Apremilast effectively inhibits TNFα-induced vascular inflammation in human endothelial cells.

BACKGROUND: Patients with chronic inflammatory diseases (e.g. psoriasis and rheumatoid arthritis) are at increased risk for the development of atherosclerosis and cardiovascular diseases (CVD). Previous studies have suggested that phosphodiesterase 4 (PDE4) inhibitors possess anti-inflammatory properties. OBJECTIVES: Here we examined the effect of the PDE4 inhibitor apremilast, a well-established anti-psoriatic drug, on pro-inflammatory responses in TNFα-activated endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVEC) were treated with tumour necrosis factor-α (TNFα) in the presence or absence of apremilast. Expression levels of pro-inflammatory cytokines, chemokines and adhesion molecules were assessed by ELISA, western blot and RT-PCR. Effects of apremilast on adhesion and transendothelial migration (TEM) of THP-1 monocytic cells were analysed in transwell assays. RESULTS: Apremilast suppressed TNFα-induced expression and secretion of important endothelial and monocytic pro-inflammatory factors, including granulocyte-macrophage colony-stimulating factor (GM-CSF), C-X-C motif chemokine ligand 10 (CXCL10), chemokine (C-C motif) ligand 2 (CCL2), vascular cell adhesion molecule 1 (VCAM-1), E-selectin and matrix metalloproteinase-9 (MMP9). Functionally, apremilast reduced adhesion of THP-1 cells to activated HUVECs and TEM in response to TNFα. Mechanistically, apremilast suppressed activation of nuclear factor κB (NFκB) and mitogen-activated protein kinases (MAPK) signalling in activated HUVECs. Furthermore, inhibition of p38, C-Jun-N-terminale Kinase (JNK) and NFκB in activated HUVECs decreased expression of GM-CSF, VCAM-1 and E-selectin. Additionally, apremilast decreased IL-17A-induced secretion of IL-6 and CCL2. CONCLUSIONS: We demonstrate that apremilast has distinct anti-inflammatory effects in activated HUVECs, indicating that apremilast could have the therapeutic potential to prevent higher risk for CVD in patients with chronic inflammatory diseases.

G protein-coupled receptor 40 expression in human melanoma - correlation with tumour thickness, AJCC stage and survival.

BACKGROUND: In melanoma, preclinical data suggest a possible role of polyunsaturated fatty acids inhibiting cell growth. A new target molecule for free fatty acids, the G protein-coupled receptor GPR40, was identified in melanoma cells. OBJECTIVES: The aim of this study was to investigate GPR40 expression in human melanocytic tissues and to evaluate its potential as a prognostic marker. METHODS AND RESULTS: A total of 114 tissue sections of naevi, primary melanoma and melanoma metastasis were immunohistochemically stained with anti-GPR40. The staining was evaluated, using the immunoreactivity scoring system. Compared to naevi, primary melanoma and melanoma metastasis showed significantly higher levels of GPR40 (P < 0.05). In primary melanoma, GPR40 expression positively correlated with tumour thickness (P = 0.044) and AJCC level (P = 0.017) and in melanoma metastasis with AJCC level (P = 0.035). Primary melanoma patients with high levels of GPR40 had a significantly poorer overall survival (P = 0.004) and shorter disease-free survival (0.040). CONCLUSION: The present study identified GPR40 as a novel target molecule in melanoma. First evidence for a potential role of the receptor in tumour progression and metastases was found, and it could be demonstrated that GPR40 expression is negatively correlated with patient's survival.

Spontaneous pregnancy during ulipristal acetate treatment of giant uterine leiomyoma.

WHAT IS KNOWN AND OBJECTIVE: Ulipristal acetate, a progesterone receptor modulator, pharmacologically inhibits endometrial proliferation and thereby prevents pregnancy. It is primarily used as emergency contraception, but also for the treatment of fibroids in women of reproductive age. There have been no published cases of pregnancy, while on therapy with ulipristal acetate. CASE DESCRIPTION: In this article, we present a case report of spontaneous pregnancy during ulipristal acetate therapy. WHAT IS NEW AND CONCLUSION: To our knowledge, this is the first patient with spontaneous conception, while on ulipristal acetate treatment. There were no drug-related complications, and the pregnancy resulted in the delivery of a healthy baby.

Consumption of rapeseed honey leads to higher serum fructose levels compared with analogue glucose/fructose solutions.

BACKGROUND: Studies suggest that honey has less influence on serum glucose concentrations than monosaccharides and disaccharides. Previous studies, however, have only analysed glucose metabolism. METHODS: This study investigated the influence of two types of honey (rapeseed and acacia) on the serum levels of glucose, fructose, insulin and C-peptide values in healthy subjects. The results were compared with honey-comparable glucose-fructose solutions. All solutions contained 75 g of glucose and/or fructose. RESULTS: We found significantly higher fructose serum levels with rapeseed honey after 2 h but no such differences for acacia honey. C-peptide levels were significantly higher after administration of both honeys after 1 and 2 h. CONCLUSIONS: For the first time it has been found out that honey ingestion leads to a rise of blood fructose concentration: in one case, this rise was lower than that achieved after fructose/glucose controls, in the other cases it was same as after the controls. Fructose metabolism may be inhibited by unidentified substances present in the rapeseed honey. Further study to elucidate underlying mechanisms may be worthwhile, as usually there is no differentiation between the different types of honey.

Human leucocyte antigen class I and class II antigen expression in malignant fibrous histiocytoma, fibrosarcoma and dermatofibrosarcoma protuberans is significantly downregulated.

BACKGROUND: Abnormalities in the expression of human leucocyte antigens (HLA) by tumour cells impair cellular immune responses promoting immune evasion and tumour survival. To date, studies analysing HLA class I and class II expression levels in malignant fibrous histiocytomas, fibrosarcomas and dermatofibrosarcoma protuberans are limited. AIMS: Therefore, we investigated the in vivo expression profile of HLA class I and class II antigens in 99 malignant fibrous histiocytomas, 20 fibrosarcomas and 34 dermatofibrosarcoma protuberans from different anatomical sites. MATERIAL AND METHODS: Immunohistochemistry using monoclonal antibodies to HLA class I and class II antigens was used to define the expression levels of these antigens on respective tumour samples. RESULTS: Frequent loss or downregulation of HLA class I and class II expression in malignant fibrous tumours was observed for the different types of tumours examined. DISCUSSION: The data presented suggest for the first time a high frequency of HLA class I and class II abnormalities in malignant fibrous histiocytomas, fibrosarcomas and dermatofibrosarcoma protuberans in vivo. CONCLUSION: This information might be useful in the practical and clinical design of tumour vaccination strategies.

Prenatal ultrasound assessment and fetal heart monitoring: analysis of dizygotic twins discordant for body stalk anomaly in the third trimester of pregnancy.

We describe a case of dizygotic twin pregnancy which was referred to our centre because of a discordant anomaly of one of the twins. The ultrasound examination revealed a large extra-abdominal mass (liver and bowel) with micromelia, severe kyphoscoliosis and a short umbilical cord of the second dizygotic discordant twin. These ultrasound findings were diagnosed as body stalk anomaly. Body stalk anomaly in twins is extremely rare. This is, to our knowledge, one of the few documented cases reported on dizygotic twins discordant for this anomaly. This finding, in association with a decrease of amniotic fluid volume, may be attributed to early amniotic membrane rupture as the primary event in the pathogenesis of body stalk anomaly.

Diffuse eosinophilic gastroenteropathy with pleural effusion and ascites.

We are reporting a case of a 39-year-old woman with a picture of constipation, who came to our department. Anamnesticly she claimed on constipation and flatulence for 6 days, and on slight cough for last two days, but no other symptoms. After complete diagnostic treatment we found a pleural effusion in right lung and ascites in a bowel. Cytologicly, we didn't find malignant cells in pleural effusion nor in ascites, but there was an amount of eosinophilic granulocytes in a gastric wall and a solid tumour mass near mesentery of a gut. We also found a lot of eosinophilic cells in a solid tumour mass. Other organs had no pathology. This finding indicated for eosinophilic gastroenteritis.

[Fatal amnioinfusion with previous choriocarcinoma in a parturient woman]. / Patientin mit fataler Fruchtwasserembolie unter der Geburt bei einem überstandenen Chorionkarzinom.

The case of 36-year-old tercipare is described who developed choriocharcinoma in a previous pregnancy. During the first term labour the patient developed cardiac arrest, so reanimation and sectio cesarea was performed. A male new-born was delivered in good condition, but even after intensive therapy and reanimation occurred death of parturient woman with picture of disseminate intravascular coagulopathia (DIK). On autopsy and on histology there was no sign of malignant disease, so it was not possible to connect previous choricarcinoma with amniotic fluid embolism. Maybe was place of choriocarcinoma "locus minoris resistentiae" which later resulted with failure in placentation what was hard to prove. On autopsy we found embolia of lung with a microthrombosis of terminal circulation with punctiformis bleeding in mucous, what stands for DIK.

[Differential diagnosis of urinary retention: aneurysm of the iliac artery]. / Aneurysma der A. iliaca als Differenzialdiagnose des Harnverhalts.

A 69-year old male presented with anuric acute renal failure. Abdominal ultrasound at admission revealed a mass in the pelvis thought to be the urinary bladder and the diagnosis of urinary retention was made. When placement of an urinary catheter did not induce urine flow, digital rectal examination was done. Palpation of a pulsating mass finally led to the diagnosis of aneurysm of the iliac artery. Based on this case, the general problem of diagnosing an iliac artery aneurysm is discussed.

[Molecular mechanisms in apoptosis]. / Molekularni mehanizmi kod apoptoze.

Apoptosis is evolutionary conserved form of cell suicide. Tumor necrosis factor-alpha (TNF-alpha) or Fas Ligand activated apoptosis by binding of the plasma membrane receptor. The activation of TNF Receptor 1 or Fas-Ligand Receptor lead to activate of caspase 8. The activation of the caspase-8 lead to activate the cell-death machinery cascade. The inhibitor of cell death machinery is Bcl-2 also fails to prevent Bax-induced cytochrome c release, activation of caspase-3, membrane blebbing, nuclear fragmentation, and cell death. Bcl-2 is important cell live-death regulator. Cleavage of specific protein subsets is a key event in the execution of apoptosis. Protein degradation may serve for the structural alterations in the process of cell self-destruction, but it may also function as a switch in the decisions between apoptosis and necrosis or apoptosis and cell proliferation.

[Results of in vitro fertilization therapy methods in Germany in 1996--the German In Vitro Fertilization Registry]. / Rezultati lijecenja IVF-metodama u Njemackoj za 1996. godinu--Njemacki IVF-registar (DIR).

We believe that on the IVF subject, which is nowadays applied exept a standard method in the world. In the next years we could expect further improvement in our success++. It is also to anticipate that next changes in the development of assistance-reproduction will be: 1. Freezing of ovums, 2. To get in vitro-meture of the immature cells, 3. Transplantation of ovarium tissue, 4. Transfer of the blastocyst, 5. Transfer of cytoplasma or the cell nucleus. We recommend that the IVF/ICSI--therapy and birth of children has to be registrated in one central register.

[Oral drug therapy options in the treatment of erectile dysfunction]. / Oralne farmakoloske terapijske opcije u lijecenju erektilne disfunkcije.

The erectile disfunction (ED) represent a disease where diagnostic and therapy are maial standardized. However in the pharmacological there exists a lot of administer justice and legal-insurent problems because there are to few registered medicines. In respect towards the new revolutionary development in the therapy of erectile disfunction, the injectionary therapy of the corpus cavernous loses it is permanent place. Without questions the modilities of the new oral therapy with sildenafil will replace many patients using the "injectionary therapy", concerving psychogenic, neurogenic and soft disturbance into bloodvint during the erection. Simply, it must be said, that there are no further results in the oral therapy, because of the short time research regarding sildenofil. Therefore it is not know what kind of side effects would resulting inffens of sildenafil. After taking one tablet the effects could be expected after half on hour. According to literature recent success with the new therapy in about 90%.