Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Characterization of Porcine Epidemic Diarrhea Virus Isolate US/Iowa/18984/2013 Infection in 1-Day-Old Cesarean-Derived Colostrum-Deprived Piglets.

Porcine epidemic diarrhea virus (PEDV) was first recognized in North America in April 2013 and has since caused devastating disease. The objective of this study was to characterize disease and viral detection associated with an original North American PEDV isolate inoculated in neonatal piglets. Thirty-six 1-day-old cesarean-derived and colostrum-deprived piglets were randomly assigned to the control (n = 16) or challenged group (n = 20); the latter were orogastrically inoculated with 1 ml of US/Iowa/18984/2013 PEDV isolate titered at 1 × 10(3) plaque-forming units per milliliter. Rectal swabs were collected from all piglets prior to inoculation and every 12 hours postinoculation (hpi) thereafter, with 4 control and 5 challenged piglets euthanized at 12, 24, 48, and 72 hpi. One piglet had a positive real-time quantitative polymerase chain reaction test on rectal swab at 12 hpi, and all remaining piglets were positive thereafter, with highest viral quantities detected at 24 and 36 hpi. Diarrhea was evident in 30% and 100% of challenged piglets at 18 and 24 hpi, respectively. Viral antigen was detected in enterocytes by immunohistochemistry in the duodenum and ileum of piglets euthanized at 12 hpi and was apparent throughout the small intestine of all piglets thereafter, with villus height:crypt depth ratios consistently below 4:1. Viremia was confirmed in 18 of 20 pigs at euthanasia. Clinical disease was severe and developed rapidly following infection with an original North American PEDV isolate, with lesions, viremia, and antigen detection possible by 12 hpi.

Shaping up: a geometric morphometric approach to assemblage ecomorphology.

This study adopts an ecomorphological approach to test the utility of body shape as a predictor of niche relationships among a stream fish assemblage of the Tickfaw River (Lake Pontchartrain Basin) in southeastern Louisiana, U.S.A. To examine the potential influence of evolutionary constraints, analyses were performed with and without the influence of phylogeny. Fish assemblages were sampled throughout the year, and ecological data (habitat and tropic guild) and body shape (geometric morphometric) data were collected for each fish specimen. Multivariate analyses were performed to examine relationships and differences between body shape and ecological data. Results indicate that a relationship exists between body shape and trophic guild as well as flow regime, but no significant correlation between body shape and substratum was found. Body shape was a reliable indicator of position within assemblage niche space.

Feasibility of magnetic resonance guided radiotherapy for the treatment of bladder cancer.

Whole bladder magnetic resonance image-guided radiotherapy using the 1.5 Telsa MR-linac is feasible. Full online adaptive planning workflow based on the anatomy seen at each fraction was performed. This was delivered within 45 min. Intra-fraction bladder filling did not compromise target coverage. Patients reported acceptable tolerance of treatment.

Magnetic resonance imaging sequence evaluation of an MR Linac system; early clinical experience.

OBJECTIVES: To systematically identify the preferred magnetic resonance imaging (MRI) sequences following volunteer imaging on a 1.5 Tesla (T) MR-Linear Accelerator (MR Linac) for future protocol development. METHODS: Non-patient volunteers were recruited to a Research and Ethics committee approved prospective MR-only imaging study on a 1.5T MR Linac system. Volunteers attended 1-3 imaging sessions that included a combination of mDixon, T1w, T2w sequences using 2-dimensional (2D) and 3-dimensional (3D) acquisitions. Each sequence was acquired over 2-7 minutes and reviewed by a panel of 3 observers to evaluate image quality using a visual grading analysis based on a 4-point Likert scale. Sequences were acquired and modified iteratively until deemed fit for purpose (online image matching or re-planning) and all observers agreed they were suitable in 3 volunteers. RESULTS: 26 volunteers underwent 31 imaging sessions of six general anatomical regions. Images were acquired in one or two of six general anatomical regions: male pelvis (n = 9), female pelvis (n = 4), chestwall/breast (n = 5), lung/oesophagus (n = 5), abdomen (n = 3) and head and neck (n = 5). Images were acquired using a pre-defined exam-card that on average, included six sequences (range 2-10), with a maximum scan time of approximately one hour. The majority of observers preferred T2-weighted sequences. The thorax teams were the only groups to prefer T1-weighted imaging. CONCLUSIONS: An iterative process identified sequence agreement in all anatomical regions. These sequences will now be evaluated in patient volunteers. ADVANCES IN KNOWLEDGE: This manuscript is the first publication sharing the results of the first systematic selection of MRI sequences for use in on-board MRI-guided radiotherapy by end-users (therapeutic radiographers and clinical oncologists) in healthy volunteers.

The importance of p53-independent apoptosis in the intestinal toxicity induced by raltitrexed (ZD1694, Tomudex): genetic differences between BALB/c and DBA/2 mice.

The thymidylate synthase inhibitor raltitrexed (ZD1694, Tomudex) induces greater intestinal toxicity, manifested as diarrhea and weight loss, in BALB/c than in DBA/2 mice. No convincing pharmacokinetic or pharmacodynamic reason for this strain difference has been established. We have investigated whether this strain difference in response to raltitrexed is related to differential susceptibilities of intestinal mucosae to undergo apoptosis and also whether p53 expression, a critical factor in 5-fluorouracil-induced intestinal apoptosis and toxicity, modulates this response. Ten mg/kg or 100 mg/kg raltitrexed were administered as single or double i.p. injections 24 h apart to BALB/c, DBA/2, and p53-/- mice. Apoptosis, mitosis, and tissue damage were assessed in intestinal epithelium, and animal weight was recorded. BALB/c mice developed diarrhea and weight loss following 100 mg/kg x2 raltitrexed, whereas DBA/2 mice did not. BALB/c mice were more sensitive than DBA/2 to induction of small-intestinal and colonic apoptosis 24 h following 100 mg/kg raltitrexed. Inhibition of mitosis was equivalent in both strains. Both strains showed histopathological damage to the small intestine after 100 mg/kg x2 raltitrexed, but only BALB/c mice demonstrated colonic damage. p53-null mice showed the same level of small intestinal apoptosis as their wild-type counterparts 24 h after 100 mg/kg x1 raltitrexed and also the same levels of intestinal toxicity 3, 5, and 7 days after 100 mg/kg x2 raltitrexed. Thus, BALB/c mice were more susceptible to induction of intestinal apoptosis by raltitrexed than DBA/2 mice and also demonstrated more histopathological damage in the colon correlating with the induction of diarrhea and weight loss. In contrast to 5-fluorouracil, the intestinal apoptosis and toxicity induced by raltitrexed were p53-independent.

Use of rapid-deployment extracorporeal membrane oxygenation for the resuscitation of pediatric patients with heart disease after cardiac arrest.

INTRODUCTION: We have recently used extracorporeal membrane oxygenation as a means of rapidly resuscitating pediatric patients with heart disease after cardiopulmonary arrest, in whom conventional resuscitation measures have failed. METHODS: We developed a fully portable extracorporeal membrane oxygenation circuit that is maintained vacuum and carbon dioxide-primed at all times. When needed, the circuit is crystalloid-primed and can be ready for use within 15 minutes. Since February 1996, we have used this rapid-deployment circuit to resuscitate 11 pediatric patients in full cardiopulmonary arrest. RESULTS: The median age of the 11 patients was 120 days (2 days to 4.6 years). Nine patients had a cardiac arrest after cardiac surgery. One patient had a cardiac arrest during cardiac catheterization and one patient had a cardiac arrest before cardiac surgery. Median duration of cardiopulmonary resuscitation was 55 minutes (range 20 to 103 minutes), with no difference in the duration of cardiopulmonary resuscitation between survivors and nonsurvivors. Ten of 11 patients (91%) were weaned from extracorporeal membrane oxygenation and seven (64%) survived to hospital discharge. Six patients are long-term survivors, five of whom are in New York Heart Association class I; one survivor is in class II. Seven patients resuscitated with extracorporeal membrane oxygenation before the use of this rapid-deployment circuit had a median duration of cardiopulmonary resuscitation of 90 minutes, with two (28.6%) survivors. CONCLUSIONS: The use of rapid-deployment extracorporeal membrane oxygenation results in shorter resuscitation times and improved survival in pediatric patients with heart disease after cardiopulmonary arrest.

Urinary excretion of glycosaminoglycans and hydroxyproline in Paget's disease of bone, compared with neoplastic invasion of bone.

Urinary glycosaminoglycan and hydroxyproline excretion was studied in 11 patients with clear evidence of Paget's disease of bone. Urinary hydroxyproline, cetyl pyridinium chloride (CPC)-precipitable uronic acid and CPC-precipitable hexosamine were expressed as ratios to urinary creatinine. Urine samples were concentrated x 1000 by vacuum dialysis and the glycosaminoglycans examined by electrophoresis on cellulose acetate followed by staining with alcian blue. All the cases studied showed markedly raised hydroxyproline excretion, whereas the uronic acid excretion was normal or only slightly raised in 10 of the 11 cases studied. One patient who had a raised uronic acid and raised hydroxyproline concentration was shown to have osteosarcoma as a complication of Paget's disease. THE VERY HIGH HYDROXYPROLINE: creatinine ratio in all cases of Paget's disease (mean 241.8 mmol hydroxyproline/mol creatinine) contrasted sharply with the cases of disseminated neoplasm, where the ratio was either normal or slightly raised (mean 29.3 mmol hydroxyproline/mol creatinine). The ratio of hydroxyproline to CPC-precipitable uronic acid was also markedly raised in cases of Paget's disease (mean 77.3 mmol hydroxyproline/mmol uronic acid) and was lower in the neoplastic group (mean 14.1 mmol hydroxyproline/mmol uronic acid) but showed no advantage over the hydroxyproline: creatinine ratio in differentiating the two groups. THE URINARY HYDROXYPROLINE: creatinine ratio promises to be of value in differentiating between Paget's disease of bone and neoplastic invasion of bone. A marked rise in CPC-precipitable uronic acid excretion alone is more suggestive of neoplastic invasion of bone, and if associated with a marked increase in hydroxyproline excretion, it raises the possibility of neoplastic change in Paget's disease of bone. The results of this study also suggest that bone collagen, rather than bone tissue in general, is primarily affected in Paget's disease.

Urinary excretion of glycosaminoglycans in disseminated neoplasm.

Urinary glycosaminoglycan excretion was studied in 24 cases of disseminated neoplasm, 12 of which had unequivocal evidence of skeletal involvement. Urinary hydroxyproline, cetylpyridinium chloride (CPC)-precipitable uronic acid, and CPC-precipitable hexosamine were expressed as a ratio to urinary creatinine. Glycosaminoglycans contained in urine concentrated x 1000 by vacuum-dialysis were separated by electrophoresis on cellulose acetate and stained with alcian blue. Of the 12 cases with clear evidence of skeletal involvement, eight (66%) showed elevation of serum alkaline phosphatase, five (42%) showed elevation of urinary hydroxyproline, and three (25%) showed elevation of urinary uronic acid. It is concluded that urinary uronic acid is not a sensitive index of skeletal involvement in disseminated neoplasm. The most striking feature of the study was the identification of a well-defined fraction indist inguishable from hyaluronic acid in seven (58%) of the cases with evidence of skeletal involvement. Hyaluronic acid is not normally identifiable in adult human urine. The hyaluronic acid excretors showed more consistent biochemical evidence of bone disease (elevation of serum alkaline phosphatase and urinary hydroxyproline) than the non-excretors. The possibility that the urinary hyaluronic acid is derived from degradation of skeletal hyaluronic acid is discussed. An alternative explanation is that the hyaluronic acid is derived from neoplastic cells as part of a reversion of glycosaminoglycan synthesis to a more ;fetal' state, a glycosaminoglycan counterpart of the production of oncofetal antigens by neoplastic cells.

Three-dimensional measurement of cerebral microvascular plasma perfusion, glial fibrillary acidic protein and microtubule associated protein-2 immunoreactivity after embolic stroke in rats: a double fluorescent labeled laser-scanning confocal microscopic study.

Early astroglial response to post-ischemic microvascular hypoperfusion may contribute to progressive cerebral microcirculatory impairment and ischemic neuronal injury. Using laser-scanning confocal microscopy and three fluorescent probes, we measured in three-dimensions cerebral microvascular plasma perfusion, astrocytic reactivity, and neuronal injury assessed by fluorescein isothiocyanate (FITC)-dextran, GFAP immunoreactivity, and microtubule associated protein-2 (MAP2) immunoreactivity, respectively, in rats subjected to 2 h of middle cerebral artery occlusion. Three-dimensional quantitative analysis revealed that 2 h of embolic ischemia resulted in a significant (P<0.05) reduction of cerebral microvascular plasma perfusion in the ipsilateral cortex and subcortex. Tissue within the ipsilateral cortex and subcortex with low plasma perfusion exhibited a significant (P<0.05) increase in GFAP immunoreactivity compared with the homologous contralateral tissue. Three-dimensional re-constructed images showed that prominent GFAP immunoreactive astrocytes surrounded large vessels with decreased plasma perfusion in downstream capillaries in the ipsilateral MCA territory when compared to the vessels in the contralateral homologous tissue. Triple fluorescence probe-stained sections showed that tissue with decreased plasma perfusion and with increased GFAP immunoreactivity was accompanied by a reduction of MAP2 immunoreactivity. The present study demonstrates that an impairment of microvascular perfusion induces an early increase in GFAP immunoreactivity, and reactive astrocytes may contribute to a further reduction of cerebral microvascular plasma perfusion. The three-dimensional quantitative imaging analysis used in the present study provides a means to investigate parenchymal cellular responses to changes of cerebral microvascular plasma perfusion after MCA occlusion.

The relationship between hyaluronidase activity and hyaluronic acid concentration in sera from normal controls and from patients with disseminated neoplasm.

Serum hyaluronidase activity (HAE) and hyaluronic acid (HA) concentration were measured in sera from patients with disseminated neoplasm and compared to those of normal controls. The serum HAE activity in disseminated neoplasm (mean, 12.6 mumol N-acetylglucosamine (NAG)/min/1; range, 5.2-24.7 mumol NAG/min/1) was significantly lower (t = 6.7, p < 0.001) than in normal controls (mean, 17.1 mumol NAG/min/1; range, 11.5-27.0 mumol NAG/min/1). The serum HA concentration in patients with disseminated neoplasm (mean, 8199.7 micrograms/l; range, 42.0-496,000 micrograms/l) was significantly higher (t = 2.63, 0.01 > p> 0.001) than in normal age-matched controls (mean, 55.6 micrograms/l; range, 10.0-348.0 micrograms/l). A negative correlation was found between the serum HAE activity and the HA concentration (r = -0.45, t = 5.92, p < 0.001). The possible reasons for the low serum HAE activity and the raised serum HA concentration in patients with disseminated neoplasm and the negative correlation between the results are discussed.

Human serum and urine glycosaminoglycans in health and in patients with chronic renal failure.

Quantitation of uronic acid precipitable by cetylpyridinium chloride (CPC) and electrophoretic separation of glycosaminoglycans were performed on sera from patients with chronic renal failure and compared to normal controls. Serum CPC-precipitable uronic acid (CpUA) levels in patients with renal failure were significantly higher (mean 13.7 mg/L, range 7.1-23.6 mg/L) than normal controls (mean 9.6 mg/L, range 5.1-13.9 mg/L) due to increased concentrations of low sulphated chondroitin sulphate. A positive correlation between serum CpUA and creatinine was found in renal failure patients. Urine CpUA excretion was raised in renal failure patients compared to normal controls with an increased excretion of chondroitin sulphate (Ch-S) of reduced electrophoretic mobility. Heparan sulphate (HS), a major glycosaminoglycan in normal urine, was absent from the urine of these patients. The possible origin of urine glycosaminoglycans and the role of the kidney in glycosaminoglycan metabolism are discussed.

The isolation and characterization of glycosaminoglycans in normal human serum.

The optimization of conditions for the isolation and characterization of human serum glycosaminoglycans (GAG) is described, together with studies of the accuracy and reproducibility of the method. The principle of the method is proteolytic digestion of serum using papain followed by precipitation of GAGs from the digested sample with cetyl pyridinium chloride (CPC). The uronic acid level and electrophoretic separations can be obtained from a 5 ml serum sample. The mean CPC-precipitable uronic acid level in pooled normal serum was 10.8 mg l(-1) serum. Using enzymatic and chemical analysis the major serum GAG was shown to be chondroitin sulphate (CS). Two distinct electrophoretic fractions were identified both consisting of CS but differing in their degree of sulphation. Dermatan sulphate, heparan sulphate and hyaluronic acid were not detected.

Measurement of hyaluronidase activity in normal human serum.

A detailed evaluation of the assay for serum hyaluronidase (HAE) activity originally developed by Bonner and Cantey [W.M. Bonner, Jr. and E.Y. Cantey, Clin. Chim. Acta, 13 (1966) 746-752] is described, together with studies of its precision. The method is based on the liberation of saccharides with N-acetylglucosamine (NAG) end-groups from hyaluronic acid. The NAG is quantitated by heating with alkaline tetraborate to form an intermediate which reacts with p-dimethylaminobenzaldehyde in acidic medium to form a coloured product. The optimised assay, which requires less that 50 microliters of serum, was used to study the HAE activity of 70 normal sera. The mean HAE activity was 17.1 mumol NAG min-1 l-1 (range 11.5-27.0 mumol NAG min-1 l-1); there was no significant difference with age (t = 1.65, 0.5 > P > 0.1) or sex (t = 0.33, P > 0.5).

Evolution of the technique of congenital diaphragmatic hernia repair on ECMO.

With the increase in popularity of delayed repair of congenital diaphragmatic hernia (CDH), many institutions are using extracorporeal membrane oxygenation (ECMO) to stabilize patients preoperatively. This practice has led to controversy regarding whether the repair should be performed while the patient is on ECMO or after decannulation. This report details the authors' experience with repair of CDH on ECMO. Of the 154 high-risk CDH patients treated at Children's Hospital, Boston, MA, since ECMO became available (1984), 97 received ECMO, including 31 who had repair performed while on ECMO. In group I (nine patients), repair was carried out only if the patients were unweanable from ECMO after 7 days. Activated clotting times (ACT) were maintained at 200 to 220 seconds. In group II (22 patients), repair was performed on ECMO electively, before decannulation. ACT were maintained at 180 to 200 seconds. Additionally, all patients in group II received aminocaproic acid before surgery. This was administered continuously for 72 hours postoperatively or until decannulation. Patients in group II had significantly less overall blood loss (P = .02), and lower transfusion requirement (P = .0003) than those in group I. Additionally, four of the nine patients in group I required reexploration because of hemorrhage; this was not required for any patient in group II (P = .005). Although the survival rates differed, this may have been because of a bias in patient selection between the two groups. From these preliminary data, the authors conclude that repair of congenital diaphragmatic hernia on ECMO can be performed safely, with a minimum of hemorrhagic complications.(ABSTRACT TRUNCATED AT 250 WORDS)

ECMO in evolution: the impact of changing patient demographics and alternative therapies on ECMO.

The incidence of neonatal extracorporeal membrane oxygenation (ECMO) is decreasing nationally. This decrease is presumed to be a result of the emergence of alternative technologies such as high-frequency oscillatory ventilation (HFOV), nitric oxide (NO), and surfactant therapy as well as others. The purposes of the present report were to determine just how rapidly the demographics of ECMO are changing and to determine the impact of competing technologies on ECMO use. The authors reviewed their entire ECMO experience of 455 cases (370 neonatal, 38 pediatric, and 47 cardiac). The neonatal cases also were separated into diagnostic groups: MAS (meconium aspiration syndrome), PPHN (persistent pulmonary hypertension of the newborn), RDS (respiratory distress syndrome), and sepsis. To allow statistical comparison, the patients were divided into four chronological groups, of equal 3-year duration, spanning the 12 years that ECMO has been available. The results of the analysis demonstrated four principle findings. (1) The total number of patients receiving ECMO per year was declining (P = .0001). This decline was attributable to a reduction in the total number of neonatal patients, with the exception of cases of congenital diaphragmatic hernia. (2) The complexity of each ECMO run was increasing, as evidenced by substantial increases in mean ECMO duration per patient and an increase in the incidence of patient complications on ECMO (P = .0001). (3) There has been a significant decrease in the overall survival rate for patients treated with ECMO (P = .0001). (4) The ECMO population mix has shifted away from straightforward neonatal cases and toward the more complex pediatric and cardiac cases. This demographic shift has occurred as a result of improvements in pre-ECMO management of neonatal patients, and is primarily responsible for the findings noted above. However, there also has been a worsening of condition severity within each diagnostic group, which also is partly responsible for the changes noted. If these trends continue, pediatric, cardiac, and CDH patients will likely account for the majority of ECMO patients. Consequently, existing ECMO centers must be prepared to adapt to the changing demographics by evolving programs that support pediatric, cardiac, and adult patients, in addition to neonates. Furthermore, the complexity associated with transporting these unstable older patients and the likelihood that the number of active ECMO centers will decline may require remaining ECMO centers to develop long-distance ECMO transport capabilities.

Resection of a massive sacrococcygeal teratoma using hypothermic hypoperfusion: a novel use of extracorporeal membrane oxygenation.

A 33-week-gestation infant with a massive sacrococcygeal teratoma weighted 4,000 g, but the actual weight of the infant was approximately 1,500 g. With the potential for massive blood loss and impaired lung compliance during resection, some type of cardiopulmonary support was necessary. Resection was undertaken with the assistance of venoarterial extracorporeal membrane oxygenation (ECMO) and hypothermic hypoperfusion. Immediately after removal of the tumor, which weighted 2,420 g, the infant was decannulated from ECMO, and the carotid artery was primarily reconstructed end-to-end. The amount of intraoperative blood loss was 550 mL Postoperatively, the child weighted 1,580 g. Follow-up head ultrasound results were normal, and the patient has done well. This is the first reported case in which ECMO with hypothermic hypoperfusion was used for resection of a massive tumor. This experience shows that ECMO is both useful and safe as a means of temporary cardiopulmonary support for resection of massive tumors in infants.

Intratracheal pulmonary ventilation and congenital diaphragmatic hernia: a report of two cases.

Previous studies from our institution have shown that neonates with congenital diaphragmatic hernia (CDH), whose best postductal PaO2 (BPDPO2) was less than 100 mm Hg while on maximal conventional mechanical ventilation (CMV), had a mortality exceeding 90%. When combined with extracorporeal membrane oxygenation (ECMO), the mortality rose to 100% in those infants who developed hypercarbia following decannulation. Historically, those patients have required increasing ventilator support, leading to iatrogenic lung damage, and eventual death. Intratracheal pulmonary ventilation (ITPV) using the reverse thrust catheter (RTC) developed by Kolobow incorporates a continuous flow of humidified gas through a reverse Venturi catheter positioned at the distal end of the endotracheal tube. In animal studies, ITPV was shown to result in a reduced physiological dead-space (VD), to facilitate expiration, and to enhance CO2 elimination. In our current study, we have applied ITPV in two neonates with CDH who could not be weaned from ECMO because of uncontrollable hypercapnia, and who met above criteria for 100% mortality. In both cases, ITPV restored normal PaCO2 at low peak inspiratory pressure (PIP) with a substantial decrease in VD. We believe ITPV is suited to ventilating newborns with CDH in whom barotrauma is known to be common. Beyond its present use, ITPV may be useful to ventilate children with other forms of respiratory failure, and should be so considered along with other now available methods of mechanical pulmonary ventilation.

Aminocaproic acid decreases the incidence of intracranial hemorrhage and other hemorrhagic complications of ECMO.

Since the inception of extracorporeal membrane oxygenation (ECMO), hemorrhage has been a major complication often limiting its usefulness. This study was undertaken to evaluate the effect of aminocaproic acid (AMICAR), an inhibitor of fibrinolysis, on all hemorrhagic complications of ECMO including intracranial hemorrhage (ICH). In 1990, 49 neonates and 5 older children received ECMO therapy. None of these patients received AMICAR. In 1991, 51 neonates and 5 older children received ECMO. Forty-two of these patients who were considered to be at high risk for bleeding complications (preexisting or anticipated surgical procedures, preexisting ICH, or profound hypoxia, acidosis, coagulopathy, or prematurity) were given AMICAR. The remaining 14 low-risk neonates did not receive AMICAR, and for purposes of analysis were combined with the 1990 group. AMICAR was administered just prior to or after cannulation (100 mg/kg, intravenously) and was infused continuously at 30 mg/kg/h until decannulation. Except for the addition of AMICAR, the ECMO protocol was identical for these two patient groups. Patients who received AMICAR had significantly less bleeding while on ECMO (P = .03) and required fewer blood transfusions (P = .01) than patients not receiving AMICAR. This difference was most significant in the congenital diaphragmatic hernia and cardiac subgroups (P = .0001) and was not significant in the meconium aspiration subgroup (P = .1). The incidence of ICH in the neonatal subgroup was also significantly reduced with no patient on AMICAR developing a new or extending a preexisting ICH (P = .007). Reexploration of the cannulation site for bleeding was also reduced in the AMICAR-treated group but the difference failed to reach statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathogenesis of porcine epidemic diarrhea virus isolate (US/Iowa/18984/2013) in 3-week-old weaned pigs.

Porcine epidemic diarrhea virus (PEDV) is associated with clinical diarrhea in naïve swine of all ages. This report describes timing of antibody generation and disease progression following infection with a US PEDV isolate by assessing fecal viral shedding, morphometric analysis of intestinal lesions, and magnitude of immunohistochemical staining. Sixty-three, 3-week-old pigs were randomly allocated into control (n=27) and challenged (n=36) groups. Challenged pigs were administered 1 mL of 1 × 10(3) PFU/mL of US/Iowa/18984/2013 PEDV isolate by oro-gastric gavage. Three control and four challenged pigs were necropsied on days post-inoculation (dpi) 1, 2, 3, 4, 7, and weekly thereafter, until study termination on dpi 35. Clinical disease, fecal shedding, body weight, and temperature were monitored during the study period. Diarrhea was observed in challenged pigs beginning for some on dpi 2, affecting a majority of pigs by dpi 6 and subsiding by dpi 10. Average daily gain was significantly lower (P<0.001) for one week post-infection in challenged pigs. PEDV was detected in feces by PCR on dpi 1 and continued in a subset of pigs until dpi 24. PEDV-specific antigen was detected in villous enterocytes of challenged pigs by immunohistochemistry (IHC) on dpi 1, 2, 3, 4, 7, and 14. Microscopic lesions included severe diffuse atrophic enteritis with significantly reduced (P<0.001) villous length observed on dpi 3, 4, and 7. Under the conditions of this study, fecal shedding of PEDV and IHC staining can precede and continue beyond the observation of clinical signs, thus increasing the risk of viral transmission.