Christopher P. Robinson

A novel NOD-derived murine model of primary Sjögren's syndrome.

OBJECTIVE The appearance of autoimmune diabetes prior to autoimmune exocrinopathy in the NOD mouse suggests that it is an excellent model of secondary, but not primary, autoimmune sicca complications. Since the unique major histocompatibility complex (MHC) I-A(g7) expression in NOD mice is essential for the development of insulitis and diabetes in these animals, we investigated exocrine gland function in NOD.B10.H2b mice, which have an MHC congenic to NOD, as a potential model for primary Sjögrens syndrome (SS). METHODS Histopathologic manifestations of lymphocytic infiltrates into the pancreas and exocrine tissues were examined by light microscopy. Sera were evaluated for the presence of antinuclear antibodies. Saliva, tears, and gland lysates were evaluated for total volume and protein concentration, the aberrant expression and processing of parotid secretory protein, and cysteine protease activity. RESULTS NOD.B10.H2b mice exhibited the exocrine gland lymphocytic infiltration typical of the SS-like disease and dysfunction observed in NOD mice, but without the insulitis and diabetes. These mice additionally expressed elevated levels of cysteine protease activity (a measure of apoptotic activity) and abnormal expression and cleavage of parotid secretory protein in the submandibular tissues. CONCLUSION The results of this study suggest that the unique NOD MHC I-A(g7) is not essential for exocrine tissue autoimmunity. Furthermore, the findings indicate that sicca syndrome occurs independently of autoimmune diabetes and that the congenic NOD.B10.H2b mouse represents a novel murine model of primary SS.

Characterization of the Changing Lymphocyte Populations and Cytokine Expression in the Exocrine Tissues of Autoimmune Nod Mice

NOD mice develop chronic lymphocytic invasion of the pancreas, submandibular, and lacrimal glands leading to loss of insulin secretion, salivary flow, and tear production. In this study, we have used flow cytometric analyses and RT-PCR to track glandular lymphocyte populations and cytokine expression spanning the initiation of autoimmune infiltration through the development of widespread autoimmune destruction of the salivary and lacrimal glands of NOD mice. Results demonstrate a predominance of CD4+ to CD8+ lymphocytes and a similar predominance of T-cells versus B-cells in both the submandibular and lacrimal gland infiltrates. A temporal increase in memory (CD3+CD45RBlo) T-cells was also detected; however, naive (CD3+CD45RBhi) T-cell populations as well as a CD3+, CD4-/CD8- double negative population were also present. In addition, a skewing of the TCR Vbeta repertoire toward Vbeta6+ and Vbeta8+ lymphocytes was evident in both glandular infiltrates. Analyses of cytokine mRNA expression in the submandibular glands demonstrated an increase between 12 and 16 wk of age of several proinflammatory cytokines including IL-1beta, IL-6, IL-7, IL-10, IFNgamma, TNFalpha, and inducible Nitric Oxide Synthase (iNOS). IL-4 synthesis was notably absent in both tissues. Cytokine mRNA transcripts detected in lacrimal tissue were similar to those seen in the submandibular glands but appeared both earlier and more intensely. These findings depict the progressive development of autoimmune exocrinopathy and can be used as a foundation to explore the similarities and potential differences in the immunopathogenic lesions of several distinct tissues within the same host.

Infiltrating Lymphocyte Populations and Cytokine Production in the Salivary and Lacrimal Glands of Autoimmune NOD Mice

It is only in the last five years that significant interest has developed in detailing the autoimmune destruction of the salivary and lacrimal tissues in the non-obese diabetic (NOD) mouse. Pioneering studies have demonstrated that the lymphocytic infiltration of the salivary and lacrimal glands correlates with a functional decline in saliva flow and tear production, respectively, that is not attributable to the loss of blood glucose regulation in NOD mice.1,2 Together, these studies indicate that the NOD mouse represents the first-described animal model for the spontaneous, autoimmune-induced loss of both tear production and saliva flow, and is, therefore, emerging as an excellent animal model for the study of human Sjogren’s syndrome.

Aberrant expression and potential function for parotid secretory protein (PSP) in the NOD (non-obese diabetic) mouse.

The protein and mucin-rich secretions derived from the salivary, lacrimal, and other minor exocrine tissues are essential for maintaining the health and integrity of the oral and ocular surfaces.1 For the most part, both tear and saliva secretions serve similar functions and contain many of the same protein constituents, e.g., EGF, NGF, TGF-α, lactoferrin, lysozyme, and immunoglobulins.1,2 These proteins provide anti-microbial defense mechanisms, growth factors important for mucosal tissue maintenance and regeneration, and mucinous lubricating agents.

Limb Remote Ischemic Conditioning: Mechanisms, Anesthetics, and the Potential for Expanding Therapeutic Options

Novel and innovative approaches are essential in developing new treatments and improving clinical outcomes in patients with ischemic stroke. Remote ischemic conditioning (RIC) is a series of mechanical interruptions in blood flow of a distal organ, following end organ reperfusion, shown to significantly reduce infarct size through inhibition of oxidation and inflammation. Ischemia/reperfusion (I/R) is what ultimately leads to the irreversible brain damage and clinical picture seen in stroke patients. There have been several reports and reviews about the potential of RIC in acute ischemic stroke; however, the focus here is a comprehensive look at the differences in the three types of RIC (remote pre-, per-, and postconditioning). There are some limited uses of preconditioning in acute ischemic stroke due to the unpredictability of the ischemic event; however, it does provide the identification of biomarkers for clinical studies. Remote limb per- and postconditioning offer a more promising treatment during patient care as they can be harnessed during or after the initial ischemic insult. Though further research is needed, it is imperative to discuss the importance of preclinical data in understanding the methods and mechanisms involved in RIC. This understanding will facilitate translation to a clinically feasible paradigm for use in the hospital setting.

A spicy status: Synthetic cannabinoid (spice) use and new-onset refractory status epilepticus—A case report and review of the literature:

Synthetic cannabinoids refer to a wide variety of chemicals engineered to bind cannabinoid receptors (CB1 and CB2) and mimic the effects of delta-9-tetrahydrocanabinol. The potential for severe toxicity and limited in vivo data make synthetic cannabinoid intake an important public health and safety concern. Neurologic toxidromes associated with their use include mental status changes, panic attacks, memory distortions, acute psychosis (e.g. paranoia, delusional thoughts), disorganized behavior, and suicidal and homicidal thoughts. Systemic complications include vomiting, sinus tachycardia, myocardial infarction, and acute kidney injury. Seizures are common; however, status epilepticus is not widely reported. In this case report, we describe a patient who developed acute psychosis and new-onset refractory status epilepticus necessitating emergent neurological life-support and prolonged admission to an intensive care unit following abuse of synthetic cannabinoids. We include a brief review of the literature to prepare the treating clinician for the broad clinical spectrum of this increasingly common intoxication.