Narrow-band imaging optical chromocolonoscopy： Advantages and limitations

Narrow-band imaging （NBI） is an innovative optical technology that modifies the center wavelength and bandwidth of an endoscope＇s light into narrow-band illumination of 415 ：1： 30 nm. NBI markedly improves capillary pattern contrast and is an in vivo method for visualizing microvessel morphological changes in superficial neoplastic lesions. The scientific basis for NBI is that short wavelength light falls within the hemoglobin absorption band, thereby facilitating clearer visualization of vascular structures. Several studies have reported advantages and limitations of NBI colonoscopy in the colorectum. One difficulty in evaluating results, however, has been nonstandardization of NBI systems （Sequential and nonsequential）. Utilization of NBI technology has been increasing worldwide, but accurate pit pattern analysis and sufficient skill in magnifying colonoscopy are basic fundamentals required for proficiency in NBI diagnosis of colorectal lesions. Modern optical technology without proper image interpretation wastes resources, confuses untrained endoscopists and delays interinstitutional validation studies. Training in the principles of ＂optical image-enhanced endoscopy＂ is needed to close the gap between technological advancements and their clinical usefulness. Currently available evidence indicates that NBI constitutes an effective and reliable alternative to chromocolonoscopy for in vivo visualization of vascular structures, but further study assessing reproducibility and effectiveness in the colorectum is ongoing at various medical centers.     

JC virus granule cell neuronopathy and GCN–IRIS under natalizumab treatment

Progressive multifocal leukoencephalopathy is the most common clinical presentation of JC virus (JCV)‐associated central nervous system (CNS) disease and has emerged as a major safety concern in multiple sclerosis patients treated with the monoclonal antibody natalizumab. Here we report clinical, radiological, and histological findings of a case of cerebellar granule cell neuronopathy (GCN), a JCV‐associated CNS disease, so far unreported amongst patients treated with natalizumab. GCN should be considered as a JCV CNS manifestation in patients with newly developed, progressive cerebellar signs under natalizumab treatment, especially in cases where cerebellar atrophy can be visualized by magnetic resonance imaging. Ann Neurol 2013;74:622–626     

Results of phase II levetiracetam trial following acute head injury in children at risk for posttraumatic epilepsy

Posttraumatic seizures develop in up to 20% of children following severe traumatic brain injury (TBI). Children ages 6–17 years with one or more risk factors for the development of posttraumatic epilepsy, including presence of intracranial hemorrhage, depressed skull fracture, penetrating injury, or occurrence of posttraumatic seizure were recruited into this phase II study. Treatment subjects received levetiracetam 55 mg/kg/day, b.i.d., for 30 days, starting within 8 h postinjury. The recruitment goal was 20 treated patients. Twenty patients who presented within 8–24 h post‐TBI and otherwise met eligibility criteria were recruited for observation. Follow‐up was for 2 years. Forty‐five patients screened within 8 h of head injury met eligibility criteria and 20 were recruited into the treatment arm. The most common risk factor present for pediatric inclusion following TBI was an immediate seizure. Medication compliance was 95%. No patients died; 19 of 20 treatment patients were retained and one observation patient was lost to follow‐up. The most common severe adverse events in treatment subjects were headache, fatigue, drowsiness, and irritability. There was no higher incidence of infection, mood changes, or behavior problems among treatment subjects compared to observation subjects. Only 1 (2.5%) of 40 subjects developed posttraumatic epilepsy (defined as seizures >7 days after trauma). This study demonstrates the feasibility of a pediatric posttraumatic epilepsy prevention study in an at‐risk traumatic brain injury population. Levetiracetam was safe and well tolerated in this population. This study sets the stage for implementation of a prospective study to prevent posttraumatic epilepsy in an at‐risk population.     

Investigation of the Possible Functions of PACAP in Human Trophoblast Cells

Pituitary adenylate cyclase activating polypeptide (PACAP) is an endogenous neuropeptide having a widespread distribution both in the nervous system and peripheral organs including the female reproductive system. Both the peptide and its receptors have been shown in the placenta but its role in placental growth, especially its human aspects, remains unknown. The aim of the present study was to investigate the effects of PACAP on invasion, proliferation, cell survival, and angiogenesis of trophoblast cells. Furthermore, cytokine production was investigated in human decidual and peripheral blood mononuclear cells. For in vitro studies, human invasive proliferative extravillous cytotrophoblast (HIPEC) cells and HTR-8/SVneo human trophoblast cells were used. Both cell types were used for testing the effects of PACAP on invasion and cell survival in order to investigate whether the effects of PACAP in trophoblasts depend on the examined cell type. Invasion was studied by standardized invasion assay. PACAP increased proliferation in HIPEC cells, but not in HTR-8 cells. Cell viability was examined using MTT test, WST-1 assay, and annexin V/propidium iodide flow cytometry assay. Survival of HTR-8/SVneo cells was studied under oxidative stress conditions induced by hydrogen peroxide. PACAP as pretreatment, but not as co-treatment, significantly increased the number of surviving HTR-8 cells. Viability of HIPEC cells was investigated using methotrexate (MTX) toxicity, but PACAP1-38 could not counteract its toxic effect. Angiogenic molecules were determined both in the supernatant and the cell lysate by angiogenesis array. In the supernatant, we found that PACAP decreased the secretion of various angiogenic markers, such as angiopoietin, angiogenin, activin, endoglin, ADAMTS-1, and VEGF. For the cytokine assay, human decidual and peripheral blood lymphocytes were separated and treated with PACAP1-38. Th1 and Th2 cytokines were analyzed with CBA assay and the results showed that there were no significant differences in control and PACAP-treated cells. In summary, PACAP seems to play various roles in human trophoblast cells, depending on the cell type and microenvironmental influences.     

Presynaptic GABA(B) receptors on glutamatergic terminals of CA1 pyramidal cells decrease in efficacy after partial hippocampal kindling

We tested the hypothesis that presynaptic GABA(B) receptors on glutamatergic terminals (GABA(B) heterosynaptic receptors) decreased in efficacy after partial hippocampal kindling. Rats were implanted with chronically indwelling electrodes and 15 hippocampal afterdischarges were evoked by high-frequency electrical stimulation of hippocampal CA1. Control rats were implanted with electrodes but not given high-frequency stimulations. One to 21 days after the last afterdischarge, excitatory postsynaptic potentials (EPSPs) were recorded in CA1 of hippocampal slices in vitro, following stimulation of the stratum radiatum. Field EPSPs (fEPSPs) were recorded in CA1 stratum radiatum and intracellular EPSPs (iEPSPs) were recorded from CA1 pyramidal cells. GABA(B) receptor agonist +/- baclofen (10 microM) in the bath suppressed the fEPSPs significantly more in control than kindled rats, at 1 or 21 days after kindling. Similarly, baclofen (10 microM) suppressed iEPSPs more in the control than the kindled group of neurons recorded at 1 day after kindling. Suppression of the fEPSPs by 1 microM N(6)-cyclopentyladenosine, which acted on presynaptic A1 receptors, was not different between kindled and control rats. Activation of the GABA(B) heteroreceptors by a conditioning burst stimulation of CA3 afferents suppressed the iEPSPs evoked by a test pulse. The suppression of the iEPSPs at 250-500 ms condition-test interval was larger in control than kindled groups of neurons. It was concluded that the efficacy of presynaptic GABA(B) receptors on the glutamatergic terminals was reduced after partial hippocampal kindling. The reduction in heterosynaptic presynaptic GABA(B) receptor efficacy will increase glutamate release and seizure susceptibility, particularly during repeated neural activity.     

Outcome and treatment quality of transfer primary percutaneous intervention in older patients with acute ST-elevation myocardial infarction (STEMI)

The aim of this study was to evaluate the outcome and treatment quality of transfer percutaneous coronary intervention (PCI) in older patients with acute STEMI. In this prospective study all patients with diagnosed acute (pain-to-balloon ≤ 12 h) STEMI transferred to our institution for primary PCI (n = 400) between January 2005 and October 2007 were under investigation. Overall 125 older patients with age ≥70 years were included (mean age 77.5 ± 4.9 years; 77 males). Pre-hospital delays were more common in older patients with longer pain-to-balloon: median (range) = 85 (5-629) vs. 66 (1-688) p = 0.031, and pain-to-first medical-contact-times: median: 206 (84-711) vs. 172 (45-720); p = 0.001. A trend towards a higher (non-significant) rate of major 5/125 (5%) vs. 5/275 (1.8%), p = 0.195 and minor 10/125 (8%) vs. 14/275 (5.1%). p = 0.256 bleeding complications in older patients was evident. In-hospital mortality was significantly higher in older patients compared to the younger patients group: 13/125, 10.4% vs. 8/275, 2.9%, p = 0.002). Overall mortality at 30-day follow-up was 11.2% in older and 3.3% in younger patients: 14/125 vs. 9/275, p = 0.002. Transfer PCI is an effective treatment strategy for older patients with acute ST-elevation myocardial infarction. Overall-30-day mortality in older STEMI-patients transferred for primary PCI is comparably low.     

Volume therapy with colloid solutions preserves intestinal microvascular perfusion in endotoxaemia

Colloid solutions have been suggested to improve microvascular perfusion due to their anti-inflammatory properties. Whether this also applies for the gut, an important immunological organ vulnerable to hypoperfusion is unknown. This study investigated intestinal microcirculation of endotoxaemic rats after volume therapy with colloid solutions such as hydroxyethyl starch (HES) and gelatin or isotonic saline (NaCl). In addition intestinal oxygenation and morphology as well as mesenteric leukocyte-endothelium interaction were quantified. Rats were anaesthetised with urethane and ketamine, mechanically ventilated, and monitored haemodynamically. Normotensive endotoxaemia was induced by a continuous intravenous infusion of Escherichia coli lipopolysaccharide (LPS, 1.5 mg kg(-1) h(-1)). After 1 h of LPS infusion either 6% HES (16 ml kg(-1)), 4% gelatin (16 ml kg(-1)) or 0.9% NaCl (64 ml kg(-1)) were infused for 1 h. Using intravital microscopy, functional capillary density (FCD) and red blood cell velocity (RBCV) were measured in the mucosa of the terminal ileum at baseline and 3 h after volume therapy. In another set of animals, mesenteric leukocyte-endothelium interaction was determined 3 h after volume therapy. In all animals intestinal lactate/pyruvate ratio and intestinal morphology were assessed. Three hours after volume therapy, FCD decreased in NaCl (808 [749/843] cm(-1); median [quartiles] P<0.05 versus baseline) but not in HES (995 [945/1036] cm(-1)) and gelatin (988 [867/1193] cm(-1)) groups. RBCV, lactate/pyruvate ratio and intestinal morphology did not differ among groups. Also mesenteric leukocyte-endothelium interaction was not significantly influenced by either treatment. In conclusion, early volume therapy with HES or gelatin, but not with NaCl, preserved gut microvascular perfusion during endotoxaemia but did not have a significant effect on tissue oxygenation nor morphological appearance in this experimental model. An anti-inflammatory effect of colloid solutions was not seen and fails to explain the changes in intestinal microcirculation.     

Diabetes control in type 2 diabetic subjects treated in primary health care

Aim of the study was to assess control of type 2 diabetes in subjects treated by general practitioners. Study was conducted in one of the primary health care centers in a big city, in which health care was provided for 27 900 inhabitants. Control of diabetes was assessed in 355 of all 936 type 2 diabetic subjects registered in the center. None of them was seen by diabetologist in the preceeding year. Mean age was 65,7 +/- 10,3 lat, diabetes duration 9,2 +/- 7,3 lat, BMI 29,9 +/- 4,9 kg/m2. Normal body weight was found in 15%, overweight in 39%, obesity in 46% of subjects. Hypertension was present in 81%, dyslipidaemia in 62% of patients. Mean HbAlc was 7,2 +/- 1,3%, fasting serum glycaemia 144 +/- 48 mg/dl, total cholesterol 204 +/- 45 mg/dL, LDL - 119 +/- 33 mg/dL, HDL - 51 +/- 13 mg/dl, triglicerides 182 +/- 108 mg/dL. Mean systolic blood pressure was 146 +/- 20 mmHg, diastolic 83 +/- 11 mmHg. Treatment goals recommended by Polish Diabetological Association in 2005 were attained as follows: HbAlc < or = 6,1% - 19,7% of subjects, fasting glycaemia < or =110 mg/dl - 24%, total cholesterol < 175 mg/dl - 26%, LDL < 100 mg/dl - 29%, triglicerides < 150 mg/dl - 46%, cholesterol HDL > 40 mg/dl in men and > 50 mg/dl in women - 65% of subjects. Recommended systolic blood pressure < 130 mmHg was found in 16 %, diastolic blood pressure < 80 mmHg - in 24%, and both values - in 8% of diabetics. In no one subject all recommended treatment goals were met. Conclusions 1. Recommended treatment goals are perceived in unacceptably low number of type 2 diabetic subjects treated by general practitioners. 2. Medical care of type 2 diabetic subjects performed in primary health care is unsatisfactory and should be essentially improved or changed.     

Transient receptor potential canonical channel 1 impacts on mechanosignaling during cell migration

Cell migration is crucial for many important physiological and pathophysiological processes ranging from embryogenesis to tumor metastasis. It requires the coordination of mechanical forces generated in different regions of the migrating cell. It has been proposed that stretch-activated, Ca²⁺-permeable channels are involved in mechanosignaling during cell migration. To date, the molecular identity of these channels is only poorly defined. Here, we investigated the contribution of TRPC1 channels to mechanosignaling during cell migration. We used primary cultures of synovial fibroblasts from TRPC1^?/? mice and the wild-type littermates or Madin?CDarby canine kidney (MDCK-F) cells with increased or decreased TRPC1 expression. TRPC1^?/? fibroblasts have the same migratory phenotype as siTRPC1 MDCK-F cells, with a largely increased projected cell area and impaired directionality. Measurements of the intracellular Ca²⁺ concentration ([Ca²⁺]_i) were combined with time-lapse video microscopic cell migration experiments. Cells were seeded on elastic silicone membranes. Uniaxial stretch elicits a graded elevation of the [Ca²⁺]_i in TRPC1-expressing cells. In contrast, TRPC1^?/? fibroblasts or siTRPC1 MDCK-F cells do not react to 0.4?%, and the response to 4?% stretch is attenuated. Similarly, siTRPC1 MDCK-F cells do not alter their direction of migration upon mechanical stimulation, which contrasts the behavior of TRPC1-overexpressing cells which turn into the direction of stretch. Impaired mechanosignaling in siTRPC1 MDCK-F cells leads to accelerated lamellipodial protrusions. Finally, artificially decreasing membrane tension with the detergent deoxycholate impairs the migration of TRPC1-overexpressing cells, but not of siTRPC1 cells. Taken together, our findings indicate that TRPC1 channels are linked to mechanosignaling during cell migration.