SVEP1 is important for morphogenesis of lymphatic system: Possible implications in lymphedema.

SVEP1, also known as Polydom, is a large extracellular mosaic protein with functions in protein interactions and adhesion. Since Svep1 knockout animals show severe edema and lymphatic system malformations, the aim of this study is to evaluate the presence of SVEP1 variants in patients with lymphedema. We analyzed DNA from 246 lymphedema patients for variants in known lymphedema genes, 235 of whom tested negative and underwent a second testing for new candidate genes, including SVEP1, as reported here. We found three samples with rare heterozygous missense single-nucleotide variants in the SVEP1 gene. In one family, healthy members were found to carry the same variants and reported some subclinical edema. Based on our findings and a review of the literature, we propose SVEP1 as a candidate gene that should be sequenced in patients with lymphatic malformations, with or without lymphedema, in order to investigate and add evidence on its possible involvement in the development of lymphedema.

Comparison of oxidative potential of PM1 and PM2.5 urban aerosol and bioaccessibility of associated elements in three simulated lung fluids.

PM1 and PM2.5 aerosol samples collected during four seasons were analysed for bioaccessibility of 21 elements and oxidative potential (OP) determined by the dithiothreitol (DTT) assay in three simulated lung fluids (SLFs): deionised water, simulated alveoli fluid and Gamble's solution. Most elements had higher bioaccessibility in the submicron fraction than in the fine size fraction. The bioaccessibility of the element not only depends on the aerosol size fraction, but also varies between the three SLFs. In addition, the bioaccessibility of elements depends on both their chemical compound and the composition of the SLF. A very high bioaccessibility (up to 98%) was observed for As, Sb and Cd in all studied SLFs. The lowest bioaccessibility was observed for Ti, Al and Fe. The OP of urban particulate matter (PM), was studied as a relevant metric for health effects. The difference of OP value in simulated alveoli fluid and Gamble's solution compared to deionised water indicate the crucial effect of individual SLFs' composition on the OP. The complexation of elements with different ligands present in the solution can influence OPDTT depletion and, therefore, the potential health effects of inhaled aerosol. The correlation coefficients between total or bioaccessible concentrations of studied elements and volume normalised OP were calculated to examine the relationship between the elements and the OP. The strong positive correlations between some elements (i.e. Cd, Pb, As, Zn, Sn, Cu, Co, Ni, Mn) and DTT activity suggest their participation in the oxidative activity of PM.

Rare PECAM1 variants in three families with lymphedema.

PECAM1 is a member of the immunoglobulin superfamily and is expressed in monocytes, neutrophils, macrophages and other types of immune cells as well as in endothelial cells. PECAM1 function is crucial for the development and maturation of B lymphocytes. The aim of this study was to link rare PECAM1 variants found in lymphedema patients with the development of lymphatic system malformations. Using NGS, we previously tested 246 Italian lymphedema patients for variants in 29 lymphedema-associated genes and obtained 235 negative results. We then tested these patients for variants in the PECAM1 gene. We found three probands with rare variants in PECAM1. All variants were heterozygous missense variants. In Family 1, the unaffected mother and brother of the proband were found to carry the same variant as the proband. Lymphoscintigraphy was performed to determine possible lymphatic malformations and showed that in both cases a bilateral slight reduction in the speed and lymphatic clearance of the lower limbs. PECAM1 function is important for lymphatic vasculature formation. We found variants in PECAM1 that may be associated with susceptibility to lymphedema.

Review of the function of SEMA3A in lymphatic vessel maturation and its potential as a candidate gene for lymphedema: Analysis of three families with rare causative variants.

SEMA3A is a semaphorin involved in cell signaling with PlexinA1 and Neuropilin-1 (NRP1) receptors and it is responsible for recruiting dendritic cells into lymphatics. Mutations in the SEMA3A gene result in abnormalities in lymphatic vessel development and maturation. We investigated the association of SEMA3A variants detected in lymphedema patients with lymphatic maturation and lymphatic system malfunction. First, we used NGS technology to sequence the SEMA3A gene in 235 lymphedema patients who carry wild type alleles for known lymphedema genes. We detected three different missense variants in three families. Bioinformatic results showed that some protein interactions could be altered by these variants. Other unaffected family members of the probands also reported different episodes of subclinical edema. We then evaluated the importance of the SEMA3A gene in the formation and maturation of lymphatic vessels. Our results determined that SEMA3A variants segregate in families with lymphatic system malformations and recommend the inclusion of SEMA3A in the gene panel for testing of patients with lymphedema.

CYP26B1 and its implications in lymphangiogenesis: Literature review and study of rare variants in two families.

CYP26B1 is a member of the cytochrome P450 family and is responsible for the break-down of retinoic acid for which appropriate levels are important for normal development of the cardiovascular and lymphatic systems. In a cohort of 235 patients with lymphatic malformations, we performed genetic testing for the CYP26B1 gene. These probands had previously tested negative for known lymphedema genes. We identified two heterozygous missense CY-P26B1 variants in two patients. Our bioinformatic study suggested that alterations caused by these variants have no major effect on the overall stability of CYP26B1 protein structure. Balanced levels of retinoic acid maintained by CYP26B1 are crucial for the lymphatic system. We identified that CYP26B1 could be involved in predisposition for lymphedema. We propose that CYP26B1 be further explored as a new candidate gene for genetic testing of lymphedema patients.

Mendelian obesity, molecular pathways and pharmacological therapies: a review.

OBJECTIVE: In this qualitative review we analyze the major pathways and mechanisms involved in the onset of genetically-determined obesity (Mendelian obesity), identifying possible pharmacological treatments and trials. MATERIALS AND METHODS: We searched PubMed with the keywords (obesity[Title/Abstract]) AND mutation[Title/Abstract], and OMIM with the keyword "obesity". In both cases, we selected non-syndromic Mendelian obesity. We then searched ClinicalTrials.gov with the following criteria: "recruitment status: active, not recruiting and completed"; "study type: interventional (clinical trial)"; "study results: with results"; type of intervention: "drug or dietary supplement". RESULTS: From the PubMed and OMIM searches we obtained a total of 15 genes associated with monogenic Mendelian obesity. From ClinicalTrials.gov we retrieved 46 completed or active trials of pharmacological treatments. CONCLUSIONS: We summarized the molecular bases of Mendelian obesity and searched for any clinical trials completed or underway for the treatment of severe forms of obesity. Most Mendelian obesities are linked to dysfunctions in the leptin/melanocortin signaling pathway, and most of the possible drugs target this pathway in order to improve energy expenditure and reduce food intake.

"Surgically created" excision of the back mimicking homicide: report of an unusual case.

Fatalities due to sharp force trauma, with respect to manner of death, may be homicidal, self-inflicted, or accidental in nature. This article presents a case of an unusual sharp force injury inflicted under very specific and seemingly obscured circumstances, initially suggestive of homicidal origin. A 69-year-old, socially isolated male was found dead with a strange, heavily blood-stained excision-like lesion on the right subscapular area. The autopsy confirmed that the wound led to fatal external blood loss. Toxicological analysis of the blood and urine revealed severe alcohol intoxication. The police investigation turned up that the man had suffered from a painful skin furuncle of the right upper back. As he was worried about receiving medical treatment, he voluntarily asked his two acquaintances for "surgical" assistance to remove the skin affection. Based on the circumstances surrounding death and findings at autopsy, it was concluded that the injury was inflicted without the intent to harm or cause death, as a result of simple negligence. Consequently, the manner of death was ultimately certified as an involuntary manslaughter. Our case has clearly illustrated that even highly suspicious and atypically shaped wounds created by sharp-edged instruments with localization in non-accessible body areas does not exclusively indicate homicidal activity, hence, the accidental, suicidal or even iatrogenic origin of the wounding mechanism must be taken into consideration.

Correlations of survivin expression with clinicomorphological parameters and hormonal receptor status in breast ductal carcinoma.

The antiapoptotic protein survivin is widely expressed in most human cancers, including carcinomas of the breast. It is rarely detected in corresponding normal adult tissues. Therefore, survivin comes into the limelight as a promising diagnostic biomarker and prognostic parameter. Immunohistochemically, we examined the expression of this protein in 126 cases of ductal breast carcinoma to determine the association with clinicomorphological parameters such as age of patients, grade, stage and size of the primary tumor, lymph node metastasis, vascular invasion as well as estrogen and progesterone status. In each section, the subcellular location of survivin antigen, the intensity of staining and the percentage of labeled cells were assessed. Overall, survivin was expressed in 111 cases (88.1%). The statistical analysis revealed a significant correlation between the nuclear location of survivin and tumor grade 3. Furthermore, a significant relation was also found between vascular invasion and nuclear and combined nuclear and cytoplasmic survivin expression, together with a higher intensity of immunoreaction. However, no significant correlations were shown with other clinicomorphological parameters, such as stage and size of the tumor, lymph node metastasis, estrogen and progesterone receptors and age. Our findings revealed that survivin was frequently overexpressed in carcinoma cells, where it was present in different subcellular compartments. The nuclear positivity of survivin or combined nuclear and cytoplasmic expression was shown to be a poor prognostic parameter in ductal breast carcinoma.

[Pohoda no. I (death on music festival)]. / Pohoda I. (Smrt' na hudobnom festivale).

A fatal accident of a young man, visitor of the summer music festival, shocked the whole Slovak society. Many unanswered questions concerned a causality of the incident arose immediately. Altough most questions have been focused to technical experts concerning the cause of a tent fall, the forensic medicine can bring some important reflections and conclusions, too. An absence of natural defense mechanisms of the accident's victim should be explained only through malignant affection of the body reflectoris reactions by exogenous substance, which might depress natural senzoric or motoric response while being in acute danger from falling tent's construction.

[Pohoda no. II (delayed death--following music festival)]. / Pohoda II (smrt' po hudobnom festivale).

A mass tragedy on the Slovak biggest music festival "POHODA", caused by a windstorm, shocked whole society, even abroad. Many questions concerned a causality and a circumstances of the incident arose immediately. The forensic autopsies of victims (29-aged man and 19-aged woman) represented a very special expertise act in police investigation of the case.

Vomitus as a cause of fatal diving accident of a commercial diver.

The forensic expertise of the victim of fatal diving accident (commercial diver), who died in depth of 41 mts due of unknown reasons, had been realised by the authors. One of the authors of the paper was present on site of the diving accident as a diving medicine specialist. The autopsy revealed, that the cause of death of the diver was suffocation due to vomitus and massive aspiration of gastric content to the airways. The commercial diving technology (full-face diving mask with oro-nasal inner mask) was used. The authors point out some peculiarities in interpretation of such a fatal diving accident.

[The forensic-anthropological expertise of a historically important person's relics, destroyed by fire--the contribution of forensic experts to the preservation of a historical heritage]. / Forenzne-antropologická expertíza termicky poskodeného tela historicky významnej osoby--prínos k zachovaniu historického dedicstva.

The forensic-anthropological expertises of the human remains being destroyed by the external heat are rather rare in general practice of the medical examiner (burned body remains in the fired houses, in traffic accidents, air crashes, explosions in coal mines etc.). In the aim to restore the identity of the burned person, such an expertises have to solve a complex set of problems, which--on the site of a forensic expert--need the application of a very specific approaches and know how. The authors describe a rare case of forensic and anthropological expertise of the 400 years old relics of a person, being important in the slovak history, whose body in the coffin was intentionally exposed to open fire.

[Forensic interpretation of postmortal ethanol neogenesis in blood samples of cadaverously decomposed bodies]. / Forenzná interpretácia postmortálnej neogenézy etanolu v krvných vzorkách z kadaverózne dekomponovaných tiel.

There is no real possibility for detail knowledge of postmortal changes of blood alcohol concentration in the near future, so that it is necessary to comment alcoholaemia with special aspect on empirical practice. Potential use of alternative (more resistant to putrefaction) body fluid or tissue can help to distinguish ratio of endogenous and exogenous ethanol. It seems that using of vitreous (eventually urine) is the best way to avoid desinterpretation mistakes of alcoholemia in cadavers. In cases where these fluids are missing we are not able to comment alcoholaemia of saprogenic blood.

[The correlation of results of breath analysers and laboratory blood examinations of blood-ethanol concentration (Czech and Slovak study)]. / Mezirepubliková Cesko-Slovenská studie korelace výsledku dechových analyzátoru a výsledku laboratorní analýzy pri zjistování hladiny alkoholu v krvi.

The target of this study was to compare the results of breath analysers and "lege artis" laboratory blood examinations when determining alcohol levels. This was then used to determine whether any differences exist between the two methods, and how large these differences are. 610 cases from 11 workplaces in the Czech Republic and Slovakia were analysed. The type of breath analyser was not taken into consideration. All cases had to be in the elimination phase. Difference of time between breath test and blood test were rectified through the use of reverse recomputation. It was detected that only 20.8% of the results of respiratory analyser tests correspond to the detected real alcohol level in blood. The maximum difference when a respiratory analyser measured more than a blood test was 1.34 g x kg(-1). and the maximum difference when the analyse measured less was 1.86 g x kg(-1).

On the origin of chloroplasts, import mechanisms of chloroplast-targeted proteins, and loss of photosynthetic ability - review.

Primary plastids of green algae (including land plants), red algae and glaucophytes are bounded by two membranes and are thought to be derived from a single primary endosymbiosis of a cyanobacterium in a eukaryotic host. Complex plastids of euglenids and chlorarachneans bounded by three and four membranes, respectively, most likely arose via two separate secondary endosymbioses of a green alga in a eukaryotic host. Secondary plastids of cryptophyta, haptophyta, heterokontophyta and apicomplexan parasites bounded by four membranes, and plastids of dinoflagellates bounded by three membranes could have arisen via a single secondary endosymbiosis of a red alga in a eukaryotic host (chromalveolate hypothesis). However, the scenario of separate tertiary origins (symbioses of an alga possessing secondary plastids in a eukaryotic host) of some (or even most) chromalveolate plastids can be also consistent with the current data. The protein import into complex plastids differs from the import into primary plastids, as complex plastids contain one or two extra membrane(s). In organisms with primary plastids, plastid-targeted proteins contain N-terminal transit peptide which ferries proteins through the protein import machineries (multiprotein complexes) of the two (originally cyanobacterial) membranes. In organisms with complex plastids, the secretory signal sequence directing proteins to endomembrane system and afterwards through extra outermost membrane(s) is generally present upstream of the classical transit peptide. Several free-living as well as parasitic eukaryotes possess non-photosynthetic plastids. These plastids have generally retained the plastid genome, functional plastid transcriptional and translational apparatus, and various metabolic pathways, suggesting that though these plastids lost their photosynthetic ability, they are essential for the mentioned organisms. Nevertheless, some eukaryotes could have lost chloroplast compartment completely.

C-13 explosion victims--peculiarities of autopsy findings.

Mass disasters such as e.g., plane or train crash, shipping accidents or huge explosions in the region of Slovak Republic are not very often, but in spite of this fact sometimes they occur. Such a terrible event--a destructive detonation of non-specified amount of explosives, happened on 2nd March 2007 in the Military Repairing Enterprise in Novaky, Slovak Republic, by which the whole enterprise was almost totally destroyed, many employees were injured and eight persons died due to consequences of the explosion. Investigation of this disaster took several months, and parts of dead bodies were found in following weeks during the ruins removal; authors describe the autopsy findings on the explosion victim's bodies and the possibilities of unknown human remains identification found in the area of the detonation often provided only by DNA analysis.

Ritual suicide of a Japanese girl in the Slovak Republic.

The body of a young Japanese woman was found buried in the mass of snow in February 2006 near the town of Liptovsky Mikulas in the Slovak Republic. Hypothermia was declared as the cause of her death, the body of the deceased was deeply frozen. The autopsy and police investigation classified her death as a suicide, having some features of an Eastern Asian suicidal ritual. The case shows that the era of world globalization and migration of people bring together also the curious cases of human tragedies. Thus the forensic expert of nowadays must expect that s/he might be faced with cases of death unseen before.

Gravidity complicated by abdominal neoplastic process.

The case of 31-year-old pregnant woman in the 28th week of pregnancy is presented. She was brought in a bad condition to a small hospital by her parents. The case history of only 5 h included e.g. nausea, multiple emesis, cephalea, deteriorated respiration. Shock status was diagnosed in the hospital intensive care unit. After the patient lost her consciousness, resuscitation, intubation and artificial ventilation breath control were realised immediately, the doses of 13 mg of adrenalin were applied.

Beneficial health effects of milk and fermented dairy products--review.

Milk is a complex physiological liquid that simultaneously provides nutrients and bioactive components that facilitate the successful postnatal adaptation of the newborn infant by stimulating cellular growth and digestive maturation, the establishment of symbiotic microflora, and the development of gut-associated lymphoid tissues. The number, the potency, and the importance of bioactive compounds in milk and especially in fermented milk products are probably greater than previously thought. They include certain vitamins, specific proteins, bioactive peptides, oligosaccharides, organic (including fatty) acids. Some of them are normal milk components, others emerge during digestive or fermentation processes. Fermented dairy products and probiotic bacteria decrease the absorption of cholesterol. Whey proteins, medium-chain fatty acids and in particular calcium and other minerals may contribute to the beneficial effect of dairy food on body fat and body mass. There has been growing evidence of the role that dairy proteins play in the regulation of satiety, food intake and obesity-related metabolic disorders. Milk proteins, peptides, probiotic lactic acid bacteria, calcium and other minerals can significantly reduce blood pressure. Milk fat contains a number of components having functional properties. Sphingolipids and their active metabolites may exert antimicrobial effects either directly or upon digestion.

[The taphonomic aspects of cadaverous changes in corpses, buried in the plastic foils]. / Tafonomické aspekty kadaveróznych zmien u mrtvol ulozených do zeme v plastových obaloch.

The forensic expertise of the 6 human bodies, being murdered in organised crime activities, had been realised by the authors. All the cadavers were packed in plastic bags or plastic foils, then buried to the illegal graves, being prepared in advance. The detail overlook and autopsy of the bodies had disclosed, that due of almost airtight sealing of the cadavers in plastic materials, the postmortal cadaverous changes went on much slower and were manifested under a different picture, as seen in the human cadavers being buried in the standard wooden coffins. The authors point out the peculiarities of such a postmortal changes, with particular focusing on the estimation of postmortal period.