Effects of Medications and Subthalamic Nucleus-Deep Brain Stimulation on the Cutaneous Silent Period in Patients With Parkinson's Disease

ObjectivesWe sought to evaluate whether the cutaneous silent period (CSP) could be an electrophysiological indicator reflective of the effects of therapy for Parkinson's disease (PD), including anti-PD medications or deep brain stimulation (DBS).Material and MethodsWe recorded the CSP in 43 patients with PD prior to and following the administration of medication during a pre-DBS evaluation (30 cases) and the “on” and “off” states of subthalamic nucleus DBS (13 cases). The CSP was elicited from the abductor pollicis brevis muscle by an electrical stimulation of the index finger that was 2, 4, and 15 times stronger than the sensory threshold (ST). We measured changes in latencies, including the onset, duration, and end of CSP, and waveform scores from 0 to 3. The correlation between the CSP score and unified PD rating score part III (UPDRS-III) also was assessed.ResultsThe onset latency and duration of CSP were significantly different between high- (15ST) and low-strength stimulations (2ST and 4ST). However, there were no significant latency changes (onset, duration, end of CSP) before and after receiving medication, or during the on and off state of the DBS. Anti-PD medications substantially increased the CSP waveform score only in the 4ST state. However, the waveform score significantly increased in all stimuli states during the DBS-on state. Both medication and the DBS-on state decreased the UPDRS-III. Nevertheless, there was no statistically significant correlation between the UPDRS-III and CSP waveform scores.ConclusionDifferent onset latencies and the duration of CSP between low- and high-strength stimuli support the hypotheses proposing two different reflex pathways. Despite being independent from the UPDRS-III, the CSP may be an electrophysiological indicator reflective of the changes in inhibitory activity to the spinal α-motoneuron in response to anti-PD medications and DBS.     

Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance

Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists. Treatment with tolerogenic nanoparticles results in the inhibition of CD4+ and CD8+ T-cell activation, an increase in regulatory cells, durable B-cell tolerance resistant to multiple immunogenic challenges, and the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis, and antibody responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. Tolerogenic nanoparticle therapy represents a potential novel approach for the treatment of allergies, autoimmune diseases, and prevention of antidrug antibodies against biologic therapies.Undesired immunogenicity can have a profound impact on human health. Allergies, including allergic asthma and severe food allergies, affect ∼20% of the population, and the prevalence has been steadily increasing over the past several decades (1). The prevalence of autoimmune diseases, including multiple sclerosis and type 1 diabetes, is ∼4.5% (2). Unwanted immunogenicity can also affect both efficacy and safety of biologic drugs (3), particularly in the case of protein replacement therapies for the treatment of genetic deficiencies, such as hemophilia A (4) and Pompe Disease (5). Immunomodulatory agents commonly used to control immunogenicity are often broadly immunosuppressive and typically require chronic administration that can lead to reactivation of latent pathogens, development of tumors, and opportunistic infections (6, 7). Therefore, antigen-specific, durable tolerogenic therapy would be highly desirable from an efficacy and safety perspective.Multiple techniques for antigen-specific immunotherapy have been described, although only allergen immunotherapy, wherein low doses of antigen are delivered in the absence of immunomodulating agents, is currently used in the clinic (1). Experimental approaches have included oral administration of antigen, high dose tolerance, and the use of altered peptide ligands (8). Although these methods have been successful in preclinical models, translation to human clinical trials has been largely disappointing (8). Alternative strategies to leverage tolerogenic programming associated with apoptotic cells include conjugating antigen to splenocytes (9–12) or synthetic microparticles (13, 14) or targeting antigen to the surface of red blood cells (15). Other approaches include loading particles with MHC complexes that present relevant peptides in the absence of costimulation (16, 17), liposomal copresentation of antigen with a ligand specific for the negative signaling receptor CD22 on B cells (18), codelivery of peptide antigen with an aryl hydrocarbon receptor agonist (19), and cotreatment with pharmacological agents, such as methotrexate (20). A major concern for antigen immunotherapy is the ability to induce and maintain tolerance in the presence of proinflammatory stimuli caused by tissue stress, injury, or concurrent infections. We sought to develop an antigen-specific tolerogenic technology that could control both T-cell– and B-cell–mediated immunity and that was durable over time and to multiple challenges with the antigen, even in the presence of strong innate immune stimulants.Dendritic cells (DCs) are an attractive target for immunotherapies due to their central role in antigen presentation to T cells and their ability to induce and control regulatory responses to secure self-tolerance (21–25). Thomson and colleagues (26, 27) demonstrated that treating DCs with rapamycin, an inhibitor of the mTOR pathway, induces a tolerogenic DC phenotype capable of inducing Treg differentiation and antigen-specific immune tolerance that is resistant to the proinflammatory cascade triggered by TLR signaling. However, conventional therapy with free rapamycin requires chronic systemic administration, resulting in broad immunosuppression due to its direct effect on lymphocytes (28), whereas low doses of rapamycin may paradoxically augment effector T-cell memory (29). Thus, it would be desirable to transiently target rapamycin’s effects to DCs and other antigen-presenting cells (APCs) at the time of antigen encounter. Nanoparticles (NPs) are an ideal mechanism to deliver antigen (16, 30, 31) and drugs (32) to APCs, as these cells are keyed to capture and internalize nanoparticulates such as viruses.Here we describe the development of tolerogenic NPs (tNPs) using materials and compounds that have been well validated in the clinic. These self-assembling, biodegradable poly(lactide-coglycolide) (PLGA) tNPs containing either protein or peptide antigens and rapamycin are capable of inducing durable antigen-specific tolerance that control adaptive immune responses and withstand multiple immunogenic challenges with antigen. We demonstrate that either s.c. or i.v. administration of tNPs inhibits the activation of antigen-specific CD4+ and CD8+ T cells and B cells while inducing antigen-specific Tregs and Bregs. Swiss Jack Lambert (SJL) mice immunized with the myelin proteolipid protein 139–151 peptide in complete Freud’s adjuvant (PLP_139–151/CFA) and treated therapeutically with a single dose of tNPs at the peak of disease are completely protected from developing relapsing paralysis. In hemophilia A animals, administration of tNP before or after the establishment of an anti-factor VIII (FVIII) antibody response led to a significant reduction of the neutralizing antibody response against FVIII. Treatment of mice with tNP prevents both cellular and humoral immunity even in the presence of potent TLR agonists. These effects are dependent on the presence of the encapsulated rapamycin (not free in solution).     

Common variable immunodeficiency with unusual vegetative lesions of the tongue and labial mucosa: a case report

A case of common variable immunodeficiency with unusual vegetative lesions of the tongue and lower lip in a 28-year-old man is presented. The vegetative lesions developed over the preceding 10 months and clinically were suggestive of malignancy. The biopsy specimens showed no malignancy, and a bacterial culture of the tongue detected abundant Staphylococcus aureus. Combined treatment with a corticosteroid antibiotic ointment and povidone iodine rinse produced remarkable resolution of the lesions. Laboratory examination showed markedly decreased levels of serum immunoglobulins. Intravenous gamma globulin replacement therapy resulted in good control of infection and disappearance of the lesions.     

The effects of an incisal bite plane on rat submandibular glands

The submandibular glands of rats subjected to application of an incisal bite plane became slightly, but not significantly, enlarged. However, in comparison with control animals, they secreted additional proteins identical with those secreted by glands enlarged by periodic incisor amputation or chronic isoproterenol treatment.     

Locally administered interferon-γ accelerates lipopolysaccharide-induced osteoclastogenesis independent of immunohistological RANKL upregulation

Ayon Haro ER, Ukai T, Yokoyama M, Kishimoto T, Yoshinaga Y, Hara Y. Locally administered interferon‐γ accelerates lipopolysaccharide‐induced osteoclastogenesis independent of immunohistological RANKL upregulation. J Periodont Res 2011; 46: 361–373. © 2011 John Wiley & Sons A/S Background and Objective: Interferon‐γ (IFN‐γ) potently inhibits RANKL‐induced osteoclastogenesis in vitro. In contrast, previous studies have shown that an increase in IFN‐γ expression is correlated with an increase in lipopolysaccharide (LPS)‐induced bone loss in vivo. However, it is not clear whether local IFN‐γ accelerates osteoclastogenesis or not in vivo. Therefore, the aim of this study was to clarify the role of local IFN‐γ in LPS‐induced osteoclastogenesis. Material and Methods: We induced bone loss in calvaria by injecting LPS. One group of mice received an IFN‐γ injection together with LPS injection, while another group received IFN‐γ 2 d after LPS injection. Bone resorption was observed histologically. Next, we stimulated murine bone marrow macrophages with macrophage‐colony stimulating factor and RANKL in vitro. We added different doses of IFN‐γ and/or LPS at 0 or 48 h time points. Cells were stained with tartrate‐resistant acid phosphatase at 72 h. Results: Local administration of IFN‐γ together with LPS injection did not affect osteoclast formation. However, IFN‐γ injected after LPS injection accelerated osteoclast formation. Also, we confirmed that IFN‐γ added at 0 h inhibited RANKL‐induced osteoclastogenesis in vitro. However, inhibition by IFN‐γ added at 48 h was reduced compared with that by IFN‐γ added at 0 h. Interestingly, IFN‐γ together with a low concentration of LPS accelerated osteoclast formation when both were added at 48 h compared with no addition of IFN‐γ. Conclusion: The results suggest that local IFN‐γ accelerates osteoclastogenesis in certain conditions of LPS‐induced inflammatory bone loss.     

Influence of preparation features on retention and resistance. Part II: three-quarter crowns

Four three-quarter crown variations were tested for retention and resistance and compared with results of a previous study.¹⁵ Preparations with boxes or four grooves are the most retentive of the three-quarter crown designs used in the study. Lingual placement of proximal grooves enhanced the retention. Three-quarter crowns with V-shaped grooves are the least resistant of the preparation designs with retention/resistance features.