Expression of AMPA-type glutamate receptors in HEK cells and cerebellar granule neurons impairs CXCL2-mediated chemotaxis

We find that cerebellar granule neurons (CGN) obtained from newborn rats (p3) migrate in response to both CXC chemokine ligand-2 (CXCL2) and -12 (CXCL12), while CGN from p7 rats are unresponsive to CXCL2. The expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptor 1 (GluR1) greatly impairs the chemotaxis induced by CXCL2 in CXCR2-expressing HEK cells. By immunoprecipitation, we show that CXCR2 is associated with AMPA receptors (AMPARs) in p7 CGN, and with GluR1 co-expressed in HEK cells. Taken together, these results suggest that the association between CXCR2 and AMPARs results in the inhibition of CXCL2-dependent chemotaxis, and may represent a molecular mechanism underlying the modulation of nerve cell migration.     

The traffic light paradigm: a reaction time task to study laterally directed arm movements

Patients with unilateral brain damage may show slowed or hypometric arm movements toward the contralesional space, as compared to movements directed towards the side of the brain lesion. The present article describes a reaction time paradigm devised to study accuracy and latency of directional arm movements in normal human subjects and brain-damaged patients. Experimental paradigms hitherto used to explore directional motor disorders often do not reliably disentangle between perceptual and motor factors, because they employ lateralized perceptual stimuli. The traffic light paradigm, instead, consists of visual stimuli presented on the vertical midline (like a traffic light) and hand responses to be produced in either hemispace. Thus, participants have to produce lateralized arm responses to central visual stimuli. Performance on this 'motor' paradigm can be contrasted with performance on a 'perceptual' reaction time task, consisting of similar, but lateralized visual stimuli and central motor responses. Results obtained with these paradigms on normal participants and brain-damaged patients are presented and discussed. These results give empirical support to the claim that the traffic light paradigm is suitable to study directional motor disorders in relative isolation from perceptual biases.     

Phenotypic and functional differences between wild-type and CCR2-/- dendritic cells: implications for islet transplantation

BACKGROUND: Trafficking of dendritic cells (DC), the primary regulators of alloimmune responses, is controlled by chemokines. Here, we provide evidence that lack of CCR2 could lead to the generation of functionally and phenotypically different DC, which in part could explain the benefits observed in transplanting islets in CCR2 recipients. METHODS AND RESULTS: We show that, in contrast to the in vitro DC maturation model, in vivo DC maturation is accompanied by an increase in the expression of CCR2. Compared with wild-type (WT), DC generated in vitro from CCR2 mice, and DC extracted from CCR2 na?ve mice or from CCR2 recipients of islet allografts, display lesser allostimulatory capacity. Compared with WT DC, CCR2 DC produce more IL-4 and induce more IL-4-producing T cells. CCR2 DC also promote the generation of regulatory T cells that more efficiently suppress T cell proliferative responses by mixed leukocyte reaction. Similarly, the percentage of CD4CD25FoxP3 cells were found to be higher in CCR2 recipients of islet allografts than in WT recipients. CONCLUSIONS: In summary, lack of CCR2 interferes with the allostimulatory capacity of DC and promotes the generation of regulatory T cells. This is the first demonstration of a mechanistic link between targeting a specific chemokine pathway and the DC-regulatory T cell axis in alloimmunity.     

Incidence of Chlamydia trachomatis and other potential pathogens in neonatal conjunctivitis.

OBJECTIVE: Ocular infection in neonatology is a permanent and important health problem. To improve primary attention, prevention, and control, the study of the potential bacterial etiology of all consecutive cases of conjunctivitis was incorporated as a regular procedure in primary care from July 1995 to December 1998. MATERIALS AND METHODS: Prof. A. Posadas Hospital (Great Buenos Aires) has an average of 4294 births per year. This report analyzes the results obtained in 332 infants (age range, 0-30 d) with conjunctivitis.Clinical conjunctivitis was diagnosed in inpatients and outpatients by the same specialized staff. Isolation and characterization of bacteria were done by conventional microbiologic methods, including specific search for Neisseria gonorrhoeae and Chlamydia trachomatis. Chlamydia trachomatis was studied by antigen immunodetection and polymerase chain reaction, and genotyped by restriction fragment length polymorphism. RESULTS: Conjunctivitis had an incidence (cases per 1000 live births) of 39.6 in 1995, 25.3 in 1996, 15.4 in 1997, and 15.2 in 1998. Microbial growth was detected in 167 (50.3%) of 332 cases. Ocular C. trachomatis infection was detected in 26 cases (7.83%). Five of seven isolates in tissue cultures belonged to type E and two to type G. Bacteria from respiratory ecology were the main isolates: Haemophilus influenzae (16.9%), Streptococcus pneumoniae (12.3%), and Staphylococcus aureus (8.7%). Haemophilus influenzae isolates were not serotyped and 17.2% of them were b-lactamase producers. In 15 cases both H. influenzae and S. pneumoniae were isolated together. Of S. pneumoniae, 4.9% were oxacillin resistant. CONCLUSIONS: There has been a decline in the total number of cases of neonatal conjunctivitis, but the disease is still an important health problem. Chlamydia trachomatis also shows a decreasing profile with an incidence of (cases per 1000 live births) 4.39 in 1995, 1.85 in 1996, 1.01 in 1997, and 0.78 in 1998, and a tendency to show more incidence in spring-summer and significant accumulation of cases in babies between 7 and 9 days of age. Haemophilus influenzae alone (12.3%) or associated with S. pneumoniae (4.5%) appears as a prevalent potential bacterial pathogen. A significant accumulation of H. influenzae and S. pneumoniae cases occurs in winter. In 47.6% of cases, there was no bacterial growth. No significant seasonal differences in percentage of negative cultures or among the three-day age groups were detected. Neisseria gonorrhoeae was not found associated with ophthalmia neonatorum in this series.     

Meningitis due to penicillin-resistant Streptococcus pneumoniae in patients with chronic graft-versus-host disease.

Two episodes of meningitis due to penicillin-resistant Streptococcus pneumoniae occurring in two patients with chronic graft-versus-host disease (GVHD) are reported. Both patients were treated with ceftazidime. The first patient died, unresponsive to therapy. The second patient showed clinical improvement, reverting to her baseline mental status. This report draws attention to the fact that in chronic GVHD patients: (1) bacterial prophylaxis does not ensure protection against encapsulated bacteria; (2) rapid microbiological investigation is recommended with any upper respiratory tract infections.     

FOLFOXIRI-Bevacizumab or FOLFOX-Panitumumab in Patients with Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer: A Propensity Score-Based Analysis

BackgroundDoublets plus anti‐epidermal growth factor receptors (EGFRs) are the preferred upfront option for patients with left‐sided RAS/BRAF wild‐type metastatic colorectal cancer (mCRC). Initial therapy with FOLFOXIRI‐bevacizumab is superior to doublets plus bevacizumab independently from primary tumor sidedness and RAS/BRAF status. No randomized comparison between FOLFOXIRI‐bevacizumab versus doublets plus anti‐EGFRs is available in left‐sided RAS/BRAF wild‐type mCRC.Materials and MethodsWe selected patients with left‐sided RAS and BRAF wild‐type mCRC treated with first‐line FOLFOX‐panitumumab or FOLFOXIRI‐bevacizumab in five randomized trials: Valentino, TRIBE, TRIBE2, STEAM, and CHARTA. A propensity score‐based analysis was performed to compare FOLFOXIRI‐bevacizumab with FOLFOX‐panitumumab.ResultsA total of 185 patients received FOLFOX‐panitumumab and 132 received FOLFOXIRI‐bevacizumab. Median progression‐free survival (PFS) and median overall survival (OS) were 13.3 and 33.1 months in the FOLFOXIRI‐bevacizumab group compared with 11.4 and 30.3 months in the FOLFOX‐panitumumab group (propensity score‐adjusted hazard ratio (HR) for PFS, 0.82; 95% confidence interval (CI), 0.64–1.04; p = .11; propensity score‐adjusted HR for OS, 0.80; 95% CI, 0.59–1.08; p = .14). No significant differences in overall response rate and disease control rate were observed. A statistically nonsignificant difference in favor of FOLFOXIRI‐bevacizumab was observed for OS after secondary resection of metastases. Chemotherapy‐related adverse events were more frequent in the FOLFOXIRI‐bevacizumab group, with specific regard to grade 3 and 4 neutropenia (48% vs. 26%, adjusted p = .001).ConclusionAlthough randomized comparison is lacking, both FOLFOXIRI‐bevacizumab and FOLFOX‐panitumumab are valuable treatment options in left‐sided RAS/BRAF wild‐type mCRC.Implications for PracticeA propensity score‐based analysis of five trials was performed to compare FOLFOX‐panitumumab versus FOLFOXIRI‐bevacizumab in left‐sided RAS/BRAF wild‐type metastatic colorectal cancer (mCRC). No significant differences were observed, but FOLFOXIRI‐bevacizumab achieved numerically superior survival outcomes versus FOLFOX‐panitumumab. Chemotherapy‐related adverse events were more frequent in the FOLFOXIRI‐bevacizumab group. These observations suggest that although doublet chemotherapy plus anti‐EGFRs remains the preferred treatment in patients with left‐sided RAS/BRAF wild‐type mCRC, FOLFOXIRI‐bevacizumab is a valuable option able to provide similar, if not better, outcomes at the price of a moderate increase in toxicity and may be adopted based on patients’ preference and potential impact on quality of life.     

Endocardial impedance mapping during circumferential pulmonary vein ablation of atrial fibrillation differentiates between atrial and venous tissue

BACKGROUND: Circumferential pulmonary vein ablation (CPVA) is an effective treatment for atrial fibrillation (AF). Accurate left atrial (LA) mapping is essential for creating lesions at the LA-pulmonary vein (PV) junction, avoiding PV stenosis. OBJECTIVES: The purpose of this study was to establish whether endocardial impedance varies within the LA and PVs and whether it is a useful tool for mapping and ablation. METHODS: Pilot Phase: Three-dimensional LA maps were created using CARTO. Impedance (Z) was measured using a radiofrequency generator at multiple points in the LA, PV ostia (PVO), and deep PVs in 79 patients undergoing their first AF ablation (group 1) and 29 patients undergoing repeat CPVA (group 2). Prospective Phase: In an additional 20 patients, using pilot phase data, one operator defined catheter tip location as either LA or PVO based on CARTO and fluoroscopy. A second operator blinded to CARTO simultaneously did the same based on impedance at 15 +/- 4 points per patient. RESULTS: Group 1: Z(LA) was 99.4 +/- 9.0 omega. Z(PVO) was higher (109.2 +/- 8.5 omega), rising further as the catheter advanced into deep PV (137 omega +/- 18). Z(PVO) differed from Z(LA) by 9 +/- 4 omega. Group 2 had a lower Z(LA) and Z(PVO) compared with group 1 (P <.05). Impedance monitoring differentiated between LA and PVO, with 91% specificity and sensitivity, 96% positive predictive value, and 81% negative predictive value. At 3-month follow-up, no patients had evidence of PV stenosis on magnetic resonance imaging. CONCLUSION: Impedance mapping reliably identifies the LA-PV transitional zone, facilitating AF ablation, and its use is associated with a low incidence of PV stenosis.     

Podoplanin expression as a predictive marker of dysplasia in oral leukoplakia

Purpose

Recent studies have emphasized the role of podoplanin in oral lesions at risk of malignant transformation. We investigated a group of oral leukoplakias (OLs) to determine a possible relation between altered podoplanin expression and dysplasia, and to compare the results with those obtained by other, widely used biomarkers.