Fetal fraction-based risk algorithm for non-invasive prenatal testing: screening for trisomies 13 and 18 and triploidy in women with low cell-free fetal DNA.

OBJECTIVE: To identify pregnancies at increased risk for trisomy 13, trisomy 18 or triploidy attributable to low fetal fraction (FF). METHODS: A FF-based risk (FFBR) model was built using data from more than 165 000 singleton pregnancies referred for single-nucleotide polymorphism (SNP)-based non-invasive prenatal testing (NIPT). Based on maternal weight and gestational age (GA), FF distributions for normal, trisomy 13, trisomy 18 and triploid pregnancies were constructed and used to adjust prior risks for these abnormalities. A risk cut-off of ≥ 1% was chosen to define pregnancies at high risk for trisomy 13, trisomy 18 or triploidy (high FFBR score). The model was evaluated on an independent blinded set of pregnancies for which SNP-based NIPT did not return a result, and for which pregnancy outcome information was gathered retrospectively. RESULTS: The evaluation cohort comprised 1148 cases, of which approximately half received a high FFBR score. Compared with rates expected based on maternal age (MA) and GA, cases with a high FFBR score had a significantly increased rate of trisomy 13, trisomy 18 or triploidy combined (5.7% vs 0.7%; P < 0.001) and also of unexplained pregnancy loss (14.7% vs 10.4%; P < 0.001). For cases that did not receive a high FFBR score, the incidence of a chromosomal abnormality or pregnancy loss was not significantly different from that expected based on MA and GA. In this study cohort, the sensitivity of the FFBR model for detection of trisomy 13, trisomy 18 or triploidy was 91.4% (95% CI, 76.9-98.2%) with a positive predictive value of 5.7% (32/564; 95% CI, 3.9-7.9%). CONCLUSIONS: For pregnancies with a FF too low to receive a result on standard NIPT, the FFBR algorithm identified a subset of cases at increased risk for trisomy 13, trisomy 18 or triploidy. For the remainder of cases, the risk of a fetal chromosomal abnormality was unchanged from that expected based on MA and GA. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Rescue corticosteroids in twin pregnancies and short-term neonatal outcomes.

OBJECTIVE: To estimate the efficacy of a rescue course of antenatal corticosteroids in twin pregnancies. DESIGN: Retrospective cohort study. SETTING: Tertiary-care centre. POPULATION: Twins born from 24 to <34 weeks of gestation in a single maternal and fetal medicine practice from 2006 to 2011. METHODS: We compared neonatal outcomes in 88 twins exposed to a single course of corticosteroids with outcomes in 42 twins exposed to two courses of corticosteroids: the initial course and a single rescue course. Analyses were adjusted to control for correlation between twins born to the same mother. MAIN OUTCOME MEASURE: Short-term neonatal respiratory morbidity. RESULTS: Rescue corticosteroids were associated with fewer days of mechanical ventilation (7.3 ± 3.3 versus 33.9 ± 25.3 days, P = 0.003), fewer days with a fraction of inspired oxygen of >21% (6.3 ± 4.3 versus 33.3 ± 25.8 days, P = 0.003), a lower incidence of mechanical ventilation >14 days or death while on mechanical ventilation (0 versus 12.5%, P = 0.016), and a lower incidence of retinopathy of prematurity (0 versus 12.5%, P = 0.016). The proportion of neonates with respiratory distress syndrome did not differ between the groups (adjusted odds ratio 1.28, 95% confidence interval 0.50-3.26). There were no differences found for birthweight, head circumference and length. CONCLUSIONS: In twins born before 34 weeks of gestation, exposure to rescue corticosteroids may be associated with improved neonatal outcomes. Further studies are warranted to assess the effect of rescue corticosteroids in twin pregnancies.

Cervical length at 30-32 weeks and the risk of Cesarean delivery in twin pregnancies.

OBJECTIVES: To estimate the association between the cervical length (CL) measurement at 30-32 weeks and the mode of delivery in twin pregnancies. METHODS: This was a retrospective study of a cohort, from 2005-2010, of 265 twin pregnancies with a CL measurement at 30-32 weeks. We compared the CL measurement at 30-32 weeks based on mode of delivery. We then analyzed our data across four subgroups, based on the CL measurement quartiles at 30-32 weeks. We performed this analysis in all patients, and also performed a planned subgroup analysis of 130 patients who attempted a vaginal delivery. RESULTS: In all patients, including those who attempted a vaginal delivery, the mean CL at 30-32 weeks was significantly shorter in women who delivered vaginally compared with women who had a Cesarean section. The likelihood of Cesarean delivery increased significantly with increasing CL measurement across the groups defined by measurement quartiles. On adjusted analysis controlling for maternal age, race, in-vitro fertilization, chorionicity, induction of labor and prior vaginal delivery, the CL measurement at 30-32 weeks was independently associated with mode of delivery. CONCLUSIONS: In twin pregnancies, the CL at 30-32 weeks is significantly associated with the likelihood of Cesarean delivery. A longer CL may represent underdevelopment of the uterus, leading to a higher risk of Cesarean delivery in labor at term.

Intravaginal misoprostol versus Foley catheter for labour induction: a meta-analysis.

BACKGROUND: There are a number of agents used for cervical ripening prior to the induction of labour. Two commonly used agents are intravaginal misoprostol and a transcervical Foley catheter. OBJECTIVE: To review the evidence comparing misoprostol and transcervical Foley catheter placement for induction of labour, and perform a meta-analysis comparing these two induction agents. SEARCH STRATEGY: We conducted database searches of PubMed, Embase, the Cochrane Library Database, and the ClinicalTrials.gov website. Bibliographies of all relevant articles were reviewed. SELECTION CRITERIA: Prospective, randomised trials comparing the use of intravaginal misoprostol and transcervical Foley catheter for the purpose of cervical ripening and induction of labour were included. We excluded studies in which the patients in these two intervention groups also received other induction agents concurrently, such as oral misoprostol, oxytocin, or other prostaglandins. DATA COLLECTION AND ANALYSIS: The primary outcomes selected were time to delivery, and the rates of caesarean section, uterine tachysystole, and chorioamnionitis. Random-effects generalised linear models with a poisson distribution and log link function were used to compare the two induction agents across the studies. MAIN RESULTS: Nine studies (1603 patients) were identified as eligible to be included in this meta-analysis. There were no significant differences in the mean time to delivery (mean difference 1.08 ± 2.19 hours shorter for misoprostol, P = 0.2348), the rate of caesarean delivery (RR 0.991; 95% CI 0.768, 1.278), or in the rate of chorioamnionitis (RR 1.130; 95% CI 0.611, 2.089) between women who received misoprostol compared with transcervical Foley catheter. Patients who received misoprostol had significantly higher rates of tachysystole compared with women who received a transcervical Foley catheter (RR 2.844; 95% CI 1.392, 5.812). CONCLUSIONS: Intravaginal misoprostol and transcervical Foley catheter have similar effectiveness as induction agents. Transcervical Foley catheter is associated with a lower incidence of tachysystole.

Broadband diffuse optical spectroscopy measurement of hemoglobin concentration during hypovolemia in rabbits.

Serial blood draws for the assessment of trauma patients' hemoglobin (sHgb) and hematocrit (sHct) is standard practice. A device that would allow for continuous real-time, non-invasive monitoring of hemoglobin and tissue perfusion would potentially improve recognition, monitoring and resuscitation of blood loss. We developed a device utilizing diffuse optical spectroscopy (DOS) technology that simultaneously measures tissue scattering and near-infrared (NIR) absorption to obtain non-invasive measurements of oxy- (Hb-O(2)), deoxyhemoglobin (Hb-R) concentrations and tissue hemoglobin concentration (THC) in an animal model of hypovolemic shock induced by successive blood withdrawals. Intubated New Zealand White rabbits (N = 16) were hemorrhaged via a femoral arterial line every 20 min until a 20% blood loss (10-15 cc kg(-1)) was achieved to attain hypovolemia. A broadband DOS probe placed on the inner thigh was used to measure muscle concentrations of Hb-O(2) and Hb-R, during blood withdrawal. THC and tissue hemoglobin saturation (S(T)O(2)) were calculated from DOS [Hb-O(2)] and [Hb-R]. Broadband DOS-measured values were compared against traditional invasive measurements: systemic sHgb, arterial oxygen saturation (S(a)O(2)) and venous oxygen saturation (S(v)O(2)) drawn from arterial and central venous blood. DOS and traditional invasive measurements versus blood loss were closely correlated (r(2) = 0.96) showing a decline with removal of blood. S(T)O(2) and [Hb-O(2)] followed similar trends with hemorrhage, while [Hb-R] remained relatively constant. These measurements may be limited to some extent by the inability to distinguish between hemoglobin and myoglobin contributions to DOS signals in tissue at this time. Broadband DOS provides a potential platform for reliable non-invasive measurements of tissue oxygenated and deoxygenated hemoglobin and may accurately reflect the degree of systemic hypovolemia and compromised tissue perfusion.

Two-dimensional and 3-dimensional optical coherence tomographic imaging of the airway, lung, and pleura.

BACKGROUND: Methods for obtaining real-time in vivo histologic resolution by means of noninvasive endoscopic optical imaging would be a major advance for thoracic surgical diagnostics and treatment. Optical coherence tomography is a rapidly evolving technology based on near-infrared interferometry that might provide these capabilities. The purpose of this study is to investigate the feasibility of real-time 2- and 3-dimensional optical coherence tomographic imaging of airway, pleural, and subpleural lung tissues in normal, inflammatory, and malignant animal models and patients with known or suspected airway malignancy. METHODS: Freshly excised lungs and pleural tissue obtained from rabbits with inhalation lung injury and induced empyema, metastatic sarcomas, and pleural sarcomas and from patients with airway disease were imaged by using 2- and 3-dimensional optical coherence tomography with a prototype superluminescent diode optical coherence tomographic system constructed in our laboratory. Lungs and pleural tissue were subsequently processed for standard hematoxylin and eosin histology for comparison with optical coherence tomography. RESULTS: Optical coherence tomographic imaging achieved an ex vivo resolution of 10 microm and an in vivo resolution of about 30 microm with a depth penetration of 1 to 2 mm with 2- and 3- dimensional reconstruction capabilities. Tumors as small as 500 microm were detectable with optical coherence tomography. The acquired images closely matched histologic images, demonstrating details at the level of mucosal layers, glands, alveoli, and respiratory bronchioles. CONCLUSIONS: Optical coherence tomography with near-infrared interferometric methods enables near real-time in vivo near-histologic resolution optical imaging. With further advances, optical coherence tomography has the potential for real-time accurate and early pleural and subpleural diagnostics by using small-diameter flexible fiberoptic endoscopic probes for a wide range of thoracic surgical applications.

Liver and circulating NK1.1(+)CD3(-) cells are increased in infection with attenuated Salmonella typhimurium and are associated with reduced tumor in murine liver cancer.

An attenuated (DeltacyA, Deltacrp) strain of Salmonella typhimurium (chi4550) containing a gene for human IL-2 (chi4550pIL2) reduces hepatic tumor burden when orally inoculated into mice with liver cancer; however, wild-type S. typhimurium is also associated with cancer regression. Therefore, experiments were designed to clarify the invasiveness and the anti-tumor properties of three strains of S. typhimurium. S. typhimurium chi4550pIL2, chi4550, or wild type (WT) was incubated with mature Caco-2 and HT-29 enterocytes, and S. typhimurium internalization was assessed. For infectivity experiments, mice were orally inoculated with saline or 10(9)S. typhimurium chi4550pIL2, chi4550, or WT; 48 h later mice were sacrificed for analysis of cecal bacteria and S. typhimurium translocation to mesenteric lymph nodes. For experiments involving tumor implantation, four groups were studied: saline control, tumor alone, chi4550pIL2+tumor, and chi4550+tumor. Mice were orally inoculated with saline or S. typhimurium and underwent laparotomy 24 h later with 5 x 10(4) MCA38 murine adenocarcinoma cells injected into the spleen. On day 14, liver tumors were counted and peripheral blood and hepatic lymphocyte populations were analyzed by FACScan. Attenuated S. typhimurium exhibited decreased internalization by cultured enterocytes and decreased infectivity after oral inoculation. Mice treated with chi4550pIL2 or chi4550 had fewer liver tumors and increased populations of hepatic and circulating NK1.1(+)CD3(-) lymphocytes compared to mice treated with saline (P < 0.01). These data suggest that attenuated S. typhimurium may have an application as an anti-tumor agent.

Recurrent congenital diaphragmatic hernia: A novel repair.

BACKGROUND/PURPOSE: Repair of recurrent diaphragmatic hernia continues to be a difficult problem. An innovative method using a nonabsorbable polypropylene prosthetic mesh plug placed via the thoracic approach using minimal dissection is presented. METHODS: A retrospective analysis showed 39 children with congenital diaphragmatic hernia (CDH) who underwent repair between January 1997 and March 2000. Five children suffered a recurrence and underwent repair via the thoracic approach using the Bard Marlex Mesh Perfix Plug (C.R. Bard Inc, Billerica, MA). Follow-up was available in all children and ranged from 1 to 33 months (average, 13.8 months). RESULTS: Age at recurrence ranged from 2 to 48 months (average, 14.8 months), and the average time between initial repair and recurrence was 8.2 months (range, 2 to 16 months). There were no recurrences after the transthoracic mesh plug diaphragmatic hernioplasty. One child died of multiple congenital anomalies 6 months after repair. CONCLUSION: The transthoracic repair of recurrent diaphragmatic hernias using a nonabsorbable polypropylene prosthetic mesh plug represents an innovative approach to a difficult problem in which 5 repairs have been accomplished without recurrence in nearly 14 months of follow-up. J Pediatr Surg 36:1768-1769.

The slipping rib syndrome in children.

The slipping rib syndrome is an infrequent cause of thoracic and upper abdominal pain and is thought to arise from the inadequacy or rupture of the interchondral fibrous attachments of the anterior ribs. This disruption allows the costal cartilage tips to sublux, impinging on the intercostal nerves. Children with this entity are seldom described in the literature. We present a retrospective review of 12 children and young adults with slipping rib syndrome and a systematic approach for evaluation and treatment.

Prospective results of a standardized algorithm based on hemodynamic status for managing pediatric solid organ injury.

BACKGROUND: Controversy surrounds the need for ICU admission, prolonged bed rest, and the duration of activity restrictions for children sustaining blunt trauma. Adult literature supports management based on hemodynamic status, not CT grade. STUDY DESIGN: A 3-year prospective study of a standardized management algorithm for hemodynamically normal pediatric patients with blunt liver or spleen injury was performed. Patient selection was based on vital signs, irrespective of injury grade on CT. Patients requiring ICU admission for nonliver or nonspleen injury were excluded. Patients were admitted to a surgical ward with serial hematocrit levels. Discharge occurred 48 hours postinjury if patients had no abdominal tenderness, tolerated a regular diet, and had a stable hematocrit. Patients were allowed noncontact activity, including school, after discharge. Patients were followed up at 1 month with ultrasonographic imaging. RESULTS: Eighty-nine patients sustained blunt liver or spleen injury. Forty-five patients were excluded for other injuries (Glasgow Coma Scale < 13, 32 of 45); the remaining 44 patients had a mean age of 8.9 years (range 2 to 17 years), Injury Severity Score 10.6 (range 4 to 33), liver grade 2.1, and splenic injury grade 2.3. Mechanisms of injury were predominately motor vehicle collisions (59%). All patients were managed nonoperatively without transfusion; 43 of 44 patients completed the algorithm. Mean observation was 55.2 +/- 12.3 hours. One-month followup occurred in 33 of 44 patients, with one complication detected and no delayed bleeding. CONCLUSION: Management of pediatric solid organ injury should be guided by hemodynamic status and not injury grade on CT. Hemodynamically normal children can be safely managed without intensive care monitoring, do not need prolonged hospitalization, and can resume school on discharge.

Congenital abdominal aortic aneurysm in the infant: case report and review of the literature.

Congenital abdominal aortic aneurysms are a distinct entity from acquired aortic aneurysms. The authors present the case of a 6-week-old boy with a 6-cm aneurysm involving the abdominal aorta and common iliac arteries. Three other cases of congenital aortic aneurysms are reviewed, and an approach to these rare patients is discussed. J Pediatr Surg 36:657-658.

Acidification of formula reduces bacterial translocation and gut colonization in a neonatal rabbit model.

BACKGROUND/PURPOSE: The authors hypothesized that gastric acidity is protective because it is bactericidal. They tested acidified formula for protection against gut colonization and bacterial translocation. METHODS: In vitro: Formula was acidified to pH of 2, 3, 4, 5 and innoculated with Enterobacter. Growth over time was quantitatively assessed. In vivo: 442 premature rabbit pups were sorted randomly and fed formula of pH 2, 3, 4, or 7, with ranitidine. Two models were utilized: (1) with bacterial challenge using a known acid sensitive organism, (2) without bacterial challenge to simulate natural gut colonization and to test against organisms of unknown acid sensitivity. Normal acid animals received pH 7 formula, no ranitidine. On day 3, the mesenteric lymph nodes (MLN), spleen, liver, and cecum were harvested and cultured. RESULTS: Bacterial growth was inhibited at pH 2 and 3, growth was logarithmic above pH 4 (P<.001). Total and organ-specific translocation was reduced at pH 3 and below in both models (P<.05). Translocation with formula pH 3 equaled normal acid animals. Quantitative cecal colonization was reduced in pups receiving pH 3 and below in both models (P<.05). CONCLUSION: Acidification of formula below pH 4 is bactericidal to enteric organisms. Acidified formula decreases bacterial translocation and gut colonization.

Catheter materials affect the incidence of late blood-borne catheter infection.

BACKGROUND: Adherence of bacteria and subsequent catheter-related infections (CRI) are greatly enhanced by the fibrin sheath that develops on indwelling catheters. Since the infection rate of catheters without fibrin sheaths is low and the fibrin sheath mediates bacterial adherence, catheter material is not thought to affect the incidence of late catheter-related infection. METHODS: A total of 276 rats had catheters placed in the right jugular vein with the proximal end buried subcutaneously to eliminate exit site infection. Rats were divided into two groups: silastic catheters (SC; n = 133) and polyurethane catheters (PC; n = 143). Injections of 1 x 10(8) CFU/mL of Staphylococcus epidermidis were given via the tail vein on either the day of surgery, day 0 (n = 53 SC, n = 51 PC), or on postoperative day 10 (n = 50 SC, n = 62 PC). Thirty animals from each group (SC, PC) received sterile saline injections on day 10 and served as controls. Animals were sacrificed on postinjection day 3. Catheters were removed via the chest and placed into trypticase soy broth. Broth was incubated at 37 degrees C for 48 h. Microscopy for the fibrin sheath was done on 20 randomly selected catheters (10/group). Data were compared using Fisher's exact test, with p < 0.05 considered significant. RESULTS: Incidence of CRI was equal prior to the formation of the fibrin sheath, while CRI was significantly higher in silastic catheters in the presence of a fibrin sheath. Without a fibrin sheath (day 0), 8/53 silastic catheters and 3/51 polyurethane catheters were infected (p = NS). With a fibrin sheath (day 10), 31/50 silastic catheters were infected versus 20/62 polyurethane catheters (p < 0.05). Control catheters were all culture negative (30/group). With light microscopy, 20/20 catheters had fibrin sheaths at day 10 with no visible difference between silastic and polyurethane catheters. CONCLUSION: Catheter material does affect the incidence of catheter-related infection even when catheters are coated with a fibrin sheath. This difference may relate to a difference in the fibrin sheath itself as it forms on different catheter materials.

Complications and risks of central venous catheter placement in children.

BACKGROUND: Since Aubaniac's first description in 1952, the use of central venous catheters has increased dramatically; they are now considered commonplace. Placement of these catheters, however, has an associated risk of morbidity and mortality. In most cases, this risk is outweighted by the benefit gained, especially when long-term access to the central venous system is needed for multiple transfusions, chemotherapy, antibiotics, or parenteral nutrition. A large number of central venous catheters are placed in children at our institution, usually by interns and residents. METHODS: To identify associated risks and complications, we reviewed the records of 1435 consecutive catheterizations in children over a 10-year period. Data collected included age, sex, site of catheterization, type of catheter, primary disease, prior catheterizations, indication for placement, failed attempts, number of attempts, catheter misplacement, level of physician training, new needle punctures, and complications. We then used logistic regression analysis to identify independent risk factors for complications. RESULTS: We noted 39 (3.1%) perioperative complications, including 19 (1.5%) arterial punctures, 10 (0.8%) pneumothoraces, 6 (0.5%) hemothoraces, 2 (0.2%) cases of superior vena cava syndrome, 1 (0.1%) episode of ventricular fibrillation that required cardioversion, and 1 episode of bleeding that required a cutaneous suture. Univariate analysis revealed that catheters placed in a subclavian vein (vs all other sites combined, P < .01) were less likely to have an associated complication. In addition, multiple attempts (vs success on first attempt, P < .0001), failed attempt (vs success at initial site, P < .0001), catheter misplacement (vs proper initial position, P < .01), and prior catheterizations (vs no prior catheterization, P < .0005) were associated with complications. Logistic regression revealed multiple attempts (vs success on first attempt, odds ratio (OR) = 5.4), failed attempt (vs success at initial site, OR = 5.2), and catheter misplacement (vs proper initial position, OR = 6.9) to be independent risk factors for complications. Age, sex, type of catheter, primary disease, indication for placement, and level of physician training (intern or resident vs staff) were not associated with complications. CONCLUSIONS: Central venous catheterization in children is relatively safe, with only a 3.2% complication rate and no mortality in our series.

Timing of colonic necrosis in hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) consists of an acute onset of microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. HUS-associated colitis can be seen in up to 100% of patients and is usually associated with severe abdominal pain and distention. Colonic perforation is a complication of HUS that has a reported incidence of 1%-2%, and although there are several case reports in the literature describing perforation of the colon, it is still very difficult to discern the abdominal symptoms associated with HUS colitis from perforation. Four cases of colonic perforation are reported here from a consecutive series of 57 patients, in which a trend in the length of time from the onset of symptoms of HUS to colonic perforation was determined. A review of the literature for cases of HUS-associated colonic perforation was also performed. The time from the onset of HUS symptoms to colonic perforation in our series was similar to that found in the literature review (11 +/- 5 vs 14 +/- 8 days). Awareness that this complication has a tendency to occur towards the end of the 2nd week during the course of HUS is essential to avoid an unnecessary and untimely surgical intervention.

Cystic renal lymphangiectasia: a distinctive clinicopathologic entity in the pediatric age group.

This report describes the features of unilateral cystic renal lymphangiectasia in a 2-year-old child who presented with hypertension, massive ascites, a left flank mass, and no evidence of familial renal cystic disease. The child became normotensive and is now asymptomatic more than 3 years after surgery. The clinical presentation and diffuse pathologic involvement are similar to findings for the few pediatric patients with cystic lymphangiectasia described in the literature and appear distinct from the more localized form of the disease seen in adults.

Patterns of hepatic and splenic colonization by an attenuated strain of Salmonella typhimurium containing the gene for human interleukin-2: a novel anti-tumor agent.

Currently, there is no effective treatment for unresectable hepatic malignancies. Salmonella sp. are known to naturally track to the liver during active infection. A live biological vector was developed for delivery of Interleukin-2 (IL-2) to the liver for anti-tumor purposes. The avirulent and highly immunogenic c4550 strain of Salmonella typhimurium was used to express the IL-2 protein [renamed c4550(pIL-2)]. We have previously demonstrated that the c4550(pIL-2) produces biologically active IL-2 (up to 46.2 IU/ml) and that a single gavage feeding of 10(7) colony forming units (cfu) of c4550(pIL-2) significantly reduced the number of hepatic metastases when compared to animals fed salmonella lacking the IL-2 gene or non-treated controls. The goal of the current studies was to determine the pattern of splenic and hepatic colonization of Salmonella-IL2. Hepatic and splenic colonization was determined following administration of 10(7) cfu of c4550(pIL-2) and c4550(pYA292) via a single gavage feeding to C57BL/6 mice. Five experiments of antibiotic regimen administration were conducted where splenic and hepatic homogenates were cultured after 14 days of parenteral and/or oral antibiotics. The natural history of hepatic and splenic colonization was also determined for animals without antibiotic treatment. Despite administration of various antibiotic regimens using different routes, eradication of salmonella with and without IL-2 was not achieved. Salmonella, however, was not cultured from hepatic and splenic tissue at 4 months after a single gavage feeding of salmonella with no specific treatment. In conclusion, oral administration of c4550(pIL-2) may represent a novel form of in vivo biotherapy for unresectable hepatic malignancies. Antibiotics do not accelerate eradication of this bacteria and it appears that c4550(pIL-2) follows the natural pathophysiological of salmonella infection in which eradication from the splenic and hepatic tissue occurs over a period of 2-4 months.

Microvascular oxygen delivery and interstitial oxygenation during sodium pentobarbital anesthesia.

BACKGROUND: Anesthesia may represent a considerable bias in experimental medicine, particularly in conditions of stress (such as hemorrhage). Sodium pentobarbital (PB), widely used for cardiovascular investigations, may impair oxygen delivery by hemodynamic and respiratory depression. The critical issue, however, is whether the microcirculation can still maintain tissue oxygenation during anesthesia. To answer this question, the authors studied the effect of PB anesthesia on subcutaneous microvascular oxygen delivery and interstitial oxygenation in Syrian golden hamsters. METHODS: Sodium pentobarbital anesthesia was induced by intravenous injection (30 mg/kg body weight) and maintained by a 15-min infusion (2 mg.kg-1.min-1), with animals breathing spontaneously (PB-S) or ventilated with air (PB-V). Systemic parameters evaluated were mean arterial pressure (MAP), heart rate, cardiac index (CI), arterial oxygen tension (PaO2), arterial carbon dioxide tension (PaCO2), base excess, and pH. Microvascular and interstitial oxygen tension (PO2), vessel diameter, red blood cell velocity (vRBC), and blood flow (Qb) were measured in a dorsal skinfold preparation. Microcirculatory PO2 values were determined by phosphorescence decay. RESULTS: Sodium pentobarbital anesthesia significantly decreased CI, MAP, vRBC, and Qb. During PB infusion, PaO2 values were 56 +/- 12.8 mmHg (PB-S) and 115.9 +/- 14.6 mmHg (PB-V) compared with 69.4 +/- 18.2 mmHg and 61.4 +/- 12.6 mmHg at baseline. However, microvascular PO2 was reduced by 25-55% in both groups, resulting in an interstitial PO2 decrease from 23.9 +/- 5.6 mmHg (control) to 13.1 +/- 9.1 mmHg (PB-S) and 15.2 +/- 7 mmHg (PB-V). Microcirculatory PO2 values were restored 30 min after PB infusion, even though hemodynamic depression and a light anesthetic plane were maintained. CONCLUSIONS: Sodium pentobarbital anesthesia caused impairment of microvascular oxygen delivery and interstitial oxygenation, effects that were not prevented by mechanical ventilation. Although these effects were restricted to deep anesthetic planes, prolonged hemodynamic depression suggests that caution is warranted when using PB as an anesthetic in cardiovascular investigations.

Antitumor mechanisms of attenuated Salmonella typhimurium containing the gene for human interleukin-2: a novel antitumor agent?

Currently, there is no long-term effective treatment for unresectable hepatic malignancies. Salmonella species are known to naturally track to the liver during active infection. To develop a biological vector for delivery of interleukin-2 (IL-2) to the liver for antitumor purposes, the thi 4550 attenuated strain of Salmonella typhimurium was used as a vector for IL-2. The gene for human IL-2 was cloned into plasmid pYA292 and inserted into the attenuated S typhimurium and renamed (thi 4550(pIL-2)]. MCA-38 murine adenocarcinoma cells were injected intrasplenically into C57BL/6 mice to produce hepatic metastases that were subsequently enumerated after 12 days. We previously have demonstrated that the thi 4550(pIL-2) produces biologically active IL-2 and that a single gavage feeding of 10(7) thi 4550(pIL-2) significantly reduced the number of hepatic metastases when compared with animals fed salmonella lacking the IL-2 gene or nontreated controls. The aims of the current studies were to determine which host effector cell populations were responsible for the antitumor effect seen with thi 4550(pIL-2) by depletion of natural killer (NK), cytotoxic T lymphocytes (CD8+), T helper (CD4+) cells, and Kupffer cells. Multiple experiments were conducted for each host effector cell population depleted. We found a consistent reduction in the mean number of hepatic metastases in animals fed thi 4550(pIL-2) (55.6 metastases; n = 54) when compared with controls (162.3 metastases; n = 53) (P < .0001). Depletion of NK cells and CD8+ T cells significantly inhibited the antitumor effect of thi 4550(pIL-2) (analysis of variance [ANOVA], P < .01). Elimination of CD4+ T cells and Kupffer cells had no significant impact on the antitumor effect of thi 4550(pIL-2) (ANOVA, P value was not significant). Salmonella IL-2 may represent a novel form of in vivo biotherapy for unresectable hepatic malignancies that employs the oral route of administration. Furthermore, both NK cells or CD8+ cells are required for the antitumor effect seen while CD4+ T cells and Kupffer cells do not appear to be as essential.

Fluid resuscitation with O2 vs. non-O2 carriers after 2 h of hemorrhagic shock in conscious hamsters.

Efficacy of a cell-free o-raffinose cross-linked and oligomerized hemoglobin (Hemo-link) solution in restoring macro- and microcirculatory conditions after 2 h of hemorrhagic shock (40 mmHg) was compared with conventional treatment with autologous whole blood, Ringer lactate (RL), and Dextran 70. Studies were conducted in the dorsal skinfold microcirculation of conscious hamsters. Initial infusion was equivalent to shed blood volume (SBV) for RL and 50% of SBV for remaining solutions. After 2 h all animals received blood at 50% of SBV. Vessel diameter, functional capillary density, microvascular red blood cell velocity, and flow were measured. Arteriolar, venular, and tissue PO2 were determined by phosphorescence decay. Systemic parameters included mean arterial blood pressure, heart rate, arterial blood gases, pH, and base excess. Autologous whole blood and Hemolink, but not Dextran 70 and RL, restored mean arterial blood pressure, systemic blood gas, and metabolic parameters. Tissue PO2 recovered to 40-50% with blood and Hemolink but remained significantly lower (10-15% of control) with Dextran 70 and RL. Initial volume replacement after shock with blood or Hemolink yields equivalent macro- and microhemodynamic improvements not attainable with non-O2-carrying plasma expanders.