close relation between suicide and depression in the elderly is an important guideline on suicide prevention programs and therapy of psychogeriatric patients.

[The completed and attempted suicide in Krakow: similarities and differences]. / Samobójstwa dokonane i usilowane w Krakowie--podobienstwa i róznice.

The study presents the results of the interdisciplinary research conducted on the basis of cooperation between the Institute of Forensic Medicine, the Department of Clinical Toxicology, and the Clinic of Psychiatry in Kraków. The aim of the research was to determine similarities and differences between attempted and completed suicide from the point of view of socio-demographic and clinical traits. The authors analysed 220 cases of completed suicide committed in Kraków and its environs in the year 2000. The material presented in the study was based on the archive data from post mortem examinations conducted in the Institute of Forensic Medicine in Kraków. The sample consisted of 177 males and 43 females ranging in age from 13 to 89 years. The mean age was 43.6 years for the entire group, 42 years for males and 50 years for females. The majority of subjects were males, either unemployed, or pensioners. A similar tendency was observed in the group of female subjects. Mental disorders and alcoholic addiction in anamnesis were discovered in a significant number of cases, both in the group of males and in the group of females. Subjects, in whom serious somatic diseases had been detected, constituted a separate group of cases. According to the archive data, in the last century, suicide was most frequently committed by hanging. Similarly, in the sample examined, in 133 cases, suicide was committed by hanging. In 37% of cases, the level of alcohol in the suicides' blood was between 0.5 and 3 or more g/L. In 2000/2001, within the analogical period of 12 months, the group of 200 patients after a suicide attempt by drug intoxication was examined in the Department of Clinical of Toxicology Jagiellonian University College of Medicine. This group included 49 males and 150 females, ranging in age from 18 to 79 years (mean age 35). The examination was conducted by means of structured investigation and medical documentation. Contrary to completed suicide, in the group of suicide attempters, females outnumbered males. Young people under thirty, living in a large city, possessing elementary or secondary education, and either unemployed, or pensioners, constituted the majority of the examined group. A significant percentage of females was divorced and lived with their children only. The majority of the examined population of suicide attempters had used alcohol during the attempt, had suffered from depression, personality or behavioural disorders, had undergone psychiatric treatment, or had had cases of suicide among their friends or relatives.

[Fatal suicidal poisoning using chemicals and drugs in the Jagiellonian University Institute of Forensic Medicine, in the years 1991-2000]. / Samobójcze zatrucia srodkami chemicznymi i lekami w latach 1991-2000 w materiale krakowskiego Zakladu Medycyny Sadowej.

191 cases of fatal suicidal poisonings in the years 1991-2000 were analysed. Postmortem examinations were conducted in the Institute of Forensic Medicine of the Jagiellonian University. The group of poisonings was selected from a total of 1937 fatal suicidal cases examined in our Institute. Frequency of suicidal attempts, kind of chemicals/drugs used, age and sex relationships, probable motives and seasonal a variables were taken into account in our investigation. The results were compared to previous studies. Poisonings comprise about 10% of the total number of suicidal cases. The most frequent are poisonings using drugs, then using chemicals. The number of cases of males committing suicide by poisoning is about twice as many as seen in females in such cases. The most important motives were mental disturbances, the latter most frequent motives were alcoholism and somatic illnesses. The peak of number of cases was noted in the summer months, June and July (about 1/3 of the total number of cases). In the last decade we systematically observed both a rise in the total number of suicides and a lower percentage of poisonings.

[Crimes against life in the material of Cracow's Institute of Forensic Medicine--comparative analysis in the years 1986-2000 and 1996-2000]. / Przestepstwa przeciwko zyciu--analiza porównawcza materialu krakowskiego Zakladu Medycyny Sadowej w latach 1986-1990 i 1996-2000.

The authors presented a comparative analysis of crimes against life in five year periods of the past and present political systems based on autopsy material of Cracow's Institute of Forensic Medicine. Investigation of these types of crime confirmed sociological observations of arising the criminal trends in the last years. The incident of these types of crimes arose in the last period by about 40% in a relation of male to female victims 3.7:1. Probable motives of these crimes were: drinking 8%, decline in family relationships 12%, fight and revenge 9% robbery 8%, sexual offenses only in 1%. In 61% of analyzed cases the motives were unknown. Among the weapons of crime the most often used were blunt objects and death due to stabbings and cuts. A very high incidence of fire arm crimes in comparison to previous period was observed--from 2 cases in 1986-1990 to 25 in the five year period of 1996-2000. 78% of victims were in a state of insobriety at the moment of crime.