OBJECTIVES Recent evidence suggests that functional deficiency in regulatory T cells (Tregs), an innate immuno-modulator, exacerbates brain damage after cerebral ischemia. We therefore evaluated the effect of Treg transfer in rodent models of ischemic stroke and further investigated the mechanism underlying Treg-afforded neuroprotection. METHODS We examined the therapeutic potential of Tregs and the mechanisms of neuroprotection in vivo in 2 rodent models of ischemic stroke and in vitro in Treg-neutrophil co-cultures using a combined approaches including cell-specific depletion, gene knockout mice, and bone marrow chimeras. RESULTS Systemic administration of purified Tregs at 2, 6 or even 24 hours after MCAO resulted in a marked reduction of brain infarct and prolonged improvement of neurological functions lasting out to 4 weeks. Treg-afforded neuroprotection was accompanied by attenuated blood-brain barrier (BBB) disruption during early stages of ischemia, decreased cerebral inflammation and reduced infiltration of peripheral inflammatory cells into the lesioned brain. Surprisingly, Tregs exerted early neuroprotection without penetrating into the brain parenchyma or inhibiting the activation of residential microglia. Rather, both in vivo and in vitro studies demonstrated that Tregs suppressed peripheral neutrophil-derived matrix metallopeptidase-9 production, thus preventing proteolytic damage of the BBB. In additions to its potent central neuroprotection, Treg treatment was shown to ameliorate post-stroke lymphopenia, suggesting a beneficial effect on immune status. INTERPREATION Our study suggests that Treg adoptive therapy is a novel and potent cell-based therapy targeting post-stroke inflammatory dysregulation and neurovascular disruption.

Emerging evidence describe heat shock proteins (HSPs) as critical regulators in normal neural physiological function as well as in cell stress responses. The functions of HSPs represent an enormous and diverse range of cellular activities, far beyond the originally identified role in protein folding and chaperoning. Now understood to be involved in processes such as synaptic transmission, autophagy, ER stress response, protein kinase and cell death signaling as well as protein chaperone and folding, manipulation of HSPs have robust effects on the fate of cells in neurological injury and disease states. The ongoing exploration of multiple HSP superfamilies has underscored the pluripotent nature of HSPs in the cellular context, and demanded the recent restructuring of the nomenclature referring to these families to reflect a re-organization based on structure and function. In keeping with this re-organization, we have first discussed the HSP superfamilies in terms of protein structure, regulation and expression and distribution in the brain. We then explore major cellular functions of HSPs that are relevant to neural physiological states, and from there discuss known and proposed HSP impact on major neurological disease states. This review article presents a three-part discussion on the array of HSPs families relevant to neuronal tissue, their cellular functions, and the exploration of therapeutic targets of these proteins in the context of neurological diseases.

Although percutaneous renal mass biopsy with cross-sectional imaging guidance has long been considered to be safe and accurate, there have been recent advances in imaging, interventional, and cytologic techniques that have increased the role of percutaneous biopsy in the diagnosis of renal masses. Today, biopsy plays a fundamental role in the care of patients with a renal mass. Biopsy results are used to confirm the diagnosis of renal cancers, metastases, and infections, and there is increasing evidence to suggest that biopsy can help subtype and grade many primary renal cancers. Because a considerable fraction of small solid renal masses are benign and do not need treatment, there is an increasing need to diagnose them. Biopsy after a full imaging work-up can help prevent unnecessary and potentially morbid surgical and ablation procedures in a substantial number of patients. Although more data are needed to understand the overall accuracy of biopsy for the diagnosis of benign lesions, many can be diagnosed with the aid of biopsy findings. This article reviews reported experience with percutaneous renal mass biopsy, discusses the technical factors that contribute to results, and details seven specific clinical settings that should prompt the clinician to consider percutaneous biopsy when encountering a renal mass.

Preconditioning is a phenomenon in which brief episodes of a sublethal insult induce robust protection against subsequent lethal injuries. Preconditioning has been observed in multiple organisms and can occur in the brain as well as other tissues. Extensive animal studies suggest that the brain can be preconditioned to resist acute injuries, such as ischemic stroke, neonatal hypoxia/ischemia, trauma, and agents that are used in models of neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. Effective preconditioning stimuli are numerous and diverse, ranging from transient ischemia, hypoxia, hyperbaric oxygen, hypothermia and hyperthermia, to exposure to neurotoxins and pharmacological agents. The phenomenon of “cross-tolerance,” in which a sublethal stress protects against a different type of injury, suggests that different preconditioning stimuli may confer protection against a wide range of injuries. Research conducted over the past few decades indicates that brain preconditioning is complex, involving multiple effectors such as metabolic inhibition, activation of extra- and intracellular defense mechanisms, a shift in the neuronal excitatory/inhibitory balance, and reduction in inflammatory sequelae. An improved understanding of brain preconditioning should help us identify innovative therapeutic strategies that prevent or at least reduce neuronal damage in susceptible patients. In this review, we focus on the experimental evidence of preconditioning in the brain and systematically survey the models used to develop paradigms for neuroprotection, and then discuss the clinical potential of brain preconditioning. In a subsequent components of this two-part series, we will discuss the cellular and molecular events that are likely to underlie these phenomena.