Cytokeratin-positive interstitial reticulum cell (CIRC) tumor in the lymph node: a case report of the transformation from the epithelioid cell type to the spindle cell type.

BACKGROUND: Cytokeratin-positive interstitial reticulum cells (CIRCs), which are a subgroup of fibroblastic reticular cells (FRCs), are known to be present in the lymph nodes. There have been only a few cases of tumors derived from CIRCs. CASE PRESENTATION: We have reported a new case involving a CIRC tumor in a 75-year-old man and reviewed the literature. The resected mediastinal lymph nodes showed epithelial-like proliferation of large atypical round and polygonal epithelioid cells. The tumor cells expressed CK8, CK18, CAM5.2, AE1/AE3, epithelial membrane antigen, vimentin, fascin, and some FRC markers, which is consistent with the diagnosis of a CIRC tumor. Following chemotherapy, the CIRC tumor was observed to have responded very well and became difficult to confirm on imaging, but a small cell lung carcinoma developed 12 months later. Chemoradiotherapy was performed, but the patient passed away 29 months after the initial diagnosis. The autopsy revealed the recurrence of the CIRC tumor, residual small cell lung carcinoma, and a very small latent carcinoma of the prostate. The relapsed CIRC tumor cells had a spindle shape; they were highly pleomorphic and had invaded the superior vena cava. CONCLUSION: We first reported autopsy findings of CIRC tumors and demonstrated the transformation of the tumor from the epithelioid cell type to the spindle cell type.

Cross talk between vascular smooth muscle cells and monocytes through interleukin-1ß/interleukin-18 signaling promotes vein graft thickening.

OBJECTIVE: Interleukin (IL)-1ß and IL-18 are key proinflammatory cytokines that play important roles in the pathophysiology of vein graft remodeling. However, the mechanism of IL-1ß/IL-18 production and its role in the development of graft remodeling remain unclear. APPROACH AND RESULTS: IL-1ß/IL-18 were rapidly expressed in venous interposition grafts. Vascular smooth muscle cell (VSMC) death and monocytic inflammasome activation occurred in grafted veins. Necrotic VSMCs induced the expression of IL-1ß, IL-18, and other inflammasome-associated proteins in monocytes, which was partially inhibited by their antagonist, recombinant IL-1ra-Fc-IL-18bp. Activated monocytes stimulated proliferation of VSMCs by activating cell growth-related signaling molecules (AKT, STAT3, ERK1/2, and mTOR [AKT/protein kinase B, signal transducer and activator of transcription 3, extracellular signal-regulated kinase 1/2, mammalian target of rapamycin]) and increasing production of platelet-derived growth factor-bb; these effects were suppressed by IL-1ra-Fc-IL-18bp. Activated monocytes also promoted migration of VSMCs, which was independent of IL-1ß/IL-18 signaling. Importantly, administration of IL-1ra-Fc-IL-18bp inhibited activation of cell growth-related signaling molecules, VSMC proliferation, and vein graft thickening in vivo. CONCLUSIONS: Our work identified an interaction among necrotic VSMCs, monocytes, and viable VSMCs through IL-1ß/IL-18 signaling, which might be exploited as a therapeutic target in vein graft remodeling.

Evaluation of intravascular microdialysis for continuous blood glucose monitoring in hypoglycemia: an animal model.

We have previously shown that intravascular microdialysis in a central vein is an accurate method for continuous glucose monitoring in patients undergoing cardiac surgery. However, no hypoglycemia occurred in our earlier studies, prompting further evaluation of the accuracy of intravascular microdialysis in the hypoglycemic range. Thus, this animal study was performed. A porcine model was developed; hypoglycemia was induced using insulin injections. The pigs were monitored with intravascular microdialysis integrated in a triple-lumen central venous catheter. As reference, venous blood gas samples were taken every 5 minutes and analyzed in a blood gas analyzer. Ethical permission for the animal experiments was obtained from the Stockholm Regional Ethical Committee, reference no N397/09. A total of 213 paired samples were obtained for analysis, and 126 (59.2%) of these were in the hypoglycemic range (<74 mg/dl). Using Clarke error grid analysis, 100% of the paired samples were in region AB and 99% in region A. The ISO standard (ISO15197) was met. Bland-Altman analysis showed bias (mean difference) ± limits of agreement was -0.18 ± 16.2 mg/dl. No influence from glucose infusions was seen. The microdialysis monitoring system was found to be very responsive in rapid changes in blood glucose concentration. This study shows that intravascular microdialysis in a central vein is an accurate method for continuous glucose monitoring in hypoglycemia in a porcine experimental model. Furthermore, the system was not influenced by glucose administration and was found to be responsive in rapid blood glucose fluctuations.

Discrepancy between superior vena cava oxygen saturation and mixed venous oxygen saturation can predict postoperative complications in cardiac surgery patients.

OBJECTIVE: To determine if increases in discrepancy between ScvO2 and SvO2 (ScvO2 - SvO2 = ΔSO2) during surgery in cardiac surgery patients can predict postoperative complications. DESIGN: Prospective, observational study. SETTING: University hospital. PARTICIPANTS: One hundred two patients undergoing cardiac surgery were enrolled. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Central venous oxygen saturation (ScvO2) and mixed venous oxygen saturation (SvO2) values during surgery automatically were collected. The average value of ΔSO2 for every minute was calculated. The area under the receiver operating characteristic curve for prolonged postoperative ICU stay (≥3 days) was 0.745 for ΔSO2, which was significantly different from those of ScvO2 and SvO2 (p<0.05) (ScvO2; 0.584, SvO2; 0.598). The optimal threshold value of ΔSO2 to predict prolonged ICU stay (≥3 days) was 12% (sensitivity: 72.0%, specificity: 76.9%). Postoperative ICU duration, ventilation time, and hospital stay were significantly longer in Group D patients (intraoperative maximum ΔSO2 ≥12%) than those in Group N patients (intraoperative maximum ΔSO2<12%). As for postoperative complications, the number of patients with postoperative use of intra-aortic balloon pumping, delirium, respiratory failure requiring tracheotomy, and severe complications was significantly higher in Group D patients. Multivariate logistic regression models were used to evaluate the independent effects of perioperative variables on the risk of developing prolonged ventilation (>24 hours) and prolonged ICU stay (≥3 days). A discrepancy in intraoperative ΔSO2 was an independent risk factor for prolonged postoperative ventilation and ICU stay. CONCLUSION: The discrepancy between ScvO2 and SvO2 during cardiac surgery is an independent risk factor of postoperative complications such as prolonged ICU stay and ventilation time.

Cerebral NIRS as a marker of superior vena cava oxygen saturation in neonates with congenital heart disease.

OBJECTIVES: To investigate the correlation between cerebral near-infrared spectroscopy (NIRS) (rSO2c) and superior vena cava venous oxygen saturation (ScvO2) in newborn patients with congenital heart disease (CHD). BACKGROUND: NIRS is a noninvasive method to monitor hemoglobin oxygen saturation using nonpulsatile oximetry. METHODS: We retrospectively analyzed perioperative data from 100 newborn patients who underwent cardiac surgery for CHD. rSO2c, ScvO2 from 24 h before to 72 h after surgery were recorded. RESULTS: rSO2c had a fair correlation with ScvO2 (r 0.37; P <0.001). The relationship between rSO2c and ScvO2 did not change when analyzed between patients with cyanotic or acyanotic CHD. During the preoperative period, rSO2c levels overestimated ScvO2; in the first 18 postoperative hours, rSO2c underestimated ScvO2; after that period, they showed very close trends. Hypocapnia caused rSO2c to underestimate ScvO2; in normocapnic patients, rSO2c-ScvO2 average differences were close to zero; in hypercapnic neonates, rSO2c tended to overestimate ScvO2. The best performance of rSO2c as a surrogate of ScvO2 was found in the venous saturation ranges from 40% to 60% (r 0.3, P: 0.03). CONCLUSIONS: rSO2c in newborn patients with cyanotic and acyanotic CHD provides a continuous noninvasive information with a fair correlation with ScvO2%: some predictable variables (i.e., time from surgery, carbon dioxide, and venous saturation levels), should guide the operators to adjust rSO2c values in terms of ScvO2. Serial measures of ScvO2 seem recommended to tailor rSO2c information on actual venous saturation percentage.

Postoperative management: the role of mixed venous oxygen saturation monitoring.

The results of the Norwood operation have improved considerably over the last decade, due in part to improvement in postoperative care. Mixed venous oxygen saturation (MvO2) monitoring has been an important addition to postoperative management. Our use of MvO2 monitoring in Norwood patients has included 96 infants operated from 1996 to the present. This strategy has proven to be technically straightforward and adds information not provided by monitoring systemic saturation alone. MvO2 has a nadir at 6-12 hours after surgery and below a value of 30% is associated with anaerobic metabolism. It identifies patients at risk for early mortality. It also allows evaluation of management of treatment strategies that evolve over time and of specific interventions in individual patients. Optimizing MvO2 constitutes an important goal of postoperative management after the Norwood procedure.

Depopulated vena caval homograft: a new venous conduit.

OBJECTIVE: Completion of the Fontan procedure is frequently performed by using an extracardiac conduit between the inferior vena cava and the pulmonary artery. Most centers use a polytetrafluoroethylene graft for the extracardiac conduit, and because re-endothelialization is unlikely, anticoagulation is used for a variable period. This study explores the use of an alternate large-caliber venous conduit. METHODS: The superior vena cava was replaced in 8 minipigs with either a polytetrafluoroethylene interposition graft (2 pigs) or a depopulated (acellular), cryopreserved superior vena caval homograft (6 pigs). After 6 months, the animals were killed, and the grafts were examined for patency and histology, including immunostaining. No anticoagulation was used. RESULTS: Polytetrafluoroethylene grafts have a cross-sectional luminal narrowing, ranging from 16% to 40%. Histology showed only partial intimal ingrowth, with excessive subendothelial fibrosis and early calcification. In contrast, the depopulated venous homografts showed minimal luminal narrowing, ranging from 2% to 9%. These grafts were completely repopulated by the recipient with an endothelial lining, which stained positively for factor VIII, and a subendothelial region appropriately recellularized by myofibroblasts, which stained positively for smooth muscle actin and procollagen. There was no evidence of an immune response to the venous homografts, as judged by staining for T-cell surface antigen, CD4, and CD8. Thrombus was not seen in any of the grafts. CONCLUSION: Depopulated, cryopreserved vena caval homografts might be superior conduits for cavopulmonary connection during completion of the Fontan operation by using the extracardiac conduit technique.

Oxytocin and its receptors are synthesized in the rat vasculature.

Produced and released by the heart, oxytocin (OT) acts on its cardiac receptors to decrease the cardiac rate and force of contraction. We hypothesized that it might also be produced in the vasculature and regulate vascular tone. Consequently, we prepared acid extracts of the pulmonary artery and vena cava of female rats. OT concentrations in dog and sheep aortae were equivalent to those of rat aorta (2745 +/- 180 pg/mg protein), indicating that it is present in the vasculature of several mammalian species. Reverse-phase HPLC of aorta and vena cava extracts revealed a single peak corresponding to the amidated OT nonapeptide. Reverse-transcribed PCR confirmed OT synthesis in these tissues. Using the selective OT receptor ligand compound VI, we detected a high number of OT-binding sites in the rat vena cava and aorta. Furthermore, OT receptor (OTR) mRNA was found in the vena cava, pulmonary vein, and pulmonary artery with lower levels in the aorta, suggesting vessel-specific OTR distribution. The abundance of OTR mRNA in the vena cava and pulmonary vein was associated with high atrial natriuretic peptide mRNA. In addition, we have demonstrated that diethylstilbestrol treatment of immature female rats increased OT significantly in the vena cava but not in the aorta and augmented OTR mRNA in both the aorta (4-fold) and vena cava (2-fold), implying regulation by estrogen. Altogether, these data suggest that the vasculature contains an intrinsic OT system, which may be involved in the regulation of vascular tone as well as vascular regrowth and remodeling.

Postnatal development of the rat intrinsic cardiac nervous system: a confocal laser scanning microscopy study in whole-mount atria.

We used confocal laser scanning microscopy and fluorescent immunohistochemistry to study the developmental pattern and distribution of specific neuronal phenotypes within the intrinsic cardiac nervous system in whole-mount atrial preparations from newborn to 5 week old rats. Individual ganglia and neuronal cell bodies were localized by means of two general neuronal markers: protein gene product 9.5 (PGP) and microtubule-associated protein two (MAP). In rats < or =2 weeks old there were two main subpopulations of intrinsic neurons located in the intraatrial septum and around the origin of the superior vena cava. The more abundant was a population of strongly tyrosine hydroxylase (TH) immunoreactive (IR) neurons (10-40 microm in diameter) most of which were also PGP-IR. The second, less numerous (approximately 60-70% than the TH-IR group) type of neurons exhibited ChAT-IR which colocalized with MAP-IR. Towards the end of the second postnatal week and during the third, the ganglia containing these neurons became more numerous and their localization also included tissues around the origins of the inferior vena cava and the pulmonary veins, as well as both atrial walls close to the AV junction. During the second and third postnatal weeks, when the extrinsic innervation of the adrenergic and cholinergic phenotypes largely increases, the intrinsic innervation also changed greatly, and around the 21st postnatal day it appeared to acquire mature characteristics. The TH-IR neurons changed their characteristics and formed two types of ganglia. The larger ganglia containing large cells (20-40 microm in diameter) expressed TH-IR mostly close to their inner body surface (approximately 80-90% of identified neurons). Most of these neurons also expressed neuropeptide Y (NPY)-IR, specifically around their nuclei. The second type of small strongly TH-IR neurons (approximately 10% of all identified neurons) were contained in smaller groups (20-50 cells) which were usually embedded into much larger ganglia (100-400 cells), containing large (20-50 microm) neurons. Unlike all other intrinsic neurons, these small TH-IR cells did not exhibit any PGP-IR or MAP-IR. The number of ChAT-IR neurons increased at this stage, reaching approximately 90% of the neurons identified by the general neuronal markers. These neurons were surrounded by a rich network of cholinergic varicose nerve fibers, some of which were likely of an extrinsic origin. We have also identified relatively small ganglia expressing immunoreactivity to vasoactive intestinal polypeptide (VIP), and to substance P (SP). The presented data indicate that the phenotypes of intrinsic neurons in the rat heart change greatly during the first month of postnatal development. This may be at least partially related to the development and maturation of functional extrinsic nervous control of the heart.

Acute effects of nitroglycerin depend on both plasma and intracellular sulfhydryl compound levels in vivo. Effect of agents with different sulfhydryl-modulating properties.

BACKGROUND: Changes in sulfhydryl (SH) compound availability may alter the hemodynamic effect of nitroglycerin (NTG). Data on the relation between NTG effect and thiol levels are, however, limited to in vitro experiments. The present study investigates how intracellular and extracellular changes in SH group concentrations (cysteine and glutathione [GSH]) affect the responsiveness to NTG in vivo. METHODS AND RESULTS: GSH and cysteine levels in plasma, vena cava, and aorta were measured after administration of N-acetylserine (placebo, n = 6), N-acetylcysteine (NAC, extracellular and intracellular SH donor, n = 6), oxothiazolidine (OXO, intracellular SH donor, n = 6), buthionine sulfoximine (BSO, intracellular GSH-depleting agent, n = 6), BSO+NAC (n = 6), and BSO+OXO (n = 6) in chronically catheterized conscious rats. In addition, the effect of 2.5 mg NTG/kg i.v. on mean arterial pressure (MAP) was determined before and after the same treatment. NAC (5 mmol/kg i.v. for 2 hours) significantly (p < 0.05) increased extracellular cysteine and GSH levels and potentiated the hypotensive effect of NTG (from 26 +/- 3 to 31 +/- 4 mm Hg [mean +/- SEM], p < 0.05). OXO (5 mmol.kg-1 x hr-1 i.v. for 2 hours) significantly increased intracellular cysteine and GSH levels but had no effect on NTG responsiveness (p > 0.05). BSO (1 g i.p. three times within 24 hours) significantly decreased intracellular GSH levels (p < 0.05) and attenuated the effect of NTG (from 28 +/- 3 to 16 +/- 2 mm Hg). CONCLUSIONS: The results suggest that the acute hypotensive effect of NTG in vivo is: 1) increased by high extracellular GSH and/or cysteine levels (NAC), 2) decreased by low intracellular GSH levels (BSO), and 3) unaffected by high intracellular levels of cysteine and GSH (OXO).

Determination of optimal perfusion flow rate for deep hypothermic cardiopulmonary bypass in the adult based on distributions of blood flow and oxygen consumption.

To determine the optimal perfusion flow in deep hypothermic cardiopulmonary bypass at 20 degrees C in human beings, we studied the relationship of perfusion flow to the whole body and to regional oxygen consumption. In adult patients (n = 11, average age 54 years) with valvular or coronary heart disease, the distributions of perfusion flow rate and oxygen consumption were analyzed by dividing into the superior and inferior vena caval areas. Measurements (n = 39) were made at various perfusion flow rates (perfusion flow rate in the superior vena caval area plus that in the inferior vena caval area equals whole-body perfusion flow rate: 0.4 to 2.2 L/min/m2) in a setting of average hemoglobin levels of 8.1 gm/dl. Between whole-body perfusion flow rate and oxygen consumption (total oxygen consumption equals superior plus inferior vena caval oxygen consumption), there was a hyperbolic correlation (r = 0.73; p less than 0.001; asymptote = 29.0 ml/min/m2). A positive linear correlation was found between whole-body perfusion flow rate and inferior vena caval oxygen consumption (r = 0.75; p less than 0.001), whereas no significant relation was seen between whole-body perfusion flow rate and superior vena caval oxygen consumption. For distributional changes in inferior vena caval perfusion flow rate/whole body perfusion flow rate and inferior vena caval oxygen consumption/whole body oxygen consumption, the broken-line regression analysis showed respective critical points where both parameters started to drop when whole-body perfusion flow rate was gradually reduced: 1.2 L/min/m2 for inferior vena caval perfusion flow rate/whole-body perfusion flow rate and 0.8 L/min/m2 for inferior vena caval oxygen consumption/whole-body oxygen consumption. The results indicate that (1) the oxygen consumption to the superior vena caval area was maintained independent of the perfusion in a relatively wide range in contrast to that for the inferior vena caval area and (2) when the redistribution of oxygen consumption is considered as undesirable under low-flow perfusion, the optimal perfusion flow for 20 degrees C deep hypothermic cardiopulmonary bypass appeared to be 0.8 L/min/m2.

Further characterization of the 5-HT receptor mediating vascular relaxation and elevation of cyclic AMP in porcine isolated vena cava.

1. 5-Hydroxytryptamine (5-HT) and 5-carboxamidotryptamine (5-CT) produce both smooth muscle relaxation and elevation of tissue adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels in isolated rings of neonatal porcine vena cava. We now present studies attempting to characterize in more detail the 5-HT receptor mediating these responses. 2. Both 5-HT and 5-CT relaxed porcine isolated vena cava rings (EC50 values 200 nM and 4 nM respectively) and elevated tissue cyclic AMP levels (EC50 values 1500 nM and 16 nM respectively). For both responses 5-CT was approximately 50-100 fold more potent than 5-HT. 3. Both 5-CT-induced smooth muscle relaxation and cyclic AMP elevation were potently and specifically antagonized to a similar extent by methiothepin, methysergide and spiperone. 4. At concentrations up to 1 microM, 8-hydroxy-2-(di-n-propylamino) tetralin, buspirone, ipsapirone, n,n-dipropyl-5-CT, cyanopindolol, RU24969, ketanserin, GR38032 and GR43175 were devoid of both agonist and antagonist activity for both responses. 5. These findings suggest that the same 5-HT1-like receptor mediates both smooth muscle relaxation and elevation of cyclic AMP. This receptor is unlike any known 5-HT1 ligand binding site or adenylate cyclase-coupled 5-HT receptor in brain tissues.