Platelet-derived growth factors induced lymphangiogenesis: evidence,unanswered questions and upcoming challenges

Crosstalk between angiogenesis and lymphangiogenesis in embryonic development continues during postnatal life and has specific mechanisms involving factors that initiate activation of the intracellular cascade for their specific receptors. Platelet-derived growth factors (PDGFs) and their corresponding receptors (PDGFRs) are known as important regulators of blood vessel development in both normal and pathologic angiogenesis. Despite some recent papers which reported a potential role of the PDGF/PDGFR axis in lymphatic spread of tumor cells, a few papers have suggested the potential role of PDGFs in tumor lymphangiogenesis development. The present paper summarizes the potential lymphangiogenic role of the PDGF/PDGFR axis, underlying upcoming challenges in the field.     

Howell‐Jolly bodies on peripheral smear leading to the diagnosis of congenital hyposplenism in a patient with septic shock

We present a case of isolated congenital hyposplenism that was discovered after the peripheral smear revealed Howell‐Jolly bodies. This case serves as the basis for a review of hyposplenism for the general practitioner.     

Local synaptic integration of mitogen-activated protein kinase and protein kinase A signaling mediates intermediate-term synaptic facilitation in Aplysia

It is widely appreciated that memory processing engages a wide range of molecular signaling cascades in neurons, but how these cascades are temporally and spatially integrated is not well understood. To explore this important question, we used Aplysia californica as a model system. We simultaneously examined the timing and subcellular location of two signaling molecules, MAPK (ERK1/2) and protein kinase A (PKA), both of which are critical for the formation of enduring memory for sensitization. We also explored their interaction during the formation of enduring synaptic facilitation, a cellular correlate of memory, at tail sensory-to-motor neuron synapses. We find that repeated tail nerve shock (TNS, an analog of sensitizing training) immediately and persistently activates MAPK in both sensory neuron somata and synaptic neuropil. In contrast, we observe immediate PKA activation only in the synaptic neuropil. It is followed by PKA activation in both compartments 1 h after TNS. Interestingly, blocking MAPK activation during, but not after, TNS impairs PKA activation in synaptic neuropil without affecting the delayed PKA activation in sensory neuron somata. Finally, by applying inhibitors restricted to the synaptic compartment, we show that synaptic MAPK activation during TNS is required for the induction of intermediate-term synaptic facilitation, which leads to the persistent synaptic PKA activation required to maintain this facilitation. Collectively, our results elucidate how MAPK and PKA signaling cascades are spatiotemporally integrated in a single neuron to support synaptic plasticity underlying memory formation.During signal transduction, single molecules often generate different cellular effects, depending on their temporal dynamics, spatial distribution, and interacting partners (1). In considering the wide range of molecules implicated in memory processing, the question of how multiple signaling cascades are integrated in time and space to contribute to memory formation and its underlying synaptic plasticity remains a fundamental issue.We have begun to explore this general question in Aplysia californica, a model system well suited for mechanistic analyses of simple forms of learning. We focused on two molecules, MAPK (ERK1/2) and protein kinase A (PKA), both known to be engaged in many forms of memory and synaptic plasticity (2–4). Recent studies, however, suggest the timing, cellular location, and cross-talk between these kinases are critical in determining their ultimate effects (5–10). Thus, in addition to knowing that MAPK and PKA are required, it also is important to understand their spatiotemporal dynamics and their interactions during memory formation.Aplysia provides unique advantages for analyzing these questions. In Aplysia, memory for sensitization induced by tail shock (TS) is supported in large measure by synaptic facilitation at identified tail sensory-to-motor neuron (SN-MN) synapses (11). As an analog of behavioral training, tail nerve shock (TNS) also induces synaptic facilitation (12–14). A single TNS induces short-term facilitation (STF) lasting <30 min, whereas repeated spaced TNS induces intermediate-term (ITF) and long-term facilitation (LTF) lasting hours and days, respectively. TS/TNS triggers the release of serotonin (5-HT) around SN soma and SN-MN synapses, which activates a series of signaling cascades, including MAPK and cAMP/PKA (11, 12). MAPK activation is required for the formation of ITF and LTF, but not for STF, whereas cAMP/PKA is required for all three (15–18). Finally, although signaling in the synaptic compartment is critical for all forms of synaptic facilitation, it has not yet been established that MAPK and PKA can indeed be activated and exert their function locally at the SN-MN synapse. Nor is it known how they interact with each other during synaptic facilitation.In the present paper, we simultaneously examined MAPK and PKA activation in two subcellular compartments (SN soma and synaptic neuropil) at two time points (immediately and 1 h) after TNS. We found that MAPK was activated immediately and persistently in both compartments after repeated TNS. In contrast, although immediate and persistent PKA activation by repeated TNS also occurred in synaptic neuropil, we observed only delayed PKA activation in SN soma. Interestingly, MAPK activation during, but not after, TNS was essential for synaptic, but not somatic, PKA activation. Synaptic integration of these two signaling cascades in turn led to ITF. These results provide unique insights into both the spatial and temporal features of these two critical molecular cascades, and suggest a model of how they interact to regulate synaptic plasticity underlying memory formation.     

Salivary antioxidant biomarkers in non-ferrous metals mine workers--a pilot study

J Oral Pathol Med (2012) 41 : 490–493 Objective: The purpose of the present study is to evaluate the relationships between occupational exposure to mine dust, salivary antioxidants and their possible implications in the pathogenicity of different exposure diseases. Material and methods: We studied 30 individuals with long‐term occupational exposure to non‐ferrous metal mine conditions and a control group consisted of 30 healthy volunteers. Salivary uric acid, gammaglutamyltransferase (GGT), albumin and the total antioxidant capacity (TAC) were measured. Results: Statistically significant differences in salivary GGT (P = 0.004), TAC (P < 0.001) and uric acid (P = 0.02) were noted between the two groups. A strong positive correlation between TAC and uric acid was recorded in controls (r = 0.76, P = 0.0002). Conclusions: Saliva may provide an important line of antioxidant defense in humans exposed to oxidant threats. These components may also serve as convenient biomarkers to monitor oxidant exposure.     

Photomicrographic evaluation of the apical sealing capacity of three types of gutta-percha master cones: an in vitro study

The purpose of this study was to compare the apical sealing capacity of three types of gutta-percha master cones of the same apical size and different tapers following root canal preparation with nickel–titanium ProTaper Universal rotary instruments and microstructural replication with System B and Obtura III. Thirty extracted human incisors having one single straight root canal (type I Weine) were instrumented with rotary ProTaper to an F3 (30/.09) and gauged to confirm a final apical size of #30. Teeth were divided into three groups (n = 10) to be obturated as follows: Group 1: master cone Meta 0.06 taper/AH Plus, Group 2: master cone fine-medium Autofit 0.08 taper/AH Plus, and Group 3: master cone ProTaper F3 0.09 taper/AH Plus. The chosen technique was the continuous wave of compaction (System B and Obtura III). Teeth were embedded in acrylic and incrementally reduced at 0.5 and 1.0 mm from the apical foramina in a grinding machine for metallographic samples. Sections were examined and digitally photographed under a metallographic optical microscope in normal and polarized light and the images were processed. The total cross-sectional area of the root canal, the gutta-percha/sealer/voids’ areas were quantified for each sample and statistically compared using one-way ANOVA and Kruskal–Wallis tests. No statistically significant differences between groups were observed (P > 0.05); however, the mean percentage of the gutta-percha-filled area was slightly higher in Group 1 at both levels of observation. Despite different tapers, all the three types of cones provided a good sealing capacity in the last apical millimeter of the root canal, with good gutta-percha–sealer ratio and few or no voids.     

The Mandibular Ridge Oral Mucosa Model of Stromal Influences on the Endothelial Tip Cells: An Immunohistochemical and TEM Study

This study aimed to evaluate by immunohistochemistry and transmission electron microscopy (TEM) the morphological features of the oral mucosa endothelial tip cells (ETCs) and to determine the immune and ultrastructural patterns of the stromal nonimmune cells which could influence healing processes. Immune labeling was performed on bioptic samples obtained from six edentulous patients undergoing surgery for dental implants placement; three normal samples were collected from patients prior to the extraction of the third mandibular molar. The antibodies were tested for CD34, CD117(c‐kit), platelet derived growth factor receptor‐alpha (PDGFR‐α), Mast Cell Tryptase, CD44, vimentin, CD45, CD105, alpha‐smooth muscle actin, FGF2, Ki67. In light microscopy, while stromal cells (StrCs) of the reparatory and normal oral mucosa, with a fibroblastic appearance, were found positive for a CD34/CD44/CD45/CD105/PDGFR‐α/vimentin immune phenotype, the CD117/c‐kit labeling led to a positive stromal reaction only in the reparatory mucosa. In TEM, non‐immune StrCs presenting particular ultrastructural features were identified as circulating fibrocytes (CFCs). Within the lamina propria CFCs were in close contact with ETCs. Long processes of the ETCs were moniliform, and hook‐like collaterals were arising from the dilated segments, suggestive for a different stage migration. Maintenance and healing of oral mucosa are so supported by extensive processes of angiogenesis, guided by ETCs that, in turn, are influenced by the CFCs that populate the stromal compartment both in normal and reparatory states. Therefore, CFCs could be targeted by specific therapies, with pro‐ or anti‐angiogenic purposes. Anat Rec, 2013. © 2012 Wiley Periodicals, Inc.     

The influence of excipients on physical and pharmaceutical properties of oral lyophilisates containing a pregabalin-acetaminophen combination

Objectives: The purpose of the study was to investigate and characterize the oral lyophilisates containing the pregabalin-acetaminophen drug combination and as xcipients mannitol with microcrystalline cellulose or hydroxypropyl methylcellulose, in order to conclude upon drug-excipient interactions and their stability implications, impact of excipients on drug release and on the physicochemical and mechanical properties of the pharmaceutical formulations.

Methods: The oral tablets were made by using a Christ freeze-dryer alpha 2–4-LSC lyophilizer, and evaluated for stability, drug-excipient compatibility and homogeneity of the prepared pharmaceutical formulations. The formulations were evaluated for in vivo absorption in rabbits by histopathological exams.

Results: FTIR and thermogravimetric analyses, DLS technique, SEM and NIR-CI studies confirmed the compatibility between compounds. From the determined physical and biochemical parameters of the formulations it was established that they are stable, homogeneous, and meet the conditions for orally disintegrating tablets.

Conclusion: In the case of the investigated pharmaceutical formulations the study evidenced the assembling through physical bonds between the excipients and the ‘codrug’ complex, which do not affect the release of the bioactive compounds.