Transdermal Pharmacology of Small Molecule Cyclic C5a Antagonists

Overproduction or underregulation of the proinflammatory complement component C5a has been implicated in numerous immune and inflammatory conditions. Therefore, targeting the C5a receptor (C5aR) has become an innovative strategy for antiinflammatory drug development. The novel cyclic peptide C5aR antagonist, AcF-[OP(D-Cha)WR] (PMX53), attenuates injury in numerous animal models of inflammation following intravenous, subcutaneous, intraperitoneal, and oral administration. In the present study the transdermal pharmacology of PMX53 and three analogs designed with increased lipophilicity, hydrocinnamate-[OP(D-Cha)WCit] (PMX200), AcF-[OP(D-Cha)WCit] (PMX201) and hydrocinnamate-[OP(D-Cha)WR] (PMX205), have been examined in order to assess their transdermal permeability and inhibitory effect on C5a-mediated lipopolysaccharide (LPS)-induced systemic responses. In the rat, PMX53, PMX201, and PMX205, were bioavailable following topical dermal administration (10 mg/50 cm(2) site/rat). All analogs functionally antagonized neutropenia and hypotension induced by systemic challenge with LPS (I mg/kg i.v.). Interestingly, PMX200 attenuated LPS-induced neutropenia more effectively than other analogs, despite undetectable (< 5 ng/ml) circulating levels following topical administration. In conclusion, we have demonstrated that cyclic peptide C5aR antagonists can penetrate transdermally sufficiently to have systemic effects. However, increasing lipophilicity in these compounds did not result in increased blood levels. Nonetheless, topical application of C5aR antagonists produced circulating levels of the drugs that antagonized the LPS-induced systemic responses of neutropenia and hypotension. This suggests that these small-molecule C5aR antagonists may be developed for topical administration for the treatment of local and systemic inflammatory conditions in the human and veterinary pharmaceutical markets.

Estimation of R(0) from the initial phase of an outbreak of a vector-borne infection

The magnitude of the basic reproduction ratio R(0) of an epidemic can be estimated in several ways, namely, from the final size of the epidemic, from the average age at first infection, or from the initial growth phase of the outbreak. In this paper, we discuss this last method for estimating R(0) for vector-borne infections. Implicit in these models is the assumption that there is an exponential phase of the outbreaks, which implies that in all cases R(0) > 1. We demonstrate that an outbreak is possible, even in cases where R(0) is less than one, provided that the vector-to-human component of R(0) is greater than one and that a certain number of infected vectors are introduced into the affected population. This theory is applied to two real epidemiological dengue situations in the southeastern part of Brazil, one where R(0) is less than one, and other one where R(0) is greater than one. In both cases, the model mirrors the real situations with reasonable accuracy.

GLOBAL POSTURAL REEDUCATION AND STATIC STRETCHING EXERCISES IN THE TREATMENT OF MYOGENIC TEMPOROMANDIBULAR DISORDERS: A RANDOMIZED STUDY

Objective: The purpose of this study was to compare 2 different interventions, global postural reeducation (GPR) and static stretching exercises (SS), in the treatment of women with temporomandibular disorders (TMDs). Methods: A total of 28 subjects with TMDs were randomized into 2 treatment groups: GPR, where therapy involved muscle global chain stretching, or SS, with conventional static stretching; but only 24 completed the study. Eight treatment sessions lasting 40 minutes each (weekly) were performed. Assessments were conducted at baseline, immediately after treatment end, and 2 months later. Measurements included pain intensity at the temporomandibular joint, headache, cervicalgia, teeth clenching, ear symptoms, restricted sleep, and difficulties for mastication, using a visual analogue scale. In addition, electromyographic activity and pain thresholds were measured at the masseter, anterior temporalis, stemocleidomastoid, and upper trapezius muscles. Two-way analysis of variance with Tukey post hoc test was used for between-group comparisons. Significance level was .05. Results: Comparing the pain assessments using the visual analogue scale, no significant differences were seen with the exception of severity of headaches at treatment end (GPR, 3.92 +/- 2.98 cm; SS, 1.64 +/- 1.66 cm; P < .024). In addition, no significant differences were seen for pain thresholds and for electromyographic activity (P > .05). Conclusions: For the subjects in this study, both GPR and SS were similarly effective for the treatment of TMDs with muscular component. They equally reduced pain intensity, increased pain thresholds, and decreased electromyographic activity. (J Manipulative Physiol Ther 2010;33:500-507)

The neuroprotective effect of dental pulp cells in models of Alzheimer`s and Parkinson`s disease

Aim of the present study was to investigate the neuroprotective effect of dental pulp cells (DPCs) in in vitro models of Alzheimer and Parkinson disease. Primary cultures of hippocampal and ventral mesencephalic neurons were treated for 24 h with amyloid beta (A beta(1-42)) peptide 1-42 and 6-OHDA, respectively. DPCs isolated from adult rat incisors were previously cultured in tissue culture inserts and added to the neuron cultures 2 days prior to neurotoxin treatment. Cell viability was assessed by the MTT assay. The co-culture with DPCs significantly attenuated 6-OHDA and A beta(1-42)-induced toxicity in primary cultures of mesencephalic and hippocampal neurons, and lead to an increase in neuronal viability in untreated cultures, suggesting a neurotrophic effect in both models. Furthermore, human dental pulp cells expressed a neuronal phenotype and produced the neurotrophic factors NGF, GDNF, BDNF, and BMP2 shown by microarray screening and antibody staining for the representative proteins. DPCs protected primary neurons in in vitro models of Alzheimer`s and Parkinson`s disease and can be viewed as possible candidates for studies on cell-based therapy.

Precise Insertion of Orthodontic Miniscrews with a Stereolithographic Surgical Guide Based on Cone Beam Computed Tomography Data: A Pilot Study

Purpose: Orthodontic miniscrews are commonly used to achieve absolute anchorage during tooth movement. One of the most frequent complications is screw loss as a result of root contact. Increased precision during the process of miniscrew insertion would help prevent screw loss and potential root damage, improving treatment outcomes. Stereo lithographic surgical guides have been commonly used for prosthetic implants to increase the precision of insertion. The objective of this paper was to describe the use of a stereolithographic surgical guide suitable for one-component orthodontic miniscrews based on cone beam computed tomography (CBCT) data and to evaluate implant placement accuracy. Materials and Methods: Acrylic splints were adapted to the dental arches of four patients, and six radiopaque reference points were filled with gutta-percha. The patients were submitted to CBCT while they wore the occlusal splint. Another series of images was captured with the splint alone. After superimposition and segmentation, miniscrew insertion was simulated using planning software that allowed the user to check the implant position in all planes and in three dimensions. In a rapid-prototyping machine, a stereolithographic guide was fabricated with metallic sleeves located at the insertion points to allow for three-dimensional control of the pilot bur. The surgical guide was worn during surgery. After implant insertion, each patient was submitted to CBCT a second time to verify the implant position and the accuracy of the placement of the miniscrews. Results: The average differences between the planned and inserted positions for the ten miniscrews were 0.86 mm at the coronal end, 0.71 mm at the center, and 0.87 mm at the apical tip. The average angular discrepancy was 1.76 degrees. Conclusions: The use of stereolithographic surgical guides based on CBCT data allows for accurate orthodontic mini screw insertion without damaging neighboring anatomic structures. INT J ORAL MAXILLOFAC IMPLANTS 2011;26:860-865

The suitability of different FEA models for studying root fractures caused by wedge effect

Finite element analysis (FEA) utilizing models with different levels of complexity are found in the literature to study the tendency to vertical root fracture caused by post intrusion (""wedge effect""). The objective of this investigation was to verify if some simplifications used in bi-dimensional FEA models are acceptable regarding the analysis of stresses caused by wedge effect. Three plane strain (PS) and two axisymmtric (Axi) models were studied. One PS model represented the apical third of the root entirely, in dentin (PS-nG). The other models included gutta-percha in the apical third, and differed regarding dentin-post relationship: bonded (PS-B and Axi-B) or nonbonded (PS-nB and Axi-nB). Mesh discretization and material properties were similar for all cases. Maximum principal stress (sigma(max)) was analyzed as a response to a 165 N longitudinal load. Stress magnitude and orientation varied widely (PS-nG: 10.3 MPa; PS-B: 0.8 MPa; PS-nB: 10.4 MPa; Axi-13: 0.2 MPa, Axi-nB: 10.8 MPa). Axi-nB was the only model where all (sigma(max) vectors at the apical third were perpendicular to the model plane. Therefore, it is adequate to demonstrate the tendency to vertical root fractures caused by wedge effect. Axi-13 showed only part of the (sigma(max) perpendicular to the model plane while PS models showed sigma(max) on the model plane. In these models, sigma(max) orientation did not represent a situation where vertical root fracture would occur due to wedge effect. Adhesion between post and dentin significantly reduced (c) 2007 Wiley Periodicals, Inc.

Algebraic Bethe ansatz for integrable extended Hubbard models arising from supersymmetric group solutions

Integrable extended Hubbard models arising from symmetric group solutions are examined in the framework of the graded quantum inverse scattering method. The Bethe ansatz equations for all these models are derived by using the algebraic Bethe ansatz method.