Reactive Oxygen Species (ROS)-Activatable Prodrug for Selective Activation of ATF6 after Ischemia/Reperfusion Injury.

We describe here the design, synthesis, and biological evaluation of a reactive oxygen species (ROS)-activatable prodrug for the selective delivery of 147, a small molecule ATF6 activator, for ischemia/reperfusion injury. ROS-activatable prodrug 1 and a negative control unable to release free drug were synthesized and examined for peroxide-mediated activation. Prodrug 1 blocks activity of 147 by its inability to undergo metabolic oxidation by ER-resident cytochrome P450 enzymes such as Cyp1A2, probed directly here for the first time. Biological evaluation of ROS-activatable prodrug 1 in primary cardiomyocytes demonstrates protection against peroxide-mediated toxicity and enhances viability following simulated I/R injury. The ability to selectively target ATF6 activation under diseased conditions establishes the potential for localized stress-responsive signaling pathway activation as a therapeutic approach for I/R injury and related protein misfolding maladies.

Body wall tears during late pregnancy in mares: 13 cases (1995-2006).

OBJECTIVE: To review management of pregnant mares with body wall defects and assess the effect of various management strategies on the outcome of mares and their foals. DESIGN: Retrospective case series. ANIMALS: 13 mares. PROCEDURES: Medical records of eligible mares were reviewed. Signalment, history, admitting complaint, clinical findings, parity, type of body wall defect, concurrent diagnoses, postpartum complications, outcome of fetus, outcome of mare, and type of clinical case management were recorded. RESULTS: 8 mares received conservative management and 5 mares received interventional management. Survival of mares to discharge was good, and no difference in mare survival was identified on the basis of type of management, type of body wall defect, or presence of hydrops. Foal survival was significantly better in the conservative management group, compared with those managed by interventional management, and was also better without hydrops. CONCLUSIONS AND CLINICAL RELEVANCE: Foal survival can be improved in mares with body wall defects that occur during parturition without compromising mare survival by use of conservative management strategies that avoid induction of parturition or elective caesarian section and allow for natural parturition. Potentially, improved fetal readiness for birth may play a role.

Clinical pathology of the foal.

The neonatal foal is in a period of transition between fetal and extrauterine life. The clinicopathologic findings in this period often reflect the in utero environment; thus, results need to be interpreted with the knowledge of changes that intrauterine life may produce. These changes can also assist the veterinarian in identifying a foal at high risk for developing clinical problems. The veterinarian should also be aware of the normal variations in clinicopathologic findings that occur as the foal matures. As with results from all diagnostic testing, the clinicopathologic results need to be interpreted with reference to the physical examination findings of the foal.

Culture-positive sepsis in neonatal camelids: 21 cases.

BACKGROUND: There is limited literature on neonatal bacterial sepsis in New World (NW) camelids. HYPOTHESIS: Bacterial culture-positive crias have clinical differences based on the specific bacterial genera isolated. ANIMALS: Bacterial culture-positive NW camelid crias <21 days of age from 1990 to 2005 were included. METHODS: Historic physical examination and cliniopathologic data were retrieved from medical records as were the identity and antibiograms of bacterial isolates. Cases were categorized by outcome (survival versus nonsurvival) and type of sepsis (gram-negative or gram-positive). Kruskal-Wallis and chi-square testing were used to evaluate differences between groups. RESULTS: Twenty-one crias met the inclusion criteria. Median age was 2 days. Failure of passive transfer was common. There were few differences identified on the basis of outcome or type of sepsis. Crias without gastrointestinal or central nervous system involvement survived in greater numbers. Forty-six percent of isolates were gram-positive. The most common isolates were the following: Escherichia coli, Enterococcus spp., Listeria monocytogenes, and Citrobacter spp. Overall survival was 67% (14/21). CONCLUSIONS AND CLINICAL IMPORTANCE: Crias with sepsis do not appear to present with major biochemical, hematologic, or blood gas abnormalities, potentially complicating diagnosis. Affected crias may not have localizing signs at presentation and are not usually febrile, although hypothermia, tachypnea, and tachycardia are relatively common. Total protein concentration was not a substitute for immunoglobulin G measurement in septic crias in this study. Familiarity with the clinical presentation and common pathogens isolated should improve early recognition and treatment and ultimately outcome of crias with sepsis.

Neonatal foal resuscitation.

Cardiac arrest in foals is generally secondary to other serious systemic diseases. Although it can often be anticipated, a clear plan is vital to success. Establishing cardiac output through chest compressions is the most important first step. This step should be followed by ventilation, drug therapy, identifying the nonperfusing cardiac rhythm, and following a preplanned treatment algorithm. Birth resuscitation requires special treatment considerations. The clinician should be prepared to perform resuscitation any time a birth is attended.

Management of bilateral choanal atresia in a foal.

CASE DESCRIPTION: A 1-day-old Standardbred foal with a history of extreme respiratory distress after birth consistent with upper airway obstruction was evaluated. A temporary tracheostomy tube was placed by the referring veterinarian. CLINICAL FINDINGS: On initial examination, there was evidence of hypoxic-ischemic syndrome, secondary to perinatal asphyxia. Endoscopy revealed obstruction of both nares at the level of the choanae; a diagnosis of bilateral choanal atresia was made. TREATMENT AND OUTCOME: The foal was anesthetized and underwent transendoscopic laser fenestration of the buccopharyngeal membranes. Three weeks after surgery, cicatricial narrowing of the choanae was apparent and further transendoscopic ablation was performed. Recurrent stenosis necessitated revision surgeries involving a combination of laser ablation with topical administration of mitomycin and, subsequently, a combination of radial incisions into the stenotic tissue and repeated bougienage with a cuffed endotracheal tube. The degree of stenosis decreased, and at 1 year of age, the horse was an appropriate size for its age, had choanae that were almost maximally open (> 85%), and had entered training. Mild stenosis was still evident when the horse was reexamined the following year, although there was no evidence of exercise intolerance or respiratory compromise. CLINICAL RELEVANCE: Bilateral choanal atresia in a foal can be successfully treated via transendoscopic fenestration of the buccopharyngeal membranes, enabling the horse to subsequently participate in athletic activities. Secondary problems resulting from initial asphyxia and recurrent stenosis at the surgical site can be overcome but may require prolonged and extensive treatment.

Endothelin-1 concentrations in clone calves, their surrogate dams, and fetal fluids at birth: association with oxygen treatment.

Increased endothelin-1 (ET-1) plasma concentration in human infants is associated with persistent pulmonary hypertension of the newborn, a problem also identified in calves derived from somatic cell clone technology. Increased ET-1 also is present in the amnionic fluid and plasma of the infant and mother in preeclampsia, a condition associated with abnormal placentation. Abnormalities in placentation are identified in clone calves. We measured ET-1 in fetal fluid, calf plasma, and surrogate dam plasma in 40 clone calves at the time of term delivery. Calves were subsequently identified as being either oxygen treated (O2) or non-oxygen treated based on their postpartum clinical course. Fetal fluid ET-1 concentration greater than 1.4 ng/mL carried a 3-fold increase in odds of the calf being treated with oxygen. Maternal plasma ET-1 concentration was greater in the O2 group (13 pg/ mL: [8-23 pg/mL] versus 25 pg/mL [12-40 pg/mL]; median, 25-75 percentile). Plasma ET-1 concentration in calves was not significantly different between groups. Fetal fluid ET-1 may serve as a marker for neonatal disorders of oxygenation in clone calves and the source of ET-1 may be the placenta.

Uroperitoneum in 32 foals: influence of intravenous fluid therapy, infection, and sepsis.

Foals may present to a referral hospital with the primary diagnosis of uroperitoneum (UP), or they may develop UP while hospitalized for other reasons. Historical, physical, laboratory, and diagnostic variables of foals presenting with UP were compared to those developing UP while hospitalized. Emphasis was placed on the presence of electrolyte abnormalities, evidence of sepsis or infection, and development of anesthetic complications during surgical correction of the defect. Foals developing UP while in the hospital frequently had a history of dystocia and presented at a very young age (< 48 hours) with primary clinical signs compatible with intrauterine compromise or presumed hypoxic or ischemic insult with or without sepsis. Foals referred with suspected UP often had additional problems unrelated to the urinary system. These foals had hyponatremia and hyperkalemia on presentation, whereas foals receiving intravenous fluid therapy consisting of a balanced electrolyte solution did not develop the classical pattern of electrolyte abnormalities, yet a similar increase in serum creatinine and, frequently, decreasing urine production were noted. Infection was present in 63% of the foals, and 78% of foals revealed signs suggestive of sepsis or infection. Intrauterine compromise, presumed hypoxia or ischemia, and sepsis may predispose foals to development of UP. Anesthetic complications occurred in 16% of the foals undergoing surgical correction of the defect, although hyperkalemia was only present in half of the foals with anesthetic complications.

Rupture of the gastrocnemius muscle in six foals.

Rupture of the gastrocnemius muscle and subsequent disruption of the reciprocal mechanism of the hind limb was diagnosed in 6 foals examined at 7 hours to 3 weeks of age. In 2 foals, the musculoskeletal injury was detected as an ancillary finding to clinical signs of neurologic dysfunction ascribed to hypoxic ischemic insult during delivery, whereas in the other 4 foals, musculoskeletal injury, manifested as inability to rise or stand unsupported, was the chief complaint at admission. Five foals had a history of dystocia and assisted delivery. Common clinical signs were inability to rise, disruption of the reciprocal mechanism, swelling in the caudal aspect of the thigh, instability of the stifle joint, and stifle joint effusion. For mild gastrocnemius injury, exercise restriction via forced recumbency, with minimal or no bandaging, may be sufficient treatment. For more severe disruption of the muscle, limb stabilization via splinting and intensive nursing and monitoring are necessary. Four foals had important concurrent problems, including musculoskeletal deformations (joint contractures), hypoxic ischemic disease, and failure of passive transfer and associated problems (ie, sepsis, polyarthritis, and pneumonia). Moderate to severe gastrocnemius muscle injury is difficult to treat successfully, and the long-term prognosis for athletic function should be regarded as guarded.

Botulism in foals less than 6 months of age: 30 cases (1989-2002).

Botulism has been recognized as a clinical entity in foals since the 1960s. Also known as "Shaker foal" disease, the toxicoinfectious form of botulism affects foals, with the highest incidence in the United States seen in Kentucky and the mid-Atlantic region. The disease is characterized by progressive muscular weakness caused by the action of botulism neurotoxin at cholinergic neuromuscular junctions. Increased number of episodes and duration of recumbency, muscular trembling, and dysphagia are seen in affected foals. Left untreated, the disease can be rapidly fatal, with death occuring secondary to respiratory muscle paralysis within 24 to 72 hours of the onset of clinical signs. Very mildly affected foals can survive with minimal treatment Despite advances made in treatment of these foals, including administration of botulism antitoxin early in the course of the disease, there is still an impression that the disease carries a high mortality rate. The purpose of this study was to evaluate outcome in 30 foals <6 months of age diagnosed with botulism between 1989 and 2002 at the George D. Widener Large Animal Hospital, New Bolton Center. Two foals were euthanized for economic reasons early in the disease course, and I died while being treated. Survival of treated cases was greater than 96%. Approximately 50% of the cases required oxygen therapy, whereas 30% required mechanical ventilation. All foals, excepting 1 mildly affected foal, received botulism antitoxin. Mean duration of hospitalization was 14 days. With appropriate treatment, foals with botulism have a high survival rate.

Mechanical ventilation in foals with botulism: 9 cases (1989-2002).

"Shaker foal" disease, toxicoinfectious botulism of foals, was 1st described as a clinical entity in 1967. The reported mortality rate was 90%, with death occurring within 24-72 hours of the onset of the characteristic clinical signs. The mortality rate decreased when equine-origin botulism antitoxin became available; however, a certain percentage of foals continued to die of respiratory failure. Mechanical ventilation is an important part of the treatment of infant botulism and is essential to the survival of many affected infants. We report a retrospective study of 9 foals with toxicoinfectious botulism where early mechanical ventilation was employed as part of the treatment. Foals receiving mechanical ventilation were progressively acidemic and had increased PaCO2 tensions before mechanical ventilation. These arterial blood gas abnormalities were ameliorated with mechanical ventilation. One foal was euthanized for economic reasons; survival in treated foals was 87.5%. Mechanical ventilation of foals with botulism and respiratory failure appears to be an effective therapy.

Colic in equine neonates: 137 cases (2000-2010).

OBJECTIVE: To document causes of colic in equine neonates, evaluate clinical features of neonates managed medically versus surgically, determine short- and long-term survival rates for neonates with specific medical and surgical lesions, and assess ability of patients to achieve intended use. DESIGN: Retrospective case series. ANIMALS: 137 client-owned equine neonates (< 30 days old) with a history of colic or signs of colic within 1 hour after hospital admission examined between 2000 and 2010. PROCEDURES: Signalment, history, results of physical examination, laboratory data, ancillary diagnostic tests, details of treatment, primary diagnosis, concurrent diseases and short-term survival rate were obtained from the medical records. Long-term follow-up information was obtained through phone survey. RESULTS: 137 neonates with colic were included. The majority (122 [89%]) of neonates were managed medically. The 3 most common diagnoses associated with colic were enterocolitis (37 [27%]), meconium-associated colic (27 [20%]), and transient medical colic (26 [19%]). The most common reason for surgery was small intestinal strangulating obstruction, and these neonates were more likely to have severe, continuous pain and were less responsive to analgesics. Concurrent diseases were common (87 [64%]) but did not significantly impact survival rate. Short-term survival rate was not significantly different between medically (75%) and surgically (73%) managed neonates. Long-term survival rate was excellent (66/71 [93%]) for horses that survived to hospital discharge. Most neonates surviving to maturity were used as intended (49/59 [83%]). CONCLUSIONS AND CLINICAL RELEVANCE: Most neonates examined for signs of colic can be managed medically. Short-term survival rate in medically and surgically treated neonates was good. Long-term survival rate of foals discharged from the hospital was excellent, with most achieving intended use.

Comparison of viscoelastic coagulation analysis and standard coagulation profiles in critically ill neonatal foals to outcome.

OBJECTIVE: To determine if changes in viscoelastic variables are associated with abnormalities observed in the standard coagulation profile and patient outcome in foals with suspected septicemia. DESIGN: Prospective clinical trial during 2003 and 2004 foal season. SETTING: Neonatal intensive care unit at a veterinary teaching hospital. ANIMALS: Thirty critically ill foals <72-hour-old admitted sequentially meeting criteria for systemic inflammatory response associated with infection. INTERVENTIONS: Hemostatic evaluation, using standard coagulation testing and viscoelastic analysis, was performed at admission, 24 hours following admission, and 48 hours following admission in critically ill foals. Standard coagulation tests included platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen, fibrin(ogen) degradation products, and antithrombin. Data collected from viscoelastic analysis included time to initial clot formation (ACT), clot rate, and platelet function. Signalment, blood culture results, clinicopathologic data, and outcome were collected from medical records. Equality of populations test was used to determine associations between coagulation tests and blood culture status/outcome, as well as between viscoelastic parameters and coagulopathy, blood culture status, and outcome. Logistic regression was used to quantify associations. A significance level of P<0.05 was used. MEASUREMENTS AND MAIN RESULTS: Foals with decreasing clot rate (CR) over the sample period were more likely to be euthanized or die (P=0.02). Foals with prolonged ACT (P=0.03), and decreased CR at admission (P=0.047), were more commonly coagulopathic. Identification of coagulopathy on admission (P=0.02), or persistence of hemostatic dysfunction 48 hours later (P=0.04), was associated with death. CONCLUSIONS: Viscoelastic coagulation evaluation could be used in a neonatal intensive care unit setting to further characterize coagulopathy, and identify foals at higher risk for poor outcome.

Ventilatory support of the critically ill foal.

Critically ill foals often have respiratory failure and benefit from respiratory support. Conventional mechanical ventilation using modem mechanical ventilators is easily adapted to foals. Establish-ing ventilator settings is a dynamic process aided by constant monitoring of blood gas values, end-tidal carbon dioxide, airway pressures, respiratory volumes, airway resistance, and respiratory compliance. Early weaning is as important as timely initiation of ventilation.

Echocardiographic diagnosis of transposition of the great arteries in a neonatal foal.

The clinical and echocardiographic findings in a 19-h-old female foal with a ventricular septal defect, patent foramen ovale, patent ductus arteriosus, and complete transpositon of the great vessels are described. Clinical signs were suggestive of complex congenital heart disease and echocardiography of the foal allowed definitive diagnosis prior to postmortem.

Fluid therapy in the neonate: not your mother's fluid space.

Fluid therapy is a universally used therapeutic modality in critical care patients. To effectively deliver fluids to neonates., an understanding of their fluid physiology is necessary. Neonates, as they make the transition from fetal physiology, have increased capillary filtration and a compliant interstitium producing a large ISF reserve. This reserve helps the neonate to adapt to fluid challenges, serving as a ready source of fluids in times of need, but it also frustrates therapeutic fluid administration by damping the effect of intravenous fluid therapy when treating hypovolemia. Additionally,it explains the difficulty neonates have in handling fluid overload. Successful treatment of hypovolemia requires aggressive volume repletion using 20-mL/kg fluid boluses. Once euvolemia is restored and ongoing losses are replaced, maintenance fluid rates should be conservative so as to avoid fluid overload. The neonate's unique sodium handling must also be recognized. Many critical neonates benefit from sodium restriction, whereas others may have high ongoing losses and require careful sodium replacement therapy. Careful attention to fluid therapy formulation ensures positive fluid support without adding to the physiologic stress of the critical neonate.