Systemic medication and the inflammatory cascade

Periodontal disease is caused by inflammatory processes initiated by the presence of a biofilm. The management of this disease process is largely achieved by disrupting the biofilm to allow regression of inflammation and healing. As our patients are living for longer they are likely to have been exposed to systemic medications that aim to reduce inflammation. These drugs have been shown to decrease inflammation within the periodontal tissues despite not being a primary function of their use. This paper aims to review the relative effects of common systemic medications on the periodontal tissues by analyzing their modes of action and discussing current research and the implications for periodontal treatment.     

Mucosal delivery of a transmission-blocking DNA vaccine encoding Giardia lamblia CWP2 by Salmonella typhimurium bactofection vehicle

In this study, we investigated the use of Salmonella typhimurium (STM1 strain) as a bactofection vehicle to deliver a transmission-blocking DNA vaccine (TBDV) plasmid to the intestinal immune system. The gene encoding the full length cyst wall protein-2 (CWP2) from Giardia lamblia was subcloned into the pCDNA3 mammalian expression vector and stably introduced into S. typhimurium STM1. Eight-week-old female BALB/c mice were orally immunized every 2 weeks, for a total of three immunizations. Vaccinated and control mice were sacrificed 1 week following the last injection. Administration of the DNA vaccine led to the production of CWP2-specific cellular immune responses characterized by a mixed Th1/Th2 response. Using ELISA, antigen-specific IgA and IgG antibodies were detected in intestinal secretions. Moreover, analysis of sera demonstrated that the DNA immunization also stimulated the production of CWP2-specific IgG antibodies that were mainly of the IgG2a isotype. Finally, challenge infection with live Giardia muris cysts revealed that mice receiving the CWP2-encoding DNA vaccine were able to reduce cyst shedding by approximately 60% compared to control mice. These results demonstrate, for the first time, the development of parasite transmission-blocking immunity at the intestinal level following the administration of a mucosal DNA vaccine delivered by S. typhimurium STM1.     

Guided bone regeneration in standardized calvarial defects using beta-tricalcium phosphate and collagen membrane: a real-time in vivo micro-computed tomographic experiment in rats

Guided bone regeneration (GBR) procedures using graft materials have been used for reconstruction of osseous defects. The aim of the present in vivo micro-computed tomographic (µCT) and histologic study was to assess in real time the bone regeneration at GBR sites in standardized experimental calvarial defects (diameter 3.3 mm) using β-tricalcium phosphate (β-TCP) with and without collagen membrane (CM). A single full-thickness calvarial defect was created on the left parietal bone in young female Wistar albino rats (n = 30) weighing approximately 300 g and aged about 6 weeks. The animals were randomly divided into three groups for treatment, based on calvarial defect filling material: (1) control group (n = 10); (2) β-TCP + CM group (n = 10); (3) β-TCP group (n = 10). Real-time in vivo µCT analyses were performed immediately after surgery and at 2, 4, 6 and 10 weeks to determine the volume and mineral density of the newly formed bone (BVNFB, MDNFB) and remaining β-TCP particles (VRBP, MDRBP). The animals were killed at 10 weeks and calvarial specimens were evaluated histologically. In the control group, MDNFB increased significantly at 6 weeks (0.32 ± 0.002 g/mm³, P < 0.01) compared to that at baseline. In β-TCP + CM group, BVNFB (1.10 ± 0.12 mm³, P < 0.01) and MDNFB (0.13 ± 0.02 g/mm³, P < 0.01) significantly increased at the 4th week than baseline. In the β-TCP group, BVNFB (1.13 ± 0.12 mm³, P < 0.01) and MDNFB (0.14 ± 0.01 g/mm³, P < 0.01) significantly increased at 6 weeks compared to that at baseline. Significant reduction in VRBP was neither seen in the β-TCP + CM group nor in the β-TCP group. While in the β-TCP + CM group MDRBP was reduced significantly at 6 weeks (0.44 ± 0.9 g/mm³, P < 0.01) from baseline (0.98 ± 0.03 g/mm³), similar significant reduction in MDRBP from baseline (0.92 ± 0.07 g/mm³) was seen only at 10 weeks (0.45 ± 0.06 g/mm³, P < 0.05) in the β-TCP group. Histologic findings at 10 weeks revealed greater amount of NFB with osteocytes in the matrix, in the β-TCP + CM group than in the β-TCP group. Biomechanical assessment of NFB for hardness (H) and elastic modulus (E) revealed significantly higher values for the β-TCP + CM group (H = 612.6 ± 4.28 Mpa; E = 13.57 ± 0.07 Gpa) when compared to those of the control (H = 192.1 ± 4.93 Mpa; E = 6.76 ± 0.04 Gpa) and the β-TCP groups (H = 241.9 ± 6.29 Mpa; E = 4.34 ± 0.06 Gpa). In conclusion, based on real-time assessment, NFB is formed in calvarial defects as early as 4 weeks following GBR with β-TCP + CM as compared to 6 weeks when β-TCP alone was used.     

Heteroduplex rejection during single-strand annealing requires Sgs1 helicase and mismatch repair proteins Msh2 and Msh6 but not Pms1

Recombination between moderately divergent DNA sequences is impaired compared with identical sequences. In yeast, an HO endonuclease-induced double-strand break can be repaired by single-strand annealing (SSA) between flanking homologous sequences. A 3% sequence divergence between 205-bp sequences flanking the double-strand break caused a 6-fold reduction in repair compared with identical sequences. This reduction in heteroduplex rejection was suppressed in a mismatch repair-defective msh6 Delta strain and partially suppressed in an msh2 separation-of-function mutant. In mlh1 Delta strains, heteroduplex rejection was greater than in msh6 Delta strains but less than in wild type. Deleting PMS1, MLH2,or MLH3 had no effect on heteroduplex rejection, but a pms1 Delta mlh2 Delta mlh3 Delta triple mutant resembled mlh1 Delta. However, correction of the mismatches within heteroduplex SSA intermediates required PMS1 and MLH1 to the same extent as MSH2 and MSH6. An SSA competition assay in which either diverged or identical repeats can be used for repair showed that heteroduplex DNA is likely to be unwound rather than degraded. This conclusion is supported by the finding that deleting the SGS1 helicase also suppressed heteroduplex rejection.     

Telmisartan inhibits hyperalgesia and inflammatory progression in a diabetic neuropathic pain model of Wistar rats

Objective:

To evaluate the potential therapeutic value of telmisartan (TMT) against diabetic neuropathy (DN) and associated pain in Wistar rats.

Methods:

Peripheral DN was induced by a single intraperitoneal streptozotocin injection (55 mg/kg), and 3 weeks later TMT treatment was started (5 and 10 mg/kg/day), and continued for 4 weeks. Mechanical nociceptive threshold, motor coordination, and thermal nociceptive threshold tests were performed before and after TMT treatment. In serum, glucose, pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-6 were assessed. Nerve growth factor (NGF) levels and histopathological changes were estimated in the sciatic nerve. This study was conducted at the Experimental Animal Care Center, Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia between January 2013 and May 2014.

Results:

We observed a significant reduction in mechanical nociceptive threshold, motor coordination, and thermal nociceptive threshold in diabetic animals. The TMT treatment significantly enhanced the reduced mechanical nociceptive threshold. The untreated diabetic animals revealed a significant decrease in sciatic NGF, which was markedly attenuated by TMT. The elevated serum levels of cytokines in diabetic animals were inhibited by the TMT treatments. Histopathological evaluation showed obvious nerve degeneration in the diabetic group that was eliminated in the TMT treated diabetic groups.

Conclusion:

Telmisartan has a potential neuro-protective effect on peripheral DN; this is mediated through its anti-inflammatory effects and its dual properties as an angiotensin receptor blocker, and a partial peroxisome proliferator activator receptor-g ligand.Worldwide, diabetic neuropathy (DN) is a major complication of diabetes mellitus. It affects around 15-25% in type-1, and 30-40% in type-2 diabetic patients, causing disabilities, and a high mortality rate. Neuropathic pain defined as a form of chronic pain resulting from damage or abnormal function of the central or peripheral nervous system.1 Patients with neuropathic pain frequently report sensory abnormalities such as burning sensations, hyperalgesia, allodynia, and dysesthesia.2 Diabetic neuropathy can also alter the patient’s quality of life by interfering with emotional well-being, which represents a challenge for clinicians because of its severity, chronicity, and resistance to some classical analgesics.3 The behavioral responses of diabetic rodents to thermal and mechanical hyper- and hypoalgesia as well as tactile allodynia to external stimuli have led to the identification of several mechanisms of abnormal sensation and pain in diabetes. It is confirmed that DN is characterized by neuronal degeneration and marked alterations in neural growth factors such as nerve growth factor (NGF) and insulin-like growth factor (IGF).4 Despite the availability of therapies to alleviate the symptoms of DN, a limited number of medications are available to control its basic causes. Diabetic associated disability and premature mortality are also caused by vascular complications, and several observational reports suggest the potential benefits of intensive blood pressure lowering of diabetic patients.5 The use of angiotensin converting enzyme inhibitors (ACEI) or an angiotensin receptor blocker (ARB) is recommended by current hypertension guidelines for patients with diabetes to achieve a target blood pressure level of 130/80 mm Hg or lower.5 The correlation between the renin angiotensin system and diabetic complications has been observed. Besides being clinically effective in diabetic nephropathy, ACEI or ARBs can improve nerve conduction deficit during peripheral DN in both animal models and human clinical studies. Furthermore, it has been suggested that ARBs are beneficial for nerve regeneration deficits in peripheral DN.6,7 Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor that activates cellular metabolism leading to cellular growth and differentiation,8 and improved insulin sensitivity.9 The beneficial effects of PPAR-γ ligands were demonstrated in experimental DN by suppressing the angiotensin type receptor 1 (AT1R) expression.10 The PPAR-γ ligands also have anti-inflammatory and antioxidant properties, which are known to be beneficial for microvascular complications in diabetes.9 Telmisartan (TMT) (Micardis^®) is one of the most widely used antihypertensives for diabetic patients. It is an ARB with a nephro-protective11 and neuro-protective effect against retinal inflammation.12 Recently, we reported that TMT increases the levels of neurotrophic factors, endogenous antioxidants, and reduces the signs of apoptosis efficiently in diabetic retina.13 The present study was designed to investigate the potential neuro-protective effects of TMT (Micardis^®) in a Wistar rat model of peripheral DN of streptozotocin-induced diabetes.     

Mixed pH-Sensitive Polymeric Micelles for Combination Drug Delivery

Purpose  

To prepare mixed polymeric micelles that can carry two different drugs, doxorubicin (DOX) and 17-hydroxyethylamino-17-demethoxygeldanamycin (GDM-OH), for combination cancer chemotherapy.     

The use of implants for anchorage in the correction of unilateral crossbites

The provision of orthodontic anchorage in the adult patient can be compromised due to reduced periodontal support, insufficient number of teeth and limited supra-gingival tooth tissue. Where tooth borne anchorage is unavailable for significant orthodontic movement implants represent a viable alternative. This paper describes the use of dental implants for orthodontic anchorage in a partially dentate patient with a severe unilateral cross-bite where orthognathic surgery was the only other realistic option. The implants were successfully engaged using a composite bridge and a modified quad helix appliance for correction of the malocclusion. Once orthodontics was completed the patient was restored using highly sintered ceramic crowns and bridges. This paper highlights the importance of the multi-disciplinary team and the close liaison between the restorative dentist, orthodontist and technician in treatment planning and provision.