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1.
J Physiol Pharmacol ; 74(1)2023 02.
Article in English | MEDLINE | ID: mdl-37245231

ABSTRACT

The potential of plant bioactives for the prevention and therapy of diabetes is increasingly being recognized. In the present study we investigated the antidiabetic properties of an aqueous Bistorta officinalis Delarbre extract (BODE) by employing both in-vitro assays and in-vivo models. Multiple targets in glucose homeostasis which are involved in the regulation of the blood glucose level were affected by BODE in-vitro. The extract exhibited inhibitory activities towards the intestinal carbohydrate-hydrolysing enzymes α-amylase and α-glucosidase with IC50 values of 81.5 µg/mL and 8.4 µg/mL, respectively. Furthermore, moderate reduction of the dipeptidyl peptidase-4 (DPP4) enzyme activity was evident when tested in the presence of 1.0 mg/mL BODE. A significant inhibition of the intestinal glucose transporter sodium-dependent glucose transporter 1 (SGLT1) in response to 1.0 mg/mL BODE was shown for Caco-2 cells mounted in Ussing chambers. High performance liquid chromatography-mass spectrometry analyses of the BODE revealed several plant bioactives including gallotannins, catechins and chlorogenic acid. Although our in-vitro data were promising, BODE-supplementation in the model organism Drosophila melanogaster lacked to confirm the antidiabetic effect of the extract in-vivo. Moreover, BODE failed to reduce blood glucose levels in chicken embryos (in-ovo). Hence, BODE is probably not a suitable candidate for developing a pharmaceutical against diabetes mellitus.


Subject(s)
Diabetes Mellitus , Hypoglycemic Agents , Chick Embryo , Humans , Animals , Female , Hypoglycemic Agents/pharmacology , Drosophila melanogaster , Blood Glucose , Caco-2 Cells , Chickens , Plant Extracts/pharmacology , Plant Extracts/chemistry
2.
Neurosci Biobehav Rev ; 108: 459-471, 2020 01.
Article in English | MEDLINE | ID: mdl-31790709

ABSTRACT

Magnetic resonance imaging (MRI) studies have identified neural structures implicated in the pathophysiology of mood disorders, especially bipolar disorder (BD) and major depressive disorder (MDD). However, the role of genetic and environmental influences on such brain deficits is still unclear. In this context, the present review summarizes the current evidence from structural MRI and Diffusion Tensor Imaging (DTI) studies on twin samples concordant or discordant for BD or MDD, with the aim of clarifying the role of genetic and environmental risk factors on brain alterations. Although the results showed a complex interplay between gene and environment in affective disorders, the evidence seem to underline that both genetic and environmental risk factors have an impact on brain areas and vulnerability to MDD and BD. However, the precise mechanism of action and the interaction between these factors still needs to be unveiled. Therefore, future larger studies on concordant or discordant twins should be encouraged, because this population provides a unique opportunity to probe separately genetic and environmental markers of disease vulnerability.


Subject(s)
Bipolar Disorder/diagnostic imaging , Brain/diagnostic imaging , Depressive Disorder, Major/diagnostic imaging , Diseases in Twins , Gene-Environment Interaction , Magnetic Resonance Imaging , Bipolar Disorder/genetics , Depressive Disorder, Major/genetics , Humans
3.
Mitochondrion ; 24: 122-8, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26277734

ABSTRACT

Mitochondrial dysfunction is assumed to be an important contributor to multi organ dysfunction syndrome. Here, the effects of varying degrees of sepsis on hepatic mitochondrial function were investigated. Moderate or more severe sepsis was induced in rats using a colon ascendens stent peritonitis (CASP)-model (16 G and 14 G stent respectively). Respiratory control ratio (RCR) was significantly higher in the 16 G-group and unchanged in the 14 G-group compared with healthy controls. The ADP/O ratio was similar in all groups. Our results indicate that different severities of sepsis differently influence the mitochondrial function, which could be a sign of adaptive reaction.


Subject(s)
Coinfection/complications , Coinfection/pathology , Liver/pathology , Mitochondria/pathology , Sepsis/complications , Sepsis/pathology , Animals , Cell Respiration , Disease Models, Animal , Male , Peritonitis/complications , Peritonitis/pathology , Rats, Wistar
4.
Eur J Obstet Gynecol Reprod Biol ; 194: 38-42, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26319654

ABSTRACT

OBJECTIVES: Is the saliva test, Geratherm ovu control, as accurate as the established urinary luteinizing hormone (LH) test for detecting ovulation and the following the fertile period? STUDY DESIGN: The voluntary participants were 74 healthy women with regular menstrual cycles and not using any hormonal contraceptives. The women used Geratherm ovu control, a small plastic hand-held microscope, for detecting the fertile period. A drop of saliva from sublingual was put onto the lens of the microscope. Three results were possible: non-fertile (dot pattern), transitional and fertile (ferning pattern). The participants performed the saliva test from the 5th till the 22nd day of the menstrual cycle and noted the respective result in a table. In addition to Geratherm ovu control, the EXACTO test for determining urinary LH concentration and the time of peak fertility was also performed. RESULTS: Positive LH shows a sharp increase beginning on the 10th cycle day with a maximum on the 17th cycle day. The curve for positive saliva and questionable positive saliva (one curve) is almost parallel with the curve for positive LH, reaching a maximum on the 16th cycle day. There is a high level of conformity for the same test results from the 5th (100%) till the 14th (84%) cycle day and from the 18th (80%) till the 22nd (96%) cycle day which corresponds to the pre- and post-ovulatory period. CONCLUSION: The saliva and the LH test both detect the fertile window of a menstrual cycle. Caused by the different hormones (estrogen for the saliva and LH for the LH test) leading to the respective positive test results, saliva turns positive 24h before LH. Consequently, the saliva test can be used as an ovulation test and help women maximize their chances of conceiving. There is also a high congruence between LH and saliva in the pre- and post-ovulatory period, indicating that the saliva test can also be used for contraception purposes.


Subject(s)
Estrogens/analysis , Fertility , Menstrual Cycle , Saliva/chemistry , Adult , Female , Humans , Luteinizing Hormone/urine
5.
Chem Commun (Camb) ; 50(24): 3208-10, 2014 Mar 25.
Article in English | MEDLINE | ID: mdl-24522659

ABSTRACT

A sodiated Nafion-coating on a porous polypropylene backbone was used as a cation selective separator for room temperature sodium-sulfur batteries. The capacity of the cells after 20 cycles could be enhanced by 75% to 350 mA h g(sulfur)(-1) using the new separator.

6.
Br J Anaesth ; 113(3): 433-42, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24390551

ABSTRACT

BACKGROUND: Therapeutic hypothermia, used primarily for protective effects after hypoxia, improves oral and gastric mucosal microvascular oxygenation (µHbO2) during additional haemorrhage. Therefore, we questioned whether hypothermia likewise improves µHbO2 during hypoxic challenges. Since both hypothermia and hypoxia reduce cardiac output (e.g. by myofilament Ca(2+) desensitization), and modulate vasomotor tone via K(+) ATP channels, we hypothesized that the Ca(2+) sensitizer levosimendan and K(+) ATP channel blocker glibenclamide would support the cardiovascular system. METHODS: The effects of mild hypothermia (34°C) on µHbO2 during hypoxia [Formula: see text] were analysed in a cross-over study on five anaesthetized dogs and compared with normothermia (37.5°C) and hypoxia. During hypothermia, but before hypoxia, glibenclamide (0.2 mg kg(-1)) or levosimendan (20 µg kg(-1)+0.25 µg kg(-1) min(-1)) was administered. Systemic haemodynamic variables, gastric and oral mucosal microvascular oxygenation (reflectance spectrophotometry), and perfusion (laser Doppler flowmetry) were recorded continuously. Data are presented as mean (sem), P<0.05. RESULTS: Hypoxia during normothermia reduced gastric µHbO2 by 27 (3)% and oral µHbO2 by 28 (3)% (absolute change). During hypothermia, this reduction was attenuated to 16 (3)% and 13 (1)% (absolute change). This effect was independent of microvascular flow that did not change during hypoxia and hypothermia. Additional administration of levosimendan during hypothermia restored reduced cardiac output but did not change flow or µHbO2 compared with hypothermia alone. Glibenclamide did not exert any additional effects during hypothermia. CONCLUSIONS: Hypothermia attenuates the decrease in µHbO2 during additional hypoxic challenges independent of systemic or regional flow changes. A reduction in cardiac output during hypothermia is prevented by Ca(2+) sensitization with levosimendan but not by K(+) ATP channel blockade with glibenclamide.


Subject(s)
Gastric Mucosa/blood supply , Hypothermia, Induced/methods , Hypoxia/metabolism , Mouth Mucosa/blood supply , Oxygen/metabolism , Animals , Cardiac Output/drug effects , Cardiotonic Agents/pharmacology , Cross-Over Studies , Disease Models, Animal , Dogs , Female , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , Glyburide/pharmacology , Hydrazones/pharmacology , Hypoglycemic Agents/pharmacology , Hypoxia/drug therapy , Laser-Doppler Flowmetry/methods , Microcirculation/drug effects , Mouth Mucosa/drug effects , Mouth Mucosa/metabolism , Pyridazines/pharmacology , Simendan
7.
Br J Anaesth ; 109(6): 887-96, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22945969

ABSTRACT

BACKGROUND: Intraoperative hypotension is associated with increased risk of perioperative complications. The N-methyl-d-aspartate (NMDA) receptor (NMDA-R) antagonist xenon (Xe) induces general anaesthesia without impairment of cardiac output and vascular resistance. Mechanisms involved in cardiovascular stability have not been identified. METHODS: Muscle sympathetic activity (MSA) (microneurography), sympathetic baroreflex gain, norepinephrine (NE) plasma concentration (high-performance liquid chromatography), anaesthetic depth (Narcotrend(®) EEG monitoring), and vital parameters were analysed in vivo during Xe mono-anaesthesia in human volunteers (n=8). In vitro, NE transporter (NET) expressing HEK293 cells and SH-SY5Y neuroblastoma cells were pre-treated with ketamine, MK-801, NMDA/glycine, or vehicle. Subsequently, cells were incubated with or without Xe (65%). NE uptake was measured by using a fluorescent NET substrate (n=4) or [(3)H]NE (n=6). RESULTS: In vivo, Xe anaesthesia increased mean (standard deviation) arterial pressure from 93 (4) to 107 (6) mm Hg and NE plasma concentration from 156 (55) to 292 (106) pg ml(-1), P<0.01. MSA and baroreflex gain were unaltered. In vitro, ketamine decreased NET activity (P<0.01) in NET-expressing HEK293 cells, while Xe, MK-801, and NMDA/glycine did not. Xe reduced uptake in SH-SY5Y cells expressing NET and NMDA-Rs (P<0.01). MK-801 (P<0.01) and ketamine (P<0.01) also reduced NET activity, but NMDA/glycine blocked the effect of Xe on [(3)H]NE uptake. CONCLUSIONS: In vivo, Xe anaesthesia does not alter sympathetic activity and baroreflex gain, despite increased mean arterial pressure. In vitro, Xe decreases the uptake of NE in neuronal cells by the inhibition of NET. This inhibition might be related to NMDA-R antagonism and explain increased NE concentrations at the synaptic cleft and in plasma, contributing to cardiovascular stability during Xe anaesthesia.


Subject(s)
Anesthetics, Inhalation/pharmacology , Blood Pressure/drug effects , Muscle, Skeletal/drug effects , Norepinephrine Plasma Membrane Transport Proteins/drug effects , Sympathetic Nervous System/drug effects , Xenon/pharmacology , Adult , Anesthetics, Inhalation/blood , Baroreflex/drug effects , Blood Gas Analysis/methods , Chromatography, High Pressure Liquid/methods , Electroencephalography/methods , Female , Humans , Male , Norepinephrine/blood , Norepinephrine Plasma Membrane Transport Proteins/blood , Xenon/blood
8.
Curr Cancer Drug Targets ; 12(4): 303-15, 2012 May.
Article in English | MEDLINE | ID: mdl-22385510

ABSTRACT

Angiogenesis is a key factor in the carcinogenesis process. In oncological practice, angiogenesis inhibition, mainly through the blockade of the VEGF family and its receptors, has been robustly demonstrated to produce clinical benefits and, in specific disease subsets such as colorectal cancer, to extend the overall survival of treated patients. VEGF is a multifunctional growth factor that mediates its functions through cognate receptors on endothelial cells and it has been discovered for its capability to induce macromolecule hyperpermeability in veins and venules. Several approaches have been taken to target angiogenesis in cancer: drugs that target one or more soluble ligands of the VEGF family, drugs that selectively inhibit one or more receptors of the VEGF receptor family, and drugs that inhibit VEGF receptor(s) among other, non VEGF-related targets. At present, two compounds have shown significant clinical activity, bevacizumab, Avastin® and aflibercept, Zaltrap®, and only one of these (bevacizumab) has so far been registered for use in clinical practice. In the present review, we explore and summarize the main features of the angiogenetic process, concerning in particular a common and potentially lethal disease as colorectal cancer. We overview the molecular pathways that characterize angiogenesis, focusing on VEGF family, the current applications and limitations of its blockade in oncology, and the hypothetical future perspectives of anti-angiogenic therapy.


Subject(s)
Adenomatous Polyposis Coli/drug therapy , Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/drug therapy , Adenomatous Polyposis Coli/genetics , Animals , Antibodies, Monoclonal, Humanized/therapeutic use , Bevacizumab , Biomarkers, Tumor/analysis , Colorectal Neoplasms/genetics , Female , Humans , Male , Mice , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/physiopathology , Treatment Outcome , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/physiology
9.
J Clin Neurosci ; 18(2): 197-202, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21163654

ABSTRACT

The Quality of Life after Brain Injury (QOLIBRI) is a new international instrument for assessing quality of life after traumatic brain injury (TBI). We report first use and validation. Patients previously admitted with TBI to the Royal Melbourne Hospital, Melbourne, Australia, were randomly sampled (n=66, 61% response rate) and administered the QOLIBRI. Fifty-five re-completed it at 2-week follow-up. QOLIBRI scales (with two exceptions) met standard criteria for internal consistency, homogeneity and test-re-test reliability. Correlations with the Assessment of Quality of Life, Short Form-36 version 2 and the Satisfaction with Life Scale were moderate. The QOLIBRI was sensitive to the Glasgow Outcome Scale - Extended scores, Hospital Anxiety and Depression scale, and measures of social isolation (Friendship Scale). There was evidence that further refinement may improve the QOLIBRI. The QOLIBRI should be considered as an outcome measure by clinicians and researchers conducting treatment trials, rehabilitation studies or epidemiological surveys into the treatment or sequelae of trauma.


Subject(s)
Brain Injuries/psychology , Health Surveys/methods , Health Surveys/standards , Quality of Life/psychology , Sickness Impact Profile , Surveys and Questionnaires/standards , Adult , Brain Injuries/epidemiology , Brain Injuries/rehabilitation , Cohort Studies , Comorbidity/trends , Female , Humans , Male , Middle Aged , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/standards , Self Report/standards , Young Adult
10.
Br J Anaesth ; 105(3): 347-54, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20659914

ABSTRACT

BACKGROUND: Ketamine has been shown to have neurotoxic properties, when administered neuraxially. The mechanism of this local toxicity is still unknown. Therefore, we investigated the mechanism of cytotoxicity in different human cell lines in vitro. METHODS: We incubated the following cell types for 24 h with increasing concentrations of S(+)-ketamine and racemic ketamine: (i) human Jurkat T-lymphoma cells overexpressing the antiapoptotic B-cell lymphoma 2 protein, (ii) cells deficient of caspase-9, caspase-8, or Fas-associated protein with death domain and parental cells, and (iii) neuroblastoma cells (SHEP). N-Methyl-d-aspartate (NMDA) receptors and caspase-3 cleavage were identified by immunoblotting. Cell viability and apoptotic cell death were evaluated flowcytometrically by Annexin V and 7-aminoactinomycin D double staining. Mitochondrial metabolic activity and caspase-3 activation were measured. RESULTS: Ketamine, in a concentration-dependent manner, induced apoptosis in lymphocytes and neuroblastoma cell lines. Cell lines with alterations of the mitochondrial pathway of apoptosis were protected against ketamine-induced apoptosis, whereas alterations of the death receptor pathway did not reduce apoptosis. S(+)-Ketamine and racemic ketamine induced the same percentage of cell death in Jurkat cells, whereas in neuroblastoma cells, S(+)-ketamine was slightly less toxic. CONCLUSIONS: Ketamine at millimolar concentrations induces apoptosis via the mitochondrial pathway, independent of death receptor signalling. At higher concentrations necrosis is the predominant mechanism. Less toxicity of S(+)-ketamine was observed in neuroblastoma cells, but this difference was minor and therefore unlikely to be mediated via the NMDA receptor.


Subject(s)
Anesthetics, Dissociative/pharmacology , Apoptosis/drug effects , Ketamine/pharmacology , Mitochondria/drug effects , Neurons/drug effects , T-Lymphocytes/drug effects , Apoptosis/physiology , Dose-Response Relationship, Drug , Humans , Jurkat Cells , Mitochondria/physiology , Necrosis , Neurons/pathology , Signal Transduction/drug effects , Signal Transduction/physiology , T-Lymphocytes/pathology , Tumor Cells, Cultured
11.
Oncogene ; 28(45): 3983-96, 2009 Nov 12.
Article in English | MEDLINE | ID: mdl-19734940

ABSTRACT

An elevated proteasome activity contributes to tumorigenesis, particularly by providing cancer cells with antiapoptotic protection and efficient clearance from irregular proteins. Still, the underlying mechanisms are poorly known. In this study, we report that in colon cancer patients, higher proteasome activity was detected in tumoral tissue compared with surrounding normal tissue, and also that increased levels of proteasomal subunit proteins, such as S5a/PSMD4 and alpha-5/PSMA5, could be detected. Colon tumors showed higher nuclear levels of nuclear factor E2-related factor 2 (Nrf2), a transcription factor supposed to be involved in the control of proteasomal subunit protein expression. The induction or overexpression of Nrf2 led to stronger S5a and alpha-5 expression in the human colon cancer cell lines, Colo320 and Lovo, as well as in NCM460 colonocytes along with higher proteasome activity. The small interfering RNA (siRNA)-mediated Nrf2 knockdown decreased S5a and alpha-5 expression and reduced proteasome activity. Additionally, Nrf2-dependent S5a and alpha-5 expression conferred protection from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, an effect preceded by an increased nuclear factor (NF)-kappaB activation and higher expression of antiapoptotic NF-kappaB target genes. These findings point to an important role of Nrf2 in the gain of proteasome activity, thereby contributing to colorectal carcinogenesis. Nrf2 may therefore serve as a potential target in anticancer therapy.


Subject(s)
Colorectal Neoplasms/metabolism , NF-E2-Related Factor 2/metabolism , Proteasome Endopeptidase Complex/metabolism , Blotting, Western , Cell Line, Tumor , Colorectal Neoplasms/enzymology , Colorectal Neoplasms/pathology , Epithelial Cells/cytology , Humans , Immunohistochemistry , NF-E2-Related Factor 2/genetics , Oxidative Stress , Proteasome Endopeptidase Complex/biosynthesis , Proteasome Endopeptidase Complex/genetics , Signal Transduction , Ubiquitination
12.
Br J Anaesth ; 103(5): 711-8, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19700777

ABSTRACT

BACKGROUND: Local anaesthetics are known to induce apoptosis in clinically relevant concentrations. Hitherto, it is unknown what determines the apoptotic potency of local anaesthetics. Therefore, we compared apoptosis induction by local anaesthetics related to their physicochemical properties in human neuronal cells. METHODS: Neuroblastoma cells (SHEP) were incubated with eight local anaesthetics, two of the ester and six of the amide types. At least, five concentrations of each local anaesthetic were evaluated. After incubation for 24 h, rates of cells in early apoptotic stages and overall cell death were evaluated by annexin V and 7-amino-actinomycin D double staining by flow cytometry. The concentrations that led to half-maximal neurotoxic effects (LD50) were calculated and compared for all local anaesthetics. RESULTS: All local anaesthetics were neurotoxic in a concentration-dependent manner. All drugs induced similar rates of early apoptotic cell formation at low concentrations, whereas at high concentrations, late apoptotic or necrotic cell death predominated. Comparison of LD50 values of the different local anaesthetics resulted in the following order of apoptotic potency from high to low toxicity: tetracaine>bupivacaine>prilocaine=mepivacaine=ropivacaine>lidocaine>procaine=articaine. The toxicity correlated with octanol/buffer coefficients and also with experimental potency of the local anaesthetic, but was unrelated to the structure (ester or amide type). CONCLUSIONS: All commonly used local anaesthetics induce neuronal apoptosis in clinically used concentrations. The neurotoxicity correlates with lipid solubility and thus with the conduction blocking potency of the local anaesthetic, but is independent of the chemical class (ester/amide).


Subject(s)
Anesthetics, Local/pharmacology , Apoptosis/drug effects , Neuroblastoma/pathology , Anesthetics, Local/chemistry , Chemistry, Physical , Dose-Response Relationship, Drug , Flow Cytometry/methods , Humans , Lethal Dose 50 , Tumor Cells, Cultured
13.
Neuroscience ; 159(3): 1148-53, 2009 Mar 31.
Article in English | MEDLINE | ID: mdl-19356695

ABSTRACT

It has been proposed that alterations in spinal inhibitory neurotransmission are critically involved in the pathophysiology of neuropathic pain. The mechanisms by which a relief from inhibitory tone contributes to pathological pain are not fully understood. Hitherto it is still under debate whether there is a loss of inhibitory neurons in the spinal cord in neuropathic pain. The aim of the present study was to evaluate whether a specific loss of glycinergic neurons is necessary to develop hyperalgesia and allodynia in the chronic constriction injury (CCI) model of neuropathic pain. The experiments were performed in bacterial artificial chromosome (BAC) transgenic mice which specifically express enhanced green fluorescent protein under the control of the promotor of the glycine transporter 2 gene, which is a reliable marker for glycinergic neurons. Thus, possible technical inconsistencies due to immunoreactivity in fixed tissues could be ruled out. Twelve days after CCI, in neuropathic animals and in sham-operated and naive animals, lumbar and thoracic segments were analyzed using the physical disector method. Although all animals that had undergone CCI showed pathological nociceptive behavior, stereology revealed no significant difference in glycinergic neurons-neither between the different groups nor between the ipsilateral and contralateral side of the thoracic and lumbar spinal segments. Our findings suggest that a loss of glycinergic neurons is not necessary for the development of pathological nociceptive behavior in the chronic constriction injury model of neuropathic pain in mice. A different mechanism may account for the decrease in inhibitory transmission in neuropathic pain.


Subject(s)
Glycine/metabolism , Neurons/physiology , Pain/physiopathology , Spinal Cord/physiopathology , Analysis of Variance , Animals , Cell Count , Cell Death , Chromosomes, Artificial, Bacterial , Constriction, Pathologic/physiopathology , Disease Models, Animal , Glycine Plasma Membrane Transport Proteins/genetics , Green Fluorescent Proteins/genetics , Hyperalgesia/physiopathology , Lumbar Vertebrae , Mice , Mice, Inbred C57BL , Mice, Transgenic , Pain Measurement , Thoracic Vertebrae
14.
Scand J Immunol ; 69(3): 234-41, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19281535

ABSTRACT

Cardiac surgery using cardiopulmonary bypass (CPB) causes a systemic inflammatory response. Additionally, an impairment of the responsiveness of peripheral blood mononuclear cells (PBMC) to further immunological stimuli has been observed. The aim of our present study was to evaluate the ability of antioxidant therapy with mannitol or haemofiltration during CPB to modulate this immunosuppression after CPB. Forty-five patients undergoing elective heart-surgery were prospectively enrolled and randomized into three groups (control, mannitol, haemofiltration). Blood samples were taken after induction of anaesthesia (T1), 20 min after CPB (T2) and 24 h post-operatively (T3). Expression density of the monocytic surface receptor CD14, HLA-DR expression and cytokine release (TNF-alpha and IL10) after lipopolysaccharide-stimulation were evaluated. At T2, the CD14(dim) cell population was maintained in both intervention groups while in the control group there was a decrease of this proinflammatory monocytic phenotype. No significant differences regarding HLA-DR expression or cytokine release could be demonstrated. This study shows that the suppression of the stimulated immune response after CPB can potentially be alleviated by mannitol or haemofiltration in an experimental in-vitro setting. In the light of data showing that this depression of the immune response might affect the post-operative course of patients, these results could have a potential clinical relevance.


Subject(s)
Cardiopulmonary Bypass/adverse effects , Hemofiltration/methods , Leukocytes, Mononuclear/immunology , Mannitol/therapeutic use , Adult , Aged , Aged, 80 and over , Flow Cytometry , HLA-DR Antigens/biosynthesis , HLA-DR Antigens/blood , HLA-DR Antigens/immunology , Humans , Interleukin-10/biosynthesis , Interleukin-10/blood , Interleukin-10/immunology , Leukocytes, Mononuclear/drug effects , Lipopolysaccharide Receptors/biosynthesis , Lipopolysaccharide Receptors/blood , Lipopolysaccharide Receptors/immunology , Lipopolysaccharides/pharmacology , Male , Middle Aged , Prospective Studies , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/immunology
15.
Eur Surg Res ; 42(3): 157-67, 2009.
Article in English | MEDLINE | ID: mdl-19176968

ABSTRACT

BACKGROUND: The role of hemoxygenase (HO)-1 after partial liver resection (PLR) in jaundiced animals has yet to be defined. We therefore investigated: (1) the acute effects of bile duct ligation (BDL) on bilirubin accumulation and hepatocellular integrity after PLR; (2) how BDL and PLR affect HO-1 protein expression; (3) how functional HO-1 blockade affects survival and liver regeneration after BDL and PLR. METHODS: Male Sprague-Dawley rats were subjected to BDL or a sham operation. After 3 days, a 70% hepatectomy was performed. In a second set of experiments, BDL animals received either Sn(IV) mesoporphyrin IX dichloride (SnMP) for HO-1 blockade or a vehicle. Three days later, PLR was performed and survival of the animals was observed for 7 days. RESULTS: PLR, BDL and both together cause a hepatocellular injury and HO-1 expression. Inhibition of HO-1 with SnMP in jaundiced rats that underwent PLR was associated with improved survival, attenuated postoperative weight loss and better liver synthesis. CONCLUSION: The present findings add further evidence that the protective properties of increased HO-1 expression largely depend on the model used, and that HO-1 overexpression in the model of liver resection during acute cholestasis may also be detrimental.


Subject(s)
Heme Oxygenase (Decyclizing)/antagonists & inhibitors , Jaundice, Obstructive/drug therapy , Jaundice, Obstructive/surgery , Animals , Bile Ducts , Bilirubin/metabolism , Enzyme Inhibitors/therapeutic use , Heme Oxygenase (Decyclizing)/metabolism , Hepatectomy , Jaundice, Obstructive/enzymology , Ligation , Liver/drug effects , Liver/enzymology , Liver/pathology , Liver Regeneration , Male , Mesoporphyrins/therapeutic use , Organotin Compounds/therapeutic use , Rats , Rats, Sprague-Dawley
16.
Cytogenet Genome Res ; 121(3-4): 286-7, 2008.
Article in English | MEDLINE | ID: mdl-18758173

ABSTRACT

A familial duplication in the long arm of one chromosome 1 was detected due to recurrent abortions in a couple. The duplication was present in the male partner of the couple and in his mother, both clinically healthy. By reverse FISH, the duplication was determined to be located in 1q31. Multicolor banding (MCB) and application of locus-specific probes narrowed down the breakpoints to 1q31.1 and 1q32. The duplication spans a region of 13.9 Mb. None of the two breakpoints was colocalized with a known fragile site in 1q31.2, which, however, was duplicated. To the best of our knowledge, this is the first report of an unbalanced chromosome abnormality in this region that is not correlated with any clinical consequences.


Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 1 , Chromosome Banding , Chromosomes, Artificial, Bacterial , Female , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Male , Pedigree , Phenotype
17.
FASEB J ; 22(4): 1237-45, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18048579

ABSTRACT

We constructed a single-chain variable fragment miniantibody (G11-scFv) directed toward the transactivation domain of c-Myc, which is fused with the internalization domain Int of Antennapedia at its carboxyl terminus (a cargo-carrier construct). In ELISA experiments, an EC(50) for binding saturation was achieved at concentrations of G11-scFv-Int(-) of approximately 10(-8) M. Internalization of a fluoresceinated Fl-G11-scFv-Int(+) construct was observed in intact human cultured cells with confocal microscopy. After 5 h of incubation in medium containing 1 microM Fl-G11-scFv-Int(+) or Fl-G11-scFv-Int(-), fluorescence intensity was determined in individual cells, both for cytoplasmic and nuclear compartments: concentration levels of Fl-G11-scFv-Int(+), relative to the extracellular culture medium concentration, were 4-5 times higher in the cytoplasm, 7-8 times higher in the nucleus, and 10 times higher in the nucleoli. In the same experimental conditions, the Fl-G11-scFv-Int(-) construct was 3-4 times more concentrated outside of the cells than inside. Cell membranes kept their integrity after 5 h of incubation. The antiproliferative activity of our miniantibody was studied on HCT116 cells. Incubation with 4 microM G11-scFv-Int(+) for 4 days induced very significant statistical and biological growth inhibition, whereas Int alone was completely inactive. Miniantibodies capable of penetrating cell membranes dramatically broaden the potential for innovative therapeutic agents and attack of new targets.


Subject(s)
Antennapedia Homeodomain Protein/chemistry , Antibodies, Monoclonal/metabolism , Immunoglobulin Variable Region/metabolism , Proto-Oncogene Proteins c-myc/antagonists & inhibitors , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/immunology , Cell Nucleus/metabolism , HCT116 Cells , Humans , Immunoglobulin Variable Region/genetics , Immunoglobulin Variable Region/immunology , Protein Structure, Tertiary , Proto-Oncogene Proteins c-myc/immunology , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism
18.
Article in English | MEDLINE | ID: mdl-16876469

ABSTRACT

By reaction of 4-tert-butylphenoxyacetylhydrazide with aromatic aldehydes and acetone a new series of 4-tert-butylphenoxyacetylhydrazones was synthesized. The structural peculiarities of the investigated molecules have been determined by means of X-ray analysis and IR spectroscopy. The diagnostically important IR spectral criteria required for the conformational analysis of acethylhydrazones have been considered. It was established that the 4-tert-butylphenoxyacetylhydrazide in condensed phase exists only as a ZN-C(O)-conformer. Its derivatives exist as EN-C(O) and ZN-C(O)-forms. As a rule, the prevalence of ZN-C(O)-form has been observed in CCl4 solutions. The structure of investigated compounds is also determined by a system of inter- and intramolecular hydrogen bonds. The energy of hydrogen bonds was estimated.


Subject(s)
Hydrazones/chemistry , Hydrazones/chemical synthesis , Benzaldehydes/chemical synthesis , Benzaldehydes/chemistry , Hydrogen Bonding , Molecular Structure , Spectrophotometry, Infrared
19.
Acta Anaesthesiol Scand ; 50(9): 1103-10, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16939481

ABSTRACT

BACKGROUND: Sepsis may lead to the suppression of stimulated cytokine release after Gram-negative stimuli, correlating with a fatal outcome. Treatment of sepsis includes adequate therapy with antibiotics. The aim of this study was to investigate the role of antibiotics in the modulation of the lipopolysaccharide (LPS)-stimulated cytokine response of human monocytes. METHODS: In this ex vivo, in vitro study, whole blood samples were taken from 10 healthy volunteers, stimulated with LPS in the presence or absence of various antibiotics (penicillin, amoxicillin, cefuroxime, ceftazidime, cefotaxime, piperacillin/tazobactam, imipenem/cilastatin, gentamicin, netilmicin, ciprofloxacin, vancomycin) and cultured for 24 h. Thereafter, tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) were measured in the supernatants by enzyme-linked immunosorbent assay (ELISA). Furthermore, CD14 and HLA-DR expression on monocytes was assessed using flow cytometry. RESULTS: All cephalosporins decreased LPS-stimulated IL-10 release. Cefuroxime and cefotaxime also decreased the expression density of the LPS recognition molecule CD14 on monocytes. An increase in LPS-stimulated IL-10 release was observed with vancomycin. A suppression of LPS-stimulated TNF-alpha and IL-10 release was observed in the presence of ciprofloxacin. CONCLUSION: These results indicate a modulation of the expression density of CD14 on monocytes, together with a shift from a balanced to an inflammatory cytokine release pattern, by cefuroxime and cefotaxime. Vancomycin changes the response to an anti-inflammatory release pattern. After ciprofloxacin, a profound unresponsiveness of immune-competent cells to LPS stimulation is observed. Because of the critical role of a balanced innate immune response, these data may be of importance for the selection of antibiotics in septic patients.


Subject(s)
Anti-Bacterial Agents/pharmacology , Cytokines/metabolism , Endotoxins/pharmacology , Flow Cytometry , Fluorescent Antibody Technique , HLA-DR Antigens/biosynthesis , Humans , In Vitro Techniques , Interleukin-10/biosynthesis , Lipopolysaccharide Receptors/biosynthesis , Lipopolysaccharides/pharmacology , Monocytes/drug effects , Monocytes/metabolism , Tumor Necrosis Factor-alpha/biosynthesis
20.
Vestn Khir Im I I Grek ; 165(1): 62-6, 2006.
Article in Russian | MEDLINE | ID: mdl-16568859

ABSTRACT

The reconstructive plastic operations were made in 217 patients with infected tissue defects with continuous regional infusions or with a simultaneous sanitizing operation, or within 7-15 days. Skin plasty, catheterization of the main artery (210), secondary surgical treatment and sequest-necrectomy (185), osteosynthesis (106), bone plasty (69) and others (1118 operations in all) were carried on in all the patients, i.e. 5.1 operations per each patient with artery catheterization taken into account. The method of plastic replacement was chosen individually depending on localization, depth and spread of the defect. Good and satisfactory results were obtained in all the patients with no esthetic impairments.


Subject(s)
Plastic Surgery Procedures/methods , Wound Infection/surgery , Adolescent , Adult , Female , Follow-Up Studies , Humans , Male , Middle Aged , Severity of Illness Index , Surgical Flaps , Wounds and Injuries/surgery
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