Whole lung lavage decreases physiological dead space in patients with pulmonary alveolar proteinosis: two case reports.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by progressive accumulation of the alveolar surfactant. Whole lung lavage (WLL) using a high volume of warmed saline remains the standard therapy. However, no established bedside monitoring tool can evaluate the physiological effect of WLL in the perioperative period. Indirect calorimetry, which is generally used to measure resting energy expenditure, can detect carbon dioxide (CO2) production and mixed-expired partial pressure of CO2 breath by breath. In this physiological study, we calculated CO2 elimination per breath (VTCO2,br) and Enghoff's dead space using indirect calorimetry and measured the extravascular lung water index to reveal the effect of WLL. CASE PRESENTATION: We measured VTCO2,br, Enghoff's dead space, and the extravascular lung water and cardiac indices before and after WLL to assess the reduction in shunt by washing out the surfactant. A total of four WLLs were performed in two PAP patients. The first case involved an Asian 62-year-old man who presented with a 3-month history of dyspnea on exertion. The second case involved an Asian 48-year-old woman with no symptoms. VTCO2,br increased, and the Enghoff's dead space decreased at 12 h following WLL. An increase in the extravascular lung water was detected immediately following WLL, leading to a transient increase in Enghoff's dead space. CONCLUSION: WLL can increase efficient alveolar ventilation by washing out the accumulated surfactant. However, the lavage fluid may be absorbed into the lung tissues immediately after WLL and result in an increase in the extravascular lung water.

Positive End-expiratory Pressure and Distribution of Ventilation in Pneumoperitoneum Combined with Steep Trendelenburg Position.

BACKGROUND: Pneumoperitoneum and a steep Trendelenburg position during robot-assisted laparoscopic prostatectomy have been demonstrated to promote a cranial shift of the diaphragm and the formation of atelectasis in the dorsal parts of the lungs. However, neither an impact of higher positive end-expiratory pressure (PEEP) on preserving the ventilation in the dorsal region nor its physiologic effects have been fully examined. The authors hypothesized that PEEP of 15 cm H2O during robot-assisted laparoscopic prostatectomy might maintain ventilation in the dorsal parts and thus improve lung mechanics. METHODS: In this randomized controlled study, 48 patients undergoing robot-assisted laparoscopic prostatectomy were included in the analysis. Patients were assigned to the conventional PEEP (5 cm H2O) group or the high PEEP (15 cm H2O) group. Regional ventilation was monitored using electrical impedance tomography before and after the establishment of pneumoperitoneum and 20° Trendelenburg position during the surgery. The primary endpoint was the regional ventilation in the dorsal parts of the lungs while the secondary endpoints were lung mechanics and postoperative lung function. RESULTS: Compared to that in the conventional PEEP group, the fraction of regional ventilation in the most dorsal region was significantly higher in the high PEEP group during pneumoperitoneum and Trendelenburg position (mean values at 20 min after taking Trendelenburg position: conventional PEEP, 5.5 ± 3.9%; high PEEP, 9.9 ± 4.7%; difference, -4.5%; 95% CI, -7.4 to -1.6%; P = 0.004). Concurrently, lower driving pressure (conventional PEEP, 14.9 ± 2.5 cm H2O; high PEEP, 11.5 ± 2.8 cm H2O; P < 0.001), higher lung dynamic compliance, and better oxygenation were demonstrated in the high PEEP group. Postoperative lung function did not differ between the groups. CONCLUSIONS: Application of a PEEP of 15 cm H2O resulted in more homogeneous ventilation and favorable physiologic effects during robot-assisted laparoscopic prostatectomy but did not improve postoperative lung function.

[The importance of preanesthetic evaluation: malignant tumors discovered on preoperative chest radiography, in patients scheduled for operation of benign tumors].

Preanesthetic evaluation is essential for the perioperative period. We report 2 preoperative patients with benign disease, whose preoperative chest radiography revealed intrathoracic malignant tumors. Case 1: A woman in her eighties with vascular necrosis of the femoral head was scheduled for bipolar hip arthroplasty under general anesthesia. On preanesthetic evaluation, widened mediastinum was detected on preoperative chest radiography. Instead of the scheduled operation, she underwent thoracoscopic surgery under general and epidural anesthesia. She was diagnosed with malignant thymoma. Case 2: A woman in her thirties with bilateral oviduct obstruction was scheduled for laparoscopic surgery. On preanesthetic evaluation, right middle lung lesion was detected. She underwent thoracoscopic biopsy under general and epidural anesthesia, and was diagnosed with malignant lymphoma. The result of preanesthetic chest radiography is reported to change the perioperative treatment only in 0.1%; our cases indicate the importance of preanesthetic evaluation of chest radiography in detecting possible underlying disease in the preoperative patient.

Structure-activity relationships and key structural feature of pyridyloxybenzene-acylsulfonamides as new, potent, and selective peroxisome proliferator-activated receptor (PPAR) γ Agonists.

In our search for a novel class of non-TZD, non-carboxylic acid peroxisome proliferator-activated receptor (PPAR) γ agonists, we explored alternative lipophilic templates to replace benzylpyrazole core of the previously reported agonist 1. Introduction of a pentylsulfonamide group into arylpropionic acids derived from previous in-house PPARγ ligands succeeded in the identification of 2-pyridyloxybenzene-acylsulfonamide 2 as a lead compound. Docking studies of compound 2 suggested that a substituent para to the central benzene ring should be incorporated to effectively fill the Y-shaped cavity of the PPARγ ligand-binding domain (LBD). This strategy led to significant improvement of PPARγ activity. Further optimization to balance in vitro activity and metabolic stability allowed the discovery of the potent, selective and orally efficacious PPARγ agonist 8f. Structure-activity relationship study as well as detailed analysis of the binding mode of 8f to the PPARγ-LBD revealed the essential structural features of this series of ligands.

A new class of non-thiazolidinedione, non-carboxylic-acid-based highly selective peroxisome proliferator-activated receptor (PPAR) γ agonists: design and synthesis of benzylpyrazole acylsulfonamides.

Herein, we describe the design, synthesis, and structure-activity relationships of novel benzylpyrazole acylsulfonamides as non-thiazolidinedione (TZD), non-carboxylic-acid-based peroxisome proliferator-activated receptor (PPAR) γ agonists. Docking model analysis of in-house weak agonist 2 bound to the reported PPARγ ligand binding domain suggested that modification of the carboxylic acid of 2 would help strengthen the interaction of 2 with the TZD pocket and afford non-carboxylic-acid-based agonists. In this study, we used an acylsulfonamide group as the ring-opening analog of TZD as an isosteric replacement of carboxylic acid moiety of 2; further, preliminary modification of the terminal alkyl chain on the sulfonyl group gave the lead compound 3c. Subsequent optimization of the resulting compound gave the potent agonists 25c, 30b, and 30c with high metabolic stability and significant antidiabetic activity. Further, we have described the difference in binding mode of the carboxylic-acid-based agonist 1 and acylsulfonamide 3d.

The Formin family protein, formin homolog overexpressed in spleen, interacts with the insulin-responsive aminopeptidase and profilin IIa.

Insulin stimulates translocation of glucose transporter isoform type 4 (GLUT4) and the insulin-responsive aminopeptidase (IRAP) from an intracellular storage pool to the plasma membrane in muscle and fat cells. A role for the cytoskeleton in insulin action has been postulated, and the insulin signaling pathway has been well investigated; however, the molecular mechanism by which GLUT4/IRAP-containing vesicles move from an interior location to the cell surface in response to insulin is incompletely understood. Here, we have screened for IRAP-binding proteins using a yeast two-hybrid system and have found that the C-terminal domain of FHOS (formin homolog overexpressed in spleen) interacts with the N-terminal cytoplasmic domain of IRAP. FHOS is a member of the Formin/Diaphanous family of proteins that is expressed most abundantly in skeletal muscle. In addition, there are two novel types of FHOS transcripts generated by alternative mRNA splicing. FHOS78 has a 78-bp insertion and it is expressed mainly in skeletal muscle where it may be the most abundant isoform in humans. The ubiquitously expressed FHOS24 has a 24-bp insertion encoding an in-frame stop codon that results in a truncated polypeptide. It is known that some formin family proteins interact with the actin-binding profilin proteins. Both FHOS and FHOS78 bound to profilin IIa via their formin homology 1 domains, but neither bound profilin I or IIb. Overexpression of FHOS and FHOS78 resulted in enhanced insulin-stimulated glucose uptake in L6 cells to similar levels. However, overexpression of FHOS24, lacking the IRAP-binding domain, did not affect insulin-stimulated glucose uptake. These findings suggest that FHOS mediates an interaction between GLUT4/IRAP-containing vesicles and the cytoskeleton and may participate in exocytosis and/or retention of this membrane compartment.