Emerging therapeutic opportunities for integrin inhibitors.

Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins αIIbß3, α4ß7/α4ß1 and αLß2 for cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of αv integrins, including αvß3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis. New inhibitors of the related integrins αvß6 and αvß1 have recently come to the fore and are being investigated clinically for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. The design of integrin drugs may now be at a turning point, with opportunities to learn from previous clinical trials, to explore new modalities and to incorporate new findings in pharmacological and structural biology. This Review intertwines research from biological, clinical and medicinal chemistry disciplines to discuss historical and current RGD-binding integrin drug discovery, with an emphasis on small-molecule inhibitors of the αv integrins.

Neonatal pharyngeal pseudodiverticulum mimicking esophageal atresia.

Pseudodiverticulum of the hypopharynx is an infrequent but potentially serious complication of orogastric or nasogastric tube insertion and endotracheal intubation. We report two cases of injury to the hypopharynx resulting in a pseudodiverticulum of the hypopharynx that was initially diagnosed as esophageal atresia. Both cases were managed successfully by conservative therapy. We also review the literature regarding neonatal pharyngeal pseudodiverticulum.

A prospective, randomized comparison of traditional and laparoscopic inguinal exploration in children.

The indications for routine exploration of the asymptomatic contralateral groin during pediatric herniorrhaphy remain controversial. Laparoscopy through the open hernia sac has been described as an alternative to this traditional approach and appears to offer some advantages. In deciding whether this technique should be introduced into our clinical practice, we sought to discover whether there was a significant time difference between these two methods and if there were unique complications associated with this approach. We elected to answer this question in a prospective, randomized study. A total of 18 patients completed the study. There were no significant complications in either group. The average total surgical procedure time in the laparoscopy group was 47.5 minutes versus 41 minutes in the traditional group, which is not a statistically significant difference. We conclude from this prospective, randomized pilot study that laparoscopic exploration can be introduced into a pediatric surgical practice without a significant time penalty, and we currently offer it as a reasonable and safe alternative to our patients.

Glass fragility and the stability of pharmaceutical preparations--excipient selection.

The objectives of this study were, first, to calculate the zero mobility temperatures, T0, of trehalose and sucrose by the Pikal method from the width of the glass transition and compare these to the literature, obtained by enthalpy relaxation measurement, and second, to compare the T0 values and physicochemical properties of trehalose to those of sucrose in terms of potential to stabilize labile actives in the glassy state. Differential scanning calorimetry and coulometric Karl-Fischer analysis were used. The glass transition temperatures, Tg, for the two carbohydrates at circa 0.7% moisture were 101 degrees C and 64 degrees C for trehalose and sucrose, respectively. Anhydrous amorphous trehalose had a Tg of 116 degrees C. The T0 values were found to be 44 and 3.5 degrees C for trehalose and sucrose, respectively. The Tg-T0 value for sucrose was compared, and found to be in good agreement with that found by enthalpy relaxation measurements. Trehalose was found to be resistant to crystallization above the glass temperature. The study supports the validity of the calculation method proposed by Pikal for T0. It has been proposed in the literature that T0 is a better measure of stability than Tg. Trehalose has a significantly higher T0 than sucrose and thus would work more effectively in stabilizing a labile active.

Ventilator management of infants before extracorporeal membrane oxygenation.

The aim of this project was to review the course of infants referred for consideration of extracorporeal membrane oxygenation (ECMO) to identify maximal ventilator settings that, when exceeded, did not provide clinical benefit to the patient. These settings might then be used in defining failure of conventional mechanical ventilation. We reviewed referral records and hospital charts of all infants treated for severe respiratory failure due to meconium aspiration syndrome during the 52.5 month period from March 15, 1985, to August 1, 1989. At an inspiratory pressure > 35 cm H2O, 75% (43/57) of patients eventually required ECMO, and 28% (4/14) of the infants who did not receive ECMO died. When the inspiratory pressure was > or = 40 cm H2O, 39/49 patients required ECMO, and 30% (3/10) of those not treated with ECMO died. Once the inspiratory pressure was > 45 cm H2O, 91% (29/32) of patients required ECMO, and only one third of those not treated with ECMO survived. Although the limitations for conventional therapy suggested in this paper may be helpful to clinicians, each center needs to establish guidelines for maximal conventional ventilator support. If these guidelines are clearly defined, alternative methods of therapy can be used once these criteria are achieved.

The status of pediatric surgical rotations by residents in pediatrics.

A variety of forces are reshaping the traditional relationship between physicians and their patients. One consequence of this reform movement will be increased responsibility of the pediatrician to evaluate children with surgical diseases. Pediatricians also will be encouraged to do more of the minor surgical procedures themselves. It is not clear how academic pediatric surgeons should adapt to these changes to assure that the general pediatrician is equipped with the skills to handle this increased responsibility. One obvious solution would be to have the pediatrician in training rotate on the pediatric surgery service. The authors have considered these issues at their institution, and thus became interested in learning the status of pediatric surgical rotations by pediatric house staff in this country. A survey was distributed to the 221 accredited pediatric training programs in this country, and 143 individuals responded. Only thirty-five of these programs require a rotation on pediatric surgery. Eighty-six programs offer it as an elective, but only a minority of house staff takes it. The most disturbing aspect of the survey was the 28 of the programs had required a pediatric surgical rotation in the past but had eliminated it. The most common reasons given for this action were the poor educational content of the rotation and the labor requirements of the pediatric service. Based on the survey, the authors believe that it is unlikely that mandatory rotations on pediatric surgery will be begun in pediatric training curriculums. If pediatric surgeons wish to be involved in training pediatricians, they will need to address the educational content of their electives to meet the changing educational needs of the pediatricians.

Conservative management of pediatric pancreatic pseudocyst using octreotide acetate.

Pancreatic pseudocysts in children are rare. A total of 213 cases have been reported in the literature, the majority secondary to trauma (65%). Treatment options range from conservative, non-operative management to operative drainage. Octreotide acetate, a long-acting analog of somatostatin, is a synthetic peptide with a variety of endocrine and gastrointestinal functions. Octreotide has been successfully used following pancreatic surgery to reduce exocrine function and most recently in the management of adult pancreatic pseudocysts. We report the efficacy of octreotide, as an adjunct to treatment, in two children with pancreatic pseudocyst. Each child was treated conservatively with bowel rest, hyperalimentation, and octreotide acetate (2.5 micrograms/kg SQ QD). Complete resolution of the pseudocysts occurred within 5 weeks. We conclude that octreotide acetate is a safe and potentially effective adjunct in the treatment of pediatric pancreatic pseudocyst, and should be added to the management of pseudocyst before drainage procedures.

Laparoscopic cholecystectomy in children with sickle cell disease.

Since 1991, laparoscopic cholecystectomy has been utilized in children with sickle cell disease, predominantly because of the decreased pain and shorter hospitalization. We believe that outpatient laparoscopic cholecystectomy or even a 24 hour hospitalization is not indicated in the patient with sickle cell disease. Perioperative complications include bleeding diathesis, vaso-occlusive phenomena, and delayed hemolytic transfusion reactions, although clotting parameters can be normal.

Cervical thymic cysts: CT appearance of two cases including a persistent thymopharyngeal duct cyst.

The differential diagnosis of cervical cysts in children includes common entities such as branchial cleft cysts, thyroglossal duct cysts, and cystic hygromas. Congenital thymic cysts are uncommon and often misdiagnosed as either branchial cleft cysts or cystic hygromas. However, they may have an appearance on CT that can be characteristic. The course of the descent of embryologic thymic tissue in the neck to the mediastinum indicates the potential site of deposition of an ectopic cervical thymic cyst. In a child, a cystic lesion that has an intimate relationship to the carotid sheath is likely to be a thymic cyst. Of the approximately 100 cases of vestigial cervical thymus or thymic cysts that have been reported in children, only 5 cases of a persistent thymopharyngeal duct cyst have been described [1-5]. In two of these five, the persistent thymopharyngeal duct cyst was demonstrated by CT [1,2]. We report one additional case of a cervical thymic cyst and one case of a persistent thymopharyngeal duct cyst both depicted by CT.

Thoracic empyema in a patient with acute appendicitis: a rare association.

Thoracic empyema and appendicitis rarely are concomitant. This is the first report of ultrasonography and computed tomography being used preoperatively to establish the diagnosis of ruptured appendicitis in a child with thoracic empyema. The perforated appendicitis was identified after gastrointestinal flora were cultured from the thoracostomy drainage of the empyema.

Interferon-alpha-2a for the treatment of complex hemangiomas of infancy and childhood.

OBJECTIVE: The authors describe the use of interferon-alpha-2a (IFN-alpha-2a) in the treatment of complex hemangiomas and review the role of interferon (IFN) in this example of an angiogenic disease. SUMMARY BACKGROUND DATA: Hemangiomas are the most frequent tumors of infants and children. They grow rapidly for 6 to 8 months and then resolve over a period of years. Approximately 5% produce life-, sight-, or limb-threatening complications, with mortality rates between 20% and 50%. Aggressive therapy with steroids, arterial ligation or embolization, or surgery has been used in these situations with variable results and high morbidity. Recently, IFN-alpha was found to be effective treatment in these complex hemangiomas. METHODS: Four infants and one child were treated with IFN-alpha-2a at an initial subcutaneous dose of 1 million units/m2/day and a sustained dose of 3 million units/m2/day for 5 to 11 months. Appropriate laboratory values were monitored and adverse reactions and ultimate response to therapy were recorded. RESULTS: Two patients experienced minor complications that were managed easily. Three patients had total or near-total regression of the hemangioma, one had partial (50%) regression, and one had stabilization but no regression after an average of 7.1 months of IFN therapy. CONCLUSION: Interferon-alpha inhibits angiogenesis and endothelial cell migration and proliferation in vitro. The patients in this study add to the growing number who have benefited from IFN therapy. As such, IFN-alpha should be considered as a first-line agent in treating complex hemangiomas of infants and children.

Prostaglandin-induced foveolar hyperplasia simulating pyloric stenosis in an infant with cyanotic heart disease.

Prostaglandin infusion is used to maintain patency of the ductus arteriosus in infants with cyanotic congenital heart disease. Recently, gastric outlet obstruction as a result of prostaglandin infusion has been described. In our case, an upper gastrointestinal contrast study seemed to depict the typical appearance of pyloric stenosis in an infant who had received an infusion of prostaglandin for a prolonged period. Serial ultrasonograms, however, disclosed progressive elongation of the antropyloric channel without wall thickening. This report is the second to illustrate prostaglandin-induced gastric outlet obstruction in a vomiting infant with a gastrointestinal series diagnosis of pyloric stenosis.

Successful management of an infant with a giant hemangioma of the retroperitoneum and Kasabach-Merritt syndrome with alpha-interferon.

Giant vascular neoplasms in neonates generally require aggressive medical or surgical therapy for treatment of complications. Steroids, chemotherapy, embolization, radiation, and surgery have all been used with short-term beneficial and sometimes unknown long-term side effects. A new modality of treatment, alpha-interferon, has recently been described. The majority of hemangiomas in children involute by 8 years of age. Occasionally, hemangiomas can endanger vital structures and are associated with a consumption coagulopathy and thrombocytopenia (Kasabach-Merritt Syndrome). These hemangiomas occasionally do not respond to steroids, radiation therapy, cytotoxic drugs, or embolization. The mortality rates approach 50% in nonresponders. Alpha-interferon has been used in these children with life-threatening complications of hemangiomas with relief of symptoms. This case illustrates the potential use of alpha-interferon in the management of giant hemangiomas in children. This emerging form of biological therapy avoids the risks of radiation therapy, embolization, and surgery with only minimal side effects.

Determination of the unfrozen water content of maximally freeze-concentrated carbohydrate solutions.

The heat capacity change at T'g has been studied in freeze-concentrated carbohydrate solutions. The values obtained have been compared with those found for high concentration solutions that do not undergo freezing above Tg. The analysis has indicated that the freezing process influences the degree of stress in the glassy phase. This results in a complex power-time curve when frozen solutions are heated in a differential scanning calorimeter. The endotherm produced by the stress relaxation can cause considerable error in W'g measurement obtained by any method that relies on the integration of the power-time curve. A more reliable method for W'g determination is via the intersection of T'g with a previously prepared Tg/Wg calibration curve.

Cold destabilisation of enzymes.

The thermal stability profile of chymotrypsinogen has been investigated in the temperature range 230-340 K, with special emphasis on the phenomenon of cold instability. Differential scanning calorimetry was used to study the heat capacities of the native and denatured protein in undercooled solution and the results were combined with those obtained by spectrophotometry at ordinary temperatures. The partial heat capacities of both forms decrease with decreasing temperature, assuming negative values. In the experimentally accessible temperature range (above the spontaneous nucleation temperature of ice) the heat capacity difference delta C is found to be positive with a non-linear temperature dependence. delta C is predicted to change sign at some low temperature which cannot, however, be reached by experiment for chymotrypsinogen. In contrast to earlier studies, covering a much more limited temperature range and having to employ an additional destabilisation by means of pH and/or chaotropes, the present findings permit the construction of a more reliable thermodynamic stability profile and related properties. These differ in important details from those reported for other proteins, but based on measurements only in the neighbourhood of the heat-denaturation temperature. The thermodynamic characteristics are, however, in good agreement with earlier predictions and with recent low-temperature measurements on the tetrameric enzyme lactate dehydrogenase.

The effective use of differential scanning calorimetry in the optimisation of freeze-drying processes and formulations.

The formulation and processing variables required for the effective freeze-drying of labile biologicals can be determined from an understanding of the physics of freeze-concentration. Three measurable values, Tg' (the glass temperature associated with maximum freeze-concentration), Wg' (the unfrozen water at this temperature) and Tg (the glass temperature of the dried product) are the keystones. These can be obtained by differential scanning calorimetry. This paper describes their measurement. Techniques to increase the detectability of glass transitions are discussed. Method of calculating Wg' from DSC power-time curves are critically reviewed. An example is presented in which it is demonstrated how failure to perform primary drying below the glass transition results in products on inferior quality. Finally, it is described how measurements of the glass temperature of the "dry" product can be used to predict storage stability. The limitation of using moisture determination to predict stability is high-lighted.

Graft-versus-host disease following ECMO.

Since 1973, over 3,000 newborns have been treated worldwide for respiratory failure with extracorporeal membrane oxygenation (ECMO). ECMO requires transfusion of numerous blood products including platelets and packed red blood cells. Transfusion-associated graft-versus-host disease (GVHD) developed in one of the authors' patients following treatment with ECMO. ECMO exposes newborn infants to a large number of blood components. Although a rare complication, GVHD can be prevented by irradiating blood products prior to transfusion. We now irradiate all blood products prior to use during ECMO and recommend that other institutions do the same.

Rectovulvar fistula in a child secondary to an unusual foreign body.

Foreign bodies in the female genital tract are well recognized as a cause of pain, discharge, secretions, and infection. In the small child, the presence of a vaginal discharge is usually associated with either a common object which has been inserted or sexual abuse complicated by a sexually transmitted disease. A 3-year-old child presented with a recurrent labial secretion and drainage due to an unusual foreign body. It was only during a second operation that the possibility of a foreign body was entertained, and diagnostic testing was begun. A third operation permitted removal of the foreign body, a large bone probably of animal origin. The fistula tract was closed after a colostomy was performed. This represents the first reported case of a rectovulvar fistula not of a congenital nature.

Recent experience with diaphragmatic hernia and ECMO.

In the past 4 years at the Medical College of Georgia, a total of 74 patients underwent extracorporeal membrane oxygenation (ECMO) with 62 (84%) survivors. Forty-seven of these infants had meconium aspiration syndrome and 11 had diaphragmatic hernia. The use of ECMO, when indicated, after reduction and repair of the diaphragmatic hernia, results in normal oxygen delivery, allows time for pulmonary maturation, and increases survival. A total of 27 referrals for diaphragmatic hernia were studied. Six infants had surgical repair and did not require ECMO. Eleven patients, after surgical repair, were treated with ECMO and seven survived. More importantly 10 patients died before the use of ECMO. Six infants died either before or during transport from referring hospitals and four died while in the delivery room or neonatal unit before ECMO. Of these 10 infants, eight were potential candidates for ECMO. Thirteen of the twenty-seven (48%) infants survived. Seven of eleven (64%) infants who received the benefit of ECMO survived. Eight infants who met the criteria for ECMO died before its use. Had ECMO been used in those eight infants, our data suggests that at least four may have survived. The data from this report support the concept that infants undergoing surgical repair of diaphragmatic hernia, when ECMO is not available, should be referred to an ECMO center in the early postoperative period. Furthermore infants with prenatal diagnosis of diaphragmatic hernia should be delivered at a center where surgical as well as ECMO expertise are available.