Publications by authors named "Arthur S Berg"

36 Publications

COLQ and ARHGAP15 are associated with diverticular disease and are expressed in the colon.

J Surg Res 2021 Jul 2;267:397-403. Epub 2021 Jul 2.

Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University, College of Medicine, Hershey, Pennsylvania. Electronic address:

Background: Diverticular disease is a common but poorly understood disease of the gastrointestinal tract. Recent studies have identified several single nucleotide polymorphisms (SNPs) that are associated with diverticular disease.

Materials And Methods: The genotypes of three SNPs (rs4662344 in ARHGAP15, rs7609897 in COLQ, and rs67153654 in FAM155A) were identified by Taqman assay in 204 patients with diverticular disease. Clinical characteristics were obtained from the medical record to study association with genotype. To evaluate gene expression in colon tissue, qPCR was performed on 24 patients with diverticulitis, and COLQ was localized using immunohistochemistry.

Results: The ARHGAP15 and COLQ SNPs were significantly associated with both diverticular disease and specifically diverticulitis, while the FAM155A was not associated with either. No association was found with clinical disease characteristics. Heterozygous genotypes at the ARHGAP15 SNP was associated with lower ARHGAP15 expression in colon tissues. COLQ protein localized to the myenteric plexus in the colon.

Conclusions: This study confirmed association of the ARHGAP15 and COLQ SNPs with diverticular disease in our patients but could not confirm FAM155A SNP association. Neither of these SNPs appeared to associate with more severe disease, but genotype at the ARHGAP15 SNP did impact expression of ARHGAP15 in the colon. Additionally, this study is the first to localize COLQ in the colon. Its presence in the myenteric nervous system suggests COLQ SNP variants may contribute to diverticular disease by altering motility.
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http://dx.doi.org/10.1016/j.jss.2021.05.043DOI Listing
July 2021

Acute exercise improves glucose effectiveness but not insulin sensitivity in paraplegia.

Disabil Rehabil 2021 Apr 27:1-7. Epub 2021 Apr 27.

Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, Miami, FL, USA.

Purpose: To determine the effect of a single session of arm crank ergometry (ACE) exercise on carbohydrate metabolism immediately and 24 h after the exercise bout in paraplegia and able-bodied controls (ABC).

Methods: Paraplegia ( = 11; 91% male; age 34.8 ± 11.4 years) and ABC ( = 6; 67% male; age 28.7 ± 11.9 years) underwent 45 min of ACE exercise at 75% VO. Glucose effectiveness (Sg) and insulin sensitivity (Si) were assessed. Data were analyzed with two-way mixed analysis of variance and Wilcoxon rank-sum or signed-rank test.

Results: VO was lower in paraplegia versus ABC (22.3 ± 3.99 vs. 30.8 ± 2.9 ml/kg/min,  = 0.003). Si was lower paraplegia vs. ABC immediately following exercise (3.28 ± 1.6 vs. 5.30 ± 1.2 min/[µU/mL]x10,  = 0.023). In paraplegia, Sg was higher immediately after exercise than baseline (B: 0.021 ± 0.01 vs. I: 0.026 ± 0.01 min,  = 0.037). Twenty-four hours after exercise, Sg was lower than immediately following exercise (I: 0.026 ± 0.01 vs. 24: 0.017 ± 0.01 min,  = 0.001), but not different than baseline in paraplegia (B: 0.021 ± 0.01 vs. 24: 0.017 ± 0.01 min,  = 0.216). In the ABC group, Sg was not different at all timepoints ( > 0.05). Si did not differ at all timepoints ( > 0.05).

Conclusion: A single bout of ACE at 75% VO helped to acutely control glucose metabolism in those with paraplegia by increasing Sg by nearly 27%; however, this was not sustained past 24-hours. These data provide support for regular exercise engagement.Implications for RehabilitationDisorders of glucose metabolism have been reported at a greater prevalence in persons with spinal cord injury.A single bout of arm crank ergometry exercise at 75% VO helped to acutely control glucose metabolism persons with paraplegia; however, this was not sustained past 24 h.These data provide support for regular exercise engagement in persons with paraplegia.
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http://dx.doi.org/10.1080/09638288.2021.1913517DOI Listing
April 2021

Energy Expenditure, Cardiorespiratory Fitness, and Body Composition Following Arm Cycling or Functional Electrical Stimulation Exercises in Spinal Cord Injury: A 16-Week Randomized Controlled Trial.

Top Spinal Cord Inj Rehabil 2021 ;27(1):121-134

Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, Miami, Florida.

Physical deconditioning and inactivity following spinal cord injury (SCI) are associated with multiple cardiometabolic risks. To mitigate cardiometabolic risk, exercise is recommended, but it is poorly established whether arm cycling exercise (ACE) or functional electrical stimulation (FES) leg cycling yields superior benefits. To determine the adaptations of 16 weeks of FES cycling and ACE on exercise energy expenditure (EEE), cardiorespiratory fitness (CRF), and obesity after SCI. Thirteen physically untrained individuals were randomly assigned to FES ( = 6) or ACE ( = 7) exercise 5 days/week for 16 weeks. Pre- and post-intervention EEE, peak oxygen consumption (absolute and relative VO), and work were assessed using indirect calorimetry, while body composition was measured by dual-energy x-ray absorptiometry. Main effects were found for peak power ( < .001), absolute ( = .046) and relative ( = .042) VO, and peak work ( = .013). Compared to baseline, the ACE group increased in EEE (+85%, = .002), peak power (+307%, < .001), VO (absolute +21%, relative +22%, ≤ .024), peak work (19% increase, = .003), and total body fat decreased (-6%, = .05). The FES group showed a decrease in percentage body fat mass (-5%, = .008). The ACE group had higher EEE ( = .008), peak power ( < .001), and relative VO ( = .025) compared to postintervention values in the FES group. In the current study, ACE induced greater increases in EEE and CRF, whereas ACE and FES showed similar results on body fat. Exercise promotional efforts targeting persons with SCI should use both FES and ACE to reduce sedentary behavior and to optimize different health parameters after SCI.
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http://dx.doi.org/10.46292/sci20-00065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983642PMC
April 2021

Influence of mid and low paraplegia on cardiorespiratory fitness and energy expenditure.

Spinal Cord Ser Cases 2020 12 16;6(1):110. Epub 2020 Dec 16.

Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, Miami, FL, USA.

Study Design: Observational, Cross-sectional.

Objective: Examine the influence of mid (MP) and low (LP) paraplegia on cardiorespiratory fitness (CRF), energy expenditure (EE), and physical activity levels (PAL), and compare these data to able-bodied (AB) individuals.

Setting: Academic medical center.

Methods: Persons with MP (n = 6, T6-T8, 83% male, age: 31 ± 11 y, BMI: 24 ± 7 kg/m) and LP (n = 5; T10-L1, 100% male, age: 39 ± 11 y, BMI: 26 ± 5 kg/m) and AB controls (n = 6; 67% male, age: 29 ± 12 y, BMI: 26 ± 5 kg/m) participated. All participants underwent 45-min of arm-crank exercise where CRF and exercise EE were measured. Basal metabolic rate (BMR) was measured, and total daily EE (TDEE) and PAL were estimated.

Results: Absolute VO (MP: 1.6 ± 0.2, LP: 1.9 ± 0.1, AB: 2.5 ± 0.7 l/min), peak metabolic equivalents (MP: 6.8 ± 1.3, LP: 5.7 ± 0.7, AB: 8.8 ± 0.8 METs), peak power output (MP: 72.9 ± 11.5, LP: 86.8 ± 6.1, AB: 121.0 ± 34.8 Watts), and maximal heart rate (MP: 177.7 ± 9.8, LP: 157 ± 13.6, AB: 185.2 ± 8.5 bpm) were significantly different between the three groups (p < 0.05). BMR and TDEE did not significantly differ between the three groups (p > 0.05), whereas exercise EE (MP: 7.8 ± 1.2, LP: 9.5 ± 0.7, AB: 12.4 ± 3.5 kcal/min) and PAL (MP: 1.30 ± 0.04, LP: 1.32 ± 0.04, AB: 1.43 ± 0.06) significantly differed (p < 0.05). In the AB group, 33.3% and 66.7% were classified as sedentary or having low activity levels, respectively, while all persons with paraplegia were classified as sedentary according to PAL classifications.

Conclusion: Individuals with MP and LP have lower CRF, exercise EE, and PALs compared to AB individuals.
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http://dx.doi.org/10.1038/s41394-020-00363-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744794PMC
December 2020

Clinical and Genetic Factors Associated With Complications After Crohn's Ileocolectomy.

Dis Colon Rectum 2020 03;63(3):357-364

Division of Colon and Rectal Surgery, Department of Surgery, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania.

Background: Ileocolectomy is the most common surgery performed for Crohn's disease, and postoperative complications occur frequently. There has been minimal evaluation of complications after ileocolectomy as a function of both clinical and genetic factors.

Objective: The purpose of this study was to evaluate both genetic and clinical factors associated with complications after Crohn's ileocolectomy.

Design: This was a retrospective clinical and genetic cohort study.

Settings: This study was conducted at a high-volume tertiary care center.

Patients: We identified 269 patients with Crohn's disease who had undergone 287 ileocolectomies at our institution between July 2008 and October 2018.

Main Outcome Measures: We measured the association of complications with a combination of clinical factors and 6 Crohn's-associated single nucleotide polymorphisms in NOD2 (rs2076756, rs2066844, and rs2066845), IRGM (rs4958847 and rs13361189), and ATG16L1 (rs2241880).

Results: There were 86 ileocolectomies of 287 (30%) with complications requiring intervention. The single nucleotide polymorphism rs13361189 in the gene IRGM was significantly associated with complications on univariate and multivariate analysis. There were 61 patients with a variant at the rs13361189 single nucleotide polymorphism and 26 of them had complications, although only 55 of the 208 wild-type patients had complications (43% vs 26%; OR = 2.1; p = 0.02). Other significant factors associated with complication after ileocolectomy were open surgery, placement of a proximal ileostomy, and a greater perioperative decrease in hematocrit.

Limitations: This study was limited by its retrospective design and inherent selection bias.

Conclusions: In addition to clinical risk factors, the rs13361189 single nucleotide polymorphism in the IRGM gene was independently associated with complications after ileocolectomy for Crohn's disease. The use of such genetic determinants may identify patients at increased risk for surgical complications after ileocolectomy. See Video Abstract at http://links.lww.com/DCR/B124. FACTORES CLÍNICOS Y GENÉTICOS ASOCIADOS CON COMPLICACIONES DESPUÉS DE LA ILEOCOLECTOMÍA DE CROHN: La ileocolectomía es la cirugía más común realizada para la enfermedad de Crohn y con frecuencia ocurren complicaciones postoperatorias. Ha habido una evaluación mínima de complicaciones después de la ileocolectomía, en función de factores clínicos y genéticos.Evaluar factores genéticos y clínicos asociados con complicaciones, después de la ileocolectomía por Crohn.Estudio retrospectivo de cohorte clínico y genético.Este estudio se realizó en un centro de atención terciaria de alto volumen.Identificamos a 269 pacientes con enfermedad de Crohn, sometidos a 287 ileocolectomías en nuestra institución, entre julio de 2008 y octubre de 2018.La asociación de complicaciones con una combinación de factores clínicos y seis polimorfismos de un solo nucleótido asociados a Crohn en NOD2 (rs2076756, rs2066844 y rs2066845), IRGM (rs4958847 y rs13361189) y ATG16L1 (rs2241880).Hubieron 86 ileocolectomías en 287 (30%) pacientes con complicaciones que requirieron intervención. El polimorfismo de un solo nucleótido rs13361189 en el gen IRGM se asoció significativamente con complicaciones en el análisis univariado y multivariado. Hubieron 61 pacientes con una variante en el polimorfismo de un solo nucleótido rs13361189 y 26 de ellos tuvieron complicaciones, mientras que solo 55 de los 208 pacientes de tipo salvaje (WT) tuvieron complicaciones (43% vs 26%, OR 2.1, p = 0.02). Otros factores significativos asociados con las complicaciones después de la ileocolectomía fueron, la cirugía abierta, la colocación de una ileostomía proximal y una mayor disminución perioperatoria del hematocrito.Este estudio estuvo limitado por su diseño retrospectivo y sesgo de selección inherente.Además de los factores de riesgo clínicos, el polimorfismo de un solo nucleótido rs13361189 en el gen IRGM se asoció independientemente con complicaciones después de la ileocolectomía, para la enfermedad de Crohn. El uso de tales determinantes genéticos puede identificar a los pacientes con mayor riesgo de complicaciones quirúrgicas, después de la ileocolectomía. Consulte Video Resumen en http://links.lww.com/DCR/B124.
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http://dx.doi.org/10.1097/DCR.0000000000001574DOI Listing
March 2020

Clinical and Genetic Factors Impact Time to Surgical Recurrence After Ileocolectomy for Crohn's Disease.

Ann Surg 2021 Aug;274(2):346-351

Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA.

Objective: The aim of this study was to evaluate factors associated with time to surgical recurrence after Crohn's ileocolectomy.

Summary Background Data: The most common surgery performed for Crohn's disease is ileocolectomy. Identifying patients at high risk for surgical recurrence may assist with medical and surgical decision-making.

Methods: Data were obtained from 409 patients with Crohn's disease (CD) who had undergone ≥1 ileocolectomies at Penn State Hershey Medical Center. Six single-nucleotide polymorphisms (SNPs) associated with CD were evaluated in these patients: rs2076756, rs2066844, and rs2066845 in NOD2, rs4958847 and rs13361189 in IRGM, and rs2241880 in ATG16L1. Genotype and clinical factors were analyzed to determine associations with time to recurrent ileocolectomy. A subgroup analysis was performed on 241 patients naïve to biologics before initial ileocolectomy to assess the effect of biologic therapy on time to recurrent surgery.

Results: There were 286 patients who underwent a single ileocolectomy, whereas 123 required multiple ileocolectomies. Ileocolonic involvement [hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.21-3.00, P = 0.006] and rs2066844 in NOD2 (HR 1.8, 95% CI 1.17-2.77, P = 0.007) were associated with decreased time to surgical recurrence by multivariate analysis. In patients naïve to preoperative biologics, the initiation of postoperative biologics was associated with a 40% decreased incidence of surgical recurrence (HR 0.60, CI 0.39-0.93, P = 0.02) over time.

Conclusions: Ileocolonic distribution of disease and the rs2066844 SNP in NOD2 are associated with shorter time to recurrent ileocolectomy. The initiation of postoperative biologics in naïve patients was associated with a reduced incidence of recurrence over time.
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http://dx.doi.org/10.1097/SLA.0000000000003660DOI Listing
August 2021

Caloric Intake Relative to Total Daily Energy Expenditure Using a Spinal Cord Injury-Specific Correction Factor: An Analysis by Level of Injury.

Am J Phys Med Rehabil 2019 11;98(11):947-952

From the Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, San Francisco, California (GJF); Spinal Cord Injury and Disorders Center, Hunter Holmes McGuire VA Medical Center, Richmond, Virginia (ASG); Department of Physical Therapy, William Carey University, Hattiesburg, Mississippi (DRD); Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania (ASB); and Department of Physical Medicine and Rehabilitation, Penn State College of Medicine, Hershey, Pennsylvania (DRG).

Objective: The aims of the study were to evaluate the influence of level of spinal cord injury (SCI) on caloric intake relative to total daily energy expenditure (TDEE) and body composition, and to develop a SCI-specific correction factor for the TDEE estimation.

Design: Individuals with paraplegia (PARA, n = 28) and tetraplegia (TETRA, n = 13) were analyzed. Daily caloric intake, basal metabolic rate, and TDEE were obtained using dietary recall, indirect calorimetry, and prediction equations, respectively. Caloric intake and TDEE were adjusted to bodyweight. Body composition was assessed using dual-energy x-ray absorptiometry.

Results: Total caloric (PARA 1516.4 ± 548.4, TETRA 1619.1 ± 564.3 kcal/d), fat (PARA 58.6 ± 27.4, TETRA 65.8 ± 29.7 g), and protein (PARA 62.7 ± 23.2, TETRA 71.5 ± 30.9 g) intake were significantly higher in TETRA versus PARA (P < 0.05) when adjusted for bodyweight. Adjusted and unadjusted TDEE (unadjusted: PARA 1851.0 ± 405.3, TETRA 1530.4 ± 640.4 kcal/d) and basal metabolic rate (unadjusted: PARA 1516.6 ± 398.0, TETRA 1223.6 ± 390.2 kcal/d) were significantly higher in PARA versus TETRA (P < 0.05). Bone mineral content (PARA 3.17 ± 0.6, TETRA 2.71 ± 0.5 g), lean body mass (PARA 50.0 ± 8.6, TETRA 40.96 ± 8.8 kg), and regional percent body fat (PARA 36.45 ± 8.0, TETRA 41.82 ± 9.1) were different between groups (P < 0.05). The SCI-specific correction factor was 1.15.

Conclusions: A dichotomy exists in caloric intake, TDEE, and body composition among TETRA and PARA. The SCI-specific correction factor of 1.15 is a promising tool to estimate TDEE in SCI.

To Claim Cme Credits: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Understand the influence of spinal cord level of injury on energy expenditure and body composition; (2) Appreciate that equations used to estimate total daily energy expenditure overestimate energy expenditure in individuals with spinal cord injury; and (3) Understand the importance of normalizing caloric intake to bodyweight after spinal cord injury.

Level: Advanced.

Accreditation: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
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http://dx.doi.org/10.1097/PHM.0000000000001166DOI Listing
November 2019

The Crohn's disease associated SNP rs6651252 impacts MYC gene expression in human colonic epithelial cells.

PLoS One 2019 22;14(2):e0212850. Epub 2019 Feb 22.

Department of Biochemistry & Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.

Crohn's disease (CD) is a debilitating inflammatory bowel disease (IBD) that arises from chronic inflammation in the gastrointestinal tract. Genome-wide association studies (GWAS) have identified over 200 single nucleotide polymorphisms (SNPs) that are associated with a predisposition for developing IBD. For the majority, the causal variant and target genes affected are unknown. Here, we investigated the CD-associated SNP rs6651252 that maps to a gene desert region on chromosome 8. We demonstrate that rs6651252 resides within a Wnt responsive DNA enhancer element (WRE) and that the disease associated allele augments binding of the TCF7L2 transcription factor to this region. Using CRISPR/Cas9 directed gene editing and epigenetic modulation, we find that the rs6651252 enhancer regulates expression of the c-MYC proto-oncogene (MYC). Furthermore, we found MYC transcript levels are elevated in patient-derived colonic segments harboring the disease-associated allele in comparison to those containing the ancestral allele. These results suggest that Wnt/MYC signaling contributes to CD pathogenesis and that patients harboring the disease-associated allele may benefit from therapies that target MYC or MYC-regulated genes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212850PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386311PMC
November 2019

Correction: Nutritional status in chronic spinal cord injury: a systematic review and meta-analysis.

Spinal Cord 2019 03;57(3):256

Department of Physical Medicine and Rehabilitation, Penn State College of Medicine, 500 University Drive, P.O. Box 850, Mail Code R120, Hershey, PA, 17033-0850, USA.

The authors noted that there were two typographical errors in Table 2. Under the 'Tetraplegia' group of 'Gorgey et al. [55]' the 'RMR' value was originally given as '14,101 ± 10'. This has now been corrected to '1411 ± 10'. Under the 'Tetra' group of 'Sabour et al. [22]' the 'Energy intake' was originally given as '20,123 ± 681'. This has now been corrected to '2013 ± 681'. This has been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41393-019-0252-xDOI Listing
March 2019

Nutritional status in chronic spinal cord injury: a systematic review and meta-analysis.

Spinal Cord 2019 Jan 12;57(1):3-17. Epub 2018 Nov 12.

Department of Physical Medicine and Rehabilitation, Penn State College of Medicine, 500 University Drive, P.O. Box 850, Mail Code R120, Hershey, PA, 17033-0850, USA.

Study Design: Systematic review and meta-analysis.

Objectives: The objective was to investigate nutritional status in chronic spinal cord injury (SCI), and compare macronutrient and micronutrient intake to the recommended values by the United States Department of Agriculture (USDA) 2015-2020 Dietary Guidelines for Americans.

Setting: United States of America.

Methods: A MEDLINE/PubMed, Google Scholar, Scopus, and Web of Science search was performed, identifying 268 papers. All papers included were English-language papers examining adults with chronic SCI. A meta-analysis was performed to produce weighted averages and 95% confidence intervals (CI) when summary statistics were provided.

Results: The systematic review included 15 articles, while the meta-analysis included 12. Resting metabolic rate (1492 kcal/day; CI: 1414-1569) fell below the able-bodied average, and total energy (1876 kcal/day; CI: 1694-2059) and fiber (17 g/day; CI: 14-20) intake were below USDA guidelines. Protein (319 kcal/day; CI: 294-345) and carbohydrate (969 kcal/day; CI: 851-1087) intake were above guidelines. Fat intake (663 kcal/day; CI: 590-736) was within USDA guidelines. Vitamins A, B5, B7, B9, D, E, potassium, and calcium were deficient, while vitamins B1, B2, B3, B12, C, K, sodium, phosphorus, copper, and zinc were in excess according to USDA guidelines. Vitamin B6, iron, and magnesium were within USDA guidelines.

Conclusion: Findings indicate greater energy intake relative to energy needs in those with chronic SCI, and an imbalance in fiber intake and micronutrients compared to the USDA guidelines. Future research examining nutritional health status is needed in order to establish evidence-based, SCI-specific dietary guidelines.
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http://dx.doi.org/10.1038/s41393-018-0218-4DOI Listing
January 2019

The Effect of Elevated A1C on Immediate Postoperative Complications: A Prospective Observational Study.

Clin Diabetes 2018 Apr;36(2):128-132

Department of Anesthesiology and Perioperative Medicine and.

This study examined whether elevated A1C in patients with diabetes is associated with a higher incidence of postoperative infections and other complications. Researchers followed 50 noncardiac surgical patients for 7 postoperative days. Half of the patients had an A1C <7% and the other half had an A1C ≥7%. The two groups were otherwise comparable except that the higher-A1C group had significantly higher pre-induction and postoperative blood glucose levels, with wider variability in the first 24 hours after surgery. During the first postoperative week, 11 patients developed complications, of whom 10 were in the higher-A1C group. Elevated A1C, unlike a single preoperative blood glucose value, may predict difficult postoperative glucose control and postsurgical complications.
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http://dx.doi.org/10.2337/cd17-0081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898174PMC
April 2018

Sex dimorphism in the distribution of adipose tissue and its influence on proinflammatory adipokines and cardiometabolic profiles in motor complete spinal cord injury.

J Spinal Cord Med 2019 07 21;42(4):430-436. Epub 2018 Feb 21.

a Department of Physical Medicine and Rehabilitation , Penn State College of Medicine , Hershey , Pennsylvania , USA.

We aimed to examine the influence of sex on the distribution of adipose tissue, as well as proinflammatory adipokine and cardiometabolic profiles, in chronic motor complete spinal cord injury (SCI). Cross-sectional and correlational study. Academic rehabilitation hospital. Forty-seven individuals with chronic motor complete SCI classified according to sex (males: age 44.0 ± 10.9 y, body mass index (BMI) 27.2 ± 5.8, level of injury (LOI) C4 - L1; females: 42.0 ± 13.5 y, BMI 27.8 ± 6.6, LOI C4 - T11). Not applicable. Visceral (VAT), subcutaneous (SAT), and total trunk (TTAT) adipose tissue volumes were assessed utilizing magnetic resonance imaging and a VAT:SAT ratio was calculated. Proinflammatory adipokines (tumor neurosis factor-α, interleukin-6, plasminogen activator inhibitor-1, thrombin-activatable fibrinolysis inhibitor, and high sensitivity c-reactive protein) and cardiovascular, carbohydrate, and lipid profiles were evaluated according to standard techniques. VAT and VAT:SAT ratio were significantly greater in male participates with SCI (P ≤ 0.002), while SAT volume was significantly greater in female participants with SCI (P = 0.001). No difference was noted in TTAT between groups (P = 0.341). Male participants with SCI demonstrated lower high-density lipoprotein-cholesterol (HDLC) profiles and an elevated total cholesterol to HDLC ratio (P ≤ 0.003) compared with females. No other significant differences were found between groups concerning cardiometabolic profiles or proinflammatory adipokines; however, males exhibited poorer profiles overall. Proinflammatory adipokines significantly correlated with adipose tissue depots by sex (P < 0.05). The results show that sex influences the distribution of adipose tissue, and may influence proinflammatory and cardiometabolic profiles following SCI. The findings of this study highlight the need for further research with dietary modification and exercise to decrease health risks.
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http://dx.doi.org/10.1080/10790268.2018.1436125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718133PMC
July 2019

Prevalence of metabolic syndrome in veterans with spinal cord injury.

J Spinal Cord Med 2019 01 11;42(1):86-93. Epub 2018 Jan 11.

c Division of Physical Medicine and Rehabilitation, Department of Neurosurgical Surgery , University of Louisville School of Medicine , Louisville , Kentucky.

Context/objective: Recent literature would suggest the prevalence of metabolic syndrome in persons with spinal cord injury (SCI) is higher than that of the general population, although no large cohorts have yet been reported. Part of the controversy relates to the differing definitions provided for metabolic syndrome and the characterization of obesity in persons with SCI.

Design/participants: The current retrospective investigation represents a cross-sectional cohort of 473 veterans with SCI from a single center in the mid-Atlantic region of the United States for whom modified International Diabetes Federation (IDF) criterion variables for the metabolic syndrome were available in the computerized personal record system (CPRS).

Outcome Measures: These variables included a surrogate marker of obesity appropriate to SCI (Body Mass Index (BMI) ≥ 22 kg/m), as well as indicators of diabetes, dyslipidemia and hypertension.

Results: Over 57% of the veterans assessed were determined to have metabolic syndrome by modified IDF criteria, including 76.7% with BMI ≥ 22 kg/m, 55.1% with or under treatment for hypertension, 49.7% with or previously diagnosed with diabetes mellitus, and 69.7% with or under treatment for high density lipoprotein (HDL) cholesterol under 40 mg/dl.

Conclusion: Metabolic syndrome and its constituent components appear to be more prevalent in veterans with SCI than in the general population, suggesting a greater need for identification and treatment interventions in this specialty population.
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http://dx.doi.org/10.1080/10790268.2017.1423266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340269PMC
January 2019

The influence of level of spinal cord injury on adipose tissue and its relationship to inflammatory adipokines and cardiometabolic profiles.

J Spinal Cord Med 2018 07 30;41(4):407-415. Epub 2017 Jul 30.

a Department of Physical Medicine and Rehabilitation , Penn State College of Medicine , Hershey , Pennsylvania, USA.

Objective: Level of injury (LOI) and the role of adipose tissue and its proinflammatory adipokines in cardiometabolic dysfunction following spinal cord injury (SCI) remains poorly understood. We aim to examine the influence of LOI on adipose tissue and its relationship to proinflammatory adipokines and cardiometabolic profiles following SCI.

Design: Cross sectional and correlational study.

Setting: Clinical hospital and academic setting.

Participants: Forty-seven individuals with chronic motor complete SCI (age 43.8±11.5 y, BMI: 27.3±5.3) were classified as having tetraplegia (TSCI; n=12) or paraplegia (PSCI; n=35).

Intervention: Non applicable.

Outcome Measures: Visceral (VAT) and subcutaneous (SAT) adipose tissue volumes were measured using magnetic resonance imaging. Proinflammatory adipokines (tumor neurosis factor-α, interleukin-6 (IL-6), plasminogen activatable inhibitor-1, thrombin-activatable fibrinolysis inhibitor, and high-sensitivity c-reactive protein) and cardiovascular, carbohydrate, and lipid profiles were assessed according to standard techniques.

Results: VAT volume was greater in TSCI versus PSCI (p=0.042); however, after covarying for age this significance was lost (p>0.05). IL-6 was significantly elevated in TSCI (p<0.05), while other markers of inflammation generally were elevated, but did not reach statistical significance (p>0.05). Systolic blood pressure and total cholesterol were significantly lower in TSCI (p<0.05), while fasting glucose was significantly lower in PSCI (p<0.05). A number of proinflammatory adipokines and cardiometabolic markers significantly correlated with adipose tissue depots by LOI (p<0.05).

Conclusion: The results show that LOI does not influence the distribution of adipose tissue, but does influence proinflammatory adipokines and cardiometabolic profiles following SCI. Further research is needed to evaluate impact of lean body mass on these findings.
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http://dx.doi.org/10.1080/10790268.2017.1357918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055972PMC
July 2018

Diverticulitis and Crohn's disease have distinct but overlapping tumor necrosis superfamily 15 haplotypes.

J Surg Res 2017 06 27;214:262-269. Epub 2017 Feb 27.

Division of Colon and Rectal Surgery, Department of Surgery, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania. Electronic address:

Background: Diverticulitis (DD) and Crohn's disease (CD) have overlapping features including bowel structuring, inflammation, and infection. Tumor necrosis superfamily 15 (TNFSF15) is an immunoregulatory, anti-angiogenic gene. CD has been previously associated with a haplotype of five TNFSF15 single-nucleotide polymorphism alleles: rs3810936 (G allele), rs6478108 (A), rs6478109 (G), rs7848647 (G), and rs7869487 (A). We aimed to determine the TNFSF15 risk haplotype for DD versus controls with a subgroup analysis of youthful DD patients (aged ≤55 y) versus older controls (aged ≥55 y).

Methods: A total of 148 diverticulitis patients (90 aged ≤55 y) and 200 controls (87 aged ≥55 y) were genotyped using our custom-designed Illumina Veracode microarray chip. Genotypes from rs3810936, rs6478108, rs6478109, rs7848647, rs7869487 and two additional TNFSF15 single nucleotide polymorphisms, rs3810936 and rs11554257, were analyzed. PHASE version 2.1, R with HaploStats and the Broad Institute's Haploview program were used for statistics and imputed haplotype frequency. Permutation corrected for multiple comparisons.

Results: The CD GAGGA haplotype was significantly associated with diverticulitis (P = 0.03) in the all DD versus all controls comparison. A second haplotype, rs6478108 (A), rs6478109 (G), rs7869487 (A), and rs4263839 (G), was also associated with DD in this cohort (P = 0.025). A third haplotype rs6478108 (A), rs6478109 (G), rs7848647 (G) and rs7869487 (A), rs4263839 (G) was demonstrated in the DD < 55 versus controls >55 comparison (P = 0.045).

Conclusions: Distinct but overlapping TNFSF15 haplotypes were demonstrated in diverticulitis patients versus healthy controls when compared with the known Crohn's risk haplotype suggesting similar but distinct genetic predispositions. This study strengthens the role for a genetic predisposition to diverticulitis that involves the TNFSF15 gene.
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http://dx.doi.org/10.1016/j.jss.2017.02.030DOI Listing
June 2017

Combined Medical and Surgical Approach Improves Healing of Septic Perianal Crohn's Disease.

J Am Coll Surg 2016 09 5;223(3):506-514.e1. Epub 2016 Jun 5.

Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA. Electronic address:

Background: Septic perianal Crohn's disease (SPCD) is a treatment challenge in spite of tumor necrosis factor antagonists (anti-TNF). Our aim was to define the success of SPCD management with a combined medical and surgical approach and to identify clinical and genetic factors predictive of healing.

Study Design: A retrospective chart review of patients with SPCD treated at the Penn State Milton S Hershey Medical Center was done. Primary end point was complete healing (ie normal clinical exam and no pain for at least 6 months). Genetic analysis of 185 single nucleotide polymorphisms associated with Crohn's disease was performed in 78 patients.

Results: One hundred and thirty-five episodes of SPCD were identified in 114 patients with a mean follow-up of 77 ± 7.4 months. Overall, 80 of 135 episodes healed (59.3%) and did not differ between those receiving anti-TNF and not (60.4% vs 56.8%). There appeared to be a consistent improved heal rate in each subcategory of surgically managed patients that received anti-TNF. Female sex was significantly predictive of healing in only those receiving anti-TNF agents (63.6% vs 25.0%; p = 0.0005). Twenty-two (19.3%) patients ultimately received a permanent diversion with either a total proctocolectomy or completion proctectomy. Multivariate analysis suggested several single nucleotide polymorphisms in Crohn's disease-associated genes to be possibly associated with healing, but lost significance after Bonferroni correction.

Conclusions: Overall, there is an approximate 60% rate of healing SPCD using a combined medical and surgical approach. About 20% of SPCD patients will require a permanent stoma. There were no clear genetic predictors of healing SPCD.
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http://dx.doi.org/10.1016/j.jamcollsurg.2016.05.017DOI Listing
September 2016

Outcomes of early ileocolectomy after percutaneous drainage for perforated ileocolic Crohn's disease.

Am J Surg 2016 Oct 12;212(4):728-734. Epub 2016 May 12.

Department of Surgery, The Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USA. Electronic address:

Background: The optimal treatment for an intra-abdominal abscess/infection secondary to perforating ileocolic Crohn's disease (PCD) is unclear.

Methods: Forty-seven consecutive PCD patients treated via an institutional protocol of ileocolectomy after a 7-day period of percutaneous abscess drainage were retrospectively compared with 160 consecutive patients who underwent an elective ileocolectomy for Crohn's disease (ECD) between 1992 and 2014. Outcomes were compared using univariate analysis and propensity score matching.

Results: Univariate analysis demonstrated significant differences in ileostomy rates (PCD: 48.9% vs ECD: 18.8%; P = .001), 30-day readmissions (PCD: 38.3% vs ECD: 18.8%; P = .01), and overall 30-day postoperative complications (PCD: 29.8% vs ECD: 15%; P = .03). After matching, a statistically significant difference was retained in ileostomy rates (P = .02) and 30-day readmissions (P = .01).

Conclusions: Early operative intervention after percutaneous drainage in perforating CD may be associated with a high incidence of diversions and readmissions.
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http://dx.doi.org/10.1016/j.amjsurg.2016.01.044DOI Listing
October 2016

Increasing diagnostic accuracy to grade dysplasia in Barrett's esophagus using an immunohistochemical panel for CDX2, p120ctn, c-Myc and Jagged1.

Diagn Pathol 2016 Feb 29;11:23. Epub 2016 Feb 29.

Department of Pathology, The Pennsylvania State University College of Medicine, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA, 17033, USA.

Background: Patients with non-dysplastic Barrett's esophagus (ND-BE) and low-grade dysplasia (LGD) are typically monitored by periodic endoscopic surveillance, while those with high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) are usually treated by more aggressive interventions like endoscopic mucosal resection, ablation or surgery. Therefore, the accurate grading of dysplasia in Barrett's esophagus (BE) is essential for proper patient care. However, there is significant interobserver and intraobserver variability in the histologic grading of BE dysplasia. The objective of this study was to create an immunohistochemical (IHC) panel that facilitates the grading of BE dysplasia and can be used as an adjunct to histology in challenging cases.

Methods: 100 BE biopsies were re-graded for dysplasia independently by 3 subspecialized gastrointestinal pathologists. IHC staining for CDX2, p120ctn, c-Myc and Jagged1 proteins was then performed and assessed by two separate methods of semi-quantitative scoring. Scores were integrated using a principal component analysis (PCA) and receiver operating characteristic (ROC) curve.

Results: Principal component analysis demonstrated the ability of this panel of proteins to segregate ND-BE/LGD and HGD/EAC, as the expression of the four proteins is significantly altered between the two subsets. Analysis of the receiver operating characteristic curve showed that this panel has the potential to aid in the grading of dysplasia in these two subcategories with both high sensitivity and specificity. While not able to discriminate between ND-BE and LGD, this panel of four proteins may be used as an adjunct to help discriminate subsets of ND-BE/LGD from HGD/EAC.

Conclusions: We propose that the maximum utility of this IHC panel of CDX2, p120ctn, c-Myc, and Jagged1 proteins would be to distinguish between LGD and HGD in histologically challenging cases, given the aggressive interventions still used for HGD in many institutions, and hence may aid in the optimal patient management. The results of this initial study are promising, though further validation is needed before this panel can be used clinically, including future randomized prospective studies with larger patient cohorts from diverse locations.
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http://dx.doi.org/10.1186/s13000-016-0473-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772649PMC
February 2016

Effects of age and hindlimb immobilization and remobilization on fast troponin T precursor mRNA alternative splicing in rat gastrocnemius muscle.

Appl Physiol Nutr Metab 2016 Feb 16;41(2):142-9. Epub 2015 Oct 16.

a Department of Cellular and Molecular Physiology, H166, Pennsylvania State University, College of Medicine, Hershey, PA 17033, USA.

Fast skeletal muscle troponin T (TNNT3) is an important component of the skeletal muscle contractile machinery. The precursor mRNA (pre-mRNA) encoding TNNT3 is alternatively spliced, and changes in the pattern of TNNT3 splice form expression are associated with alterations in thin-filament calcium sensitivity and force production during muscle contraction and thereby regulate muscle function. Interestingly, during aging, the muscle force/cross-sectional area is reduced, suggesting that loss of mass does not completely account for the impaired muscle function that develops during the aging process. Therefore, in this study, we tested the hypothesis that age and changes in muscle loading are associated with alterations in Tnnt3 alternative splicing in the rat gastrocnemius muscle. We found that the relative abundance of several Tnnt3 splice forms varied significantly with age among 2-, 9-, and 18-month-old rats and that the pattern correlated with changes in body mass rather than muscle mass. Hindlimb immobilization for 7 days resulted in dramatic alterations in splice form relative abundance such that the pattern was similar to that observed in lighter animals. Remobilization for 7 days restored the splicing pattern toward that observed in the nonimmobilized limb, even though muscle mass had not yet begun to recover. In conclusion, the results suggest that Tnnt3 pre-mRNA alternative splicing is modulated rapidly (i.e., within days) in response to changes in the load placed on the muscle. Moreover, the results show that restoration of Tnnt3 alternative splicing to control patterns is initiated prior to an increase in muscle mass.
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http://dx.doi.org/10.1139/apnm-2015-0381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876695PMC
February 2016

Single-Site Laparoscopic Colorectal Surgery Provides Similar Clinical Outcomes Compared With Standard Laparoscopic Surgery: An Analysis of 626 Patients.

Dis Colon Rectum 2015 Sep;58(9):862-9

1 Department of Surgery, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania 2 Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania.

Background: Compared with standard laparoscopy, single-site laparoscopic colorectal surgery may potentially offer advantages by creating fewer surgical incisions and providing a multifunctional trocar. Previous comparisons, however, have been limited by small sample sizes and selection bias.

Objective: The purpose of this study was to compare 60-day outcomes between standard laparoscopic and single-site laparoscopic colorectal surgery patients undergoing elective and urgent surgeries.

Design: This was an unselected, retrospective cohort study comparing patients who underwent elective and unplanned standard laparoscopic or single-site laparoscopic colorectal resections for benign and malignant disease between 2008 and 2014. Outcomes were compared using univariate analyses.

Settings: This study was conducted at a single institution.

Patients: A total of 626 consecutive patients undergoing laparoscopic colorectal surgery were included.

Main Outcome Measures: Morbidity and mortality rates within 60 postoperative days were measured.

Results: A total of 318 (51%) and 308 patients (49%) underwent standard laparoscopic and single-site laparoscopic procedures. No significant differences were noted in mean operative time (standard laparoscopy, 182.1 ± 81.3 vs single-site laparoscopy, 177.0 ± 86.5; p = 0.30) or postoperative length of stay (standard laparoscopy, 4.8 ± 3.4 vs single-site laparoscopy, 5.5 ± 6.9; p = 0.14). Conversions to laparotomy and 60-day readmissions were also similar for both cohorts across all of the procedures performed. A significant difference was identified in the number of patients who developed postoperative complications (standard laparoscopy, 19.2% vs single-site laparoscopy, 10.7%; p = 0.004), especially with respect to surgical-site infections (standard laparoscopy, 11.3% vs single-site laparoscopy, 5.8%; p = 0.02).

Limitations: This was a retrospective, single institution study.

Conclusions: Single-site laparoscopic colorectal surgery demonstrates similar results to standard laparoscopic colorectal surgery with regard to operative time, length of stay, and readmissions. Single-site laparoscopic colorectal surgery may provide advantages in limiting the development of certain complications, such as superficial surgical-site infections.
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http://dx.doi.org/10.1097/DCR.0000000000000435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706226PMC
September 2015

Surgical diverticulitis is not associated with defects in the expression of wound healing genes.

Int J Colorectal Dis 2015 Sep 24;30(9):1247-54. Epub 2015 May 24.

Department of Surgery, Division of Colon and Rectal Surgery, College of Medicine, The Pennsylvania State University, Hershey, PA, 17033-0850, USA.

Purpose: The development of diverticuli may represent defects in collagen vascular tissue integrity possibly from a genetic predisposition. We evaluated the tissue expression of wound healing genes in sigmoid tissue from youthful patients undergoing surgery for diverticulitis and thus would more likely suffer from a genetic predisposition (SD mean age 39 ± 0.9) versus controls in the form of patients over the age of 50 (mean age 52.9 ± 10.5 years) without evidence of diverticular disease.

Methods: The mRNA expression of 84 genes associated with the extracellular matrix, cellular adhesion, growth factors, inflammatory cytokines, and signal transduction was evaluated in 16 SD and 15 control tissues using a Qiagen Wound Healing Array. Vitronectin, the gene protein with the highest potential significance on raw analysis, was further investigated using a Taqman assay with an additional 11 SD (total n = 27) and four control (total n = 19) samples. Statistics were by Student's t and Mann-Whitney tests with Bonferroni correction.

Results: No significant differences in mRNA expression between the SD and control tissue in the 84 measured genes were demonstrated after correction. Vitronectin mRNA expression was downregulated 2.7-fold in SD tissue vs. tissue from non-neoplastic control patients (p = 0.001 raw/0.08 corrected). However, on vitronectin TaqMan analysis, no difference in expression was seen in SD vs. all controls or in all subset comparisons.

Conclusions: The lack of significant alteration in mRNA expression of traditionally associated wound healing genes/proteins in young SD patients suggests that such genes play a minor role in the genetic predisposition to youthful diverticulitis.
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http://dx.doi.org/10.1007/s00384-015-2263-1DOI Listing
September 2015

Genetic determinants associated with early age of diagnosis of IBD.

Dis Colon Rectum 2015 Mar;58(3):321-7

1 Division of Colon and Rectal Surgery, Department of Surgery, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania 2 Department of Public Health Sciences, Pennsylvania State University, College of Medicine, Hershey, Pennsylvania.

Background: Inflammatory bowel disease (IBD) is typically diagnosed at 20 to 40 years of age. However, very young versus elderly patients with IBD may have different mechanisms of disease that may affect prognosis and care.

Objectives: The purpose of this work was to identify single nucleotide polymorphisms associated with age of onset of Crohn's disease and ulcerative colitis.

Design: Patients were genotyped using a custom microarray chip containing 332 IBD-associated single nucleotide polymorphisms. Age at diagnosis as a continuous variable was assessed using linear regression. Patients were then subgrouped by age at diagnosis and compared by the Fisher exact test. Bonferroni correction was used in all of the analyses.

Settings: This study was conducted at a tertiary academic hospital.

Patients: Sixty patients with Crohn's disease and 26 with ulcerative colitis were ≤ 16 years old, 259 patients with Crohn's disease and 248 with ulcerative colitis were 17-60 years old, and 10 patients with Crohn's disease and 20 with ulcerative colitis were >60 years old at diagnosis and included in this study.

Main Outcome Measures: Age at diagnosis and single nucleotide polymorphism correlations were measured in this study.

Results: The NOD2 single nucleotide polymorphism rs2076756 was associated with younger age at Crohn's disease diagnosis (p = 0.0002). Patients with the AA/wild-type genotype were diagnosed at 31.9 ± 1.23 years, AG heterozygotes at 25.6 ± 0.99 years, and GG/at-risk allele homozygotes at 22.6 ± 1.32 years. Depending on age categories compared, single nucleotide polymorphisms in POU5F1, TNFSF15, and HLA DRB1*501 were associated with age of Crohn's disease diagnosis. No genetic associations were seen between ulcerative colitis and linear age at diagnosis; however, the G allele of the LAMB1 single nucleotide polymorphism rs886774 was found to be associated with ulcerative colitis diagnosed at ≤ 16 versus >17 years old (p = 0.008).

Limitations: This study was limited to known IBD single nucleotide polymorphisms.

Conclusions: This analysis reaffirms the association between NOD2, a molecule of innate immunity, and early Crohn's disease onset. This is the first report of a possible association between early Crohn's disease and the POU5F1, TNFSF15, and HLA DRB1*501 genes. The LAMB1 gene, associated with mucosal basement membrane integrity, was associated with early onset ulcerative colitis and, thus, suggests a fundamentally different mechanism of early disease pathogenesis in ulcerative colitis versus Crohn's disease.
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http://dx.doi.org/10.1097/DCR.0000000000000274DOI Listing
March 2015

An interleukin-4 polymorphism is associated with susceptibility to Clostridium difficile infection in patients with inflammatory bowel disease: results of a retrospective cohort study.

Surgery 2014 Oct;156(4):769-74

Department of Surgery, Division of Colon & Rectal Surgery, The Pennsylvania State University, Hershey, PA. Electronic address:

Background: Clinical studies have suggested that patients with inflammatory bowel disease (IBD) are at greater risk for developing Clostridium difficile infection (CDI). The purpose of this study was to identify single-nucleotide polymorphisms (SNPs) associated with CDI among IBD patients.

Methods: This retrospective cohort study used our biobank to compare patients with IBD who developed CDI (IBD-CDI) with those who had never contracted CDI (IBD-nCDI). Patients were genotyped for 384 IBD-associated SNPs by microarray. Student t, chi-square, and Fisher exact tests were used. Multivariate logistic regression with Bonferroni correction was used for genotype analysis.

Results: Twenty IBD-CDI (14 with Crohn disease; 6 with ulcerative colitis) and 152 IBD-nCDI (47 CD/105 UC) patients were identified. The interleukin-4-associated SNP rs2243250 was associated with the development of CDI (raw P = .00005/corrected P = .02), with 15 of 20 (75%) CDI-IBD patients harboring the at-risk "A" allele versus 52 of 152 (34%) of IBD-nCDI. When we compared Crohn disease and ulcerative colitis patients separately, rs2243250 initially was associated with CDI in both groups, although clinical relevance was lost after Bonferroni correction.

Conclusion: The interleukin-4 gene-associated SNP rs2243250 was strongly associated with CDI in our IBD population. This SNP may allow for the identification of IBD patients at greater risk for CDI.
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http://dx.doi.org/10.1016/j.surg.2014.06.067DOI Listing
October 2014

Ulcerative colitis neoplasia is not associated with common inflammatory bowel disease single-nucleotide polymorphisms.

Surgery 2014 Aug 14;156(2):253-62. Epub 2014 Mar 14.

Division of Colon and Rectal Surgery, College of Medicine, The Pennsylvania State University, Hershey, PA. Electronic address:

Background: Neoplasia complicating ulcerative colitis (UC-neoplasia) is a problem that is poorly addressed by present surveillance techniques. The association of greater than 300 single nucleotide polymorphisms (SNPs) with inflammatory bowel disease (IBD) suggests the possibility that certain genetic polymorphisms might identify patients with UC destined for malignant degeneration. This present study tested the hypothesis that presently known IBD-associated SNPs may correlate with UC-neoplasia.

Materials And Methods: A total of 41 patients with UC-neoplasia (mean age 56 ± 2.1 years) were identified from our divisional IBD Biobank (low-grade dysplasia n = 13, high-grade dysplasia n = 8, colorectal cancer [CRC] n = 20). These patients were individually age, sex, and disease duration matched with UC patients without neoplasia. Primary sclerosing cholangitis and family history of CRC were recorded. Patients were genotyped for 314 of the most commonly IBD-associated SNPs by a custom SNP microarray. Logistic regression and Fischer exact test were used for statistical analysis.

Results: After Bonferroni correction, none of the 314 IBD-associated SNPs correlated with UC-neoplasia when compared with matched UC controls. The incidence of primary sclerosing cholangitis was greater in the UC-neoplasia group (10/41, 24% vs 3/41, 7%; P = .03) compared with UC controls. The severity of neoplasia (low grade dysplasia versus high grade dysplasia versus CRC) correlated with disease duration (7.9 vs 13.4 vs 20.7 years, respectively).

Conclusion: The lack of correlation between well-known IBD-associated SNPs and UC-neoplasia demonstrated in this study suggests that the development of neoplasia in patients with UC is associated with genetic determinants other than those that predispose to inflammation or results from posttranslational modifications or epigenetic factors rather than germline polymorphisms.
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http://dx.doi.org/10.1016/j.surg.2014.03.017DOI Listing
August 2014

The TNFSF15 gene single nucleotide polymorphism rs7848647 is associated with surgical diverticulitis.

Ann Surg 2014 Jun;259(6):1132-7

*Division of Colon and Rectal Surgery and †Department of Biostatistics, Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA.

Objective: To determine if single nuclear polymorphisms (SNPs) in the TFNSF15 gene play a role in patients requiring surgery for diverticulitis.

Background: A role for a genetic predisposition in diverticulitis is suggested by its association with hereditary connective tissue disorders, youthful onset in some patients, and the observation of families with multiple affected individuals. The TNFSF15 gene has been associated with other inflammatory diseases affecting the colon such as medically refractory ulcerative colitis (UC), aggressive Crohn's disease (CD), and pouchitis after restorative proctocolectomy.

Methods: In the discovery phase of this study, 21 sporadic surgical diverticulitis (SD) patients (9 female, mean age = 52 ± 5) and 5 individuals from a single family with surgically managed diverticulitis [familial diverticulitis (FD), 4 female, mean age = 51.1 ± 7] were studied. SD patients were age and sex matched with 3 separate groups of healthy, CD and UC control patients. All patients were genotyped for 5 known TNFSF15-associated SNPs. The SNP discovered to be associated with diverticulitis (rs7848647) was then confirmed in a separate test group composed of 34 additional patients (20 female, mean age 57.7 ± 2) who also underwent surgical treatment for diverticulitis. These patients were age matched to a new control cohort of patients having no history of diverticulitis (26 female). Patients were genotyped using a TaqMan assay. In the discovery phase, logistical regression on matched subjects was performed to determine an association of TNFSF SNP with diverticulitis versus the control groups. In the test phase, significance for the rs7848647 SNP was assessed by the Fischer's exact test.

Results: In the discovery phase, the TNFSF15 SNP rs7848647 was significantly associated with SD (p = 0.0003) versus all control groups studied. The risk allele for this SNP (G substituted for A) was found in all SD patients. The homozygous GG allele was found in 62% (13/21) of SD patients versus only 5% (1/21) of healthy controls (p = 0.001) and 24% (10/42) of all UC + CD controls (p = 0.002). All 5 members of the FD cohort were homozygous for the at-risk "G" allele. In the test group, the homozygous GG genotype was found in 56% of SD patients compared with 17% of healthy controls (p = 0.006). Risk of SD seemed to increase with number of the G alleles with 8% of SD patients having AA homozygosity, 35% of SD patients having AG heterozygosity, and 56% of SD patients having GG homozygosity.

Conclusions: The SNP rs7848647 associated with the TNFSF15 gene is associated with surgical diverticulitis. This finding suggests a fundamental role for TNFSF15, a T-cell receptor gene involved in T-cell maturation, in the pathophysiology of diverticulitis requiring surgery. This SNP may be a marker of diverticular disease severity that might assist in surgical decision making.
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http://dx.doi.org/10.1097/SLA.0000000000000232DOI Listing
June 2014

Increased risk of incisional hernia after sigmoid colectomy for diverticulitis compared with colon cancer.

J Am Coll Surg 2014 May 19;218(5):920-8. Epub 2014 Feb 19.

Department of Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA. Electronic address:

Background: We aimed to determine if an increased incidence of incisional hernias is present in patients undergoing sigmoidectomy for diverticulitis vs cancer. The pathophysiology of diverticulitis is poorly understood, but might involve a collagen vascular abnormality that can predispose to incisional hernia.

Study Design: In this IRB-approved, retrospective study, patients who underwent sigmoid colectomies for diverticulitis or cancer between January 2003 and September 2012 were studied. Exclusion criteria included the development of surgical site infections and neoadjuvant chemoradiotherapy. A multivariate logistic regression was used with covariate adjustments for known risk factors for hernia development.

Results: Four hundred forty-two patients (mean age 59.3 ± 13.9 years) with a median follow-up of 30 months were analyzed. The incidence of incisional hernia was 15.1% in diverticulitis patients vs 5.8% in the cancer cohort (41 of 271 vs 10 of 171; p = 0.003). Univariate analysis of risk factors associated with postoperative incisional hernia included steroid use (p = 0.007), wound packing (p = 0.001), higher American Society of Anesthesiologists classification (p = 0.001), absorbable suture closure (p = 0.02), blood transfusion (p = 0.04), stoma formation (p = 0.02), increased body mass index (p = 0.008), and history of incisional hernia (p = 0.00008). Multivariate logistic regression demonstrated a persistent association between diverticulitis and hernia development (p = 0.01). Odds of a hernia developing after sigmoidectomy for diverticulitis were 2.82 times greater than in the cancer cohort (95% CI, 1.3-6.6).

Conclusions: The incidence of an incisional hernia developing after a sigmoid colectomy is significantly higher when performed for diverticulitis as compared with cancer. This might be due to a connective tissue disorder, which predisposes to development of both diverticula and hernias.
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http://dx.doi.org/10.1016/j.jamcollsurg.2014.01.050DOI Listing
May 2014

T-cell activation Rho GTPase-activating protein expression varies with inflammation location and severity in Crohn's disease.

J Surg Res 2014 Aug 17;190(2):457-64. Epub 2014 Jan 17.

Department of Surgery, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania. Electronic address:

Background: The T-cell activation Rho GTPase-activating protein (TAGAP) gene has a regulatory role in T cell activation. We have previously suggested a correlation between the TAGAP-associated single nucleotide polymorphism rs212388 and protection from anal sepsis in Crohn's disease (CD) patients. The present study sought to evaluate TAGAP's expression in colonic tissue of CD patients with varying disease severity and location.

Materials And Methods: Five transverse, 17 left, and five sigmoid colectomy specimens from 27 CD patients with varying disease severity (16 male, mean age at diagnosis 26.4 ± 2.2 y) were evaluated for TAGAP messenger RNA expression. Fisher exact, Mann-Whitney, and Welch two-sample t-tests were used for statistical evaluation. Immunohistochemistry confirmed results.

Results: Patients with tissue demonstrating lower TAGAP messenger RNA expression (less than the overall mean) were younger at diagnosis (mean age 21.1 ± 6.3 versus 32.5 ± 13 y, P = 0.009). Increased TAGAP expression was seen in moderate or severely diseased tissue versus tissue with no or mild disease (RQ = 1.3 ± 0.34 versus 0.53 ± 0.09, P = 0.050). This was the most dramatic in the sigmoid colon (P = 0.041). TAGAP expression was increased in more distal tissue with a significant difference seen when comparing transverse versus sigmoid colon with moderate or severe disease (0.51 ± 0.14 versus 1.9 ± 0.37, P = 0.049).

Conclusions: Colonic expression of TAGAP in CD patients varied according to disease severity and location, being the most elevated in patients with severe disease in the sigmoid colon. Whether changes in TAGAP expression are a result of disease response or inherent to the disease pathophysiology itself remains to be determined. This gene warrants further investigation for its role in CD.
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http://dx.doi.org/10.1016/j.jss.2014.01.019DOI Listing
August 2014

Single nucleotide polymorphisms of the tcdC gene and presence of the binary toxin gene predict recurrent episodes of Clostridium difficile infection.

Ann Surg 2014 Aug;260(2):299-304

Departments of *Surgery †Public Health Sciences and Statistics, The Pennsylvania State University College of Medicine, Hershey, PA.

Objective: To identify Clostridium difficile genotypes, which are associated with recurrent C difficile infection (RCDI).

Background: Reliable bacterial genetic factors predicting RCDI are currently lacking.

Methods: Inpatients and outpatients 18 years or older treated at our institution for C difficile infection (CDI) of any severity were consecutively enrolled. CDI was defined as symptoms of colitis with a positive PCR stool test. Each bacterial isolate was studied for virulence factors: tcdC mutations, including single nucleotide polymorphisms (SNPs) via PCR, the presence of genes for toxins A, B and binary toxin using restriction fragment length polymorphism, and identification of ribotype by PCR. χ tests, t tests, and logistic and linear regression were used to determine which virulence factors predicted RCDI and the need for hospital admission, with corrections made for multiple statistical comparisons.

Results: Seventy-three patients (male: 52%; mean age: 66 ± 15 years) were studied. Binary toxin gene (P = 0.03) was associated with at least 1 episode of RCDI, as was the presence of SNPs C184T (P = 0.006) and A117T (P = 0.003). The presence of the binary toxin gene with either of these tcdC SNPs increased RCDI by 80% (P = 0.0002) but did not predict the need for hospital admission. None of the other virulence factors, including ribotype 027, were predictive of RCDI.

Conclusions: The presence of the binary toxin gene and tcdC SNPs C184T and A117T strongly predict RCDI. The presence of both tcdC SNPs and the binary toxin gene significantly increased the risk of RCDI, which might warrant longer antibiotic courses to eradicate the infection.
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http://dx.doi.org/10.1097/SLA.0000000000000469DOI Listing
August 2014

Focused, high accuracy 5-methylcytosine quantitation with base resolution by benchtop next-generation sequencing.

Epigenetics Chromatin 2013 Oct 11;6(1):33. Epub 2013 Oct 11.

Background: The growing interest in the role of epigenetic modifications in human health and disease has led to the development of next-generation sequencing methods for whole genome analysis of DNA methylation patterns. However, many projects require targeted methylation analysis of specific genes or genomic regions. We have developed an approach, termed BiSulfite Amplicon Sequencing (BSAS), for hypothesis driven and focused absolute DNA methylation analysis. This approach is applicable both to targeted DNA methylation studies as well as to confirmation of genome-wide studies.

Results: BSAS uses PCR enrichment of targeted regions from bisulfite-converted DNA and transposome-mediated library construction for rapid generation of sequencing libraries from low (1 ng) sample input. Libraries are sequenced using the Illumina MiSeq benchtop sequencer. Generating high levels of sequencing depth (<1,000 ×) provides for quantitatively precise and accurate assessment of DNA methylation levels with base specificity. Dual indexing of sequencing libraries allows for simultaneous analysis of up to 96 samples. We demonstrate the superior quantitative accuracy of this approach as compared to existing Sanger sequencing methods.

Conclusions: BSAS can be applied to any genomic region from any DNA source, including tissue and cell culture. Thus, BSAS provides a new validation approach for rapid and highly quantitative absolute CpG methylation analysis of any targeted genomic regions in a high throughput manner.
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http://dx.doi.org/10.1186/1756-8935-6-33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907040PMC
October 2013
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