Faculty Bibliography

We studied the effects of LEX032, a novel serine protease inhibitor, on N(G)-nitro-L-arginine methyl ester (L-NAME) induced leukocyte-endothelium interactions in vivo, utilizing intravital microscopy of the rat mesentery. Superfusion of the rat mesentery with 50 microM L-NAME, a nitric oxide (NO) inhibitor, for 90 min resulted in a significant and time-dependent increase in leukocyte rolling, leukocyte adherence, and transmigration of leukocytes, compared to control rats superfused with Krebs-Henseleit (K-H) solution. However, systemic administration of LEX032 (15 mg/kg bolus injection followed by a 15 mg/kg per hour infusion) to L-NAME superfused rats significantly attenuated leukocyte rolling and adherence along the venular endothelium of the rat mesentery, and also inhibited transmigration of leukocytes through the microvascular endothelial wall. Moreover, no significant changes were observed in mean arterial blood pressure or local venular shear rates following systemic administration of LEX032. Our data demonstrate that systemic inhibition of serine proteases by LEX032 reduces enhanced leukocyte-endothelium interactions provoked by inhibition of NO synthesis. These results also explain some of the beneficial effects exerted by serine protease inhibitors in ischemia-reperfusion and other inflammatory states.

Learning Objective #1: Avoid premature closure when a patient presents with classic lymphoma symptoms. Our case was given a diagnosis of lymphoma by the emergency department and the hematologist oncologist consulted on the case. While the first impression was lympho-ma, there is a very rare, locally invasive neoplasm of the lymphatic vascular origin called papillary intralymphatic angioendothelioma (PILA), also referred to as Dabska tumor. Recognize that although PILA commonly presents as a slowly growing, asymptomatic (without B symptoms), violaceous patch or nodule, arising from a preexisting lymphatic or vascular anomaly that occurs typically in young adults, it may also affect the elderly and present with typical B symptoms. CASE: A 36 year-old otherwise healthy female presented with six days of acute flu-like symptoms, myalgias, persistent fever and chills associated with abdominal bloating and vomiting for three days. Physical exam was notable for temperature of 103 F, sinus tachycardia and mild tenderness at the left upper quadrant on deep palpation. Labs were notable for a normal WBC count, mildly elevated alkaline phosphatase and total bilirubin. The flu swab was negative. All infectious workup including a quantiferon-TB gold test was negative. The Chest CTshowed confluent 9 x 5 cm anterior mediastinal and 2 x 2 cm sub carinal lymphadenopathy extending to the aortopulmonary window. On abdominal CT abdomen and pelvis there was marked diffuse, bulky and confluent upper abdominal, mesenteric and retroperitoneal adenopathy. The patient underwent mediastinal video assisted thoracoscopic surgery (VATS) which showed papillary intralymphatic angioendothelioma (PILA). The patient was referred to a vascular anomalies' specialist and was prescribed Sirolimus for prophylaxis immunosuppressant therapy. IMPACT/DISCUSSION: To our knowledge, less than 40 cases of PILA have been described in literature. Presently, there are diagnostic challenges for pathologists and providers given PILA's rarity and histological complexity to distinguish it from other vascular lesions and lymphoma. We present a new and unusual case of PILAwith typical B symptoms and multifocal intra-abdominal lesions. Most case reports describe asymptomatic and external presentations. It is important to rely on final pathology prior to assuming lymphoma is the most likely diagnosis.
Conclusion(s): Premature closure is failure to consider alternative diagnoses after the initial impression is formed. This leads to diagnostic errors that can have substantial effects on our patients lives. Rare diseases are often overlooked and we need to recognize PILA as a differential diagnosis for neoplasms of the lymphatic vascular origin

Together with Hebbian plasticity, homeoplasticity presumably plays a significant, yet unclear, role in recovery postlesion. Here, we undertake a simulation study addressing the role of homeoplasticity and rehabilitation timing poststroke. We first hypothesize that homeoplasticity is essential for recovery and second that rehabilitation training delivered too early, before homeoplasticity has compensated for activity disturbances postlesion, is less effective for recovery than training delivered after a delay. We developed a neural network model of the sensory cortex driven by muscle spindle inputs arising from a six-muscle arm. All synapses underwent Hebbian plasticity, while homeoplasticity adjusted cell excitability to maintain a desired firing distribution. After initial training, the network was lesioned, leading to areas of hyper- and hypoactivity due to the loss of lateral synaptic connections. The network was then retrained through rehabilitative arm movements. We found that network recovery was unsuccessful in the absence of homeoplasticity, as measured by reestablishment of lesion-affected inputs. We also found that a delay preceding rehabilitation led to faster network recovery during the rehabilitation training than no delay. Our simulation results thus suggest that homeoplastic restoration of prelesion activity patterns is essential to functional network recovery via Hebbian plasticity.

Nitric oxide (NO) is known to be an important endogenous modulator of leukocyte-endothelial cell interactions within the microcirculation. We examined leukocyte rolling and adhesion under baseline conditions and following thrombin (0.25 U/ml) superfusion in the mesentery of wild-type, inducible NOS (iNOS)-deficient (-/-), neuronal NOS (nNOS) -/-, and endothelial cell NOS (ecNOS) -/- mice to further our understanding of NO and leukocyte function. Baseline leukocyte rolling (cells/min) was significantly elevated in both the nNOS -/- (30.0 +/- 4.0) and ecNOS -/- mice (67.0 +/- 12.0) compared with wild-type mice (11.0 +/- 1.4). In addition, baseline leukocyte adherence (cells/100 micrometers of vessel) was also significantly elevated in the nNOS -/- (5.2 +/- 1.0) and ecNOS -/- (13.0 +/- 1.3) compared with wild-type animals (1.3 +/- 0.5). Deficiency of iNOS had no effect on baseline leukocyte rolling or adhesion in the mesentery. Baseline surface expression of P-selectin was observed in 68.0 +/- 9.0% of intestinal venules in ecNOS -/- mice compared with 10.0 +/- 2.0% in wild-type mice. Additional studies demonstrated that administration of an anti-P-selectin monoclonal antibody (RB40. 34) or the soluble P-selectin ligand, PSGL-1, completely inhibited the increased rolling and firm adhesion response in nNOS -/- and ecNOS -/- mice. Transmigration of neutrophils into the peritoneum following thioglycollate injection was also significantly augmented in nNOS -/- and ecNOS -/- mice. These studies clearly indicate the NO derived from both nNOS and ecNOS is critical in the regulation of leukocyte-endothelial cell interactions.