Percutaneous Robotics in Interventional Radiology.

The accuracy of the robotic device not only relies on a reproducible needle advancement, but also on the possibility to correct target movement at chosen checkpoints and to deviate from a linear to a nonlinear trajectory. We report our experience in using the robotic device for the insertion of trocar needles in CT guided procedures. The majority of procedures were targeted organ biopsies in the chest abdomen or pelvis. The accuracy of needle placement after target adjustments did not significantly differ from those patients where a linear trajectory could be used. The steering capabilities of the robot allow correction of target movement of the fly.

Best practice in the diagnosis and treatment of varicocele in children and adolescents.

A varicocele is an abnormal dilation of the pampiniform plexus of veins in the scrotum which begins at puberty in approximately 15% of males. Although common in the general population and often asymptomatic, varicoceles are associated with gonadal dysfunction including testicular atrophy, infertility, and hypogonadism in a subset of men diagnosed later in life. Because of the high prevalence and uncertain pathogenesis, definitive management guidelines for varicoceles diagnosed in the pediatric and adolescent population remain poorly defined. The varicocele is the most common etiology of male factor infertility, and treatment in the pediatric and adolescent population may improve semen quality and improve fecundity in adulthood. Evaluation of the pediatric and adolescent varicocele should include history, physical exam, and measurement of testicular volume with orchidometer or ultrasound. Testicular volume differentials and peak retrograde flow on Doppler ultrasonography are important factors in risk stratification of the pediatric varicocele population. Semen analysis and reproductive endocrine assessment should also be considered as part of the workup for adolescent patients. A variety of treatment approaches exist for varicocele, and while the microsurgical subinguinal approach is the gold standard for the adult population, it has yet to be confirmed as superior for the adolescent population. Referral to an andrologist for the adolescent patient with varicocele should be considered in equivocal cases. While active treatment of varicocele in the pediatric and adolescent population is controversial, it is clear that some untreated patients will suffer symptoms later in life, while overtreatment remains a concern for this large, vulnerable population. Therefore, surveillance strategies and improved accuracy in diagnosis of clinically important pediatric varicoceles prompting treatment are needed in the future.

Medical and Surgical Treatment Modalities for Lower Urinary Tract Symptoms in the Male Patient Secondary to Benign Prostatic Hyperplasia: A Review.

Benign prostatic hyperplasia (BPH) with lower urinary tract symptoms (LUTS) is one of the most common ailments affecting aging men. Symptoms typically associated with BPH include weak stream, hesitancy, urgency, frequency, and nocturia. More serious complications of BPH include urinary retention, gross hematuria, bladder calculi, recurrent urinary tract infection, obstructive uropathy, and renal failure. Evaluation of BPH includes a detailed history, objective assessment of urinary symptoms with validated questionnaires, and measurement of bladder function parameters, including uroflowmetry and postvoid residual. In general, treatment of LUTS associated with BPH is based on the effect of the symptoms on quality of life (QOL) and include medical therapy aimed at reducing outlet obstruction or decreasing the size of the prostate. If medical therapy fails or is contraindicated, various surgical options exist. As the elderly population continues to grow, the management of BPH will become more common and important in maintaining patient's QOL.

In vitro desensitization of human skin mast cells.

Desensitization is a clinical procedure whereby incremental doses of a drug are administered over several hours to a sensitive patient until a therapeutic dose and clinical tolerance are achieved. Clinical tolerance may occur in part by attenuating the mast cell response. In the present study, primary human skin mast cells were used to establish and characterize an in vitro model of desensitization. Mast cells in culture were armed with allergen-specific (4-hydroxy-3-nitrophenylacety and Der p2) and non-specific IgE antibodies, and then desensitized by incremental exposures to 4-hydroxy-3-nitrophenylacety-BSA. This desensitization procedure abrogated the subsequent degranulation response to the desensitizing allergen, to an unrelated allergen, and to IgG anti-FcεRI, but not to C5a, substance P, compound 48/80, and calcium ionophore. Desensitized cells regained their FcεRI-dependent degranulation capability by 24-48 h after free allergen had been removed. Therefore, sensitized human skin mast cells are reversibly desensitized in vitro by exposure to incremental doses of that allergen, which also cross-desensitizes them to an unrelated allergen.

IL-4 and TGF-beta 1 counterbalance one another while regulating mast cell homeostasis.

Mast cell responses can be altered by cytokines, including those secreted by Th2 and regulatory T cells (Treg). Given the important role of mast cells in Th2-mediated inflammation and recent demonstrations of Treg-mast cell interactions, we examined the ability of IL-4 and TGF-beta1 to regulate mast cell homeostasis. Using in vitro and in vivo studies of mouse and human mast cells, we demonstrate that IL-4 suppresses TGF-beta1 receptor expression and signaling, and vice versa. In vitro studies demonstrated that IL-4 and TGF-beta1 had balancing effects on mast cell survival, migration, and FcepsilonRI expression, with each cytokine cancelling the effects of the other. However, in vivo analysis of peritoneal inflammation during Nippostrongylus brasiliensis infection in mice revealed a dominant suppressive function for TGF-beta1. These data support the existence of a cytokine network involving the Th2 cytokine IL-4 and the Treg cytokine TGF-beta1 that can regulate mast cell homeostasis. Dysregulation of this balance may impact allergic disease and be amenable to targeted therapy.

IgE signaling suppresses FcepsilonRIbeta expression.

Activation of the high-affinity receptor for IgE, FcepsilonRI, is known to elicit its rapid down-regulation through internalization and degradation. In keeping with this, expression of all three FcepsilonRI subunits is decreased at the protein level after cross-linkage of IgE with antigen. However, we find that the FcepsilonRI beta-subunit is also selectively suppressed at the mRNA level, through a pathway primarily involving Fyn, Syk, PI3K, and NF-kappaB. IgG or calcium ionophore, stimuli known to mimic portions of the IgE signaling cascade, similarly suppressed beta-subunit expression. LPS, a NF-kappaB-activating TLR ligand, did not alter beta-subunit expression. As IgE increases FcepsilonRI expression, we examined the coordinated regulation of FcepsilonRI subunits during culture with IgE, followed by cross-linkage with antigen. IgE increased the expression of all three FcepsilonRI subunits and strikingly induced expression of the antagonistic beta(T). The ratio of beta:beta(T) protein expression decreased significantly during culture with IgE and was reset to starting levels by antigen cross-linkage. These changes in protein levels were matched by similar fluctuations in beta and beta(T) mRNAs. FcepsilonRIbeta is a key regulator of IgER expression and function, a gene in which polymorphisms correlate with allergic disease prevalence. The ability of IgE and FcepsilonRI signaling to coordinate expression of the beta and beta(T) subunits may comprise a homeostatic feedback loop-one that could promote chronic inflammation and allergic disease if dysregulated.

Endogenous suppression of mast cell development and survival by IL-4 and IL-10.

Mast cell development is an important component of atopic and chronic inflammatory diseases such as asthma, multiple sclerosis, rheumatoid arthritis, and atherosclerosis. In this study, we found that IL-4 and IL-10 were produced constitutively in cultures of developing mast cells, correlating with mast cell purity. Deletion of either gene increased mast cell numbers and Fc epsilon RI expression during culture in IL-3 + stem cell factor (SCF). By adding exogenous IL-4 and IL-10 to bone marrow (BM) cultures containing IL-3 + SCF, we found that IL-4 + IL-10 suppressed mast cell development through mechanisms not used by either cytokine alone. IL-4 + IL-10 elicited a rapid cell death coincidental with reduced Kit receptor expression and signaling and enhanced mitochondrial damage and caspase activation. IL-4 or IL-10 costimulation, unlike either cytokine alone, altered mast cell ontogeny to yield predominantly macrophages in cultures that typically produce mast cells. This effect was observed consistently with unseparated BM cells, purified mouse BM stem cells, and erythrocyte-depleted human umbilical cord blood cells. These experiments demonstrated a major role for Stat6 and Stat3, but not the Stat3-induced transcriptional repressor Ets variant gene 3. Genetic background was also a critical factor, as BALB/c-derived BM cells were completely resistant to IL-10-mediated killing and expressed lower levels of IL-10R. Collectively, these results support the theory that IL-4 and IL-10 function as endogenous regulators of mast cell progenitor development, consistent with a role in immune homeostasis. Loss of this homeostasis, perhaps via genetic polymorphism, could contribute to the etiology of mast cell-associated disease.

Mast cell regulation of the immune response.

Mast cells are well known as principle effector cells of type I hypersensitivity responses. Beyond this role in allergic disease, these cells are now appreciated as playing an important role in many inflammatory conditions. This review summarizes the support for mast cell involvement in resisting bacterial infection, exacerbating autoimmunity and atherosclerosis, and promoting cancer progression. A commonality in these conditions is the ability of mast cells to elicit migration of many cell types, often through the production of inflammatory cytokines such as tumor necrosis factor. However, recent data also demonstrates that mast cells can suppress the immune response through interleukin-10 production. The data encourage those working in this field to expand their view of how mast cells contribute to immune homeostasis.

Cutting edge: CD4 T cell-mast cell interactions alter IgE receptor expression and signaling.

Mast cell activation is associated with atopic and inflammatory diseases, but the natural controls of mast cell homeostasis are poorly understood. We hypothesized that CD4(+)CD25(+) regulatory T cells (Treg) could function in mast cell homeostasis. In this study, we demonstrate that mast cells can recruit both Treg and conventional CD4(+) T cells (Tconv). Furthermore, Treg, but not Tconv, suppress mast cell FcepsilonRI expression. Despite the known inhibitory functions of IL-10 and TGFbeta1, FcepsilonRI suppression was independent of IL-10 and TGF-beta1 and required cell contact. Surprisingly, coculture with either Treg or Tconv cells suppressed IgE-mediated leukotriene C(4) production but enhanced cytokine production by mast cells. This was accompanied by a selective increase in FcepsilonRI-mediated Stat5 phosphorylation, which is a critical mediator of IgE-mediated cytokine secretion. These data are the first direct demonstration that mast cells can recruit Treg and illustrate that T cell interactions can alter the mast cell response.