Optimizing the Bioavailability of Subcutaneously Administered Biotherapeutics Through Mechanochemical Drivers.

The subcutaneous route offers myriad benefits for the administration of biotherapeutics in both acute and chronic diseases, including convenience, cost effectiveness and the potential for automation through closed-loop systems. Recent advances in parenteral administration devices and the use of additives which enhance drug dispersion have generated substantial additional interest in IV to SQ switching studies. Designing pre-clinical and clinical studies using SQ mediated delivery however requires deep understanding of complex inter-related physiologies and transport pathways governing the interstitial matrix, vascular system and lymphatic channels. This expert review will highlight key structural features which contribute to transport and biodistribution in the subcutaneous space and also assess the impact of drug formulations. Based on the rapidly growing interest in the SQ delivery route, a number of potential areas for future development are highlighted, which are likely to allow continued evolution and innovation in this important area.

Congenital esophageal stenosis: a case report and review of the literature.

A child with congenital esophageal stenosis (CES) demonstrates the need for accuracy in the diagnosis and management of this rare problem. Other etiologies of dysphagia must be looked into, but when the expected results are not realized CES should be considered. A range of diagnoses and diagnostic studies may help to get children with dysphagia the treatment that they need to resolve their symptoms.

Significance of peritoneal fluid as an isolated finding on abdominal computed tomographic scans in pediatric trauma patients.

BACKGROUND: Peritoneal fluid on abdominal computed tomographic (CT) scan in the absence of solid-organ injury suggests a bowel injury. We sought to determine the significance of peritoneal fluid as the sole finding on abdominal CT scans obtained to evaluate injured pediatric patients. METHODS: We performed a retrospective review of abdominal CT scans obtained during the initial survey of blunt trauma patients less than 19 years old during a 5-year period (1991-1995). All patients received intravenous and oral contrast agents. All CT scans were read by a staff radiologist. All CT scan results were retrospectively verified by one of the authors. RESULTS: Of the 259 scans, 157 (59%) were read as normal; 76 (31%) demonstrated solid-organ injury or pelvic fracture; 2 (1%) had pneumoperitoneum and 24 (9%) had peritoneal fluid as the only finding. Quantification of the fluid was done using a previously described method. Of the 16 patients with a small amount of fluid, only 2 (12%) required celiotomy. Of the eight patients with a moderate amount of fluid, four (50%) required celiotomy. At celiotomy, the six patients all had small-bowel injuries. No abdominal CT scan demonstrated extravasation of oral contrast. CONCLUSION: Intra-abdominal fluid as the sole finding on abdominal CT scan does not mandate immediate celiotomy in the bluntly injured pediatric patient. The patient with fluid in more than one location has a 50% chance of bowel injury. We also conclude that extravasated enteral contrast is rarely present to aid in the diagnosis of bowel injury in children.

Cost-effectiveness in diagnosing infantile hypertrophic pyloric stenosis.

PURPOSE: The purpose of this study was to determine which imaging study, upper gastrointestinal series (UGI) or abdominal ultrasonography (US), is more cost-effective in diagnosing infantile hypertrophic pyloric stenosis (IHPS) using a decision analysis model. METHODS: Probabilities were calculated from a review of the records of all infants less than 6 months of age referred for UGI or US to rule out IHPS over a 3-year period from January 1992 to December 1995. Cost-effectiveness was determined from hospital charges for each imaging study and its possible outcomes. RESULTS: The positive predictive value of UGI was 1.0 and US was 0.98 in the 246 infants evaluated for possible IHPS. In patients who had an initially normal study finding (UGI or US), 25% of patients undergoing US first required a second study for persistent symptoms, whereas only 6% of patients who had a negative initial UGI finding required a second study. CONCLUSIONS: Cost analysis found UGI to be more cost-effective than US because fewer secondary studies were required. UGI provides information regarding other pathological conditions as compared with US.

Evolution in the recognition of infantile hypertrophic pyloric stenosis.

PURPOSE: To analyze changes in the clinical condition at presentation and methods of establishing the diagnosis of infantile hypertrophic pyloric stenosis (IHPS). METHODS: Retrospective review of patients who underwent pyloromyotomy (PM) for suspected IHPS at two institutions from 1969 through 1994 was performed. For the purposes of comparison, the population was divided into five equal time periods. RESULTS: Over the 25-year period, 901 infants underwent PM. Patients presented at a younger age, weighed more, and had a shorter length of illness in the most recent time period. Hypochloremic alkalosis was found half as frequently in the most recent time period compared to the earliest group. A palpable pyloric tumor was present in 79% of patients in the earliest time period compared with 23% in the most recent time period. Sixty-one percent of patients in the earliest group and 96% in the latest group underwent an imaging study, reflecting the referring physician's evaluation before referral to the surgeon. CONCLUSIONS: Currently, patients with IHPS less frequently present with the clinical hallmarks of the disease. The use of imaging studies to establish the diagnosis has become common practice. The result has been the diagnosis of IHPS before alkalosis has developed, a shorter clinical course, less morbidity, and a shorter postoperative hospital stay.

Complications of pyloromyotomy for infantile hypertrophic pyloric stenosis.

BACKGROUND: Few references exist regarding contemporary complications of pyloromyotomy (PM) for infantile hypertrophic pyloric stenosis (IHPS). Therefore, we reviewed the frequency and outcome of patients with IHPS who developed complications from PM. METHOD: A 25-year retrospective review was performed in two populations. The first group included all infants who had a PM for IHPS at two pediatric surgery centers. The second group included all infants referred from other institutions who developed complications following PM for IHPS. RESULTS: Between 1969 and 1994, 901 PMs were performed. Intraoperative complications occurred in 40 patients (4%), including 39 duodenal perforations and 1 difficult intubation requiring prolonged ventilation. No unrecognized duodenal perforations or incomplete PMs were found. Postoperative complications developed in 52 patients (6%). The wound infection rate was less than 1%. Postoperative vomiting occurred in 31 infants (3%). The mortality rate was 0.1%, with 1 death due to sepsis from delayed diagnosis of Hirschsprung's disease. During the same study period, 11 patients were referred from other hospitals for postoperative complications. Five had persistent vomiting treated successfully with expectant management. Six infants needed reoperation: 3 for persistent IHPS, 1 for gastric outlet obstruction, and 1 for small bowel obstruction secondary to adhesions; 1 required wound abscess drainage. CONCLUSION: Pyloromyotomy is not without complications. Duodenal perforation should be infrequent, but when it occurs, it can usually be readily recognized and treated with minimal morbidity. Postoperative vomiting can be managed nonoperatively, but if it persists longer than 5 days, radiologic evaluation should be performed. Incomplete PM is uncommon and should not occur. A second myotomy is needed when the diagnosis of incomplete myotomy is established. A single standard of care should be expected of all surgeons who perform PM for IHPS.

Common bile duct obstruction related to intestinal polyposis in a child with Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome is characterized by hamartomatous polyposis of the small and large bowel and mucocutaneous pigmentation. The authors describe a 9-year-old girl with small bowel obstruction related to duodenal intussusception caused by polyposis in the fourth portion of the duodenum. Operative reduction of the intussusception and excision of the polyps were performed, at which time the pancreas appeared to have mild pancreatitis. A liver biopsy specimen showed mild portal fibrosis and ductal proliferation. The patient did well postoperatively, but later presented with symptoms consistent with biliary obstruction. Percutaneous transhepatic cholangiography showed pancreatic and biliary duct dilatation as well as obstruction of the common bile duct, which extended into the left upper quadrant. Exploration showed ampullary obstruction several centimeters proximal to the line of resection. Sphincteroplasty was performed. The postoperative course was uncomplicated. The authors conclude that Peutz-Jeghers syndrome with polyps in the duodenum can markedly distort duodenal and ductal anatomy and can lead to ampullary obstruction.

Preoperative diagnostic evaluation of children with Cushing's syndrome.

Recent advances in biochemical and imaging studies have improved the diagnostic accuracy of Cushing's syndrome. To better define roles for these studies in children, the authors reviewed their experience with this rare group of patients. Fifteen children, aged 11 weeks to 17 years, were treated for noniatrogenic Cushing's syndrome over a 33-year period. All children presented with signs of hypercortisolism. Nineteen different diagnostic tests were used, reflecting changes in how these patients are evaluated. Pathological diagnoses were adrenal cortical carcinoma (3), primary adrenocortical nodular dysplasia (PAND) (2), and pituitary adenoma (10). Children with adrenal cortical carcinoma presented with an adrenal mass and at a younger age (mean, 22.3 months). Key diagnostic features of patients with PAND were a low plasma adrenocorticotrophin hormone (ACTH) and no suppression with high-dose dexamethasone. Children with a pituitary cause of Cushing's syndrome presented at an older age (mean, 15.7 years) and were diagnosed using a combination of high-dose dexamethasone testing, simultaneous inferior petrosal sinus sampling, and/or ovine corticotrophin-releasing hormone stimulation test. A strategy for the diagnosis of Cushing's syndrome in children is presented.

Brucellosis: re-emergence and changing epidemiology in Queensland.

OBJECTIVE: To define the epidemiological and clinical characteristics of human brucellosis, which is being detected in increasing numbers of patients in Queensland. DESIGN AND SETTING: Thirty-four cases of brucellosis diagnosed according to standard clinical and microbiological criteria were studied either retrospectively or prospectively over a two-year period from October 1989 to October 1991. RESULTS: Cases were assessed by means of standard laboratory investigations and a questionnaire documenting clinical symptoms, occupation and recreational activities, treatment and response, relapse rate and complications. Blood cultures taken from 11 patients were positive for Brucella suis; in three others, Brucella suis was cultured from other sites. In the 12 months before diagnosis, all affected individuals were involved in the killing and slaughter of feral pigs. Most infections occurred in rural Queensland but six were contracted in metropolitan Brisbane from feral pig abattoirs. All patients responded to appropriate antibiotic therapy; the relapse rate was 66% in those treated for less than four weeks. Complications (multiple splenic abscesses, epididymitis, cervical lymphadenitis and septic arthritis) occurred in four patients, who were ill for more than one month before diagnosis. CONCLUSIONS: Brucellosis due to Brucella abortus is a disappearing disease in Australia as a result of effective eradication programs in cattle. However, the disease is re-emerging in Queensland because of recreational and occupational exposure to feral pigs infected with Brucella suis. The population at risk is increasing as the lucrative export industry based on field-shot feral pigs expands.

Perforated peptic ulcer disease in children: association of corticosteroid therapy.

Four children were treated at the Oregon Health Sciences University for perforated peptic ulcer disease over the last 15 years. All children were being treated for other severe underlying diseases at the time of perforation. All of the children were receiving corticosteroids; one was receiving ulcer prophylaxis. Presenting symptoms were those of a perforated viscus, and pneumoperitoneum was present in all patients. Simple closure and omental patching of the ulcer resulted in no operative mortality or morbidity. None of the ulcers have recurred. In reviewing the literature, corticosteroids were associated with perforated peptic ulcer disease in 17.8% of children with perforated peptic ulcer. Despite controversy regarding the role of corticosteroids in the causation of peptic ulcer, we recommend prophylaxis for all children receiving corticosteroids.

Long-segment Hirschsprung's disease.

We identified 21 children (14 boys and seven girls) with long-segment Hirschsprung's disease defined as aganglionosis extending proximal to the ileocecal valve. Long-segment Hirschsprung's disease is difficult to diagnose and treat; symptoms may be mild, and diagnosis delayed. Abdominal distention and constipation or delayed passage of meconium are the most common symptoms. Radiologic studies are unreliable in establishing the diagnosis. The morbidity rate is high because of the high transition zone and short gut. The long-term outcome of patients after the standard Duhamel procedure is satisfactory, except with extremely high transition zones. Pull-through procedures should not be performed in the small infant, but should be delayed until patients are old enough to be continent.

A method for rapid analysis of peripheral blood mononuclear leukocyte cytokine mRNA.

Interleukins, hematopoietic growth factors, and adhesion molecules mediate multiple components of the inflammatory response. Conventional methods for purification of cytokine-producing cells are time consuming and can, therefore, depending on the conditions of cell purification and the nature of the mRNA being purified, result in both over- and underestimates of mRNA content. Therefore, it has been difficult to quantify such factors in ways that are unambiguously reflective of in vivo cytokine production. We describe herein a method for such rapid preparation of peripheral blood mononuclear leukocytes (PBML) that amounts of cytokine mRNA derived from these cells, apart from readily quantifiable losses during RNA preparation, will be reflective of quantities in vivo. Small quantities (10(5) of normal PBML were isolated by density centrifugation of heparinized blood for 1.25 min in a capillary tube. Poly(A)+ RNA isolated by oligo(dT)-cellulose column chromatography was sufficient to reverse transcribe both antigen-specific T-cell-receptor beta-chain mRNA and interleukin 6 (IL-6) mRNA and subsequently amplify the cDNA with Taq polymerase in reverse transcription-polymerase chain reactions (RT-PCR). Although IL-6 mRNA was not present in normal PBML, PBML incubated in culture medium for only 3 h contained approximately one molecule per cell. Because of its rapidity this technique will permit quantification of cytokine mRNA in the steady state and in clinical setting of inflammation. Because the method requires only a small quantity of blood it can be applied to clinical research studies involving children.

Microperforation of a duodenal diaphragm as a cause of paradoxical gas in congenital duodenal obstruction.

An infant who presented with signs of duodenal atresia had proximal duodenal obstruction by upper gastrointestinal barium study, but had a small amount of air in the distal bowel. Exploration showed an annular pancreas and microperforation of a duodenal diaphragm. Prior to concluding that pancreaticobiliary duct anomalies are the path of air into the distal bowel in patients with duodenal atresia, microperforation of a duodenal diaphragm must be excluded.

Importance of fetal fluid imbalance in congenital cystic adenomatoid malformation of the lung.

Congenital cystic adenomatoid malformation (CCAM) is a regional overgrowth of bronchioles with suppression of alveolar development in fetal and newborn lung. Twelve patients with CCAM were treated. Six premature infants had acute respiratory distress. Prenatal ultrasound was performed in only five patients and was abnormal in all five. Five premature neonates also had patent ductus arteriosus complicating their courses. Six older children presented with recurrent pneumonitis. Radiographs showed asymmetry of the chest and radiolucent masses in all 12 patients. Seven had type I lesions, two had type II lesions, and three had type III lesions. Hydramnios and hydrops were present in three, and hydrops alone was present in one of the six neonates. These four patients died. One other neonate died of respiratory failure and persistent fetal circulation. Seven patients survived for an extended period. Ultrasound makes the prenatal diagnosis of hydramnios and hydrops possible. It is in this group that fetal interventions can be considered. For the remaining patients, surgical intervention is indicated at the time of diagnosis.

Neurenteric cyst: current management.

Two newborn infants with neurenteric cysts have been evaluated with recently developed imaging techniques. Magnetic resonance imaging or computed tomography can provide the evaluations needed to facilitate removal of the entire cyst at one operation. Appreciation of the extent of the problem allows for expeditious evaluation and early definitive surgical intervention.

Pars sternalis diaphragmatic hernia with omphalocele: a report of two cases.

A rare type of congenital diaphragmatic hernia occurs in which there is a large opening in the anterior diaphragm between the pericardial and peritoneal cavities without a sac. This hernia is invariably associated with defects in the anterior abdominal wall and with sternal defects. More commonly, it is associated with cardiac anomalies as in the Pentalogy of Cantrell. The etiology of this hernia is undoubtedly different from the more common hernia of Morgangni, which has a sac and few associated anomalies. The etiology may be failure of fusion of the pars sternis area of the septum transversum. Only five other cases have been described.

Pyloroplasty in association with Nissen fundoplication in children with neurologic disorders.

Previous studies have suggested that delayed gastric emptying occurs in severely mentally retarded patients with gastroesophageal reflux. Based on this data, pyloroplasty was employed in such patients. A retrospective analysis of 99 consecutive patients who underwent primary fundoplication for GER was performed. Gastric emptying, as measured by successful removal of the nasogastric tube or elevation of the gastrostomy tube, was studied. Children with neurologic disorders had no clinically significant difference in gastric emptying after fundoplication (3.31 days) when compared with neurologically normal patients (2.21 days). When added to Nissen fundoplication, pyloroplasty did not hasten the return of gastrointestinal function in the severely impaired patients (4.91 days). A prospective study employing gastric isotope bolus feedings before and after Nissen fundoplication will determine if pyloroplasty improves gastric emptying when used in conjunction with Nissen fundoplication for patients with severe neurologic disorders.