Sperm survival: relationship to age-related sperm DNA integrity in infertile men.

The purpose of our study was to evaluate the effect of age and sperm DNA integrity on sperm survival. Semen samples from fifty six unselected patients undergoing infertility evaluation were assessed in terms of standard semen parameters, DNA integrity, and sperm survival after 6-24 h of incubation. Prolonged incubation of density gradient selected sperm adversely effects sperm survival in older patients and patients with extensive sperm DNA damage. Immediate preparation of such samples prior to use for assisted reproductive technology (ART) may overcome the negative effect of extended incubation.

The effect of a venous filter on the embolic load during medullary canal pressurization: a canine study.

BACKGROUND: Acute intramedullary stabilization of femoral shaft fractures in multiply injured patients is controversial. Intravasation of medullary fat during canal pressurization has been suspected to trigger adult respiratory distress syndrome. The goal of the present study was to evaluate the effect, on the lungs, of a filter placed into the ipsilateral common iliac vein during medullary canal pressurization in a canine model. METHODS: With use of an established model of fat embolization, twelve mongrel dogs were randomized into two groups. In six dogs, a special filter was inserted percutaneously into the left common iliac vein while the dogs were under general anesthesia. In all dogs, the left femur and tibia were then pressurized by injection of bone cement and insertion of intramedullary rods. Hemodynamic measurements and echocardiographic images were recorded throughout the experiment. After one hour, the animals were killed and the lungs were harvested for histomorphometric analysis. RESULTS: Without the filter, the mean pulmonary artery pressure increased by 11.8 +/- 2.1 mm Hg (p < 0.001). With the filter, the mean pulmonary artery pressure increased by only 2.2 +/- 0.8 mm Hg (p < 0.02). Without the filter, there was a significant increase in the index of pulmonary vascular resistance as compared with the baseline value (p < 0.05). With the filter, there was no such increase. Histomorphometric analysis demonstrated that the presence of the filter reduced the absolute area of embolization and the volume percentages of lung and pulmonary vasculature embolized. CONCLUSIONS: In this canine experiment, temporary placement of a venous filter prior to medullary canal pressurization reduced the embolic load and minimized its hemodynamic effects.

Sperm DNA integrity: correlation with sperm plasma membrane integrity in semen evaluated for male infertility.

Previous independent studies have indicated that abnormally low parameters of sperm DNA integrity and sperm membrane integrity correlate to reduced fertility due in part to implantation disorders. The purpose of our study was to evaluate the relationship between sperm plasma membrane functional integrity assessed by the hypo-osmotic swelling test (HOST) and sperm DNA integriy test assesed by DNA fragmentation index (DFI). Semen samples from 102 random patients were evaluated in terms of standard semen parameters and assessed by DFI and HOST. Both tests showed a significant correlation to standard semen parameters (p < .05). In addition, patients with abnormal HOST results had a higher likehood of a subnormal or abnormal DFI result (p < .001). Our results suggest that a common sublethal insult may manifest as abnormalities in both the nucleus and the plasma membrane that act at the implantation and/or subsequent levels of development rather than at the fertilization stage.

Bilateral congenital diaphragmatic hernia: diagnostic clues at fetal sonography.

Bilateral congenital diaphragmatic hernia is a rare, life-threatening malformation. We describe a case of bilateral Bochdalek hernia diagnosed prenatally. The sonographic clues to the diagnosis were anterior displacement of the heart with relatively minimal lateral shift. The definitive diagnosis was made by demonstrating the liver in the right thorax and bowel loop and stomach in the left thorax. Color and power Doppler demonstrated the hepatic vessels embracing both sides of the heart from behind.

Validation of an orthotopic model of human lung cancer with regional and systemic metastases.

BACKGROUND: We developed an orthotopic model of human lung cancer that exhibits highly predictable regional and systemic metastases. This study examines the response of the model when treated with conventional and experimental chemotherapy. METHODS: NCI-H460 tumor fragments were implanted into the right caudal lung lobe of a nude rat. Treatment commenced 2 weeks later. We assessed response by comparing primary tumor and mediastinal lymph node weights, total body weight, and length of survival with untreated, tumor-bearing control animals. We also calculated the incidence of metastasis to kidney, bone, brain, and contralateral lung in treated versus untreated animals. RESULTS: Mitomycin and cisplatin showed broad activity against primary and metastatic disease. The matrix metalloproteinase inhibitor batimastat, low-dose cisplatin, and mitomycin significantly prolonged survival. High-dose cisplatin caused renal toxicity that shortened survival. Brain metastases did not respond to mitomycin, consistent with its poor blood-brain barrier penetration. CONCLUSIONS: Responses were similar to NCI-H460 in vitro data and consistent with clinical experience for these drugs. Drug-related toxicities similar to those seen in clinical practice were detected.

Pressure-time curve predicts minimally injurious ventilatory strategy in an isolated rat lung model.

BACKGROUND: We tested the hypothesis that the pressure-time (P-t) curve during constant flow ventilation can be used to set a noninjurious ventilatory strategy. METHODS: In an isolated, nonperfused, lavaged model of acute lung injury, tidal volume and positive end-expiratory pressure were set to obtain: (1) a straight P-t curve (constant compliance, minimal stress); (2) a downward concavity in the P-t curve (increasing compliance, low volume stress); and (3) an upward concavity in the P-t curve (decreasing compliance, high volume stress). The P-t curve was fitted to: P = a. tb +c, where b describes the shape of the curve, b = 1 describes a straight P-t curve, b < 1 describes a downward concavity, and b > 1 describes an upward concavity. After 3 h, lungs were analyzed for histologic evidence of pulmonary damage and lavage concentration of inflammatory mediators. Ventilator-induced lung injury occurred when injury score and cytokine concentrations in the ventilated lungs were higher than those in 10 isolated lavaged rats kept statically inflated for 3 h with an airway pressure of 4 cm H2O. RESULTS: The threshold value for coefficient b that discriminated best between lungs with and without histologic and inflammatory evidence of ventilator-induced lung injury (receiver-operating characteristic curve) ranged between 0.90-1.10. For such threshold values, the sensitivity of coefficient b to identify noninjurious ventilatory strategy was 1.00. A significant relation (P < 0.001) between values of coefficient b and injury score, interleukin-6, and macrophage inflammatory protein-2 was found. CONCLUSIONS: The predictive power of coefficient b to predict noninjurious ventilatory strategy in a model of acute lung injury is high.

Transplant immunosuppression increases and prolongs transgene expression following adenoviral-mediated transfection of rat lungs.

BACKGROUND: Gene therapy provides the potential to modify donor organs to better withstand transplantation, but this has yet to be realized. In vivo gene transfer using adenoviral vectors has had limited success because of host immune response that induces inflammation and limits the amount and duration of transgene expression. We hypothesize that transplantation immunosuppression can attenuate the post-transfection host-immune response to allow for improved gene transfer following adenoviral-mediated transfection. METHODS: We intratracheally transfected with adenovirus containing the beta-galactosidase gene and randomized the rats to either the immunosuppression group, receiving daily cyclosporine, azathioprine, and methylprednisolone, or the control group, receiving no immunosuppression. We evaluated transgene expression and post-transfection inflammation at time points ranging from 1 day to 5 weeks. RESULTS: Following transfection, control rats showed relatively low levels of transgene expression, which rapidly decreased to non-detectable levels. In contrast, immunosuppressed rats demonstrated significantly higher levels of transgene expression overall (p < 0.00005), peaking at almost 3 times that of the control group (p < 0.02), and showing prolonged and elevated transgene expression at 5 weeks (p < 0.02). On histologic sections of the lungs, immunosuppressed rats exhibited overall lesser grades of post-transfection inflammation. CONCLUSIONS: Transplant immunosuppression provides the means to attenuate the severe immune response to adenoviral-mediated gene transfection and thereby increase and prolong transgene expression.

A study of smoking, p53 tumor suppressor gene alterations and non-small cell lung cancer.

PURPOSE: The purpose of this study was to investigate the relationship between smoking and p53 tumor suppressor gene alterations, and their association with clinicopathologic features and prognosis in non-small cell lung cancer (NSCLC). METHODS: For 111 of 119 stage I-III NSCLC patients that had been followed prospectively, tumor p53 protein accumulation was measured immunohistochemically (IHC). Staining was evaluated as a score (p53IHCS) combining intensity and percent distribution. RESULTS: Forty-eight of 111 (43%) tumors had p53IHCS > 1. p53 IHC was associated with increasing tumor size (T) (p = 0.035), nodal status (N) (p = 0.091), stage (p = 0.054), and histology: squamous cell carcinoma (70%) and adenocarcinoma (27%) (p = 0.0002). In logistic regression analysis, p53 IHC was associated with squamous cell histology versus other histotypes [adjusted odds ratio (OR)5.90, 95% confidence interval (CI) 2.34-14.90]. p53 IHC was not associated with smoking variables. In multivariate proportional hazards analysis, p53IHCS and pack-years smoked (PY), both as continuous variables, were negative prognostic factors. The adjusted hazard ratios (HR) for the survival outcome recurrence for p53IHCS and PY were 1.20 (95% CI 1.02-1.40) and 1.03 (95% CI 1.01-1.04), and for death due to recurrent disease (DRD) were 1.35 (95% CI 1.11-1.64) and 1.03 (95% CI 1.01-1.04), respectively. Comparing the 75th percentile to the baseline 0, the adjusted HR for p53IHCS (5 vs. 0) was 4.5 and for PY (55 vs. 0) was 5.1 for the outcome DRD. Both variables demonstrated a dose-response relationship with survival. CONCLUSIONS: PY and p53IHCS are significant, independent and important predictors of recurrence and DRD in stage I-III NSCLC.

Inhaled nitric oxide does not alter pulmonary or cardiac effects of fat embolism in dogs after cemented arthroplasty.

PURPOSE: We examined the effect of inhaled nitric oxide (NO) on the acute pulmonary hypertension and right ventricular (RV) dilation after fat embolism. METHODS: A bilateral cemented arthroplasty (BCA), created fat embolism in 20 dogs. In Part A, 12 dogs were randomized to an NO group (n=6, inhaled NO 40 ppm before BCA and throughout the study) or a control group (n=6). In Part B, a third group of dogs (n=8) were given NO 20-40 ppm 2-3 min after BCA when pulmonary artery pressure (PAP) increased. Transesophageal echocardiography (TEE) and invasive hemodynamic monitoring evaluated the hemodynamic response to BCA. Postmortem, quantitative morphometry was used to estimate the number of fat emboli and diameter of lung vessel occluded by fat. RESULTS: Part A: The increase in PAP in the NO group (16 +/- 1 to 34 +/- 9 mmHg) within three minutes of BCA was not different from that in the control group (14 +/- 4 to 35 +/- 9 mmHg). Within three minutes of BCA, TEE demonstrated RV dilation in all groups (P < 0.05) but there was no difference in the change in RV area in the NO and control groups. When NO was given after BCA, no difference in PAP or RV dilation was noted from that in the control group. There were no differences, at post mortem, between the groups in the diameter of lung vessel occluded by fat CONCLUSION: Whether given before the embolic insult or two to three minutes after the onset of pulmonary hypertension, inhaled NO did not attenuate the acute pulmonary hypertension or RV dilation after cemented arthroplasty.

Characterization of a highly metastatic, orthotopic lung cancer model in the nude rat.

The prevailing subcutaneous nude rodent tumor xenograft models used for biological and preclinical studies do not optimally reflect some important biological properties of cancer, especially invasion and metastasis. Orthotopic models have been developed to address this need. However, for lung cancer none of the available models are optimal, in that none originate from an orthotopic (bronchial) primary site and exhibit extensive extrathoracic metastasis. Our goal was to develop a consistent rodent model of non-small cell lung cancer with both of these properties. Groups of male Rowett nude rats were given 500 rads of gamma radiation and then endobronchially implanted in the right caudal lobe airway with 50 mg of small NCI-H460 tumor fragments taken from an orthotopic donor tumor. They were then sacrificed at selected post-implantation times and evaluated grossly and histologically for animal weight, primary tumor take and size, and metastatic tumor incidence at multiple sites. At a late time point (32-35 days), consistency of primary tumor size and metastasis was estimated by comparing results from four groups of rats implanted on different occasions. The results showed that the primary tumors grew steadily, reaching four grams by days 32-35. Rats gained weight until days 14 to 21, but then began to show cachexia. High metastatic rates (>60%) were seen for mediastinal lymph nodes (by 21 days), and kidney, bone and brain (by 28 days). Mean primary tumor size and the incidences of both regional and systemic metastasis were consistent at 32-35 days in four different groups of six animals. In conclusion, this orthotopic lung cancer model is highly metastatic and consistent in terms of both primary tumor growth and metastatic behavior. It is the only available rodent model of human lung cancer emanating from an endobronchial site and metastasizing to multiple extrapulmonary sites, and should be very useful for both biological and preclinical studies of lung cancer, particularly where studies of antimetastatic activity are of interest, and/or where survival studies are desired.

Pulmonary and systemic fat embolization after medullary canal pressurization: a hemodynamic and histologic investigation in the dog.

BACKGROUND: The potential to produce fat embolism may be important in determining the ideal method and timing of fracture treatment in patients with preexisting lung injury. METHODS: Four dogs underwent femoral and tibial canal reaming and pressurization. Blood gas samples were analyzed, and pulmonary arterial pressure was monitored at 1 and 72 hours. Animals were killed 72 hours postoperatively, and the lungs, kidneys, and brain were examined histologically and compared with equivalent specimens from four control dogs that had not undergone femoral and tibial canal reaming and pressurization. RESULTS: Postmortem, intravascular fat persisted for 72 hours after induction of pulmonary fat embolism. Mean PaO2 was unchanged from baseline at 72 hours after canal pressurization. Canal pressurization caused a sustained increase in pulmonary arterial pressure (p=0.02) for 1 hour after canal pressurization. The mean pulmonary edema score at 72 hours was 29+/-3. Only a scant polymorph infiltrate (zero to two polymorphs per high-power field) was present at any time. No hyaline membranes were seen at any time. The percentage area occupied by intravascular fat in the lungs was 0.0214+/-0.0058 at 72 hours. No signs of ischemia or inflammation were seen in either the cerebral or the renal specimens. CONCLUSION: This study is the first to show that intravascular fat persists in the lungs, kidneys, and brain for 72 hours after canal pressurization and, by itself, does not cause pathologic evidence of acute inflammation.

Inhibition of exhaled nitric oxide production during sepsis does not prevent lung inflammation.

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.

Pulmonary effects of fixation of a fracture with a plate compared with intramedullary nailing. A canine model of fat embolism and fracture fixation.

UNLABELLED: Fat-embolism syndrome and pulmonary dysfunction may develop in multiply injured patients who have a fracture of a long bone. Although early fixation of a fracture is beneficial, intramedullary nailing may exacerbate pulmonary dysfunction by causing additional embolization of marrow fat. We examined the pulmonary effects of the timing and method of fixation of a fracture in a canine fat-embolism model. Fat embolism was induced in forty-one adult dogs by reaming the ipsilateral femur and tibia followed by pressurization of the intramedullary canal. The animals were divided into a control group of eight dogs that had induction of fat embolism alone and an experimental group of thirty-three dogs that had induction of fat embolism and internal fixation of a transverse fracture of the middle of the contralateral femoral shaft. In the control group, four dogs each were killed four hours and twenty-four hours after induction of fat embolism. In the experimental group, a femoral fracture was created and fixation was performed four hours after embolic showering in fifteen animals and twenty-four hours after embolization in eighteen animals. The two experimental groups were subdivided according to the method of fixation of the fracture: eleven dogs each had application of a plate, nailing without reaming, and nailing with reaming. The pulmonary arterial pressure and the alveolar-arterial gradient were measured preoperatively, during induction of fat embolism, and as long as one hour after fixation of the fracture but before the animal was killed. The lungs, brain, and kidneys were examined for pathological and physiological evidence of intravascular fat. The intravascular fat persisted for twenty-four hours after induction of pulmonary fat embolism. Pulmonary arterial pressure remained elevated at four hours after the embolic showering, before creation and fixation of the fracture. By twenty-four hours after the induction of fat embolism, pulmonary arterial pressure had returned to the baseline level. Neither the creation nor the fixation of the fracture affected pulmonary arterial pressure. In the animals that had fixation of a fracture four hours after embolization, both nailing with reaming and nailing without reaming produced alveolar-arterial gradients that were higher than the baseline values, whereas fixation with a plate did not change the alveolar-arterial gradient significantly from the baseline value. In addition, the alveolar-arterial gradients in the animals that had nailing with reaming and nailing without reaming four hours after embolization were, respectively, four and 3.5 times higher than that in the animals that had fixation of the femur with a plate. In the animals that had fixation twenty-four hours after embolization, none of the methods for fixation affected the alveolar-arterial gradient. The amount of embolic fat in the lungs, brain, and kidneys was not affected by fixation of the fracture when it was performed at either the four-hour or the twenty-four-hour time-interval. Scores for pulmonary edema were increased by fixation of the fracture, but there was no difference among the scores associated with the three methods of fixation. CLINICAL RELEVANCE: The findings of the present study indicated that the amount of intravascular fat persisting in the lungs, kidneys, and brain twenty-four hours after pressurization of the intramedullary canal is not affected by the method of fixation of the fracture. Fixation of a fracture is associated with minimum evidence of acute inflammation and has no effect on pulmonary artery pressure. The development of pulmonary dysfunction from fat emboli depends on other factors, not just on the presence of fat in pulmonary vessels. It appears that the method of fracture fixation has little influence on the outcome of treatment.

Relationship of fat embolism to haemodynamic and echocardiographic changes during cemented arthroplasty.

PURPOSE: Pressurisation of the medullary cavity during cemented arthroplasty causes "intravasation" of marrow fat. The purpose of this study was to examine the relationship between the amount of pulmonary intravascular fat and the haemodynamic and echocardiographic changes. METHODS: Anaesthetised mongrel dogs (n = 16) underwent bilateral cemented arthroplasty (BCA) to create a large embolic load. Haemodynamic measurements included blood pressure (BP), pulmonary artery pressure (PAP), right atrial pressure and cardiac output as well as transoesophageal echocardiographic (TEE) assessment of right ventricular (RV) and left ventricular (LV) areas. Using quantitative morphometry on postmortem lung specimens, the proportion of lung tissue occluded by fat was measured. RESULTS: Mean BP decreased within one minute of BCA, coinciding with the appearance of echogenic material in the RV. The RV area increased by 56% (P < 0.05) and LV area decreased by 34% (P < 0.05) while PAP increased from 15 +/- 3 mmHg to 39 +/- 10 mmHg within one minute (P < 0.001). The PAP remained elevated throughout the study (30 min). Stroke volume decreased in 14/15 dogs, yet cardiac output was maintained by increased heart rate. There was a curvilinear relationship (r = 0.87) between the maximum increase in PAP and the proportion of lung occupied by fat. CONCLUSION: In this model, stroke volume decreased within one minute of BCA when fat embolism accompanied prosthesis insertion. The TEE detected an increased RV area and reduced LV area associated with decreased stroke volume. The maintenance of cardiac output after intraoperative fat embolism depends primarily on the ability to increase heart rate.

Choice of anaesthetic regimen influences haemodynamic response to cemented arthroplasty.

Haemodynamic changes during bilateral cemented arthroplasty (BCA) were compared in dogs anaesthetized with isoflurane/N2O (ISOF) or diazepam/fentanyl (100 microg x kg(-1))N2O(FENT). Eight animals were anaesthetized with each regimen. After establishing monitoring and recording baseline values, BCA was performed. Haemodynamic measurements included aortic blood pressure (ABP), pulmonary artery pressure (PAP), right and left atrial pressures, and cardiac output. These were recorded at 30, 60, 180 and 300 sec after BCA. Lungs were removed and examined postmortem using quantitative morphometry. Groups demonstrated similar increases in PAP (ISOF 15 +/- 2 to 32 +/- 7, FENT 19 +/- 4 to 38 +/- 13; P> 0.05 between groups, P< 0.05 vs baseline). The proportion of lung vasculature occluded by fat was not different between groups (ISOF 9.63 +/- 3.38%, FENT 8.85 +/- 2.20%). Stroke volume decreased similarly in both groups (P> 0,05 between groups, P< 0.05 vs baseline). However, ABP decreased within one minute of BCA in ISOF (111 +/- 17 to 55 +/- mmHg, P< 0.05 and two of eight dogs died. All FENT dogs survived and hypotension (118 +/- 20 to 102 +/- 24 mmHg) was transient and less severe (P< 0.05 vs ISOF). Increased heart rate (HR) was noted in FENT following BCA (73 +/- 8 to 108 +/- 25 beats x min(-1); P< 0.05). Baseline HR was higher in ISOF (P< 0.05) and no increase in HR was noted. Systemic vascular resistance decreased in ISOF (P< 0.05), but not FENT (P> 0.05 vs baseline, P< 0.05 vs ISOF). To assess the role of slower baseline HR in FENT (73 +/-8) versus ISOF (131 +/- 5), six FENT dogs were paced (130 beats x min(-1)) with epicardial leads and an AV sequential pulse generator to simulate the ISOF group's baseline HR. Haemodynamic stability was maintained in this group in spite of a more rapid baseline HR. The choice of anaesthetic regimen strongly influenced acute haemodynamic changes in response to BCA.

Increased nitric oxide in exhaled gas as an early marker of lung inflammation in a model of sepsis.

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)

Reduced placental villous tree elaboration in small-for-gestational-age pregnancies: relationship with umbilical artery Doppler waveforms.

OBJECTIVE: Our purpose was to investigate the three-dimensional architecture of placental villi from normal and growth-restricted fetuses and relate findings to umbilical artery blood flow velocity waveforms. STUDY DESIGN: Placentas from term (n = 15) and preterm (n = 5) appropriately grown and term (n = 9) and preterm (n = 7) growth-restricted fetuses (birth weight < 10th percentile) were examined to determine the number of arteries per stem villus and the three-dimensional configuration of the villous trees and their vessels. Umbilical blood flow before delivery was assessed by Doppler ultrasonography. The effects of age and growth restriction were determined by two-way analyses of variance. RESULTS: Growth restriction was associated with reduced large vessel wall thickness (p < or = 0.05) but no reduction in the number of these vessels per stem villus. The volumes and surface areas of intermediate and terminal villi were reduced (p < or = 0.001), especially in preterm growth-restricted cases, where a marked reduction in diastolic blood flow velocity was observed in the umbilical artery. CONCLUSIONS: Reduced villous development may contribute to abnormal umbilical artery blood flood flow, as assessed by Doppler ultrasonography, in some cases of intrauterine growth restriction.

Transpulmonary systemic fat embolism. Studies in mongrel dogs after cemented arthroplasty.

We investigated the source of intravascular fat in systemic organs (brain, heart, and kidney) after massive pulmonary fat embolism during cemented arthroplasty. We used a bilateral cemented arthroplasty (BCA) in anesthetized mongrel dogs that simulates a cemented total-hip replacement procedure. We hypothesized that deformable fat globules could pass through the lung vasculature under high pulmonary artery pressure (Ppa). Using quantitative morphometry, we showed that the size of pulmonary vessel occluded by fat decreased from 12.8 +/- 15.2 microns 1 min after BCA to 4.9 +/- 5.1 microns at 120 min after BCA (p < 0.01). Ultrastructural studies demonstrated no evidence of acute inflammation around fat-occluded pulmonary vessels 3 h after BCA. Intravascular fat was found in all brain, heart, and kidney specimens examined 3 h after BCA (n = 6). No anesthetized animal in the "sham" (no BCA) group (n = 3) had intravascular fat at the same time period. Radiolabeled microspheres (15 microns diameter) did not reach the systemic circulation (< 1% nonentrapment) under the high Ppa after BCA. No patent foramen ovale was found in any dog at postmortem examination. We conclude that fat globules can traverse the pulmonary circulation within 3 h of orthopedic surgery. The difference between solid microspheres and fat in transpulmonary passage suggests that the composition, perhaps the deformability, of embolic material influences the lung's filtering capacity.

Improved engraftment of human tumours in SCID mice pretreated with radiation and anti-asialo GM1.

The effects of sublethal radiation (3 Gy) and anti-asialo GM1 (anti-ASGM1) on engraftment of human tumour cell lines and fresh tumour were evaluated in the severe combined immunodeficient (SCID) mouse. Four tumour cell lines (colonic adenocarcinoma LS174T, malignant melanoma MEWO, lung adenocarcinoma H125, chronic myelogenous leukemia K562) and a fresh colon cancer metastasis were injected subcutaneously, intraperitoneally or intravenously into SCID mice. Tumour volume and metastatic spread of implanted tumours were evaluated 3-8 weeks following inoculation. Pretreatment with radiation and anti-ASGM1 resulted in more rapid and extensive uptake of subcutaneous and intraperitoneal tumours. Tail vein injection into pretreated animals also resulted in a greater number of lung metastases of H125, MEWO and K562 cell lines. This study demonstrates that sublethal radiation and the elimination of murine NK cell activity with anti-ASGM1 improves tumour take rates. These findings should prove useful for investigations of human cancer immunotherapy using SCID mice engrafted with human lymphocytes and human tumours.