Erik G. Pearson

Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications

Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case–control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P = 1.91 × 10−3; Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 × 10−8; and Boston: P = 2.1 × 10−2]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications.

Common variants on chromosome 2 and risk of primary open-angle glaucoma in the Afro-Caribbean population of Barbados

Primary open-angle glaucoma (POAG) is the second leading cause of blindness worldwide. Although a number of genetic loci have shown association or genetic linkage to monogenic forms of POAG, the identified genes and loci do not appear to have a major role in the common POAG phenotype. We seek to identify genetic loci that appear to be major risk factors for POAG in the Afro-Caribbean population of Barbados, West Indies. We performed linkage analyses in 146 multiplex families ascertained through the Barbados Family Study of Glaucoma (BFSG) and identified a strong linkage signal on chromosome 2p (logarithm of odds score = 6.64 at θ = 0 with marker D2S2156). We subsequently performed case-control analyses using unrelated affected individuals and unaffected controls. A set of SNPs on chromosome 2p was evaluated in two independent groups of BFSG participants, a discovery group (130 POAG cases, 65 controls) and a replication group (122 POAG cases, 65 controls), and a strong association was identified with POAG and rs12994401 in both groups (P < 3.34 E−09 and P < 1.21E−12, respectively). The associated SNPs form a common disease haplotype. In summary, we have identified a locus with a major impact on susceptibility to the common POAG phenotype in an Afro-Caribbean population in Barbados. Our approach illustrates the merit of using an isolated population enriched with common disease variants as an efficient method to identify genetic underpinning of POAG.

Decompressive laparotomy for abdominal compartment syndrome in children: before it is too late

PURPOSE Abdominal compartment syndrome (ACS) in children is an infrequently reported, rapidly progressive, and often lethal condition underappreciated in the pediatric population. This underrecognition can result in a critical delay in diagnosis causing increased morbidity and mortality. This study examines the clinical course of patients treated for ACS at our institution. METHODS A review of children requiring an emergency laparotomy (n = 264) identified 26 patients with a diagnosis of ACS. ACS was defined as sustained intraabdominal hypertension (bladder pressure >12 mm Hg) that was associated with new onset organ dysfunction or failure. RESULTS Patients ranged in age from 3 months to 17 years old and were cared for in the pediatric intensive care unit (PICU). Twenty-seven percent (n = 7) were transferred from referring hospitals, 50% (n = 13) were admitted directly from the emergency department, and 23% (n = 6) were inpatients before being transferred to PICU. Admission diagnoses included infectious enterocolitis (n = 12), postsurgical procedure (n = 10), and others (n = 4). Patients progressed to ACS rapidly, with most requiring decompressive laparotomy within 8 hours of PICU admission (range, <1-96 hours). Preoperatively, all patients had maximum ventilatory support and oliguria, 85% (n = 22) required vasopressors/inotropes, and 31% (n = 8) required hemodialysis. Mean bladder pressure was 25 mm Hg (range, 12-44 mm Hg). In 42% (n = 11), cardiac arrest preceeded decompressive laparotomy. All patients showed evidence of tissue ischemia before decompressive laparotomy with an average preoperative lactate of 8 (range, 1.2-20). Decompressive laparotomy was done at the bedside in the PICU in 13 patients and in the operating room in 14 patients. Abdominal wounds were managed with open vacuum pack or silastic silo dressings. Physiologic data including fluid resuscitation, oxygen index, mean airway pressure, vasopressor score, and urine output were recorded at 6-hour intervals beginning 12 hours before decompressive laparotomy and extending 12 hours after operation. The data demonstrate improvement of all physiologic parameters after decompressive laparotomy except for urine output, which continued to be minimal 12 hours post intervention. Mortality was 58% (n = 15) overall. The only significant factor related to increased mortality was bladder pressure (P = .046; odds ratio, 1.258). Cardiac arrest before decompressive laparotomy, need for hemodialysis, and transfer from referring hospital also trended toward increased mortality but did not reach significance. CONCLUSION Abdominal compartment syndrome in children carries a high mortality and may be a consequence of common childhood diseases such as enterocolitis. The diagnosis of ACS and the potential need for emergent decompressive laparotomy may be infrequently discussed in the pediatric literature. Increased awareness of ACS may promote earlier diagnosis, treatment, and possibly improve outcomes.

Association of HTRA1 polymorphism and bilaterality in advanced age-related macular degeneration

Single nucleotide polymorphism (SNP), rs11200638, in the promoter of HTRA1 has recently been shown to increase the risk for AMD. In order to investigate the association of this HTRA1 polymorphism and the bilaterality of AMD, we genotyped rs11200638 in control, unilateral, and bilateral advanced AMD patients. The A allele for SNP rs11200638 in HTRA1, was significantly more prevalent in bilateral wet AMD and GA patients than in unilateral groups (p=.02 and p=.03, respectively). The homozygote odds ratios of bilateral wet AMD and GA are significantly greater than those seen in unilateral groups (twofold and threefold increase, respectively). This finding is consistent with the role of HTRA1 in AMD pathogenesis and will help aid in the clinical management and prognosis of AMD patients.

Elovl4 haploinsufficiency does not induce early onset retinal degeneration in mice

ELOVL4 was first identified as a disease-causing gene in Stargardt macular dystrophy (STGD3, MIM 600110.) To date, three ELOVL4 mutations have been identified, all of which result in truncated proteins which induce autosomal dominant juvenile macular degenerations. Based on sequence homology, ELOVL4 is thought to be another member within a family of proteins functioning in the elongation of long chain fatty acids. However, the normal function of ELOVL4 is unclear. We generated Elovl4 knockout mice to determine if Elovl4 loss affects retinal development or function. Here we show that Elovl4 knockout mice, while perinatal lethal, exhibit normal retinal development prior to death at day of birth. Further, postnatal retinal development in Elovl4 heterozygous mice appears normal. Therefore haploinsufficiency for wildtype ELOVL4 in autosomal dominant macular degeneration likely does not contribute to juvenile macular degeneration in STGD3 patients. We found, however, that Elovl4+/- mice exhibit enhanced ERG scotopic and photopic a and b waves relative to wildtype Elovl4+/+ mice suggesting that reduced Elovl4 levels may impact retinal electrophysiological responses.

Clinical characterization and genetic mapping of North Carolina macular dystrophy.

North Carolina macular dystrophy (NCMD) is an autosomal dominant macular disease, was mapped to 6q14-q16.2, the disease-causing gene has yet not been identified. It shares phenotypic similarity with age-related macular degeneration including drusen and choroidal neovascularization. We collected six families with NCMD including 75 members, and conducted clinical characterization and genetic mapping for these families. Forty-five patients were diagnosed as NCMD; all six NCMD families were mapped to MCDR1 locus using genetic linkage analysis. MCDR1 interval was refined to 3 cM (1.8mb) between D6S1716 to D6S1671 via fine mapping using microsatellite markers in these six families, all eleven annotated genes within the interval were analyzed by mutation screening in coding regions, no mutation was found, suggesting a potential novel gene or a new pathological mechanism causing NCMD. The refinement of MCDR1 locus will aid the disease-causing gene identification. Functional studies of NCMD genes should provide important insights into pathogenetic mechanisms of NCMD and age-related macular degeneration.

Reflux esophageal stricture—a review of 30 years' experience in children

PURPOSE Strictures of the esophagus in children may have multiple etiologies including congenital, inflammatory, infectious, caustic ingestion, and gastroesophageal reflux (peptic stricture [PS]). Current literature lacks good data documenting long-term outcomes in children. This makes it difficult to counsel some patients about realistic treatment expectations. The objective of this study is to evaluate our institutional experience and define the natural history and treatment outcomes. METHODS A retrospective review of clinical data obtained from children who underwent dilation for PS was performed. RESULTS Over the past 30 years, 114 children and adolescents received 486 dilations. The most common indications for stricture dilation were PS (42%) and esophageal atresia (38%). Other lesser indications included congenital, foreign body, corrosive, cancer, radiation, allergic, and infectious. This review focuses on the 48 children with PS. Of the children with PS, a congenital anomaly was identified in 23 children; and 12 had neurologic impairment. Average age at presentation was 10.2 years (range, 0.5-18.3 years). Most patients had had symptoms for many months before diagnosis. Peptic stricture was most common in the lower esophagus (n = 39). However, middle (n = 8) and upper (n = 1) strictures were occasionally identified. Noncompliance with medical therapy was a challenge in 12% (n = 5) of children. Children with a PS received a median of 3 dilations, but a subset of 5 patients with severe strictures underwent up to 48 dilations (range, 1-48). Repeated dilations were required for a median of 20 months (range, 1-242 months). Among patients receiving esophageal dilation for PS, 94% required an antireflux procedure (19% required a second antireflux surgery). A subgroup of patients (n = 10) was identified who required extended dilations, multiple surgeries, and esophageal resection. This subgroup had a significantly longer period of symptomatic disease and increased risk of esophageal resection compared with those patients requiring fewer dilations. Surgical resection of the esophageal stricture was ultimately required in 3 children with PS after failure of more conservative measures. CONCLUSION Children and adolescents presenting with reflux esophageal stricture (PS) frequently require antireflux surgery, redo antireflux surgery, and multiple dilations for recurrent symptoms. We hope that these data will be of use to the clinician attempting to counsel patients and parents about treatment expectations in this challenging patient population.

Roux‐en‐Y drainage of a pancreatic fistula for disconnected pancreatic duct syndrome after acute necrotizing pancreatitis

BACKGROUND After acute necrotizing pancreatitis (ANP), a pancreatic fistula may occur from disconnected pancreatic duct syndrome (DPDS) where a segment of the pancreas is no longer in continuity with the main pancreatic duct. AIM To study the outcome of patients treated using Roux-Y pancreatic fistula tract-jejunostomy for DPDS after ANP. METHODS Between 2002 and 2011, patients treated for DPDS in the setting of endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopanreatography (MRCP) documented main pancreatic duct disruption with Roux-Y pancreatic fistula tract-jejunostomy. RESULTS In all, seven patients with DPDS were treated. The median age was 62 years (range 49-78) and five were men. The cause of ANP was gallstones (2), alcohol (1), ERCP (1) and idiopathic (3). Pancreatic necrosectomy was done in six patients. Time from onset of pancreatitis to fistula drainage was 270 days (164-365). Pancreatic fistulae arose from DPDS in the head/neck (4) and body/tail (3). Patients had a median fistula output of 140 ml (100-200) per day before surgery. The median operative time was 142 min (75-367) and estimated blood loss was 150 ml (25 to 500). Patients began an oral diet on post-operative day 4 (3-6) and were hospitalized for a median of 7 days (5-12). The median follow-up was 264 days (29-740). Subsequently, one patient required a distal pancreatectomy. After surgery, three patients required oral hypoglycaemics. No patient developed pancreatic exocrine insufficiency. CONCLUSION Internal surgical drainage using Roux-en-Y pancreatic fistula tract-jejunostomy is a safe and definitive treatment for patients with DPDS.

Single-stage versus multi-stage pull-through for Hirschsprung's disease: practice trends and outcomes in infants.

PURPOSE The aim of this study was to evaluate surgical treatments and outcomes in a multi-institutional cohort of neonates with Hirschsprungs disease (HD). METHODS Using the Pediatric Health Information System (PHIS) from 1999 to 2009, neonates diagnosed with HD were identified and classified as having a single stage pull-through (SSPT) or multi-stage pull-through (MSPT). Diagnosis and classification algorithms and clinical variables and outcomes were validated by multi-institutional chart review. Groups were compared using logistic regression modeling and propensity-score matched analysis to account for baseline differences between groups. RESULTS 1555 neonates with HD were identified; 77.2% underwent SSPT and 22.8% underwent MSPT. Misclassification of disease or surgical treatment was <2%. Rates of SSPT increased over time (p=0.03). Compared to SSPT, patients undergoing MSPT had significantly lower birth weights and higher rates of prematurity, non-HD gastrointestinal anomalies, enterocolitis, and preoperative mechanical ventilation. Patients undergoing MSPT had significantly higher rates of readmissions (58.5 vs. 37.9%) and additional operations (38.7 vs. 26%). Results were consistent in the propensity-score matched analysis. CONCLUSION Most neonates with HD undergo SSPT. In patients with similar observed baseline characteristics, MSPT was associated with worse outcomes suggesting that some infants currently selected to undergo MSPT may have better outcomes with SSPT. However, there remains a subgroup of MSPT patients who were too ill to be adequately compared to SSPT patients; for this subgroup of severely ill infants with HD, MSPT may be the best option.

The first 100 infant thoracoscopic lobectomies: Observations through the learning curve and comparison to open lobectomy

OBJECTIVE The objective of the study is to describe our initial 100 attempted infant thoracoscopic lobectomies for asymptomatic, prenatally diagnosed lung lesions, and compare the results to contemporaneous age-matched patients undergoing open lobectomy. BACKGROUND Infant thoracoscopic lobectomy is a technically challenging procedure, which has only gained acceptance worldwide in recent years. METHODS This is a retrospective review of all patients undergoing thoracoscopic or open lung lobectomy between March 2005 and January 2014. Included were all asymptomatic infants younger than 4months. Excluded were patients undergoing emergent lobectomy and patients with isolated extralobar bronchopulmonary sequestrations. RESULTS A total of 100 attempted thoracoscopic lobectomies were compared with 188 open lobectomies. In the thoracoscopic group, mean age and weight at surgery were 7.3weeks and 4.8kg, mean operative time was 185minutes, and mean hospital stay was 3days. Twelve cases were converted to open (12%). Ten conversions occurred within the first third of the series and none in the last third. There were no mortalities. There were no differences between the thoracoscopic and open groups in perioperative complications or hospital stay. There was a significant difference in the operative time: 111minutes vs. 185minutes (open vs. thoracoscopic; p<0.001). There was a higher mean end-tidal carbon dioxide (ETCO2) and lower mean peripheral capillary oxygen saturation (SpO2) in the thoracoscopic group versus the open group (51.7 versus 38.6mmHg and 97.5 versus 99.1%, respectively). CONCLUSION In high volume centers, the learning curve of thoracoscopic lobectomy can be overcome and the procedure can be performed with equivalent outcomes and, in our opinion, superior cosmetic results to open lobectomy.