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Major findings of the pilot study involving 21 critically ill patients during the week after admission to the critical care unit specialized for COVID-19 are presented. Fourteen patients have recovered, while seven passed away. There were no differences between them in respect to clinical or laboratory parameters monitored. However, protein adducts of the lipid peroxidation product 4-hydroxynonenal (HNE) were higher in the plasma of the deceased patients, while total antioxidant capacity was below the detection limit for the majority of sera samples in both groups. Moreover, levels of the HNE-protein adducts were constant in the plasma of the deceased patients, while in survivors, they have shown prominent and dynamic variations, suggesting that survivors had active oxidative stress response mechanisms reacting to COVID-19 aggression, which were not efficient in patients who died. Immunohistochemistry revealed the abundant presence of HNE-protein adducts in the lungs of deceased patients indicating that HNE is associated with the lethal outcome. It seems that HNE was spreading from the blood vessels more than being a consequence of pneumonia. Due to the limitations of the relatively small number of patients involved in this study, further research on HNE and antioxidants is needed. This might allow a better understanding of COVID-19 and options for utilizing antioxidants by personalized, integrative biomedicine approach to prevent the onset of HNE-mediated vitious circle of lipid peroxidation in patients with aggressive inflammatory diseases.

In the present study, we investigated genetic and epigenetic changes and protein expression levels of negative regulators of Wnt signaling, DKK1, DKK3, and APC as well as glycogen synthase kinase 3 (GSK3β) and β-catenin in 64 human astrocytomas of grades II–IV. Methylation-specific PCR revealed promoter methylation of DKK1, DKK3, and GSK3β in 38%, 43%, and 18% of samples, respectively. Grade IV comprised the lowest number of methylated GSK3β cases and highest of DKK3. Evaluation of the immunostaining using H-score was performed for β-catenin, both total and unphosphorylated (active) forms. Additionally, active (pY216) and inactive (pS9) forms of GSK3β protein were also analyzed. Spearman’s correlation confirmed the prevalence of β-catenin’s active form (rs = 0.634, p ˂ 0.001) in astrocytoma tumor cells. The Wilcoxon test revealed that astrocytoma with higher levels of the active pGSK3β-Y216 form had lower expression levels of its inactive form (p &lt, 0.0001, Z = −5.332). Changes in APC’s exon 11 were observed in 44.44% of samples by PCR/RFLP. Astrocytomas with changes of APC had higher H-score values of total β-catenin compared to the group without genetic changes (t = −2.264, p = 0.038). Furthermore, a positive correlation between samples with methylated DKK3 promoter and the expression of active pGSK3β-Y216 (rs = 0.356, p = 0.011) was established. Our results emphasize the importance of methylation for the regulation of Wnt signaling. Large deletions of the APC gene associated with increased β-catenin levels, together with oncogenic effects of both β-catenin and GSK3β, are clearly involved in astrocytoma evolution. Our findings contribute to a better understanding of the etiology of gliomas. Further studies should elucidate the clinical and therapeutic relevance of the observed molecular alterations.

Simple Summary Astrocytomas are the most common type of primary brain tumor in adults. In this study, 64 astrocytoma samples of grades II–IV were analyzed for genetic and epigenetic changes as well as protein expression patterns in order to explore the roles of the Wnt pathway components, such as DKK1, DKK3, GSK3β, β-catenin, and APC in astrocytoma initiation and progression. Our findings on DKK1 and DKK3 show the importance of methylation in the regulation of Wnt signaling activity and also indicate pro-oncogenic effects of GSK3β on astrocytoma development and progression. Close connections between large deletions and mutations in the APC gene and increased β-catenin expression in glioblastoma were also established. Our results suggest that Wnt pathway related genes and proteins play an active role in the etiology of astrocytic brain tumors. Abstract In the present study, we investigated genetic and epigenetic changes and protein expression levels of negative regulators of Wnt signaling, DKK1, DKK3, and APC as well as glycogen synthase kinase 3 (GSK3β) and β-catenin in 64 human astrocytomas of grades II–IV. Methylation-specific PCR revealed promoter methylation of DKK1, DKK3, and GSK3β in 38%, 43%, and 18% of samples, respectively. Grade IV comprised the lowest number of methylated GSK3β cases and highest of DKK3. Evaluation of the immunostaining using H-score was performed for β-catenin, both total and unphosphorylated (active) forms. Additionally, active (pY216) and inactive (pS9) forms of GSK3β protein were also analyzed. Spearman’s correlation confirmed the prevalence of β-catenin’s active form (rs = 0.634, p < 0.001) in astrocytoma tumor cells. The Wilcoxon test revealed that astrocytoma with higher levels of the active pGSK3β-Y216 form had lower expression levels of its inactive form (p < 0.0001, Z = −5.332). Changes in APC’s exon 11 were observed in 44.44% of samples by PCR/RFLP. Astrocytomas with changes of APC had higher H-score values of total β-catenin compared to the group without genetic changes (t = −2.264, p = 0.038). Furthermore, a positive correlation between samples with methylated DKK3 promoter and the expression of active pGSK3β-Y216 (rs = 0.356, p = 0.011) was established. Our results emphasize the importance of methylation for the regulation of Wnt signaling. Large deletions of the APC gene associated with increased β-catenin levels, together with oncogenic effects of both β-catenin and GSK3β, are clearly involved in astrocytoma evolution. Our findings contribute to a better understanding of the etiology of gliomas. Further studies should elucidate the clinical and therapeutic relevance of the observed molecular alterations.

There is a lot of evidence showing that lipid peroxidation plays very important role in development of various diseases, including neurodegenerative diseases and brain tumors. Lipid peroxidation is achieved by two main pathways, by enzymatic or by non-enzymatic oxidation, respectively. In this paper, we focus on non-enzymatic, self-catalyzed chain reaction of poly-unsaturated fatty acid (PUFA) peroxidation generating reactive aldehydes, notably 4-hydroxynonenal (4-HNE), which acts as second messenger of free radicals and as growth regulating factor. It might originate from astrocytes as well as from blood vessels, even within the blood-brain barrier (BBB), which is in case of brain tumors transformed into the blood-brain-tumor barrier (BBTB). The functionality of the BBB is strongly affected by 4-HNE because it forms relatively stable protein adducts thus allowing the persistence and the spread of lipid peroxidation, as revealed by immunohistochemical findings. Because 4-HNE can act as a regulator of vital functions of normal and of malignant cells acting in the cell type- and concentration-dependent manners, the bioactivities of this product of lipid peroxidation be should further studied to reveal if it acts as a co-factor of carcinogenesis or as natural factor of defense against primary brain tumors and metastatic cancer.

Autoimmune encephalitis (AE) refers to a group of dis-orders that are mainly characterized by the presence of specific antibodies. A subtype of encephalitis with no detectable antibodies in serum or cerebrospinal fluid (CSF) is termed seronegative autoimmune encephalitis (SNAE). This sub-type of encephalitis accounts for 7–11% of patients with AE [1]. We report on two patients with somewhat different disease patterns who both fulfilled diagnostic criteria for SNAE and were followed up for more than 5 years.

Tumor growth is associated with oxidative stress, which causes lipid peroxidation. The most intensively studied product of lipid peroxidation is 4-hydroxy-2-nonenal (HNE), which is considered as a &ldquo, second messenger of free radicals&rdquo, that binds to proteins and acts as a growth-regulating signaling factor. The incidence of squamous cell carcinoma of the oropharynx is associated with smoking, alcohol and infection of human papilloma virus (HPV), with increasing incidence world-wide. The aim of this retrospective study involving 102 patients was to determine the immunohistochemical appearance of HNE-protein adducts as a potential biomarker of lipid peroxidation in squamous cell carcinoma of the oropharynx. The HNE-protein adducts were detected in almost all tumor samples and in the surrounding non-tumorous tissue, while we found that HNE is differentially distributed in squamous cell carcinomas in dependence of clinical stage and histological grading of these tumors. Namely, the level of HNE-immunopositivity was increased in comparison to the normal oropharyngeal epithelium in well- and in moderately-differentiated squamous cell carcinoma, while it was decreasing in poorly differentiated carcinomas and in advanced stages of cancer. However, more malignant and advanced cancer was associated with the increase of HNE in surrounding, normal tissue. This study confirmed the onset of lipid peroxidation, generating HNE-protein adducts that can be used as a valuable bioactive marker of carcinogenesis in squamous cell carcinoma of the oropharynx, as well as indicating involvement of HNE in pathophysiological changes of the non-malignant tissue in the vicinity of cancer.

Key regulators of the Wnt signalling, DVL1, DVL2 and DVL3, in astrocytomas of different malignancy grades were investigated. Markers for DVL1,DVL2 and DVL3 were used to detect microsatellite instability (MSI) and gross deletions (LOH), while immunohistochemistry and immunoreactivity score were used to determine the signal strengths of the three DVL proteins and transcription factors of the pathway, TCF1 and LEF1. Our findings demonstrated that MSI at all three DVL loci was constantly found across tumour grades with the highest number in grade II (P = 0.008). Collectively, LOHs were more frequent in high‐grade tumours than in low grade ones. LOHs of DVL3 gene were significantly associated with grade IV tumours (P = 0.007). The results on protein expressions indicated that high‐grade tumours expressed less DVL1 protein as compared with low grade ones. A significant negative correlation was established between DVL1 expression and malignancy grades (P

Background Infantile free sialic acid storage disease (ISSD) is a severe multisystemic disorder characterized by the accumulation of free sialic acid in lysosomes. Case presentation The patient presented prenatally with fetal ascites and large scrotal hernias, without pleural or pericardial effusion. During the infantile period, he was diagnosed with permanent isolated immunoglobulin G (IgG) hypogammaglobulinemia, which thus far has rarely been associated with ISSD. The analysis of the SLC17A5 gene revealed a novel homozygous 94 bp gene deletion. We further provide a detailed description of pre- and postnatal clinical and radiographic findings. Conclusions Fetal ascites could be the first sign of several lysosomal storage diseases (LSDs), including ISSD. The analysis of LSD gene panels is an effective approach to diagnosis in the case of non-specific symptoms and when specific biochemical tests are not easily available.

The Aim of the study was to reveal if PET-CT analysis of primary and of secondary lung cancer could be related to the onset of lipid peroxidation in cancer and in surrounding non-malignant lung tissue. Methods: Nineteen patients with primary lung cancer and seventeen patients with pulmonary metastasis were involved in the study. Their lungs were analyzed by PET-CT scanning before radical surgical removal of the cancer. Specific immunohistochemistry for the major bioactive marker of lipid peroxidation, 4-hydroxynonenal (HNE), was done for the malignant and surrounding non-malignant lung tissue using genuine monoclonal antibody specific for the HNE-histidine adducts. Results: Both the intensity of the PET-CT analysis and the HNE-immunohistochemistry were in correlation with the size of the tumors analyzed, while primary lung carcinomas were larger than the metastatic tumors. The intensity of the HNE-immunohistochemistry in the surrounding lung tissue was more pronounced in the metastatic than in the primary tumors, but it was negatively correlated with the cancer volume determined by PET-CT. The appearance of HNE was more pronounced in non-malignant surrounding tissue than in cancer or stromal cells, both in case of primary and metastatic tumors. Conclusions: Both PET-CT and HNE-immunohistochemistry reflect the size of the malignant tissue. However, lipid peroxidation of non-malignant lung tissue in the vicinity of cancer is more pronounced in metastatic than in primary malignancies and might represent the mechanism of defense against cancer, as was recently revealed also in case of human liver cancer. Keywords: Lipid peroxidation (LPO), 4-hydroxynonenal (HNE), Positron emission tomography and computed tomography (PET-CT), Cell growth regulation, Inflammation, Immunohistochemistry

Eosinophilia is characterized by more than 0.5 × 109 eosinophils per liter in the full blood count. A wide range of conditions, from asthma to parasitic infections, autoimmune diseases, and certain forms of cancer, have been known to trigger abnormally high amount of eosinophils. It is essential to reach the correct diagnosis and treat the underlying disease aggresively. Definition of the eosinophilia-myalgia syndrome was offered in 1980s by Centers for Disease Control and Prevention for surveillance purposes, and criteria were revised in 2001, with high specificity. We report a case of 59-year old female who started a special weight-reducing diet regimen that included excessive cashew nut ingestion. Several months after she has presented with periferal blood eosinophilia and constitutional symptoms. Detailed work-up has not found elements for haematological, systemic autoimmune, neoplastic or infectious disease. She was diagnosed with eosinophilia-myalgia syndrome due to extreme L-tryptophan intake, a compound found in the cashew nut’s oil. She responded well to cashew nut withdrawal and steroid therapy. In the follow-up period she remained stable with normal eosinophil count and there was not a need for any specific therapy.

Otosclerosis is a complex disease characterized by an abnormal bone turnover of the otic capsule resulting in conductive hearing loss. Recent findings have shown that angiotensin II (Ang II), a major effector peptide of the renin–angiotensin system, plays an important role in the pathophysiology of otosclerosis, most likely by its proinflammatory effects on the bone cells. Because reactive oxygen species play a role both in inflammation and in the cellular signaling pathway of Ang II, the appearance of protein adducts of the “second messenger of free radicals,” the aldehyde 4-hydroxynonenal (HNE), in otosclerotic bone has been analyzed. Immunohistochemical analysis of HNE-modified proteins in tissue samples of the stapedial bones performed on 15 otosclerotic patients and 6 controls revealed regular HNE–protein adducts present in the subperiosteal parts of control bone specimens, whereas irregular areas of a pronounced HNE–protein adduct presence were found within stapedial bone in cases of otosclerosis. To study possible interference by HNE and Ang II in human bone cell proliferation, differentiation, and induction of apoptosis we used an in vitro model of osteoblast-like cells. HNE interacted with Ang II in a dose-dependent manner, both by forming HNE–Ang II adducts, as revealed by immunoblotting, and by modifying its effects on cultured cells. Namely, treatment with 0.1 nM Ang II and 2.5 μM HNE stimulated proliferation, whereas treatment with 10 μM HNE or in combination with Ang II (0.1, 0.5, and 1 nM) decreased cell proliferation. Moreover, 10 μM HNE alone and with Ang II (except if 1 nM Ang II was used) increased cellular differentiation and apoptosis. HNE at 5 μM did not affect differentiation nor significantly change apoptosis. On the other hand, when cells were treated with lower concentrations of HNE and Ang II we observed a decrease in cellular differentiation (combination of 1.0 or 2.5 μM HNE with 0.1 nM Ang II) and decrease in apoptosis (0.1 and 0.5 nM Ang II). Cellular necrosis was increased with 5 and 10 μM HNE if given alone or combined with Ang II, whereas 0.5 nM Ang II and combination of 1 μM HNE with Ang II (0.1 and 0.5 nM) reduced necrosis. These results indicate that HNE and Ang II might act mutually dependently in the regulation of bone cell growth and in the pathophysiology of otosclerosis.

Angiofibromas are rare tumors of the head and neck that mostly occur in the sphenopalatine region. We present a case of angiofibroma in a young male patient with an unusual and extremely rare localization, which to our knowledge has not been described before. It was situated in the tentorium and spread to the supratentorial and infratentorial regions. The patient initially presented with symptoms of increased intracranial pressure. After a diagnostic evaluation was done, the whole tumor was successfully removed using the supratentorial and infratentorial approach and the microsurgical technique.

Gliome središnjega živčanog sustava čine tumori glijalnog podrijetla niskog i visokoga gradusa. Liječe se multidisciplinarnim pristupom kirurški, radioterapijom i kemoterapijom. Vrsta i redoslijed liječenja ovise o osobitostima tumora i bolesnika. U tekstu koji slijedi nalaze se kliničke upute za dijagnostičke postupke, operativno liječenje, onkološko liječenje i praćenje bolesnika s ovom vrstom tumora u Republici Hrvatskoj. Smjernice su pisane u ime Hrvatskoga onkološkog društva Hrvatskoga liječničkog zbora. Cilj je smjernica postići izjednačenost liječenja gliomskih tumora u onkološkim centrima Republike Hrvatske., Gliomas of the central nervous system are glial cell tumors that are divided in low and high grade group. Multidisciplinary approach to treatment consists of surgery, radiotherapy and chemotherapy. The type and order of treatment depend on the characteristics of the tumor and the patient. We present the clinical guidelines for diagnostic procedures, surgical treatment, oncological treatment and follow up of patients with this type of tumor in the Republic of Croatia.

No abstract available

We report two siblings of Croatian consanguineous healthy parents with a novel homozygous missense mutation in the POMT1 gene, presenting with intellectual disability and psychotic, in particular hallucinatory symptoms and abnormal brain MRIs, preceding classical symptoms of limb-girdle muscular dystrophy by several years. Weakness became apparent in early adulthood and both siblings remained ambulant into the 3rd and 4th decade of life. The muscle biopsy showed reduced α-dystroglycan compatible with the POMT1 defect. This case report extends the phenotypic spectrum of POMT1 associated muscular dystrophies to the adult onset limb girdle muscular dystrophies with psycho-organic deficits.

A 69-year-old male was presented with a 2-month history of cognitive decline. The most profound deficit was observed in short-term verbal and visual memory and recognition. He was otherwise healthy, apart from atrial fibrillation diagnosed 5 months before. Brain MRI revealed T2 hyperintensities in the left thalamus, right pulvinar thalami, both putamina and right head of caudate nucleus without diffusion restriction on DWI sequences. CSF examination revealed elevated proteins. He was HIV negative. The course of the disease was complicated with gram negative sepsis and the patient died 14 days later. Autopsy revealed the brain lesions to have been caused by toxoplasmic encephalitis. Toxoplasmic encephalitis is an extremely rare cause of rapidly progressive dementia in immunocompetent patients. In patients with multiple lesions, hyperintense on T2 and hypointense on T1 weighted sequences, without diffusion restriction and some expansive effect, infectious causes should be considered, even in the absence of classical signs of infectious diseases and CSF pleocythosis.

Summary: The lack of control of tumour behaviour is manifested in different ways, depending primarily on the type of tumour. This results in numerous problems of tumour diagnosis and therapy. In the case of "benign" tumours, like pituitary adenomas, in vitro studies are often used for evaluation of the tumour. The use of tissue explant cultures of human pituitary adenomas and the comparison of the feature of cultured tumours with their behaviour in vivo showed that corticotropin is released not only from the tumours associated with Gushing^ disease, but also from clinically non-functioning tumours. Hence, it was supposed that the release of corticotropin in vivo from non-secreting tumours is probably under the influence of certain neuroendocrine and/or systemic humoral factors. To test this possibility, samples of 22 tumours were cultured in plain culture medium or in the presence of the "human plasma ultrafiltrate bioactive fraction" (tentatively termed as TBP) prepared by anion-exchang e chromatography. In the presence of TBP the release of corticotropin was strongly inhibited in adenomas showing relatively high spontaneous secreting activity in vitro (> 200 ng/1 in 24 hours), while immunohistochemistry of these tumours indicated accumulation of corticotropin inside the cells. In contrast, TBP stimulated corticotropin release from tumours that showed relatively low basic corticotropin release (< 200 ng/1 in 24 hours), with no obvious change in cellular corticotropin immunoreactivity. Such a dual activity of TBP was not observed for 8 samples of adenomas cultured in the presence of surrounding pituitary tissue, probably because TBP did not affect corticotropin secretion by the normal pituitary cells (as indicated by immunohistochemistry). From these results, it appears that TBP could be one of the humoral factors involved in the regulation of corticotropin release from pituitary adenoma tissue. Its possible involvement in the regulation of corticotropin release from normal pituitary tissue, however, is uncertain.

This paper describes a patient with demyelination changes occurring after treatment for primary CNS lymphoma, instead of, as usually, before treatment.

Acute disseminated encephalomyelitis (ADEM) is an acute, monophasic neurologic syndrome that occurs after vaccination against various viruses and after many viral infections and rarely occurs again in the same patient. Weston Hurst disease or acute hemorrhagic encephalomyelitis (AHE) is a hyperacute ADEM variant that shares many pathological similarities with ADEM. ADEM clinically and neuropathologically faithfully reflects the animal model of experimental allergic encephalomyelitis (EAE), and animal studies have provided us with new insights into pathogenesis of this disorder. Although there is much controversy whether ADEM is a separate disease or just one of possible manifestations of multiple sclerosis, there are clear histopathological characteristics that support ADEM as a separate disease This mini review will focus on pathological characteristics of ADEM emphasizing differences from other types of idiopathic demyelinating diseases.

Oxidative stress (OS) is the condition that occurs when the anti-oxidative capacity of tissues and cells is overcome. The oxidative damage of cells is caused by free radicals which are products of OS. Lipid peroxidation is an autocatalitic process caused by OS which damages lipids and causes production of highly reactive species such as 4-hyroxynonenal (HNE). Recent findings have shown an increase in HNE-immunopositivity when compared to grade of astrocytic tumors. The cancer stem cell hypothesis suggests that not all cells in the tumor have the same ability to proliferate and maintain the growth of the tumor. Only a relatively small fraction of cells in the tumor, termed cancer stem cells, posses the ability to proliferate and self-renew extensively and expresses the surface marker CD133 (prominin-1). CNS tissue damage via trauma, viruses and ishaemia, increases the amount of OS production, which damages endothelial cells and consequently results in excess production of bone marrow-derived endothelial progenitor cells (EPCs). EPCs are immunoreactive for CD133 and CD34 and are thus important in the process of angiogenesis. Results of our study confirmed the main hypothesis, i.e.the proportional expression and distribution of CD133 and HNE in tumor cells, mesenchymal stroma, blood vessels and in the areas of necrosis, probably due to permanent OS in tumors, whose products continue to damage the endothelial cells and cause an excess production of EPCs. Identification of coexpression HNE and CD133 in GBM has important implication for the understanding of propagation of tumors into higher grade.

Cilj: Rosai-Dorfman bolest (RDD) je idiopatska histiocitna proliferacijska bolest koja zahvaæa limfne èvorove. RDD se rijetko pojavljuje kao izolirana intrakranijska bolest, bez zahvaæenosti ostalih regija. U ovom èlanku prikazat æemo dva sluèaja RDD koja su se manifestirala kao izolirani intrakranijski procesi. Prikaz sluèaja: Prvi bolesnik je tridesetdevetogodišnji muškarac s dobro ogranièenom lezijom desnog temporalnog režnja, za koju se preoperativno smatralo da je meningeom. Histološkom i imunohistokemijskom analizom ustanovljeno je da se radi o RDD. Intracerebralna pojava ove bolesti ima benigan tijek. Drugi bolesnik je èetrdesetjednogodišnji muškarac koji se klinièki prezentirao vertiginoznim sindromom i blagom cerebelarnom ataksijom. Raèunalna tomografija prikazala je solitarnu leziju lokaliziranu desno cerebelarno. Imunohistopatološke karakteristike takoðer su ukazale na to da se radi o RDD. Rasprava i zakljuèak: U èlanku æemo prikazati znaèajke, diferencijalnu dijagnozu i terapiju intrakranijske lokalizacije RDD. Detaljna preoperativna priprema bolesnika je obavezna, a kad god je moguæe treba uèiniti i biopsiju. Neurokirurško lijeèenje ovog tumora nije uvijek nužno, no bitno je za postavljanje prave dijagnoze. Ishod bolesti i rizik od recidiva manji je kod kompletnog odstranjenja tumora. Recidiv tumora nije opažen prilikom kompletnog odstranjenja tumora, te u tim sluèajevima ne postoji potreba za daljnjom terapijom. S klinièkog stajališta, RDD se može smatrati važnim intracerebralnim tumorskim entitetom zato što može oponašati druge tumorske procese., Aim: Rosai-Dorfman Disease (RDD) is an idiopathic histiocytic proliferation affecting lymph nodes. Rosai-Dorfman disease rarely affects intracranial structures without involvement of other sites. In this paper we are presenting two cases of RDD with isolated intracranial involvement. Case report: The first patient is a 39-year-old male presenting with an isolated well-circumscribed brain mass in the right temporal lobe, preoperatively thought to be a meningioma. Histological and immunohistochemical analysis confirmed that the lesion was RDD. The intraparenchymal brain location of RDD appears to have a benign course. We also describe the case of 41-year-old man presenting with vertiginous symptoms and mild cerebellar ataxia who was diagnosed with a solitary lesion localised deep in the right cerebellar hemisphere. Immunohistological findings also revealed Rosai-Dorfman disease. Discussion and conclusion: In this paper we are presenting the clinical features, tumor characteristics, differential diagnosis and treatment options. Thorough preoperative evaluation is mandatory and biopsy should be done whenever possible. Surgical treatment of this type of tumour is not always necessary, however, it is essential for postulating the right diagnosis. When total tumor removal is achieved, the outcome is generally better. Recurrence was not observed in our cases where total surgical excision was performed and there was no need for additional therapy. From the clinical point of view RDD might be an important intracerebral entity because it might mimic other lesions, particularly other histiocytic disorders.,îÿÀ

Skeletal-extraskeletal angiomatosis is defined as a benign vascular proliferation affecting the medullar cavity of the bone and at least one other type of tissue, including skin, subcutaneous tissue, viscera, muscle, or synovium, and which does not spread to avascular tissue such as cartilage. Primary hemangiomas/cavernous hemangiomas (cavernomas) are exceedingly rare in the skull, accounting for 0.2% of all osseous neoplasms and are usually located in frontal and parietal bones. The authors present the case of a 66-year-old man who was admitted with right-side hemiparesis. MRI revealed a destructive bone lesion of the left frontal bone. Digital subtraction angiography of the brain did not reveal pathological vascularization, but a minor submucous hemangioma was seen in the nasal airway. Urine test for Bence-Jones proteins was positive for IgG λ light chain. Bone marrow aspiration and CSF analysis revealed no evidence of systemic myelomatosis suggesting a monoclonal gammopathy of undetermined significance. A highly vascular tumor was surgically removed. The histopathology verified cavernous hemangioma of the skull and the nasal submucous hemangioma. We discuss the diagnostic procedure, possible pathophysiological mechanisms and treatment implementation. It is possible that immunoglobulins from monoclonal gammopathies have an etiologic role in the development of the bone and skin changes in older patients, as an acquired condition, by producing a vascular injury that could lead to the multiple hemangiomas in skeletal-extraskeletal angiomatosis. To prevent misdiagnosis with lesions of other origins, multiple lesions of the head must be resected and histopathologically verified. In conclusion, to the best of our knowledge, this is the first case of giant cavernous hemangioma of the skull associated with paraproteinemia and skeletalextraskeletal angiomatosis limited to the head.

The aim of this study was to detect the antitumor properties of Croatian propolis in BALB/c male and female mice injected with 4T1 mammary carcinoma. Furthermore, the gender- dependence of this effect and the possible involvement of combined effect of propolis and 5-Fluorouracil (5FU) on dihydropyrimidine dehydrogenase (DPD) transcriptional and translational level, were determined. In combination with 5FU propolis treatment induced gender-related effects. The results of the study revealed that pretreatment of mice with propolis combined with 5FU treatment prolonged the suppressive effect of 5FU on tumor growth and reduced the number of metastasis only in male mice. Only males pretreated with propolis prior to 5FU administration had decreased DPD protein level indicating higher sensitivity to 5FU. Thus, benefitial effects of propolis in male tumor-bearing mice treated with 5FU might be explained by increased sensitivity to 5FU as the result of translationally downregulated DPD.

Oxidative stress and resulting lipid peroxidation is involved in various and numerous pathological states including inflammation, atherosclerosis, neurodegenerative diseases and cancer. This review is focused on recent advances concerning the formation, metabolism and reactivity towards macromolecules of lipid peroxidation breakdown products, some of which being considered as 'second messengers' of oxidative stress. This review relates also new advances regarding apoptosis induction, survival/proliferation processes and autophagy regulated by 4-hydroxynonenal, a major product of omega-6 fatty acid peroxidation, in relationship with detoxication mechanisms. The use of these lipid peroxidation products as oxidative stress/lipid peroxidation biomarkers is also addressed., Lipid peroxidation is highly associated with chronic degenerative diseases such as cancer. 4-hydroxy-2-nonenal is one of the major products of lipid peroxidation. 4-hydroxy-2-nonenal can interact with biomolecules, changing their conformation and activity. This study presents 4-hydroxy-2-nonenal-protein adducts formation in the first stages of Long-Evans Cinnamon rat hepatitis, a well recognized model for oxidative stress-associated hepatocarcinogenesis. 4-hydroxy-2-nonenal-protein adducts appeared in hepatocyte cytoplasm before the beginning of hepatitis and their presence was very strong during hepatitis, while a transient perinuclear expression of 4-hydroxy-2-nonenal-protein adducts was shown mainly at early hepatitis stages. 4-hydroxy-2-nonenal-protein adducts formation correlated to the expression of the tumour marker glutathione S-transferase P-form. These results show that lipid peroxidation modification of proteins might be implicated in the first stages of hepatocyte cancer initiation in Long-Evans Cinnamon rats.

We have with great interest read the paper by Ng and colleagues, recently published in the Journal of Clinical Neuroscience.1 Authors have reported a case of a young female patient who initially experienced an episode of neurological symptoms caused by histologically proven demyelinating lesion, and who after four years of remission developed primary central nervous system lymphoma (PCNSL). The conclusion was made that demyelinating lesions of the central nervous system (CNS) may precede development of PCNLS for more than four years.

Introduction: Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder, initially characterized by normal brain MRI. Case report: In a 34-year-old female patient with AT, magnetic resonance imaging (MRI) revealed extensive and diffuse white matter dismyelination, T1 and T2 hypointense lesions, T1 hypointense but T2 hyperintense lesions, and numerous dilated telangiectases upon gadolinium enhancement. Discussion: In our patient, brain MRI confirmed extensive extracerebellar lesions in AT. Conclusion: Our report broadens the spectrum of brain MRI abnormalities in AT and supports the hypothesis on cerebrovascular abnormalities occurring in later stages of AT.

In this report, the authors present a detailed immunological and virological assessment of an immunocompetent 17-year-old Caucasian male with a fatal Epstein-Barr virus (EBV) infectious mononucleosis presenting with meningoencephalitis and hemophagocytic syndrome. The patient with serologically confirmed EBV infectious mononucleosis was admitted to the hospital because of 3 weeks' fever. Fine-needle aspiration of lymph nodes showed reactive hyperplasia with prominent hemophagocytosis. Percentages of intracellular interferon-gamma (IFN-gamma) in CD4(+) and CD8(+) T cells in the peripheral blood progressively increased during the course of disease (10.2% and 8.5% on day 35 ; 30.1% and 53.2% on day 44 ; 42.2% and 75.2% on day 50 ; 36.1% and 50.6% on day 59, respectively). On day 50, the patient developed meningoencephalitis. Brain computed tomography (CT) was normal. Brain magnetic resonance imaging (MRI) showed multifocal inflammatory lesions in frontal and temporal cortex of the right hemisphere as well as severe perivascular inflammatory reaction. The patient was treated with steroids, cyclosporin A, and methotrexate intratecally. Following treatment, EBV viremia in the blood and cerebrospinal fluid (CSF) decreased from pretreatment values (54, 490 copies of EBV DNA/ml and 39, 500 copies/ml, respectively) to 8715 copies/ml in the blood and 14, 690 in the CSF. Despite treatment, the patient remained unconscious and died of sepsis and pneumonia 3 months after initial symptoms. Immunohistochemical staining showed the presence of EBV in both perivascular infiltrates and grey matter. Enhanced Th1 response as shown by high levels of IFN-gamma in peripheral blood lymphocytes may be a predictor of severe complications during acute EBV infection. Early implementation of immunosuppressive therapy in these patients should be considered.

We present a 68-year-old woman who presented with symptoms of frontotemporal dementia. Brain MRI revealed tumor mass in both thalami and according to WHO classification, the tumor corresponded to diffuse fibrillary astrocytoma grade II. This case points to the role of neuroimaging in patients presenting with classical symptoms of dementia.

The objective of this study was to characterise porcine circovirus type 2 (PCV2) from pigs with naturally occurring postweaning multisystemic wasting syndrome (PMWS) in Croatia, and to determine the epizootiological, clinical and pathomorphological features of the disease. During a systematic health monitoring programme conducted in the period from January 2002 to June 2003, PMWS was suspected on eight different pig-producing farms in Croatia. The diagnosis of PMWS met all three key criteria: the presence of compatible clinical signs, the presence of the characteristic microscopic lymphoid lesions, and the detection of PCV2 within the lesions by polymerase chain reaction (PCR) and by in situ hybridisation (ISH). Moreover, PCV2 DNA from swine tissues was extracted and sequenced. The phylogenetic analysis of 4 Croatian PCV2 strains showed close relationship to PCV2 strains isolated in Slovenia, France, the Netherlands, the United Kingdom, China and Hungary. PCV2 was also demonstrated by electron microscopy in the lymph node of an affected animal. This is the first demonstration of PMWS in Croatia based on all scientifically accepted diagnostic criteria.

Oxidative stress, excessive production of reactive oxygen species, is considered an important part of different disorders, as well as of physiological processes (inflammation). The difference between physiological and pathological oxidative stress is often the occurrence of lipid peroxidation and its final toxic products, among which is 4-hydroxy-2-nonenal (HNE), a reactive aldehyde that forms protein conjugates. The aim of this study was to determine the distribution of HNE-histidine conjugates in leukocytes during systemic inflammation. We used genuine monoclonal antibodies against HNE-histidine conjugates for immuno-cytochemical, immuno- histochemical and immuno-electronmicroscopical analyses of HNE in inflammatory cells. Spleen tissue, leukocytes from blood and macrophages from the peritoneum of rats intraperitoneally (i.p.) injected with micronized zeolite (MZ) were analyzed. HNE-histidine conjugates were predominantly detected near cell membranes, phagosomes and macrophage granules. Immunodetection of HNE-histidine conjugates may be used as an analytical immunochemical method to study HNE formation in pathological and physiological processes and for pathomorphological diagnostic procedures., Oksidacijski stres, stanje prekomjernoga stvaranja reaktivnih kisikovih tvari, bitna je sastavnica različitih bolesti, ali i fizioloških procesa (upala). Često je razlika između fiziološkoga i patološkoga oksidacijskoga stresa pojava lipidne peroksidacije i njenih završnih toksičnih produkata, među kojima posebnu ulogu ima 4-hidroksi- 2-nonenal (HNE), reaktivni aldehid koji tvori konjugate s bjelančevinama. Cilj ovoga istraživanja bio je utvrditi distribuciju HNE-histidinskih konjugata u leukocitima tijekom nespecifične upalne reakcije. Rabili smo izvorna monoklonalna protutijela na HNE-histidinski konjugat, za imuno-citokemijsko, histokemijsko i elektronskomikroskopsko dokazivanje HNE-a u upalnim stanicama. Analizirano je tkivo slezene, leukociti iz krvi te makrofazi štakora kojima je intraperitonealno injiciran mikronizirani zeolit (MZ). HNE-histidinski konjugati pretežito su uočeni uz stanične membrane te pored fagosoma i makrofagnih granula. Imunodetekcija HNE-histidinskih konjugata mogla bi se stoga rabiti kao analitička imunokemijska metoda za istraživanja fizioloških i patoloških procesa te u patomorfološkim dijagnostičkim postupcima.

Advanced glycation endproducts (AGE) accumulate over proteins as a consequence of diabetic hyperglycemia, and thus contribute to the pathogenesis of diabetic complications. To improve the understanding of the pathology of diabetic neuropathy, AGE accumulation was analyzed in sural and/or femoral nerves obtained under spinal anesthesia from 8 type 2 diabetic patients with both distal symmetrical polyneuropathy and proximal neuropathy. Pronounced AGE immunoreactivity was detected on axons and myelin sheaths in 90% of diabetic peripheral nerves but not in the control specimen. The intensity of axonal AGE immunopositivity significantly correlated with the severity of morphological alterations (p0.005). AGE localization, demonstrated by immunohistochemical methods, was also present in the endoneurium, perineurium and microvessels. Morphometric analysis of the diabetic peripheral nerve showed perineurial thickening (diabetic vs. control, 15.5+/-4.9 vs. 6.6+/-2.1 microm, p0.001), narrowing of the microvessel lumina (66.6+/-50.5 vs. 579.5+/-38.4 x10(3) microm(2), p0.001) and significant reduction in the number of preserved axons (3.6+/-3 vs. 8.9+/-2.3 per 10(5) microm(2) per area, p0.037). The sera of diabetic patients contained epitope(s) of AGE structure and soluble immune complexes containing AGE moiety. In conclusion, to the best of our knowledge, this is the first study providing evidence for excessive AGE formation on peripheral nerve components, primarily axons, and a significantly higher level of circulating AGE-immune complexes in patients with both distal diabetic polyneuropathy and proximal neuropathy. Humoral immune mechanisms, including the production of anti-AGE autoantibody, may potentially be involved in the development of structural abnormalities described in this report.

We described before that the chromatographically purified "human plasma ultrafiltrate bioactive fraction" (humoral factor tentatively denoted as tumor basic protein--TBP) regulates in vitro release of ACTH from pituitary adenomas stimulating the hormone release from the tumors showing low hormonal activity in vitro and inhibiting ACTH production in vitro by highly hormonally active pituitary tumors. In this study we describe growth promoting effects (determined by 3H-TdR incorporation assay) of TBP (5 microg/l, i.e. 10% w/v plasma equivalent concentration) for 10 non-functioning pituitary tumors. The effects of TBP appeared to negatively correlate with the in vitro growth abilities of the tumors that were otherwise dependent on the duration of the clinical symptoms of the tumor presence. Hence, similar to its effects on hormonal activity of the pituitary tumors, TBP stimulated the growth of the tumors which did not express high spontaneous 3H-TdR intensity, but did not stimulate the cells with high capacity of spontaneous 3H-TdR incorporation. Moreover, all the tumors that were stimulated by TBP were nononcocytic adenomas while oncocytoma cells were not stimulated at all. Thus, TBP shows activity of humoral (plasma) factor involved in the growth regulation of pituitary adenomas that might be used to define the growth abilities of these tumors, especially in case of null cell adenomas and oncocytomas as were the tumors used in this study.