Robotic nipple-sparing mastectomy complication rate compared to traditional nipple-sparing mastectomy: a systematic review and meta-analysis.

Breast cancer is worldwide the most common cause of cancer in women and causes the second most common cancer-related death. Nipple-sparing mastectomy (NSM) is commonly used in therapeutic and prophylactic settings. Furthermore, (preventive) mastectomies are, besides complications, also associated with psychological and cosmetic consequences. Robotic NSM (RNSM) allows for better visualization of the planes and reducing the invasiveness. The aim of this study was to compare the postoperative complication rate of RNSM to NSM. A systematic search was performed on all (R)NSM articles. The primary outcome was determining the overall postoperative complication rate of traditional NSM and RNSM. Secondary outcomes were comparing the specific postoperative complication rates: implant loss, hematoma, (flap)necrosis, infection, and seroma. Forty-nine studies containing 13,886 cases of (R)NSM were included. No statistically significant differences were found regarding postoperative complications (RNSM 3.9%, NSM 7.0%, p = 0.070), postoperative implant loss (RNSM 4.1%, NSM 3.2%, p = 0.523), hematomas (RNSM 4.3%, NSM 2.0%, p = 0.059), necrosis (RNSM 4.3%, NSM 7.4%, p = 0.230), infection (RNSM 8.3%, NSM 4.0%, p = 0.054) or seromas (RNSM 3.0%, NSM 2.0%, p = 0.421). Overall, there are no statistically significant differences in complication rates between NSM and RNSM.

painPREDICT: first interim data from the development of a new patient-reported pain questionnaire to predict treatment response using sensory symptom profiles.

Objective: Sensory symptom patterns may be useful for predicting treatment response, and, thus, improve individual therapy in patients suffering from neuropathic pain (NeP). Existing screening questionnaires focus predominately on neuropathic mechanisms without consideration of nociceptive mechanisms or mixed pain states. This study aimed to develop a new questionnaire, painPREDICT, using a wide set of patient-reported descriptors potentially associated with neuropathic and nociceptive pain mechanisms, and to explore sensory symptom patterns. Methods: PainPREDICT was constructed based on exploratory (n = 27 patients) and cognitive debriefing interviews (n = 49 patients and nine physicians), across five NeP conditions. The pilot questionnaire was then administered in a non-interventional, cross-sectional, multi-center study to 840 pain patients across the US and Germany. The identification of a sensory symptom pattern was based on hybrid clustering resulting from items standardization followed by principal component analysis. Results: The final questionnaire included 20 items covering: pain intensity, location of pain, course of pain, and sensory symptoms. Most patients participating in the cross-sectional study suffered either from painful diabetic polyneuropathy (n = 330) or radiculopathy (n = 349), fewer from central pain (n = 61) or other types of NeP (n = 100). The hybrid clustering of the new questionnaire data identified three different characteristic sensory symptom profiles in patients with NeP: "Irritable nociceptors", "deafferentation pain", and "pain attacks with nociceptive component". Although some differences in the distribution of the sensory profiles were found, all profiles were represented in all NeP etiology groups. Conclusions: This study set the ground of painPREDICT and showed promising results for its use to categorize patients according to sensory symptom patterns.

[Attitudes towards using eHealth in psychiatry and psychotherapy : A pilot survey at the DGPPN Congress 2014]. / Einstellungen gegenüber eHealth-Angeboten in Psychiatrie und Psychotherapie : Eine Pilotumfrage auf dem DGPPN-Kongress 2014.

The use of modern communication and information technology in the health sector, known as eHealth, has the potential to reduce gaps in psychiatric and psychotherapeutic healthcare. In order to successfully implement eHealth it is important to assess the attitude of all stakeholders. The attitude of the patients towards eHealth has been frequently investigated but there is a lack of research on the side of the professionals. The attitude towards eHealth from the perspective of professionals has only rarely been evaluated in German-speaking countries; therefore, we carried out a survey at the German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN) congress in 2014 that included 282 psychiatrists, neurologists and psychologists in order to explore their attitudes towards eHealth . Furthermore, the professionals were asked in which therapeutic areas, for which age groups and for which clinical pictures they would expect benefits. In general, the participants expressed a positive attitude towards eHealth . They expected benefits for a multitude of therapeutic areas, particularly for adolescents and adults and especially for the treatment of depression and anxiety disorders; however, they felt only minimally informed about eHealth opportunities indicating a high need for educational and training requirements.

Association of Venous Disorders with Leg Symptoms: Results from the Bonn Vein Study 1.

OBJECTIVES: The aim was to study the association between venous disorders and leg symptoms in the population based cross sectional Bonn Vein Study 1 (BVS1). METHODS: A total of 1,350 men and 1,722 women aged 18-79 years were enrolled into BVS1. Chronic venous insufficiency (CVI), varicose veins (VVs), and clinical classes (C-classes/CEAP [Clinical, Etiological, Anatomical, and Pathophysiological]) were determined by clinical and duplex investigation. Leg symptoms (heaviness, tightness, swelling, pain after standing or sitting, pain while walking, muscle cramps, itching, and restless legs) were assessed in a standardized interview. For 2,624 subjects (48.7% male) with complete information on venous disorders, relevant characteristics and information on at least one leg symptom, multivariate logistic regression analysis was performed. RESULTS: More women (929/63.0%) reported at least one leg symptom within the last 4 weeks than men (560/48.7%). Prevalence of reported symptoms increased with age (45.4% of the 18-29 year olds, 73.9% of the 70-79 year olds). Leg symptoms were more frequent in obese and underweight subjects. As confirmed by clinical and duplex examination 22.6% had VV and 15.8% had CVI. VV (OR: 1.4; CI: 1.1-1.7) and CVI (OR: 1.8; CI: 1.3-2.3) were significantly associated with reporting at least one leg symptom. In particular, there was a positive association of VV and CVI with itching, feeling of heaviness, tightness, swelling, and pain after standing or sitting. C2-C6 showed a statistically significant association with feeling of heaviness, tightness, swelling, and itching, while for pain on walking and muscle cramps this was shifted towards C classes C3-C6 and C3-C4, respectively. CONCLUSIONS: Venous disorders show significant associations with several leg symptoms. Itching, feeling of heaviness, or tightness seem to be more closely related than other symptoms. The associations between C classes and symptoms seem to be restricted to classes C2 or higher.

Phase I study of panobinostat and imatinib in patients with treatment-refractory metastatic gastrointestinal stromal tumors.

BACKGROUND: Panobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with refractory GIST. METHODS: Following a 7-day run-in phase of IM (400 mg per day), escalating doses of panobinostat were added following a '3 plus 3' design. Twelve heavily pretreated GIST patients were enrolled in two dose levels. RESULTS: Most common adverse events were thrombocytopenia, anaemia, fatigue, creatinine elevation, nausea, emesis and diarrhoea. Twenty micrograms of panobinostat and 400 mg IM were declared the MTD. Pharmacologically active concentrations of panobinostat and IM were achieved as evidenced by histone H3 acetylation in blood mononuclear cells in vivo and inhibition of the IM-resistant KIT (D816) mutation in vitro. In FDG-PET-CT scans after IM run-in and following 3 weeks panobinostat treatment, 1 out of 11 evaluable patients showed a metabolic partial response, 7 patients were metabolically stable and 3 patients progressed. Longest treatment duration was 17 weeks (median 6). CONCLUSION: Panobinostat and IM can be administered at doses achieving target inhibition in vivo. Further clinical exploration of patients with treatment-refractory GIST is warranted. Correlative studies in this trial may help to optimise dosing schedules in GIST.

The neural cell adhesion molecule-derived peptide, FGL, attenuates lipopolysaccharide-induced changes in glia in a CD200-dependent manner.

Fibroblast growth loop (FGL) is a neural cell adhesion molecule (NCAM)-mimetic peptide that mimics the interaction of NCAM with fibroblast growth factor receptor (FGFR). FGL increases neurite outgrowth and promotes neuronal survival in vitro, and it has also been shown to have neuroprotective effects in vivo. More recent evidence has indicated that FGL has anti-inflammatory effects, decreasing age-related changes in microglial activation and production of inflammatory cytokines. These changes have been associated with an FGL-induced increase in expression of the glycoprotein, CD200, which interacts with its receptor to help maintain microglia in a quiescent state. However whether the FGL-induced anti-inflammatory effects are CD200-dependent has not been examined. The objective of this study was to address this question. Mixed glia were prepared from brain tissue of neonatal wildtype and CD200-deficient mice and preincubated with FGL prior to stimulation with lipopolysaccharide (LPS). Cells were assessed for mRNA expression of markers of microglial activation, CD11b, CD40 and intercellular adhesion molecule 1 (ICAM-1) and also the inflammatory cytokines, interleukin (IL)-1ß, IL-6 and tumour necrosis factor (TNF)-α, while supernatant concentrations of these cytokine were also assessed. LPS significantly increased all these parameters and the effect was greater in cells prepared from CD200-deficient mice. Whereas FGL attenuated the LPS-induced changes in cells from wildtype mice, it did not do so in cells from CD200-deficient mice. We conclude that the FGL-induced changes in microglial activation are CD200-dependent and demonstrate that the interaction of astrocytes with microglia is critically important for modulating microglial activation.

ABI derived from the highest and lowest ankle pressure. What is the difference?

AIM: Different modes of ankle-brachial -index (ABI) calculation lead to different information. We looked for the peripheral arterial disease (PAD) prevalence estimated from ABI-high and ABI-low and analysed the effect of age and classical risk factors. METHODS: Based on the Arteriomobil Project data, ABI was calculated considering the lowest of the four ankle artery pressures (ABI-low) or the higher ankle artery pressure of each leg (ABI-high), respectively. ABI <0.9 were defined to prove PAD. RESULTS: Prevalence of PAD estimated using ABI-low was much higher than those using ABI- high (15.7% vs. 8.0%). Thus 8% of men and 7.5% of women suspected for PAD were not detected if prevalence rates are based on ABI-high alone. Estimating PAD prevalence only by measuring posterior tibial artery (ATP) pressure, prevalence rates were lowest with 2.4% for the left and 2.7% for the right ATP. Estimating PAD prevalence only by measuring anterior tibial artery pressure, prevalence rates were slightly higher, but still low. ABI-high systematically shows lower prevalence rates compared to ABI-low without divergence of the prevalence rates with increasing age. This parallelism of the curves remained unchanged when prevalence rates were separated for self-reported risk-factors; smoking, hypertension, hypercholesterolemia and diabetes. CONCLUSION: The presented analysis of the Arteriomobil Project data support the hypothesis that the differences in prevalence rates estimated from ABI-high and ABI-low are mainly determined by anatomic variations of the plantar arch. Additional angiographic controlled studies are necessary to prove this hypothesis.

The Arteriomobil Project for peripheral arterial disease.

BACKGROUND: Peripheral Arterial Disease in Germany is underestimated with regard to incidence and the consequences. In 1997 the Federal Association of the Peripheral Arterial Disease Self Help Groups started the Arteriomobil Project to increase the awareness for venous and arterial diseases in the general population. We report peripheral arterial disease (PAD) prevalence rates and discuss the unique concept of this project. PATIENTS AND METHODS: The Arteriomobil is a mobile home modified to a simple investigation room with an examination couch, a Doppler equipment and a computer for data acquisition. From April 1997 to April 2007, a total of 14.785 volunteers aged 18 to 102 years (mean age +/- SD: 64 +/- 11 years, 63% females) were investigated. Patients were recruited as a result of their active visit to the Arteriomobil and their active participation in the investigation. In all participants the medical history was documented according to a standardized computer-assisted interview and a standardized Ankle Brachial Index (ABI) determined. RESULTS: PAD prevalence in females (ABI < 0.9) increased from 2% in the 5th decade of life to 33% in 10th decade and in males from 4.8% to 41% accordingly. Age- and gender-adjusted odds ratios for PAD were highest in smoker: Odds ratio 2.85 (95% Confidence interval 2.5-3.2) and Diabetes mellitus 1.91 (95%CI 1.7-2.2). Hypertension and hypercholesterolemia had a lower impact. Family history of known PAD, CHD or CVD had no impact. Although 49.5% of all participants complained of "leg disorders during exercise" intermittent claudication turned out to be the most discriminating symptom for PAD 5.87 (95%IC 5.18-6.66). Previous myocardial infarction (MI) was the most frequently reported vascular co-morbidity in those with PAD (OR 2.23, 95%IC 1.9-2.7) followed by stroke (2.12, 1.7-2.7), angina pectoris (1.50, 1.3-1.8) and paresis (2.01, 1.6-2.6). The incidence of anti-platelet treatment was significantly higher in participants with coronary heart disease than in those with PAD or cerebrovascular disease. CONCLUSIONS: The Arteriomobil Project is the largest database regarding the prevalence of PAD in the German population. and the data underlines the high prevalence of PAD in Germany.

Signaling mechanisms of neurite outgrowth induced by the cell adhesion molecules NCAM and N-cadherin.

Formation of appropriate neural circuits depends on a complex interplay between extracellular guiding cues and intracellular signaling events that result in alterations of cytoskeletal dynamics and a neurite growth response. Surface-expressed cell adhesion molecules (CAMs) interact with the surroundings via the extracellular domain and bind to the cytoskeleton via their intracellular domain. In addition, several CAMs induce signaling events via direct interactions with intracellular proteins or via interactions with cell surface receptors. Thus, CAMs are obvious candidates for transmitting extracellular guidance cues to intracellular events and thereby regulating neurite outgrowth. In this review, we focus on two CAMs, the neural cell adhesion molecule (NCAM) and N-cadherin, and their ability to mediate signaling associated with a neurite outgrowth response. In particular, we will focus on direct interaction between NCAM and N-cadherin with a number of intracellular partners, as well as on their interaction with the fibroblast growth factor receptor (FGFR).

Dimerization effect of sucrose octasulfate on rat FGF1.

Fibroblast growth factors (FGFs) constitute a family of at least 23 structurally related heparin-binding proteins that are involved in regulation of cell growth, survival, differentiation and migration. Sucrose octasulfate (SOS), a chemical analogue of heparin, has been demonstrated to activate FGF signalling pathways. The structure of rat FGF1 crystallized in the presence of SOS has been determined at 2.2 A resolution. SOS-mediated dimerization of FGF1 was observed, which was further supported by gel-filtration experiments. The major contributors to the sulfate-binding sites in rat FGF1 are Lys113, Lys118, Arg122 and Lys128. An arginine at position 116 is a consensus residue in mammalian FGF molecules; however, it is a serine in rat FGF1. This difference may be important for SOS-mediated FGF1 dimerization in rat.

The NCAM-derived P2 peptide facilitates recovery of cognitive and motor function and ameliorates neuropathology following traumatic brain injury.

The neural cell adhesion molecule (NCAM) plays a crucial role during development and regeneration of the nervous system, mediating neuronal differentiation, survival and plasticity. Moreover, NCAM regulates learning and memory. A peptide termed P2, corresponding to a 12-amino-acid sequence in the second immunoglobulin (Ig)-like module of NCAM, represents the natural cis-binding site for the first NCAM Ig module. The P2 peptide targets NCAM, thereby inducing a number of intracellular signaling events leading to the stimulation of neurite outgrowth and promotion of neuronal survival in vitro. The present study evaluated the effect of the P2 peptide on functional and histological outcomes following traumatic brain injury inflicted by a cortical cryogenic lesion. Lesioned rats were injected subcutaneously with P2 peptide, 5 mg/kg daily for 15 days beginning 2 h after injury. This treatment significantly improved postlesion recovery of motor and cognitive function, reduced neuronal degeneration, protected cells against oxidative stress, and increased reactive astrogliosis and neuronal plasticity in the sublesional area. P2 appeared rapidly in blood and cerebrospinal fluid after subcutaneous administration and remained detectable in blood for up to 5 h. The results suggest that P2 has therapeutic potential for the treatment of traumatic brain injury.

Experimental gastritis in mice enhances anxiety in a gender-related manner.

There is a gender-related comorbidity of pain-related and inflammatory bowel diseases with psychiatric diseases. Since the impact of experimental gastrointestinal inflammation on the emotional-affective behavior is little known, we examined whether experimental gastritis modifies anxiety, stress coping and circulating corticosterone in male and female Him:OF1 mice. Gastritis was induced by adding iodoacetamide (0.1%) to the drinking water for at least 7 days. Inflammation was assessed by gastric histology and myeloperoxidase activity, circulating corticosterone determined by enzyme immunoassay, anxiety-related behavior evaluated with the elevated plus maze and stress-induced hyperthermia tests, and depression-like behavior estimated with the tail suspension test. Iodoacetamide-induced gastritis was associated with gastric mucosal surface damage and an increase in gastric myeloperoxidase activity, this increase being significantly larger in female mice than in male mice. The rectal temperature of male mice treated with iodoacetamide was enhanced, whereas that of female mice was diminished. The circulating levels of corticosterone were reduced by 65% in female mice treated with iodoacetamide but did not significantly change in male mice. On the behavioral level, iodoacetamide treatment caused a decrease in nocturnal home-cage activity, drinking and feeding. While depression-related behavior remained unaltered following induction of gastritis, behavioral indices of anxiety were significantly enhanced in female but not male mice. There was no correlation between the estrous cycle and anxiety as well as circulating corticosterone. Radiotracer experiments revealed that iodoacetamide did not readily enter the brain, the blood-brain ratio being 20:1. Collectively, these data show that iodoacetamide treatment causes gastritis in a gender-related manner, its severity being significantly greater in female than in male mice. The induction of gastritis in female mice is associated with a reduction of circulating corticosterone and an enforcement of behavioral indices of anxiety. Gastric inflammation thus has a distinct gender-dependent influence on emotional-affective behavior and its neuroendocrine control.

Effects of P2, a peptide derived from a homophilic binding site in the neural cell adhesion molecule on learning and memory in rats.

The neural cell adhesion molecule (NCAM) plays a pivotal role in neural development, regeneration, synaptic plasticity, and memory processes. P2 is a 12-amino-acid peptide derived from the second immunoglobulin-like (Ig) module of NCAM mediating cis-homophilic interactions between NCAM molecules present on the same cell. P2 is a potent NCAM agonist, capable of promoting neuronal differentiation and survival in vitro. The aim of this study was to assess the effect of P2 on learning and memory. Rats treated with P2 intracerebroventricularly (1 h prior to test) performed significantly better than controls in the reinforced T-maze, a test of spatial working memory. Further, rats treated with P2 exhibited decreased anxiety-like behavior while learning the T-maze task. In the social recognition test, both intracerebroventricular (1 h prior to test) and systemic (1 and 24 h prior to test) P2 treatment enhanced short-term social memory and counteracted (administration 24 h prior test) scopolamine-induced social memory impairment. In contrast, P2 (1 h prior to test) did not significantly improve long-term (24 h) retention of social memory, nor did it have any significant effects on long-term memory evaluated by the Morris water maze (administration between 2 days before training and 5.5 h posttraining). In the open field test, P2 (1 h prior to test) decreased general locomotion and rearing, but did not influence any other anxiety-related behaviors, indicating only a minimal influence on baseline anxiety levels. Taken together, these data indicate that in vivo P2 enhances short-term memory and protects against the amnestic effects of scopolamine, while modulating emotional behavior in a learning or novelty-related task.

Increase in gastric acid-induced afferent input to the brainstem in mice with gastritis.

Acid challenge of the gastric mucosa is signaled to the brainstem. This study examined whether mild gastritis due to dextrane sulfate sodium (DSS) or iodoacetamide (IAA) enhances gastric acid-evoked input to the brainstem and whether this effect is related to gastric myeloperoxidase activity, gastric histology, gastric volume retention or cyclooxygenase stimulation. The stomach of conscious mice was challenged with NaCl (0.15 M) or HCl (0.15 and 0.25 M) administered via gastric gavage. Two hours later, activation of neurons in the nucleus tractus solitarii (NTS) was visualized by c-Fos immunocytochemistry. Gastritis was induced by DSS (molecular weight 8000; 5%) or IAA (0.1%) added to the drinking water for 7 days. Relative to NaCl, intragastric HCl increased the number of c-Fos protein-expressing cells in the NTS. Pretreatment with DSS or IAA for 1 week did not alter the c-Fos response to NaCl but significantly enhanced the response to HCl by 54 and 74%, respectively. Either pretreatment elevated gastric myeloperoxidase activity and induced histological injury of the mucosal surface. In addition, DSS caused dilation of the gastric glands and damage to the parietal cells. HCl-induced gastric volume retention was not altered by IAA but attenuated by DSS pretreatment. Indomethacin (5 mg/kg) failed to significantly alter HCl-evoked expression of c-Fos in the NTS of control, DSS-pretreated and IAA-pretreated mice. We conclude that the gastritis-evoked increase in the gastric acid-evoked c-Fos expression in the NTS is related to disruption of the gastric mucosal barrier, mucosal inflammation, mucosal acid influx and enhanced activation of the afferent stomach-NTS axis.

A neural cell adhesion molecule-derived peptide reduces neuropathological signs and cognitive impairment induced by Abeta25-35.

By means of i.c.v. administration of preaggregated oligomeric beta-amyloid (Abeta)25-35 peptide it was possible in rats to generate neuropathological signs related to those of early stages of Alzheimer's disease (AD). Abeta25-35-administration induced the deposition of endogenously produced amyloid protein. Furthermore, quantitative immunohistochemistry demonstrated time-related statistically significant increases in amyloid immunoreactivity, tau phosphorylation, microglial activation, and astrocytosis, and stereological investigations demonstrated statistically significant increased neuronal cell death and brain atrophy in response to Abeta25-35. Finally, the Abeta25-35-administration led to a reduced short-term memory as determined by the social recognition test. A synthetic peptide termed FGL derived from the neural cell adhesion molecule (NCAM) was able to prevent or, if already manifest, strongly reduce all investigated signs of Abeta25-35-induced neuropathology and cognitive impairment. The FGL peptide was recently demonstrated to be able to cross the blood-brain-barrier. Accordingly, we found that the beneficial effects of FGL were achieved not only by intracisternal, but also by intranasal and s.c. administration of the peptide. Furthermore, FGL-treatment was shown to inhibit the activity of GSK3beta, a kinase implicated in signaling regulating cell survival, tau phosphorylation and the processing of the amyloid precursor protein (APP). Thus, the peptide induced a statistically significant increase in the fraction of GSK3beta phosphorylated on the Ser9-position, a posttranslational modification known to inhibit the activity of the kinase. Hence, the mode of action of FGL with respect to the preventive and curative effects on Abeta25-35-induced neuropathological manifestations and cognitive impairment involves the modulation of intracellular signal-transduction mediated through GSK3beta.

[Psychopharmacological drug treatment in Munich nursing homes]. / Psychopharmakologische behandlungspraxis in Münchener altenpflegeheimen.

The survey of Munich nursing homes with 888 residents showed that 56.4% received psychotropic drugs and a twice as frequent prescription of antipsychotics to residents of double rooms than of single rooms. In a subsample of 397 residents the last review of the prescriptions of 17.5% of the psychotropic drugs was at least 3 months to partly years ago. Based on the American Beers-criteria 13.6% of the consumers of psychotropic drugs received psychotropic drugs, which preferably should not be taken by older people.

A neural cell adhesion molecule-derived fibroblast growth factor receptor agonist, the FGL-peptide, promotes early postnatal sensorimotor development and enhances social memory retention.

The neural cell adhesion molecule (NCAM) belongs to the immunoglobulin (Ig) superfamily and is composed extracellularly of five Ig-like and two fibronectin type III (F3) modules. It plays a pivotal role in neuronal development and synaptic plasticity. NCAM signals via a direct interaction with the fibroblast growth factor receptor (FGFR). A 15-amino-acid long peptide, the FG loop (FGL) peptide, that is derived from the second F3 module of NCAM has been found to activate FGFR1. We here report that the FGL peptide, when administered intranasally to newborn rats, accelerated early postnatal development of coordination skills. In adult animals s.c. administration of FGL resulted in a prolonged retention of social memory. We found that FGL rapidly penetrated into the blood and cerebrospinal fluid after both intranasal and s.c. administration and remained detectable in the fluids for up to 5 hours.

IL-1beta-induced pro-apoptotic signalling is facilitated by NCAM/FGF receptor signalling and inhibited by the C3d ligand in the INS-1E rat beta cell line.

AIMS/HYPOTHESIS: IL-1beta released from immune cells induces beta cell pro-apoptotic signalling via mitogen-activated protein kinases (MAPKs) and nuclear factor-kappaB (NF-kappaB). In neurons, the neural cell adhesion molecule (NCAM) signals to several elements involved in IL-1beta-induced pro-apoptotic signalling in beta cells. Pancreatic beta cells express NCAM, but its biological effects in these cells are unclear. The aim of this study was to investigate whether there is cross-talk between NCAM signalling and cytokine-induced pro-apoptotic signalling. MATERIALS AND METHODS: Western blotting was used to investigate levels of NCAM and inducible nitric oxide synthase, phosphorylation of Src and MAPKs, and cleavage of caspase-3. MAPK activity was investigated with an in vitro kinase assay. Apoptosis was detected by cleaved caspase-3 and a Cell Death Detection ELISA(plus) assay. NCAM-induced fibroblast growth factor receptor (FGFR) activation was investigated in NCAM(-/-) Trex293 cells where FGFR phosphorylation was measured by Western blotting after NCAM transfection. RESULTS: Pre-exposure of INS-1E cells to the FGFR-inhibitor SU5402, but not to the Src-inhibitor PP2, dose-dependently inhibited IL-1beta-mediated MAPK activity. A synthetic peptide, C3d, reported to bind NCAM, did not activate MAPK or Akt as reported in neurons but inhibited IL-1beta-induced MAPK activity, thereby mimicking the effect of SU5402. Furthermore, C3d inhibited NCAM-induced FGFR phosphorylation and apoptosis induced by IL-1beta plus IFN-gamma, but did not affect IL-1beta-induced NF-kappaB signalling. CONCLUSIONS/INTERPRETATION: We suggest that NCAM signalling through FGFR is required for efficient IL-1beta pro-apoptotic signalling by facilitating IL-1beta-induced MAPK activation downstream of the NF-kappaB-MAPK branching point. Further, these data identify a novel function of C3d as an inhibitor of NCAM-induced FGFR activity and of IL-1beta-induced MAPK activation in beta cells.

Contrast-enhanced ultrasonography with SonoVue after infliximab therapy in Crohn's disease.

The introduction of biological treatments like monoclonal anti TNF-a antibodies (infliximab), is changing the clinical history of Crohn's disease (CD). The effects of these therapies are monitored emplying clinical indexes of active disease, laboratory parameters, endoscopy and histology, and also with imaging techniques. A new ultrasound contrast agent, SonoVue (Bracco SpA, Milano, Italy), is opening new perspectives in the study of microvasculature of several organs. Aim of this study is to evaluate by SonoVue enhanced ultrasonography (US) the occurrence of modifications in bowel wall microvasculature of CD patients and to correlate them with parameters of disease activity and to follow up the findings during infliximab therapy. After performing a basal color-doppler ultrasonography, the study of the affected bowel loop is performed after i.v. injection of SonoVue and the enhancement is evaluated on a qualitative basis. We report on the preliminary results obtained in twenty patients, eight of which have been treated with three infusions of infliximab (induction cycle) and evaluated at baseline and after the treatment. While at baseline we describe a positive correlation of SonoVue enhancement of the affected bowel loop with CRP, alpha1-glycoprotein and white blood cell number, after infliximab treatment in 6/8 cases a definite improvement was detected. Ultrasonographic evaluation of the changes of bowel wall enhancement after i.v. SonoVue during infliximab therapy might represent an useful, not invasive and relatively low cost imaging modality for the clinical monitoring of activity of small bowel Crohn's disease.

Cell-cycle-dependent regulation of cell motility and determination of the role of Rac1.

To study cell motility in different phases of the cell cycle, time-lapse recording by computer-assisted microscopy of unsynchronised cells from three mammalian cell lines (L929, BT4Cn, HeLa) was used for the determination of the displacements of individual cells. The displacements were used for calculation of three key parameters describing cell motility: speed, persistence time and rate of diffusion. All investigated cell lines demonstrated a lower cell displacement in the G2 phase than in the G1/S phases. This was caused by a decrease in speed and/or persistence time. The decrease in motility was accompanied by changes in morphology reflecting the larger volume of cells in G2 than in G1. Furthermore, L-cells and HeLa-cells appeared to be less adherent in the G2 phase. Transfection of L-cells with constitutively active Rac1 led to a general increase in the speed and rate of diffusion in G2 to levels comparable to those of control cells in G1. In contrast, transfection with dominant-negative Rac1 reduced cell speed and resulted in cellular displacements, which were identical in G1 and G2. These observations indicate that migration of cultured cells is regulated in a cell-cycle-dependent manner, and that an enhancement of Rac1 activity is sufficient for a delay of the reduced cell displacement otherwise seen in G2.