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Background: The role of prognostic variables in the treatment of hepatocellular carcinoma (HCC) by transarterial chemoembolisation (TACE) is controversial., Aims: To evaluate the survival of patients with HCC on cirrhosis treated with TACE and to analyse the prognostic factors affecting survival., Methods: From 1996 to 2006, 580 consecutive patients with HCC in cirrhosis were observed. Of these 194 patients underwent TACE. The primary end-point was survival. Independent predictors of survival were identified using the Cox model., Results: The cumulative 1-year, 3-year, and 5-year survival rates were 96%, 60%, and 41%, respectively. The multivariate analysis showed significant reduction of survival among patients with serum bilirubin values >2mg/dl compared to patients with values <2mg/dl (Hazard ratio 3.84; CI 95% 1.70-8.66; p-value=0.001). Multivariate analysis performed in the group of patients treated with TACE alone showed that elevated serum bilirubin (Hazard ratio 2.96; CI 95% 1.20-7.3; p-value 0.02) and incomplete tumour response (Hazard ratio 2.88; CI 95% 1.18-7.05; p-value 0.02) are correlated with a worse outcome., Conclusions: TACE was well tolerated and overall survival rate was 41% after 5 years. Complete tumour response and serum bilirubin <2mg/dl were identified as predictors of survival., ((c) 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Laparoscopy is widely used in the surgical treatment of a number of diseases. Its advantages are generally believed to lie on its minimal invasiveness, better cosmetic outcome and shorter length of hospital stay based on surgical expertise and state-of-the-art equipment. Thousands of laparoscopic surgical procedures performed safely prove that mechanical ventilation during anaesthesia for laparoscopy is well tolerated by a vast majority of patients. However, the effects of pneumoperitoneum are particularly relevant to patients with underlying lung disease as well as to the increasing number of patients with higher-than-normal body mass index. Moreover, many surgical procedures are significantly longer in duration when performed with laparoscopic techniques. Taken together, these factors impose special care for the management of mechanical ventilation during laparoscopic surgery. The purpose of the review is to summarise the consequences of pneumoperitoneum on the standard monitoring of mechanical ventilation during anaesthesia and to discuss the rationale of using a protective ventilation strategy during laparoscopic surgery. The consequences of chest wall derangement occurring during pneumoperitoneum on airway pressure and central venous pressure, together with the role of end-tidal-CO2 monitoring are emphasised. Ventilatory and non-ventilatory strategies to protect the lung are discussed.

Recruitment maneuvers have been the subject of intense investigation. Their role in the acute care setting is debated given the lack of information on their influence on clinical outcomes. Oxygenation improvement is often a striking effect, together with changes of respiratory mechanics. However, hemodynamic compromise is frequently associated with the maneuver, sometimes even barotrauma. Another possible downside is bacterial translocation secondary to lung overdistention, as suggested by experimental and initial clinical data. When a recruitment maneuver is performed, the patho-physiological consequences of lung recruitment should guide clinicians more than oxygenation improvement alone.

Many age-related changes are described in the nervous system of different species, but detailed studies of brain lesions in ageing horses are lacking. The aim of the present study was to systematically characterize lesions in the brains of 60 horses aged from 7 to 23 years. No gross changes were present in any brain. Microscopically, spongiform changes, lipofuscin storage, corpora amylacea, gliosis and satellitosis were common, together with axonal and neuronal swellings. The most important findings were the presence of pseudocalcium-calcium (pCa-Ca) deposits and arterial wall degeneration. Scanning electron microscopical examination of two cases with vascular mineralization revealed marked deposition of an amorphous substance in the vessel walls that was probably formed by a polyanionic protein matrix and a mineral component. Immunohistochemically, numerous axonal spheroids were positively labelled for ubiquitin. No PrPsc was detected in sections with neuronal vacuolation. Neuronal swelling, corpora amylacea, hippocampal Tau-positive neurons and methenamine-positive diffuse (preamyloid) plaques were also detected. Congo red staining failed to detect amyloid deposition. The characterization of age-related lesions in the brains of these horses will allow these changes to be discriminated from pathological processes in future studies. Some lesions described here, including some vascular changes, the presence of diffuse plaques and tau accumulation in hippocampal neurons, have not been described previously in the horse.

Renal dysplasia is defined as a condition of disorganised development of renal parenchyma due to abnormal differentiation. The case of a 5-month-old intact male Norwegian Forest Cat with a history of polyuria and polydipsia is reported. Ultrasonographic examination showed a slight enlargement of kidneys. Biochemical parameters, haematological examinations and clinical signs were compatible with chronic renal failure (CRF). Histological examination was correlated with a primary tubular disorganisation and modification of glomerular compartment. The clinical history together with the histological lesions is consistent with bilateral juvenile renal dysplasia in this cat. To our knowledge, feline renal dysplasia has been reported in fetal infections with panleukopenia virus; no reports indicate the idiopathic origin in feline dysplastic lesions.

Introduction: The aim of this observational study was to investigate the prevalence of endotoxemia after surgery and its association with ICU length of stay., Methods: 102 patients admitted to a university ICU after surgery were recruited. Within four hours of admission, functional data were collected and APACHE II severity score calculated. Arterial blood samples were taken and endotoxemia was measured by chemiluminescence (Endotoxin Activity (EA)). Patients were stratified according to their endotoxin levels (low, intermediate and high) and according to their surgical procedures. Differences between endotoxin levels were assessed by ANOVA, accepting P < 0.05 as significant. Data are expressed as mean +/- SD., Results: EA levels were low in 68 (66%) patients, intermediate in 17 (17%) and high in 17 (17%). Age (61 +/- 17 years) and APACHE II score 8.3 +/- 3.7 (P = 0.542) were not significantly different in the three EA groups. Functional parameters on admission were similar between EA groups: white blood cells 11093 +/- 4605 cells/mm3 (P = 0.385), heart rate 76 +/- 16 bpm (P = 0.898), mean arterial pressure 88.8 +/- 13.6 mmHg (P = 0.576), lactate 1.18 +/- 0.77 mmol/L (P = 0.370), PaO2/FiO2 383 +/- 109 mmHg (P = 0.474). Patients with high levels of EA were characterized by longer length of stay in the ICU: 1.9 +/- 3.0 days in the low EA group, 1.8 +/- 1.4 days in intermediate and 5.2 +/- 7.8 days in high group (P = 0.038)., Conclusions: 17% of our patients were characterized by high levels of endotoxemia as assessed by EA assay, despite their low level of complexity on admission. High levels of endotoxin were associated with a longer ICU length of stay.

Mechanism of renal fibrosis leading to end stage kidney remains still a challenge of interest in humans. The pathogenesis of chronic kidney disease is characterized by progressive loss of kidney function and fibrosis. The mechanism of epithelial-mesenchymal transition (EMT) has been predominantly studied in in vitro studies, and we previously demonstrated the EMT of tubular epithelial cells in dogs. In this study, we examined and quantified the modifications of cadherin-catenin complex by immunohistochemistry of E-cadherin and beta-catenin and the mesenchymal marker vimentin in 25 dogs with three different spontaneous inflammatory renal diseases. Results showed a significant down-expression of levels of E-cadherin and beta-catenin directly correlated with the tubular-interstitial damage (TID). In TID grades 2 and 3, E-cadherin expression was significantly reduced (p < 0.001). beta-catenin expression was overall similar to E-cadherin. The mesenchymal-associated protein, vimentin, was de novo identified in tubules within areas of inflammation. In this work, we identified the loss of cadherin or catenin expression as a progressive mechanism in tubulo-interstitial fibrosis, which allows dissociation of structural integrity of renal epithelia and loss of epithelial polarity. The dog might result more significant as model for new therapies.

An adenocarcinoma of the disseminated prostate gland with pulmonary, myocardial and renal metastases is described in a 12-year-old, neutered male European cat. Histologically, the tumour was localised in the spongy layer of the prostatic urethra and showed an epithelial alveolar pattern. Considering the anatomic, microscopic and immunohistochemical findings, the tumour was diagnosed as an adenocarcinoma of the disseminated prostate gland. To our knowledge this is the first report of adenocarcinoma of the disseminated prostate gland in a cat.

Rationale: Lung injury caused by a ventilator results from nonphysiologic lung stress (transpulmonary pressure) and strain (inflated volume to functional residual capacity ratio)., Objectives: To determine whether plateau pressure and tidal volume are adequate surrogates for stress and strain, and to quantify the stress to strain relationship in patients and control subjects., Methods: Nineteen postsurgical healthy patients (group 1), 11 patients with medical diseases (group 2), 26 patients with acute lung injury (group 3), and 24 patients with acute respiratory distress syndrome (group 4) underwent a positive end-expiratory pressure (PEEP) trial (5 and 15 cm H2O) with 6, 8, 10, and 12 ml/kg tidal volume., Measurements and Main Results: Plateau airway pressure, lung and chest wall elastances, and lung stress and strain significantly increased from groups 1 to 4 and with increasing PEEP and tidal volume. Within each group, a given applied airway pressure produced largely variable stress due to the variability of the lung elastance to respiratory system elastance ratio (range, 0.33-0.95). Analogously, for the same applied tidal volume, the strain variability within subgroups was remarkable, due to the functional residual capacity variability. Therefore, low or high tidal volume, such as 6 and 12 ml/kg, respectively, could produce similar stress and strain in a remarkable fraction of patients in each subgroup. In contrast, the stress to strain ratio-that is, specific lung elastance-was similar throughout the subgroups (13.4 +/- 3.4, 12.6 +/- 3.0, 14.4 +/- 3.6, and 13.5 +/- 4.1 cm H2O for groups 1 through 4, respectively; P = 0.58) and did not change with PEEP and tidal volume., Conclusions: Plateau pressure and tidal volume are inadequate surrogates for lung stress and strain. Clinical trial registered with www.clinicaltrials.gov (NCT 00143468).

Tubulo-interstitial fibrosis in dogs may result from primary injury to the interstitium or develop secondary to other renal diseases. As in human renal pathology, tubular epithelial cells (TEC) are believed to actively participate in the mechanisms of renal fibrosis. In this study, we examined the changes in the tubular epithelial component in two specific canine diseases. Immunohistochemistry showed the expression of the epithelial marker cytokeratin, the smooth muscle marker alpha-SMA, the mesenchymal marker vimentin and PCNA in 20 dogs with membranous glomerulonephritis and membrano-proliferative glomerulonephritis. Results showed that the loss of the epithelial marker in TEC was directly correlated to the grade of tubulo-interstitial disease present and independent of the type of glomerulonephritis. Varying degrees of vimentin positivity were detected in tubular epithelium in areas of inflammation, and low numbers of scattered alpha-SMA-positive cells were also observed. Immunohistochemistry showed that epithelial tubular cells lose their cytokeratin staining characteristics and transdifferentiate into cells exhibiting key mesenchymal immunophenotypic feature of vimentin-positive staining in both diseases investigated. The integrity of the tubular basement membrane is likely to be fundamental in maintaining the epithelial phenotype of TEC. Animal models provide opportunities for investigating the pathogenesis of renal fibrosis in humans.

In this report a 9-year-old female German Shepherd dog with a membranoproliferative glomerulonephritis (MPGN) type III associated with concomitant infection of Dirofilaria immitis and Leishmania infantum is presented. Light microscopic evaluation of kidney revealed a diffuse hypercellularity and thickening of glomerular basement membrane. Heavy and coarse granular complement C(3) deposition and a weaker positive reaction to immunoglobulin G were present along peripheral glomerular basement membrane and in the mesangium in the immunofluorescent study. Transmission electron microscopy revealed deposits in the mesangium, subendothelium, and subepithelium. These lesions are compatible with membranoproliferative glomerulonephritis type III in humans.

CT has provided new insights on the pathophysiology of acute respiratory distress syndrome (ARDS), demonstrating that ARDS does not affect the lung parenchyma homogeneously. These findings suggest that lung edema, as assessed by CT scan, should be included in the definition. Lung CT findings may provide a firm rationale for tailoring tidal volume during mechanical ventilation. Ideally, tidal volume should be proportional to the portion of the lung open to ventilation, as assessed by CT scan, rather than to the body weight. CT assessment of lung recruitability seems to be a prerequisite for a rational setting of positive end-expiratory pressure.

To define the characteristics of malignancy we performed routine histology and an immunohistochemical study on seventeen aortic body tumors in dogs. We essayed tumors using a panel of immunohistochemical markers: neuron specific enolase (NSE), chromogranin A (CrA) and S-100. Among 17 cases, the neoplastic cells were positive for NSE (17 cases, 100%), S-100 (9 cases, 53%), and CrA (8 cases, 47%), respectively. The sustentacular cells density and chief cell staining intensity were both inversely related to tumor grade. The most relevant data was consistent with a negative staining of S-100 correlated with absence or decreased number of sustentacular cells in tumors grade III. This report indicates that the immunohistochemical panel has utility for the diagnosis of chemodectoma and the negative staining to CrA and S-100 markers in tumors grade III expresses an indication of malignant behaviour of the tumor.

Objective: To investigate if prone position delays the progression of experimental ventilator-induced lung injury, possibly due to a more homogeneous distribution of strain within lung parenchyma., Design: Prospective, randomized, controlled trial., Setting: Animal laboratory of a university hospital., Subjects: Thirty-five Sprague Dawley male rats (weight 257 +/- 45 g)., Interventions: Mechanical ventilation in either supine or prone position and computed tomography scan analysis., Measurements: : Animals were ventilated in supine (n = 15) or prone (n = 15) position until a similar ventilator-induced lung injury was reached. To do so, experiments were interrupted when respiratory system elastance was 150% of baseline. Ventilator-induced lung injury was assessed as lung wet-to-dry ratio and histology. Time to reach lung injury was considered as a main outcome measure. In five additional animals, computed tomography scans (GE Light Speed QX/I, thickness 1.25 mm, interval 0.6 mm, 100 MA, 100 Kv) were randomly taken at end-expiration and end-inspiration in both positions, and quantitative analysis was performed. Data are shown as mean +/- sd., Measurements and Main Results: Similar ventilator-induced lung injury was reached (respiratory system elastance, wet-to-dry ratio, and histology). The time taken to achieve the target ventilator-induced lung injury was longer with prone position (73 +/- 37 mins vs. 112 +/- 42, supine vs. prone, p = .011). Computed tomography scan analysis performed before lung injury revealed that at end-expiration, the lung was wider in prone position (p = .004) and somewhat shorter (p = .09), despite similar lung volumes (p = .455). Lung density along the vertical axis increased significantly only in supine position (p = .002). Lung strain was greater in supine as opposed to prone position (width strain, 7.8 +/- 1.8% vs. 5.6 +/- 0.9, supine vs. prone, p = .029)., Conclusions: Prone position delays the progression of ventilator-induced lung injury. Computed tomography scan analysis suggests that a more homogeneous distribution of strain may be implicated in the protective role of prone position against ventilator-induced lung injury.

Objective: To investigate whether negative extra-abdominal pressure (NEXAP) improves respiratory function and induces a blood shift from the intrathoracic compartment and to assess whether these effects are influenced by abdominal pressure., Design and Setting: Prospective, randomized, controlled trial in the animal laboratory of a university hospital., Subjects: Eight sedated and paralyzed pigs (19.6+/-3.4 kg)., Interventions: Application of NEXAP (-20 cmH(2)O)., Measurements and Results: Airway, esophageal, gastric and central venous pressures were recorded simultaneously. Intrathoracic blood volume was assessed by PiCCO. The effects of NEXAP were assessed with and without abdominal hypertension by intraperitoneal insufflation of helium. NEXAP caused a lasting drop of gastric (1.97+/-2.26 mmHg) and esophageal (1.21+/-0.67 mmHg) pressures, while end-expiratory airway pressure was similar, hence transpulmonary pressure increased. Intrathoracic blood volume dropped from 358+/-47 to 314+/-47 ml. The fall was associated with a decrease in central venous pressure (R(2)=0.820). When peritoneal pressure was raised (24.7+/-5.5 mmHg), the effects were less marked. However, the difference between negative pressure around the abdomen and the pressure inside the abdomen (effective NEXAP) was correlated with the proportional changes in intrathoracic blood volume (R(2)=0.648), being greater with more negative effective NEXAP. NEXAP improved chest wall elastance during abdominal hypertension (from 0.067+/-0.023 to 0.056+/-0.021 cmH(2)O/ml)., Conclusions: NEXAP increases lung volume and causes a shift of blood from the intrathoracic compartment. It needs to be tailored against abdominal pressure to be effective.

Lactate measurement in the critically ill has been traditionally used to stratify patients with poor outcome. However, plasma lactate levels are the result of a finely tuned interplay of factors that affect the balance between its production and its clearance. When the oxygen supply does not match its consumption, organisms such as man who are forced to produce ATP for their integrity adapt in many different ways up to the point when energy failure occurs. Lactate, being part of the adaptive response, may then be used to assess the severity of the supply/demand imbalance. In such a scenario, the time to intervention becomes relevant: early and effective treatment may allow the cell to revert to a normal state, as long as the oxygen machinery (i.e. mitochondria) is intact. Conversely, once the mitochondria are deranged, energy failure occurs even in the presence of normoxia. The lactate increase in critically ill patients may therefore be viewed as an early marker of a potentially reversible state.

Background and Objective: The aim of this study was to test the efficacy of positive end-expiratory pressure (PEEP) to the dependent lung during one-lung ventilation, taking into consideration underlying lung function in order to select responders to PEEP., Methods: Forty-six patients undergoing open-chest thoracic surgical procedures were studied in an operating room of a university hospital. Patients were randomized to receive zero end-expiratory pressure (ZEEP) or 10 cmH2O of PEEP to the dependent lung during one-lung ventilation in lateral decubitus. The patients were stratified according to preoperative forced expiratory volume in 1 s (FEV1) as an indicator of lung function (below or above 72%). Oxygenation was measured in the supine position, in the lateral decubitus with an open chest, and after 20 min of ZEEP or PEEP. The respiratory system pressure-volume curve of the dependent hemithorax was measured in supine and open-chest lateral decubitus positions with a super-syringe., Results: Application of 10 cmH2O of PEEP resulted in a significant increase in PaO2 (P < 0.05). This did not occur in ZEEP group, considered as a time matched control. PEEP improved oxygenation only in patients with high FEV1 (from 11.6+/-4.8 to 15.3+/-7.1 kPa, P < 0.05). There was no significant change in the low FEV1 group. Dependent hemithorax compliance decreased in lateral decubitus, more in patients with high FEV1 (P < 0.05). PEEP improved compliance to a greater extent in patients with high FEV1 (from 33.6+/-3.6 to 48.4+/-3.9 mLcmH2O(-1), P < 0.05)., Conclusions: During one-lung ventilation in lateral decubitus, PEEP applied to the dependent lung significantly improves oxygenation and respiratory mechanics in patients with rather normal lungs as assessed by high FEV1.

The importance of chest wall elastance in characterizing acute lung injury/acute respiratory distress syndrome patients and in setting mechanical ventilation is increasingly recognized. Nearly 30% of patients admitted to a general intensive care unit have an abnormal high intra-abdominal pressure (due to ascites, bowel edema, ileus), which leads to an increase in the chest wall elastance. At a given applied airway pressure, the pleural pressure increases according to (in the static condition) the equation: pleural pressure = airway pressure x (chest wall elastance/total respiratory system elastance). Consequently, for a given applied pressure, the increase in pleural pressure implies a decrease in transpulmonary pressure (airway pressure - pleural pressure), which is the distending force of the lung, implies a decrease of the strain and of ventilator-induced lung injury, implies the need to use a higher airway pressure during the recruitment maneuvers to reach a sufficient transpulmonary opening pressure, implies hemodynamic risk due to the reductions in venous return and heart size, and implies a possible increase of lung edema, partially due to the reduced edema clearance. It is always important in the most critically ill patients to assess the intra-abdominal pressure and the chest wall elastance.

In the last several years, we definitely learned that the acute respiratory distress syndrome lung is small, nonhomogeneous, and that mechanical ventilation in this baby lung may cause physical damage as well as inflammatory reaction. The clinical benefit of the gentle lung treatment, based on a decrease of global/regional stress and strain into the lung, has been finally proved. However, we forgot the importance of lung perfusion and its distribution in this syndrome and, besides a low tidal volume, we still do not know how to handle the other variables of mechanical ventilation. Measurements of variables as transpulmonary pressure and end expiratory lung volume, for a rational setting of mechanical ventilation, should be introduced in routine clinical practice.

Increased abdominal pressure is common in intensive care unit patients. To investigate its impact on respiration and hemodynamics we applied intraabdominal pressure (aIAP) of 0 and 20 cm H(2)O (pneumoperitoneum) in seven pigs. The whole-lung computed tomography scan and a complete set of respiratory and hemodynamics variables were recorded both in healthy lung and after oleic acid (OA) injury. In healthy lung, aIAP 20 cm H(2)O significantly lowered the gas content, leaving the tissue content unchanged. In OA-injured lung at aIAP 0 cm H(2)O, the gas content significantly decreased compared with healthy lung. The excess tissue mass (edema) amounted to 30 +/- 24% of the original tissue weight (455 +/- 80 g). The edema was primarily distributed in the base regions and was not gravity dependent. Heart volume, central venous, pulmonary artery, wedge, and systemic arterial pressures significantly increased. At aIAP 20 cm H(2)O in OA-injured lung, the central venous and pulmonary artery pressures further increased. The gas content further decreased, and the excess tissue mass rose up to 103 +/- 37% (tissue weight 905 +/- 134 g), with homogeneous distribution along the cephalocaudal and sternovertebral axis. We conclude that in OA-injured lung, the increase of IAP increases the amount of edema.

Objective: To investigate the possibility of artificially decreasing intra-abdominal pressure (IAP) by applying continuous negative pressure around the abdomen., Material and Methods: We investigated the effects of negative extra-abdominal pressure (NEXAP) on IAP and central venous pressure (CVP) in 30 patients admitted to our intensive care unit (age 57+/-17 years, BMI 26.1+/-4.0 kg/m2, SAPS II 41.8+/-17.0). Patients with severe hemodynamic instability and/or those admitted following a laparotomy were not studied. Measurements included bladder pressure as an estimate of IAP, CVP, invasive mean arterial pressure (MAP) and heart rate (HR). In five patients extensive hemodynamic measurements were also taken using a Swan-Ganz catheter. Following measurements at baseline (Basal), NEXAP (Life Care - Nev 100, Respironics) was applied on the abdomen, in random order, at a pressure equal to IAP (NEXAP0), 5 cmH(2)O (NEXAP-5) or 10 cmH(2)O (NEXAP-10) more negative than NEXAP0., Results: Basal IAP ranged from 4 to 22 mmHg. NEXAP decreased IAP from 8.7+/-4.3 mmHg to 6+/-4.2 (Basal vs NEXAP0 p<0.001). There was a further decrease of IAP when more negative pressure was applied: 4.3+/-3.2 mmHg, 3.8+/-3.7 mmHg (NEXAP-5 and NEXAP-10 vs NEXAP0, respectively, p<0.001). Similarly, CVP decreased from 9.3+/-3.4 mmHg to 7.5+/-3.8 (Basal vs NEXAP-10, p<0.001). The lower the IAP when NEXAP was applied, the lower the CVP (r2=0.778, p<0.001, multiple linear regression). When measured, cardiac output did not significantly change with NEXAP., Conclusions: Negative extra-abdominal pressure may be applied in critically ill patients to decrease intra-abdominal pressure non-invasively.

A 13-year-old, male German Shepherd dog was euthanasized for a frontal temporal mass revealed by the MRI. The histological examination showed a proliferation composed of small round undifferentiated cells arranged in sheets or nests and sometimes in pseudorosettes interrupted by hypocellular zones of fibrovascular stroma. Immunohistochemical studies revealed the expression of neuroblastic epitopes. The presented neoplasm has many histological and immunohistochemical features in common with the group of olfactory neuroblastomas reported in man, so it could be classified as primitive neuroectodermal tumor with neuronal differentiation.

Objective: Many studies have investigated the protective role of positive end-expiratory pressure (PEEP) on ventilator-induced lung injury. Most assessed lung injury in protocols involving different ventilation strategies applied for the same length of time. This study, however, set out to investigate the protective role of PEEP with respect to the time needed to reach similar levels of lung injury., Design: Prospective, randomized laboratory animal investigation., Setting: The University Laboratory of Ospedale Maggiore, Milano, IRCCS., Subjects: Anesthetized, paralyzed, and mechanically ventilated Sprague-Dawley rats., Interventions: Three groups of five Sprague-Dawley rats were ventilated using zero end-expiratory pressure ZEEP (PEEP of 0 cm H(2)O) and PEEP of 3 and 6 cm H(2)O and a similar index of lung overdistension (Paw(p)/P(100) congruent with 1.1; where Paw(p) is peak airway pressure and P(100) is the pressure corresponding to total lung capacity). To obtain this, tidal volume was reduced depending on the PEEP. To reach similar levels of lung injury, we measured respiratory system elastance while ventilating the animals and killed them when respiratory system elastance was 150% of baseline. Once target respiratory system elastance was reached, the lung wet-to-dry ratio was obtained., Results: Rats were ventilated with comparable high airway pressure (Paw(p) of 42.8 +/- 3.1, 43.5 +/- 2.6, and 46.2 +/- 4.4, respectively, for PEEP 0, 3, and 6) obtaining similar overdistension (Paw(p)/P(100) - index of overdistension: 1.17 +/- 0.2, 1.06 +/- 0.1, and 1.19 +/- 0.2). The respiratory system elastance target was reached and wet-to-dry ratio was not different in the three groups, suggesting a similar degree of lung damage. The time taken to achieve the target respiratory system elastance was three times longer with PEEP 3 and 6 (55 +/- 14 mins and 60 +/- 17) as compared with zero end-expiratory pressure (18 +/- 3 mins, p <.001)., Conclusion: These findings confirm that PEEP is protective against ventilator-induced lung injury and may enable the clinician to "buy time" in the progression of lung injury.

Objective: We hypothesized that a 50% increase in respiratory system elastance (Ers) would indicate similar degree of lung damage (equi-damage, ED), independently of ventilation strategy., Design and Setting: A prospective, randomized animal laboratory investigation at a university hospital laboratory., Subjects: 35 anesthetized, paralyzed, mechanically ventilated male Sprague-Dawley rats., Interventions: Each rat was ventilated with a different combination of tidal volume, positive end-expiratory pressure, and inspired fraction of oxygen. Ers was determined throughout the experiment; the studies were interrupted when Ers reached 150% (ED) of its baseline value, or after 5 h., Measurements and Results: Lung wet to dry weight ratio (W/D) was assessed. Morphological damage of the lung was scored on a grading of perivascular edema, hemorrhage, and breaks in the alveolar septa to obtain a total injury score. Twenty-four rats achieved an Ers of 150%: nine within 1 h (class 1), nine in 1-2 h (class 2), and six in 2-5 h (class 3). Eleven rats did not reach the target 50% increase in Ers (class 4). W/D was higher in rats that reached the target than in those that did not. W/D did not differ among rats that reached ED. Similarly, the total injury score did not differ among classes 1-3 but was higher than class 4., Conclusions: In the setting of VILI a 50% increase in Ers corresponds to an equal level of lung damage, irrespective of ventilatory setting and time of ventilation.

Objective: To study the influence of different mechanical ventilatory support strategies on organs distal to the lung, we developed an in vivo rat model, in which the effects of different tidal volume values can be studied while maintaining other indexes., Design: Prospective, randomized animal laboratory investigation., Setting: University laboratory of Ospedale Maggiore di Milano-Instituto di Ricovero e Cura a Carattere Scientifico., Subjects: Anesthetized, paralyzed, and mechanically ventilated male Sprague-Dawley rats., Interventions: Two groups of seven rats each were randomized to receive tidal volumes of either 25% or 75% of inspiratory capacity (IC), calculated from a preliminary estimation of total lung capacity. Ventilation strategies for the two groups were as follows: a) 25% IC, 9.9+/-0.8 mL/kg; frequency, 59+/-4 beats/min; positive end-expiratory pressure, 3.6+/-0.8 cm H2O; and peak inspiratory airway pressure (Paw), 13.2+/-2 cm H20; and b) 75% IC, 29.8+/-2.9; frequency, 23+/-13; positive end-expiratory pressure, 0; peak inspiratory Paw, 29.0+/-3., Measurements and Main Results: Mean arterial pressure (invasively monitored) remained well above adequate perfusion pressure values throughout, and no significant difference was seen between the two groups. PaO2, pHa, and PaCO2 values were compared after 60 mins of ventilation and again, no significant difference was seen between the two groups (PaO2, 269+/-25 and 260+/-55 torr; pHa, 7.432+/-0.09 and 7.415+/-0.03; PaCO2, 35.4+/-8 and 32.5+/-2 torr, for the 25% IC and 75% IC groups, respectively). Mean Paws were not different (6.4+/-0.8 cm H2O in the 25% IC groups, and 6.1+/-1.2 in the 75% IC groups, respectively). At the end of the experiment, animals were killed and the liver and kidney isolated, fixed in 4% formalin, cut, and stained for optic microscopy. Kidneys from rats ventilated with 75% IC showed increased Bowman's space with collapse of the glomerular capillaries. This occurred in a greater percentage of rats ventilated with 75% IC (0.67+/-0.2 vs. 0.29+/-0.2, 75% IC vs. 25% IC, respectively; p < .05). Perivascular edema was also present in rats ventilated with 75% IC (p < .05). Morphometric determinations of the empty zones (index of edema) demonstrated a trend toward differences between 75% IC livers and 25% IC (0.14+/-0.05 vs. 0.11+/-0.02, respectively)., Conclusion: We conclude that it is possible to study the effects of mechanical ventilatory support on organs distal to the lung by means of an in vivo rat model.

Aim of the study was to test individual mechanical and functional responses to open chest lateral decubitus during one lung ventilation. We measured dependent lung pressure volume (P-V) curves of 19 patients during supine and lateral decubitus. We found that patients characterized by high FEV1 developed greater changes in P-V curve shape than those characterized by low FEV1. Based on these results we decided to test a ventilation strategy characterized by the use of ZEEP or PEEP = 10 cm H2O applied to the dependent lung. In a preliminary set of patients stratified by FEV1 we found that PEEP deteriorated PaO2/FiO2 in patients with low FEV1, while there was a trend towards improvement in patients with high FEV1. It is possible that dependent lung PEEP counteracts atelectasias in normal lungs, while it may divert blood flow or create dead space in patients with sick and stiff lungs. We conclude that during one lung ventilation in open chest lateral decubitus, ventilatory setting need to be individually tailored.

As a preliminary in vivo approach in order to study the mechanism of toxicity of the veterinary anticoccidial monensin, male Wistar rats were orally administered 0, 2 and 12 mg kg-1 body wt. day-1 of monensin for 7 days. At the end of the experiment, effects of the ionophore on serum creatine kinase, lactic dehydrogenase and selected drug metabolising enzyme activities were investigated. Furthermore, liver, heart and quadriceps femoris muscle samples were submitted to morphological investigations. Clinical signs or increasing levels of enzymic markers of muscle injury attributable to monensin toxicosis have never been observed in treated animals. As a matter of fact all drug metabolising enzymes activities checked have not shown significant changes, except for a significant decrease of ethoxyresorufin O-deethylase (up to 31%) and aminopyrine N-demethylase (17%) activities. Morphologically, mitochondrial cristae fragmentation and initial formation of 'myelinic sheaths-like' structures have been noticed in heart and muscle fibres. As far as rat study is concerned, these results confirm heart and muscle as target organs of monensin toxicity. In addition, these findings suggest that the inhibition of hepatic biotransformation processes following the i.p. administration of the ionophore, as reported previously by other authors, might reflect unspecific cellular toxic effects rather than a specific enzyme damage., (Copyright 1999 The Italian Pharmacological Society.)

Objectives: Increases in exhaled nitric oxide have been demonstrated to originate from the lungs of rats after septic lung injury. The aim of this study was to investigate whether treatment with the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) would prevent lipopolysaccharide (LPS)-induced increases in exhaled nitric oxide and whether this would have an effect on septic lung inflammation., Design: Prospective, randomized, placebo-controlled animal laboratory investigation., Setting: University laboratory., Subjects: Male, anesthetized, paralyzed, and mechanically ventilated Sprague-Dawley rats (n = 27)., Interventions: Rats were mechanically ventilated with air filtered to remove nitric oxide (expiratory rate 40 breaths/min, tidal volume 3 mL, positive end-expiratory pressure 0, FIO2 0.21). They were then randomized to receive intravenous injections of either L-NAME (25 mg/kg/hr x 4 hrs) (n = 11) or saline (n = 10). Both groups were again randomized to receive either LPS (Salmonella typhosa: 20 mg/kg i.v. x 1 dose) or an equal volume of saline 5 mins later. Thereafter, exhaled gas was collected in polyethylene bags for measurements of nitric oxide concentration. After 4 hrs, the rats were killed and the lungs were preserved and examined histologically. To examine the effect of L-NAME and LPS on mean arterial blood pressure, six additional rats underwent the same ventilation protocol with cannulation of the right internal carotid artery so that systemic arterial pressures could be measured., Measurements and Main Results: Exhaled gas was collected and measurements of NO concentrations were made using chemiluminescence every 20 mins for 240 mins during ventilation. A total lung injury score was calculated by determining the extent of cellular infiltrate, exudate and hemorrhage. Mean arterial pressure was recorded every 5 mins for 20 mins and then at 20-min periods for 120 mins. Exhaled nitric oxide concentrations increased in all the LPS-treated rats that did not receive L-NAME by 120 mins; a plateau was reached by 190 mins that was approximately 4 times greater than control rats not treated with LPS (p < .001). In contrast, rats treated with L-NAME and LPS did not show an increase in exhaled NO. Administration of L-NAME induced a 10-min nonsustained increase in mean arterial pressure in two rats treated with L-NAME followed by LPS. This increase in mean arterial pressure was not seen in two placebo and two LPS-treated rats that did not receive L-NAME. Lung inflammation was significantly worse in the two groups of rats which received LPS compared with the two that did not. L-NAME did not cause lung inflammation in rats that did not receive LPS; however, LPS-treated rats that received L-NAME had more inflammatory interstitial infiltrate (p < .05) and a trend toward worse lung injury than did LPS-treated rats that did not receive L-NAME., Conclusion: We conclude that L-NAME can inhibit the increase in exhaled NO from the lungs of septic rats, but that this inhibition does not reduce lung inflammation, and may worsen it.

We studied 16 patients with acute lung injury receiving volume-controlled ventilation to assess the relationships between gas exchange and respiratory mechanics before, during, and after 2 h in the prone position. We measured the end-expiratory lung volume (EELV, helium dilution), the total respiratory system (Cst,rs), the lung (Cst,L) and the thoracoabdominal cage (Cst,w) compliances (end-inspiratory occlusion technique and esophageal balloon), the hemodynamics, and gas exchange. In the prone position, PaO2 increased from 103.2 +/- 23.8 to 129.3 +/- 32.9 mm Hg (p < 0.05) without significant changes of Cst,rs and EELV. However, Cst,w decreased from 204.8 +/- 97.4 to 135.9 +/- 52.5 ml/cm H2O (p < 0.01) and the decrease was correlated with the oxygenation increase (r = 0.62, p < 0.05). Furthermore, the greater the baseline supine Cst,w, the greater its decrease in the prone position (r = 0.82, p < 0.01). Consequently, the oxygenation changes in the prone position were predictable from baseline supine Cst,w (r = 0.80, p < 0.01). Returning to the supine position, Cst,rs increased compared with baseline (42.3 +/- 14.4 versus 38.4 +/- 13.7 ml/cm H2O; p < 0.01), mainly because of the lung component (57.5 +/- 25.1 versus 52.4 +/- 23.3 ml/cm H2O; p < 0.01). Thus, (1) baseline Cst,w and its changes may play a role in determining the oxygenation response in the prone position; (2) the prone position improves Cst,rs and Cst,L when the supine position is resumed.

The distribution of tidal volume (VT) and recruitment was investigated by chest computed tomography (CT) in eight sedated-paralyzed patients with the adult respiratory distress syndrome (ARDS). A CT section was obtained in the supine position at 0, 5, 10, 15, and 20 cm H2O positive end-expiratory pressure (PEEP) and at the corresponding inspiratory plateau pressure (21 +/- 1.8, 26 +/- 1.4, 31 +/- 1.8, 38 +/- 2.1, and 46 +/- 3.2 cm H2O [mean +/- SE]), keeping VT constant. Each CT section was divided along its ventral-dorsal height into 10 equally spaced intervals (levels). Vi(insp) and Vi(exp) were defined as the gas volume for level i (i = 1 to 10) at end-inspiration and at end-expiration, respectively. The following variables were computed at each lung level: (1) distribution of CT section tidal volume (VTct), i.e., the fraction of VT that inflates a given lung level; (2) the plateau-induced and PEEP-induced recruitment, i.e., the amount of lung tissue previously collapsed that inflates at plateau pressure and at PEEP, respectively; (3) the reopening-collapsing tissue, i.e., the amount of lung tissue that regains inflation at plateau pressure and collapses at PEEP. With increasing PEEP from 0 to 20 cm H2O, the VTct distribution decreased significantly (p < 0.01) in the upper levels, did not change in the middle levels, and increased significantly (p < 0.01) in the lower levels.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of subchronic administration (90 d) of zineb were studied in male New Zealand White rabbits. Rabbits were allotted to 3 groups of 8 animals each and offered diets containing 0, 0.3 or 0.6% zineb. A marked decline in weight gain, hemoglobin concentration, hematocrit, and erythrocyte and leucocyte counts occurred at the highest zineb dosage. There was a dose-related depression in circulating thyroid hormones, whereas serum lipid concentration, particularly that of cholesterol and triglycerides, increased. Hepatic lipid concentration was considerably reduced in rabbits exposed to 0.6% zineb. Neither serum testosterone nor the activities of selected testicular enzymes showed changes suggestive of testicular involvement. Pathological changes were in agreement with biochemical findings; there was a marked dose-related enlargement of the thyroid showing histological colloid struma. An increase in relative weight and moderate glycogenosis were detected in liver, whereas no lesions occurred in testes. It was concluded that thyroid and liver are the main targets for zineb toxicity in the rabbit. Unlike the results from previous studies conducted on other food-producing species, repeated exposure of rabbits to zineb failed to cause testicular damage. This might be related to the inability of zineb to significantly accumulate in the testes.

Nitric Oxide (NO) has been implicated in the pathologic vasodilation of sepsis. Because NO can be measured in the exhaled gas of animals and humans, we hypothesized that increases in exhaled NO would occur in a septic model. Using a blinded design, 10 male Sprague-Dawley rats (300 to 400 g) were anesthetized, paralyzed, tracheotomized, and randomized (5/group) to receive an intravenous injection of either lipopolysaccharide (LPS) (Salmonella typhosa, 20 mg/kg) or placebo (equal volume of saline). Thereafter, exhaled gas was collected and measurements of NO concentration were made using chemiluminescence every 20 min for 300 min during ventilation (RR 40 breaths/min, VT 3 ml; PEEP 0, FIO2 0.21). Another group of 10 animals (5 LPS; 5 control) were treated in the same fashion and then killed at 240 min and an arterial blood sample obtained for blood gas and TNF alpha determinations. Pressure volume (PV) curves were constructed and lungs removed, preserved, and submitted for histologic evaluation. LPS-treated rats had lower mean arterial pressures than the control group, p < 0.0001. No significant differences in static lung compliance and PV curves were found in the two groups. TNF alpha levels were greater in the LPS group (1.40 +/- 0.24 ng/ml) versus control group (0.09 +/- 0.04 ng/ml), p < 0.001. By contrast to the control group, exhaled NO concentration rose in all LPS-treated rats at approximately 100 min and at about 160 min reached a plateau that was 6 times greater than control levels (p < 0.0001). There was greater interstitial, airspace, and total lung injury in the LPS group (p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Organotins are used worldwide in agricultural practice as fungicides and herbicides. In this study morphological and ultrastructural investigations related with the subacute administration of the fungicide triphenyltin acetate (TPTA) were carried out in rabbits and lambs. Twenty-eight New Zealand White male rabbits were fed diets containing 0, 15, 75 or 150 ppm TPTA for 70 d; comparable doses (1 or 7.5 mg/kg bw) were administered daily to immature male lambs. After 70 d of treatment dose-dependent decreases in body weight gain and thymus relative weights were seen in both species. In rabbits, the main histological lesions were found in the thymus and mesenteric and retropharyngeal lymph nodes, confirming the immunosuppressive activity reported by TPTA in other rodents. Lambs showed similar, but less severe lesions. However, the involvement of the immune system was noted in both species, but at doses much higher than those reported for rats and guinea pigs. This different immunotoxic activity of TPTA might be related to species differences in the toxicokinetics of the fungicide.

The toxicity of zinc ethylene-bis-dithiocarbamate (zineb), a widely used fungicide, was studied in four 4-week-old Friesian calves with immature rumen function. Calves were first subjected to liver biopsy, and thereafter, 3 of them were orally administered 200 mg of zineb/kg of body weight daily for 80 days, whereas the fourth calf served as control and remained untreated. Clinical, hematologic, and pathologic (including ultrastructural) findings were recorded. The distribution in body fluids and tissues of the parent compound and one of its main metabolites, ethylenethiourea (ETU), also was examined. Treated calves had unthrifty appearance and reduction in weight gain. They also had remarkable impairment of thyroid function, as reflected by reduction in serum concentrations of triiodothyronine and thyroxine and increase in weight of the thyroid gland associated with epithelial vacuolization and foci of hyperplasia. Moderate increase in liver glycogen content and impairment in maturation of germ cells were recorded consistently. Whereas zineb was widely distributed in body tissues, ETU accumulated mainly in the liver and the thyroid gland, although noticeable concentrations also were attained in muscle. Data were consistent with involvement of ETU mainly in the pathogenesis of thyroid gland lesions, and indicate that unweaned calves given zineb develop a clinicopathologic syndrome that does not differ qualitatively from that already described in adult cattle exposed to zineb.

The authors found during a study concerning the gastric pathology in pigs 2828 cases of hypertrophic gastropathy in 8408 regularly slaughtered animals. After a description of the morphologic patterns of the lesions, the authors make some pathogenetic hypothesis and conclude that this lesion is like Ménétrier's disease of man.

Viral hepatitis in chimpanzees produces negligible symptomatology, and serum aminotransferase changes may be minimal. To maximize the predictive value of these determinations, which are the only serum indicators available for non-A non-B (NANB) hepatitis infection, normal ranges for aspartate and alanine aminotransferases (AST, ALT) were examined and categorized according to age and sex. Males were found to have higher values than females, and adults higher values than juveniles. The kinetic method used and the values obtained are described. Differences in methodologies and reporting units are discussed.

Normal ranges for gamma glutamyl transferase (GGT) in chimpanzees were determined and categorized according to age and sex. Enzyme patterns presented for 36 cases of non-A, non-B (NANB) hepatitis and compared to others with hepatitis A and/or B show that the response of this enzyme to these viral agents in chimpanzees is comparable to that seen in human patients. The value of GGT determinations, in addition to aspartate aminotransferase and alanine aminotransferase for the differentiation of various types of viral hepatitis, is described.

Testis structure and functions were monitored in male Wistar rats chronically exposed to various levels of sodium selenite (Na2SeO3) in drinking water (4, 8 or 16 ppm). The most remarkable testicular changes were observed in the 16 ppm group: intertubular oedema, oligospermia, scattered foci of degenerated spermatids were found. In addition, marked changes in several specific enzymes of testicular cells occurred along with a significant reduction of mean-tubular-diameters, mean-tubular-areas and mean-tubular-perimeters. These results clearly demonstrate a testicular involvement during chronic exposure of the rat to selenium.