Intercellular adhesion molecule-1 inhibition attenuates neurologic and hepatic damage after resuscitation in mice

BACKGROUND: Cardiac arrest and cardiopulmonary resuscitation may result in multiorgan damage after global hypoxia due to neutrophil recruitment. Patients display all signs of a systemic inflammatory response syndrome. Reducing neutrophil recruitment may thus preserve organ function. METHODS: Mice were subjected to cardiac arrest and resuscitation. CD18/CD11b expression on circulating neutrophils was assessed by flow cytometry. Intercellular adhesion molecule-1 expression was analyzed by Western blot and immunofluorescence. Neutrophil recruitment was quantified by immunohistochemistry. Neurologic function was assessed by a balance test. For liver and kidney function, plasma alanine aminotransferase activity and creatinine concentrations were determined. To reduce neutrophil recruitment, mice received 100 microg anti-intercellular adhesion molecule-1 antibody intraperitoneally. RESULTS: Resuscitation led to severe hypoxia, acidosis, and hypercarbia. Adhesion molecule expression and neutrophil recruitment were increased in the liver, kidney, and brain. Neurologic performance was impaired 24 h after cardiac arrest. Creatinine and alanine aminotransferase concentrations were significantly increased. Immunoneutralization of intercellular adhesion molecule-1 attenuated neutrophil influx in the liver along with alanine aminotransferase activity, whereas creatinine concentrations and neutrophil influx in the kidney remained unchanged. Neurologic function was improved in the treatment group. CONCLUSIONS: Global hypoxia induces activation of the endothelium in the brain, liver, and kidney. The resulting damage to the brain and liver are due to infiltration of neutrophils, whereas kidney damage is not, because reduction of neutrophil recruitment after cardiopulmonary resuscitation improves recovery of neurologic and hepatic but not renal function. Inhibition of intercellular adhesion molecule-1 after global hypoxia may be beneficial in patients experiencing cardiac arrest and resuscitation.     

Treatment and outcome of intrahepatic cholangiocellular carcinoma

BACKGROUND: Treating intrahepatic cholangiocarcinoma (ihCCC) tumor resection leads to the best patient survival. The aim of this study was to investigate prognostic factors in resected patients. METHODS: This was a clinical observational series of 31 resected patients with ihCCC. Univariate analysis of clinical and pathologic factors in relation to patient survival and tumor recurrence were performed. Possible benefit of chemotherapy, although not given randomly, was investigated separately. RESULTS: The median follow-up time was 37.3 months. Of 31 resected patients a tumor-free resection (R0) was achieved in 26; 2 patients died postoperatively. Chemotherapy was administered to 19 patients. Overall survival was significantly better in patients with R0 resection, negative lymph nodes, a solitary tumor, and a width of resection margin greater than 3 mm. Recurrence-free survival was prolonged in patients with negative lymph nodes, early International Union Against Cancer (UICC) stages and solitary tumors. In UICC stages III and IV, patients receiving chemotherapy experienced a better overall survival. CONCLUSIONS: Impact of various parameters on recurrence-free and overall survival was identified; a possible beneficial effect of adjuvant chemotherapy in advanced tumor stages was observed. A prospective, randomized trial is necessary to fully evaluate the role of adjuvant therapy.     

Optimisation of pyrogen testing in parenterals according to different pharmacopoeias by probabilistic modelling

The rabbit test to detect pyrogenic contamination in parenterals is crucial to ensure patient safety. The pharmacopoeial tests in Europe, the US and Japan are based on the fever reaction of rabbits, but differ in their experimental design and in their algorithms to assess contamination. Employing an international reference endotoxin, fever can be induced in rabbits. Data from 171 rabbits built the base for probabilistic modelling of the fever reaction and for the comparison of the pharmacopoeial tests. The rabbit fever reaction could be modelled as a function of the amount of injected endotoxin (per kg body weight) by linear regression. Combining the pharmacopoeial algorithms of the rabbit pyrogen test with the developed model allowed analysis of differences regarding test results and animal consumption. This showed that the assessment of pyrogenic contamination strongly depends on the respective pyrogen test stipulated by regulations. Additionally, the approach was used to develop a new experimental design. Two specific versions of this design resulted in a reduction of the number of animals used by about 30% while the safety of the test was maintained. A need for harmonisation is evident, allowing optimisation of the experimental design, which promotes animal welfare.     

The molecular make-up of a tumour: proteomics in cancer research

The enormous progress in proteomics, enabled by recent advances in MS (mass spectrometry), has brought protein analysis back into the limelight of cancer research, reviving old areas as well as opening new fields of study. In this review, we discuss the basic features of proteomic technologies, including the basics of MS, and we consider the main current applications and challenges of proteomics in cancer research, including (i) protein expression profiling of tumours, tumour fluids and tumour cells; (ii) protein microarrays; (iii) mapping of cancer signalling pathways; (iv) pharmacoproteomics; (v) biomarkers for diagnosis, staging and monitoring of the disease and therapeutic response; and (vi) the immune response to cancer. All these applications continue to benefit from further technological advances, such as the development of quantitative proteomics methods, high-resolution, high-speed and high-sensitivity MS, functional protein assays, and advanced bioinformatics for data handling and interpretation. A major challenge will be the integration of proteomics with genomics and metabolomics data and their functional interpretation in conjunction with clinical results and epidemiology.     

The Structure of Maladaptive Schemas: A Confirmatory Factor Analysis and a Psychometric Evaluation of Factor-Derived Scales

One thousand and thirty-seven psychiatric patients and non-patients from six different sites completed the 205-item Young Schema Questionnaire or its shortended form, the 75-item Young Schema Questionnaire-S. Among 888 of the subjects, who all were patients, a confirmatory factor analysis (CFA) of the 75 items included in both forms of the questionnaire clearly yielded the 15 Early Maladaptive Schema (EMS) factors rationally developed by J. E. Young (1990). Confirmatory factor analyses, testing three models of the higher-order structure of the 15 EMSs, indicated that a four-factor model was the best alternative. The results slightly favored a correlated four second-order factor model over one also including a third-order global factor. The four factors or schema domains were Disconnection, Impaired Autonomy, Exaggerated Standards, and Impaired Limits. Scales derived from the four higher-order factors had good internal and test–retest reliabilities and were related to DSM-IV Cluster C personality traits, agoraphobic avoidance behavior, and depressive symptoms.     

BH3-only proteins Puma and Bim are rate-limiting for gamma-radiation- and glucocorticoid-induced apoptosis of lymphoid cells in vivo

Numerous p53 target genes have been implicated in DNA damage-induced apoptosis signaling, but proapoptotic Bcl-2 (B-cell leukemia 2) family members of the BH3 (Bcl-2 homolog region [BH] 3)-only subgroup appear to play the critical initiating role. In various types of cultured cells, 3 BH3-only proteins, namely Puma (p53 up-regulated modulator of apoptosis), Noxa, and Bim (Bcl-2 interacting mediator of cell death), have been shown to initiate p53-dependent as well as p53-independent apoptosis in response to DNA damage and treatment with anticancer drugs or glucocorticoids. In particular, the absence of Puma or Bim renders thymocytes and mature lymphocytes refractory to varying degrees to death induced in vitro by growth factor withdrawal, DNA damage, or glucocorticoids. To assess the in vivo relevance of these findings, we subjected mice lacking Puma, Noxa, or Bim to whole-body gamma-radiation or the glucocorticoid dexamethasone and compared lymphocyte survival with that in wild-type and BCL2-transgenic mice. Absence of Puma or Bcl-2 overexpression efficiently protected diverse types of lymphocytes from the effects of gamma-radiation in vivo, and loss of Bim provided lower but significant protection in most lymphocytes, whereas Noxa deficiency had no impact. Furthermore, both Puma and Bim were found to contribute significantly to glucocorticoid-induced killing. Our results thus establish that Puma and Bim are key initiators of gamma-radiation- and glucocorticoid-induced apoptosis in lymphoid cells in vivo.     

Placental defence is considered sufficient to control lipid peroxidation in pregnancy

Oxidative stress is characterized by an overweight of pro-oxidants against antioxidant forces and is associated with atherosclerosis, aging, and reproductive complications. Placenta is the major source of pro-oxidant agents, antioxidant enzyme-systems, and hormones and is able to keep the lipid peroxidation under control in normal pregnancy. As oxidation processes are increased in pregnancy, we would expect a shortening of lag phase of low density lipoprotein (LDL)-oxidation. LDL oxidation assessed by measuring conjugated diene formation is a marker for the early part of lipid peroxidation process and the balance of pro-oxidants and antioxidants influences length of lag phase. Our results show that resistance of LDL oxidation is unchanged during normal pregnancy in the second and third trimester. Only antioxidants are able to protect LDL. Estriol is an antioxidant, increases the lag-phase of LDL-oxidation in vitro, and its serum concentration raises enormous during late pregnancy. Thus the biological role of high levels of estriol during pregnancy may be part of the self-protection to limit oxidative damages.     

Altered motor cortex excitability in tinnitus patients: a hint at crossmodal plasticity

Idiopathic tinnitus is a frequent and often debilitating auditory phantom perception of largely unknown pathological conditions. In electrophysiological and functional neuroimaging studies, affected subjects have shown excessive spontaneous activity in the central auditory system. To further investigate the underlying central nervous component, we assessed motor cortex excitability in 19 patients with chronic tinnitus by means of transcranial magnetic stimulation (TMS). When results were compared with data from 19 healthy controls matched for age and sex, we found significantly enhanced intracortical facilitation in tinnitus patients. These findings parallel excitability changes after limb amputation and experimental deafferentation. Our results give further support to crossmodal interactions involving neuroplastic changes in some forms of tinnitus and may help to better understand mechanisms of maladaptive cortical reorganisation involved in phantom perceptions.