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1.  Male Sex Is Independently Associated with Faster Disability Accumulation in Relapse-Onset MS but Not in Primary Progressive MS 
PLoS ONE  2015;10(6):e0122686.
Background
Multiple Sclerosis is more common in women than men and females have more relapses than men. In a large international cohort we have evaluated the effect of gender on disability accumulation and disease progression to determine if male MS patients have a worse clinical outcome than females.
Methods
Using the MSBase Registry, data from 15,826 MS patients from 25 countries was analysed. Changes in the severity of MS (EDSS) were compared between sexes using a repeated measures analysis in generalised linear mixed models. Kaplan-Meier analysis was used to test for sex difference in the time to reach EDSS milestones 3 and 6 and the secondary progressive MS.
Results
In relapse onset MS patients (n = 14,453), males progressed significantly faster in their EDSS than females (0.133 vs 0.112 per year, P<0.001,). Females had a reduced risk of secondary progressive MS (HR (95% CI) = 0.77 (0.67 to 0.90) P = 0.001). In primary progressive MS (n = 1,373), there was a significant increase in EDSS over time in males and females (P<0.001) but there was no significant sex effect on the annualized rate of EDSS change.
Conclusion
Among registrants of MSBase, male relapse-onset patients accumulate disability faster than female patients. In contrast, the rate of disability accumulation between male and female patients with primary progressive MS is similar.
doi:10.1371/journal.pone.0122686
PMCID: PMC4457630  PMID: 26046348
2.  Epstein-Barr Virus Specific Antibody Response in Multiple Sclerosis Patients during 21 Months of Natalizumab Treatment 
Disease Markers  2015;2015:901312.
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. Natalizumab, a humanized anti-α4 integrin monoclonal antibody, is a highly effective treatment approved for MS. An association between MS and an exposure to Epstein-Barr Virus (EBV) sustained by the levels of antiviral capsid antigen (VCA) and anti-Epstein-Barr nuclear antigen-1 (EBNA-1) IgG has been described. Our goal was to verify the utility of EBV-specific IgG as a marker in Natalizumab treated MS. Twenty patients (17 female and 3 male) in treatment with Natalizumab were enrolled. Serum levels of anti-VCA and anti-EBNA-1 IgG were determined and expressed as arbitrary units (AU) before treatment and every three months for 21 months of therapy. Anti-VCA IgG levels were increased at the 15th month (235410 ± 196712 AU) comparing with the 3rd (98146 ± 47145 AU) and the 6th (109866 ± 52270 AU) months of therapy (p < 0.05). No significant differences were found for serum anti-EBNA-1 IgG levels. Our data indicate that a transient, self-limited, EBV reactivation can occur in MS during Natalizumab therapy but our results do not support the use of serum EBV-specific antibody levels as biomarkers for monitoring therapeutic response to Natalizumab in the course of MS.
doi:10.1155/2015/901312
PMCID: PMC4460255  PMID: 26101453
3.  The Effect of Race/Ethnicity on the Age of Colon Cancer Diagnosis 
BACKGROUND
Colorectal cancer is the third most commonly diagnosed cancer in the United States. Notably, racial/ethnic disparities exist in both incidence and mortality.
PURPOSE
The aim of this case study was to investigate the impact of race/ethnicity on age at diagnosis of colorectal cancer in a defined population in Suffolk County, NY.
METHODS
Data were retrospectively collected on race/ethnicity, health insurance status, age at diagnosis, stage at diagnosis, gender, smoking status, alcohol intake, tumor location, and body mass index for colorectal cancer patients with medical records in the Stony Brook University Medical Center database (2005–2011). Population-based data on Hispanic and non-Hispanic Whites were obtained from the Surveillance, Epidemiology, and End Results registry of New York State for an overlapping time period. Permutation-based ANCOVA and logistic regression with stepwise variable selection were conducted to identify covariates and first-order interactions associated with younger age at diagnosis and cancer stage as a dependent categorical variable.
RESULTS
Of 328 colorectal cancer patients, Hispanics were diagnosed at a median younger age of 57y vs. 67y than non-Hispanic Whites (FDR = 0.001). Twenty-six percent of Hispanics were diagnosed with colorectal cancer prior to the recommended age (50y) for colorectal cancer surveillance compared to 11% of non-Hispanic Whites (FDR =0.007). Analysis of New York State registry data corroborated our findings that Hispanic colorectal cancer patients were diagnosed at a median younger age than non-Hispanic Whites. Permutation-based ANCOVA identified race/ethnicity and health insurance as significantly associated with age of diagnosis (P=0.001). Logistic regression selected (younger) age at diagnosis as being significantly associated with stage IV disease. The limitations of the case study reside in the use of self-reporting of race and ethnicity and in the small sample sizes.
CONCLUSIONS
Hispanics may be at higher risk for colorectal cancer (<50>y) and younger age at diagnosis is associated with advanced disease.
PMCID: PMC4434597  PMID: 25995971
age; ethnicity; race; colorectal cancer; Hispanic; permutation based ANCOVA
4.  Predictors of disability worsening in clinically isolated syndrome 
Objective
To assess demographic, clinical, magnetic resonance imaging, and treatment exposure predictors of time to 3 or 12-month confirmed disability worsening in clinically isolated syndrome (CIS) and early multiple sclerosis (MS).
Methods
We utilized the MSBase Incident Study (MSBasis), a prospective cohort study of outcome after CIS. Predictors of time to first 3 and 12-month confirmed expanded disability status scale worsening were analyzed using Cox proportional hazards regression.
Results
About 1989 patients were analyzed, the largest seen-from-onset cohort reported to-date. A total of 391 patients had a first 3-month confirmed disability worsening event, of which 307 were sustained for 12 months. Older age at CIS onset (adjusted hazard ratio: aHR 1.17, 95% 1.06, 1.30), pyramidal (aHR 1.45, 95% CI 1.13, 1.89) and ambulation (HR 1.60, 95% CI 1.09, 2.34) system dysfunction, annualized relapse rate (aHR 1.20, 95% CI 1.18, 1.22), and lower proportion of observation time on treatment were associated with 3-month confirmed worsening. Predictors of time to 12-month sustained worsening included pyramidal system dysfunction (Hazard ratio: aHR 1.38, 95% CI 1.05, 1.83), and older age at CIS onset (aHR 1.17, 95% CI 1.04, 1.31). Greater proportion of follow-up time exposed to treatment was associated with greater reductions in the rate of worsening.
Interpretation
This study provides class IV evidence for a strong protective effect of disease-modifying treatment to reduce disability worsening events in patients with CIS and early MS, and confirms age and pyramidal dysfunction at onset as risk factors.
doi:10.1002/acn3.187
PMCID: PMC4435703  PMID: 26000321
5.  Establishment of Highly Tumorigenic Human Colorectal Cancer Cell Line (CR4) with Properties of Putative Cancer Stem Cells 
PLoS ONE  2014;9(6):e99091.
Background
Colorectal cancer (CRC) has the third highest mortality rates among the US population. According to the most recent concept of carcinogenesis, human tumors are organized hierarchically, and the top of it is occupied by malignant stem cells (cancer stem cells, CSCs, or cancer-initiating cells, CICs), which possess unlimited self-renewal and tumor-initiating capacities and high resistance to conventional therapies. To reflect the complexity and diversity of human tumors and to provide clinically and physiologically relevant cancer models, large banks of characterized patient-derived low-passage cell lines, and especially CIC-enriched cell lines, are urgently needed.
Principal Findings
Here we report the establishment of a novel CIC-enriched, highly tumorigenic and clonogenic colon cancer cell line, CR4, derived from liver metastasis. This stable cell line was established by combining 3D culturing and 2D culturing in stem cell media, subcloning of cells with particular morphology, co-culture with carcinoma associated fibroblasts (CAFs) and serial transplantation to NOD/SCID mice. Using RNA-Seq complete transcriptome profiling of the tumorigenic fraction of the CR4 cells in comparison to the bulk tumor cells, we have identified about 360 differentially expressed transcripts, many of which represent stemness, pluripotency and resistance to treatment. Majority of the established CR4 cells express common markers of stemness, including CD133, CD44, CD166, EpCAM, CD24 and Lgr5. Using immunocytochemical, FACS and western blot analyses, we have shown that a significant ratio of the CR4 cells express key markers of pluripotency markers, including Sox-2, Oct3/4 and c-Myc. Constitutive overactivation of ABC transporters and NF-kB and absence of tumor suppressors p53 and p21 may partially explain exceptional drug resistance of the CR4 cells.
Conclusions
The highly tumorigenic and clonogenic CIC-enriched CR4 cell line may provide an important new tool to support the discovery of novel diagnostic and/or prognostic biomarkers as well as the development of more effective therapeutic strategies.
doi:10.1371/journal.pone.0099091
PMCID: PMC4055451  PMID: 24921652
6.  Environmental Factors and Multiple Sclerosis Severity: A Descriptive Study 
Growing evidence suggests that environmental factors play a key role in the onset of multiple sclerosis (MS). This study was conducted to examine whether environmental factors may also be associated with the evolution of the disease. We collected data on smoking habits, sunlight exposure and diet (particularly consumption of vitamin D-rich foods) from a sample of 131 MS patients. We also measured their serum vitamin D concentration. The clinical impact of MS was quantified using the Multiple Sclerosis Severity Score (MSSS); MS was considered “severe” in patients with MSSS ≥ 6, and “mild” in patients with MSSS ≤ 1. The results showed a strong association between serum vitamin D concentration and both sunlight exposure (26.4 ± 11.9 ng/mL vs. 16.5 ± 12.1 ng/mL, p = 0.0004) and a fish-rich diet (23.5 ± 12.1 ng/mL vs. 16.1 ± 12.4 ng/mL, p = 0.005). Patients reporting frequent sunlight exposure had a lower MSSS (2.6 ± 2.4 h vs. 4.6 ± 2.6 h, p < 0.001). The mild MS patients reported much more frequent sunlight exposure (75% mild MS vs. 25% severe MS p = 0.004, Chi square test). A higher serum vitamin D concentration determined a lower risk of developing severe MS, adjusted for sunlight exposure (OR = 0.92 for one unit increase in vitamin D, 95% CI: 0.86–0.97, p = 0.005). A stronger inverse association emerged between frequent sunlight exposure and the risk of severe MS (OR = 0.26, 95% CI: 0.09–0.71, p = 0.009). Our data show that an appropriate diet and adequate expose to sunlight are associated with less aggressive MS.
doi:10.3390/ijerph110606417
PMCID: PMC4078587  PMID: 24950063
multiple sclerosis; environment; disease severity; vitamin D; sunlight exposure
7.  Differential expression of miRNAs in colon cancer between African and Caucasian Americans: Implications for cancer racial health disparities 
International Journal of Oncology  2014;45(2):587-594.
Colorectal cancer (CRC) incidence and mortality are higher in African Americans (AAs) than in Caucasian Americans (CAs) and microRNAs (miRNAs) have been found to be dysregulated in colonic and other neoplasias. The aim of this exploratory study was to identify candidate miRNAs that could contribute to potential biological differences between AA and CA colon cancers. Total RNA was isolated from tumor and paired adjacent normal colon tissue from 30 AA and 31 CA colon cancer patients archived at Stony Brook University (SBU) and Washington University (WU)-St. Louis Medical Center. miRNA profiles were determined by probing human genome-wide miRNA arrays with RNA isolated from each sample. Using repeated measures analysis of variance (RANOVA), miRNAs were selected that exhibited significant (p<0.05) interactions between race and tumor or significant (fold change >1.5, p<0.05) main effects of race and/or tumor. Quantitative polymerase chain reaction (q-PCR) was used to confirm miRNAs identified by microarray analysis. Candidate miRNA targets were analyzed using immunohistochemistry. RANOVA results indicated that miR-182, miR152, miR-204, miR-222 and miR-202 exhibited significant race and tumor main effects. Of these miRNAs, q-PCR analysis confirmed that miR-182 was upregulated in AA vs. CA tumors and exhibited significant race:tumor interaction. Immunohistochemical analysis revealed that the levels of FOXO1 and FOXO3A, two potential miR-182 targets, are reduced in AA tumors. miRNAs may play a role in the differences between AA and CA colon cancer. Specifically, differences in miRNA expression levels of miR-182 may contribute to decreased survival in AA colon cancer patients.
doi:10.3892/ijo.2014.2469
PMCID: PMC4091964  PMID: 24865442
African American; Caucasian American; microRNA; colon cancer; quantitative reverse transcriptase-polymerase chain reaction; repeated measures analysis of variance; racial health disparity
8.  The effects of the histone deacetylase inhibitor 4-phenylbutyrate on gap junction conductance and permeability 
Longitudinal resistance is a key factor in determining cardiac action potential propagation. Action potential conduction velocity has been shown to be proportional to the square root of longitudinal resistance. A major determinant of longitudinal resistance in myocardium is the gap junction channel, comprised connexin proteins. Within the ventricular myocardium connexin43 (Cx43) is the dominantly expressed connexin. Reduced numbers of gap junction channels will result in an increase in longitudinal resistance creating the possibility of slowed conduction velocity while increased numbers of channels would potentially result in an increase in conduction velocity. We sought to determine if inhibition of histone deacetylase (HDAC) by 4-phenylbutyrate (4-PB), a known inhibitor of HDAC resulted in an increase in junctional conductance and permeability, which is not the result of changes in single channel unitary conductance. These experiments were performed using HEK-293 cells and HeLa cells stably transfected with Cx43. Following treatment with increasing concentrations of 4-PB up-regulation of Cx43 was observed via Western blot analysis. Junctional (gj) conductance and unitary single channel conductance were measured via whole-cell patch clamp. In addition intercellular transfer of lucifer yellow (LY) was determined by fluorescence microscopy. The data in this study indicate that 4-PB is able to enhance functional Cx43 gap junction coupling as indicated by LY dye transfer and multichannel and single channel data along with Western blot analysis. As a corollary, pharmacological agents such as 4-PB have the potential, by increasing intercellular coupling, to reduce the effect of ischemia. It remains to be seen whether drugs like 4-PB will be effective in preventing cardiac maladies.
doi:10.3389/fphar.2013.00111
PMCID: PMC3759747  PMID: 24027526
connexin43; 4-phenylbutyrate; gap junction; conductance; permeability
9.  Persistence on Therapy and Propensity Matched Outcome Comparison of Two Subcutaneous Interferon Beta 1a Dosages for Multiple Sclerosis 
Kalincik, Tomas | Spelman, Timothy | Trojano, Maria | Duquette, Pierre | Izquierdo, Guillermo | Grammond, Pierre | Lugaresi, Alessandra | Hupperts, Raymond | Cristiano, Edgardo | Van Pesch, Vincent | Grand’Maison, Francois | La Spitaleri, Daniele | Rio, Maria Edite | Flechter, Sholmo | Oreja-Guevara, Celia | Giuliani, Giorgio | Savino, Aldo | Amato, Maria Pia | Petersen, Thor | Fernandez-Bolanos, Ricardo | Bergamaschi, Roberto | Iuliano, Gerardo | Boz, Cavit | Lechner-Scott, Jeannette | Deri, Norma | Gray, Orla | Verheul, Freek | Fiol, Marcela | Barnett, Michael | van Munster, Erik | Santiago, Vetere | Moore, Fraser | Slee, Mark | Saladino, Maria Laura | Alroughani, Raed | Shaw, Cameron | Kasa, Krisztian | Petkovska-Boskova, Tatjana | den Braber-Moerland, Leontien | Chapman, Joab | Skromne, Eli | Herbert, Joseph | Poehlau, Dieter | Needham, Merrilee | Bacile, Elizabeth Alejandra Bacile | Arruda, Walter Oleschko | Paine, Mark | Singhal, Bhim | Vucic, Steve | Cabrera-Gomez, Jose Antonio | Butzkueven, Helmut | Roger, Elaine | Despault, Pierre | Marriott, Mark | Van der Walt, Anneke | King, John | Kilpatrick, Trevor | Buzzard, Katherine | Jokubaitis, Vilija | Byron, Jill | Morgan, Lisa | Skibina, Olga | Haartsen, Jodi | De Luca, Giovanna | Di Tommaso, Valeria | Travaglini, Daniela | Pietrolongo, Erika | di Ioia, Maria | Farina, Deborah | Mancinelli, Luca | Paolicelli, Damiano | Iaffaldano, Pietro | Ignacio Rojas, Juan | Patrucco, Liliana | Roullet, Etienne | Correale, Jorge | Ysrraelit, Celica | Elisabetta, Cartechini | Pucci, Eugenio | Williams, David | Dark, Lisa | Shaygannejad, Vahid | Zwanikken, Cees | Vella, Norbert | Sirbu, Carmen-Adella
PLoS ONE  2013;8(5):e63480.
Objectives
To compare treatment persistence between two dosages of interferon β-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics.
Methods
Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon β-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon β-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded.
Results
Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as “lack of efficacy” (3.3% vs. 1.7%), “scheduled stop” (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages.
Conclusions
Treatment discontinuations were more common in interferon β-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from “real-world” database the results of the pivotal randomised trial. Propensity score matching effectively minimised baseline covariate imbalance between two directly compared sub-populations from a large observational registry.
doi:10.1371/journal.pone.0063480
PMCID: PMC3660604  PMID: 23704913
10.  Correction: Search for Cellular Stress Biomarkers in Lymphocytes from Patients with Multiple Sclerosis: A Pilot Study 
PLoS ONE  2012;7(11):10.1371/annotation/8c8710a2-bd43-4f65-b21e-69ec522c4f22.
doi:10.1371/annotation/8c8710a2-bd43-4f65-b21e-69ec522c4f22
PMCID: PMC3514333
11.  Geographical Variations in Sex Ratio Trends over Time in Multiple Sclerosis 
PLoS ONE  2012;7(10):e48078.
Background
A female/male (F/M) ratio increase over time in multiple sclerosis (MS) patients was demonstrated in many countries around the world. So far, a direct comparison of sex ratio time-trends among MS populations from different geographical areas was not carried out.
Objective
In this paper we assessed and compared sex ratio trends, over a 60-year span, in MS populations belonging to different latitudinal areas.
Methods
Data of a cohort of 15,996 (F = 11,290; M = 4,706) definite MS with birth years ranging from 1930 to 1989 were extracted from the international MSBase registry and the New Zealand MS database. Gender ratios were calculated by six decades based on year of birth and were adjusted for the F/M born-alive ratio derived from the respective national registries of births.
Results
Adjusted sex ratios showed a significant increase from the first to the last decade in the whole MS sample (from 2.35 to 2.73; p = 0.03) and in the subgroups belonging to the areas between 83° N and 45° N (from 1.93 to 4.55; p<0.0001) and between 45° N to 35° N (from 1.46 to 2.30; p<0.05) latitude, while a sex ratio stability over time was found in the subgroup from areas between 12° S and 55° S latitude. The sex ratio increase mainly affected relapsing-remitting (RR) MS.
Conclusions
Our results confirm a general sex ratio increase over time in RRMS and also demonstrate a latitudinal gradient of this increase. These findings add useful information for planning case-control studies aimed to explore sex-related factors responsible for MS development.
doi:10.1371/journal.pone.0048078
PMCID: PMC3485003  PMID: 23133550
12.  Search for Cellular Stress Biomarkers in Lymphocytes from Patients with Multiple Sclerosis: A Pilot Study 
PLoS ONE  2012;7(9):e44935.
Multiple Sclerosis (MS) is a chronic disease of the central nervous system, the etiology of which, although not completely known, involves inflammation and autoimmunity. In the present study we aimed at identifying molecular markers of apoptosis, cellular stress and DNA damage in isolated peripheral blood mononuclear cells (PBMCs) of MS patients. The analysis was carried on 19 relapsing-remitting untreated MS patients and 13 healthy individuals. We investigated the emergency-driven synthesis of poly(ADP-ribose) (PAR), the expression level of the constitutive enzyme poly(ADP-ribose) polymerase-1 (PARP-1) and the DNA damage-induced phosphorylation of histone H2AX. PAR accumulation, PARP-1 and phosphorylated H2AX (γH2AX) were detected by immunofluorescence experiments on PBMCs isolated from 19 patients and 13 healthy volunteers. Our results show for the first time a net increased amount in PAR and γH2AX in MS patients compared to healthy individuals. Patients were further subdivided in three groups, according to the neuroimaging (MRI)-based classification of disease phase. Remarkably, we found a positive correlation between the level of γH2AX and MS aggressiveness. In addition, apoptosis in PBMCs was monitored by flow cytometry of both phosphatidylserine exposure (revealed by Annexin V-FITC labeling) and membrane permeability to propidium iodide. Our observations provide the evidence that the number of apoptotic cells was significantly higher in patients compared to healthy individuals, thus suggesting that apoptosis could affect MS lymphocyte function.
doi:10.1371/journal.pone.0044935
PMCID: PMC3441649  PMID: 23028690
13.  Country, Sex, EDSS Change and Therapy Choice Independently Predict Treatment Discontinuation in Multiple Sclerosis and Clinically Isolated Syndrome 
PLoS ONE  2012;7(6):e38661.
Objectives
We conducted a prospective study, MSBASIS, to assess factors leading to first treatment discontinuation in patients with a clinically isolated syndrome (CIS) and early relapsing-remitting multiple sclerosis (RRMS).
Methods
The MSBASIS Study, conducted by MSBase Study Group members, enrols patients seen from CIS onset, reporting baseline demographics, cerebral magnetic resonance imaging (MRI) features and Expanded Disability Status Scale (EDSS) scores. Follow-up visits report relapses, EDSS scores, and the start and end dates of MS-specific therapies. We performed a multivariable survival analysis to determine factors within this dataset that predict first treatment discontinuation.
Results
A total of 2314 CIS patients from 44 centres were followed for a median of 2.7 years, during which time 1247 commenced immunomodulatory drug (IMD) treatment. Ninety percent initiated IMD after a diagnosis of MS was confirmed, and 10% while still in CIS status. Over 40% of these patients stopped their first IMD during the observation period. Females were more likely to cease medication than males (HR 1.36, p = 0.003). Patients treated in Australia were twice as likely to cease their first IMD than patients treated in Spain (HR 1.98, p = 0.001). Increasing EDSS was associated with higher rate of IMD cessation (HR 1.21 per EDSS unit, p<0.001), and intramuscular interferon-β-1a (HR 1.38, p = 0.028) and subcutaneous interferon-β-1a (HR 1.45, p = 0.012) had higher rates of discontinuation than glatiramer acetate, although this varied widely in different countries. Onset cerebral MRI features, age, time to treatment initiation or relapse on treatment were not associated with IMD cessation.
Conclusion
In this multivariable survival analysis, female sex, country of residence, EDSS change and IMD choice independently predicted time to first IMD cessation.
doi:10.1371/journal.pone.0038661
PMCID: PMC3387159  PMID: 22768046
14.  Short and Long Term Variation in Ultraviolet Radiation and Multiple Sclerosis 
We examined the role of ultraviolet radiation (UVR) in persons diagnosed with multiple sclerosis (MS) in four different populations, Italians, Danish, White and African Americans. We tested whether variation in UVR as determined by seasons (short term variation) and solar cycles (long term variation) is related to MS birth month and to survival as measured by lifespan. Cases were selected from three Italian MS Case Registries (2,737); from the United States National Center for Health Statistics (56,020); and from the Danish Multiple Sclerosis registry (15,900). Chi-square tests were used to study the pattern of month of birth distribution in patients with MS comparing with general population data. T-tests were employed to study solar cycles association with lifespan. A surplus of births was observed in June for White Americans. A decrease of births in October and November, though not significant after multiple testing correction, was observed in the three populations. In White American with MS overall, males and females, we found that solar cycle is associated with lifespan. We found that season and solar cycles have some role in MS susceptibility and life duration. However, this is an exploratory analysis and further work is needed to discern the association.
doi:10.3390/ijerph9030685
PMCID: PMC3367270  PMID: 22690156
multiple sclerosis; seasonality; solar cycles; variation in ultraviolet radiation
16.  Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis 
Sawcer, Stephen | Hellenthal, Garrett | Pirinen, Matti | Spencer, Chris C.A. | Patsopoulos, Nikolaos A. | Moutsianas, Loukas | Dilthey, Alexander | Su, Zhan | Freeman, Colin | Hunt, Sarah E. | Edkins, Sarah | Gray, Emma | Booth, David R. | Potter, Simon C. | Goris, An | Band, Gavin | Oturai, Annette Bang | Strange, Amy | Saarela, Janna | Bellenguez, Céline | Fontaine, Bertrand | Gillman, Matthew | Hemmer, Bernhard | Gwilliam, Rhian | Zipp, Frauke | Jayakumar, Alagurevathi | Martin, Roland | Leslie, Stephen | Hawkins, Stanley | Giannoulatou, Eleni | D’alfonso, Sandra | Blackburn, Hannah | Boneschi, Filippo Martinelli | Liddle, Jennifer | Harbo, Hanne F. | Perez, Marc L. | Spurkland, Anne | Waller, Matthew J | Mycko, Marcin P. | Ricketts, Michelle | Comabella, Manuel | Hammond, Naomi | Kockum, Ingrid | McCann, Owen T. | Ban, Maria | Whittaker, Pamela | Kemppinen, Anu | Weston, Paul | Hawkins, Clive | Widaa, Sara | Zajicek, John | Dronov, Serge | Robertson, Neil | Bumpstead, Suzannah J. | Barcellos, Lisa F. | Ravindrarajah, Rathi | Abraham, Roby | Alfredsson, Lars | Ardlie, Kristin | Aubin, Cristin | Baker, Amie | Baker, Katharine | Baranzini, Sergio E. | Bergamaschi, Laura | Bergamaschi, Roberto | Bernstein, Allan | Berthele, Achim | Boggild, Mike | Bradfield, Jonathan P. | Brassat, David | Broadley, Simon A. | Buck, Dorothea | Butzkueven, Helmut | Capra, Ruggero | Carroll, William M. | Cavalla, Paola | Celius, Elisabeth G. | Cepok, Sabine | Chiavacci, Rosetta | Clerget-Darpoux, Françoise | Clysters, Katleen | Comi, Giancarlo | Cossburn, Mark | Cournu-Rebeix, Isabelle | Cox, Mathew B. | Cozen, Wendy | Cree, Bruce A.C. | Cross, Anne H. | Cusi, Daniele | Daly, Mark J. | Davis, Emma | de Bakker, Paul I.W. | Debouverie, Marc | D’hooghe, Marie Beatrice | Dixon, Katherine | Dobosi, Rita | Dubois, Bénédicte | Ellinghaus, David | Elovaara, Irina | Esposito, Federica | Fontenille, Claire | Foote, Simon | Franke, Andre | Galimberti, Daniela | Ghezzi, Angelo | Glessner, Joseph | Gomez, Refujia | Gout, Olivier | Graham, Colin | Grant, Struan F.A. | Guerini, Franca Rosa | Hakonarson, Hakon | Hall, Per | Hamsten, Anders | Hartung, Hans-Peter | Heard, Rob N. | Heath, Simon | Hobart, Jeremy | Hoshi, Muna | Infante-Duarte, Carmen | Ingram, Gillian | Ingram, Wendy | Islam, Talat | Jagodic, Maja | Kabesch, Michael | Kermode, Allan G. | Kilpatrick, Trevor J. | Kim, Cecilia | Klopp, Norman | Koivisto, Keijo | Larsson, Malin | Lathrop, Mark | Lechner-Scott, Jeannette S. | Leone, Maurizio A. | Leppä, Virpi | Liljedahl, Ulrika | Bomfim, Izaura Lima | Lincoln, Robin R. | Link, Jenny | Liu, Jianjun | Lorentzen, Åslaug R. | Lupoli, Sara | Macciardi, Fabio | Mack, Thomas | Marriott, Mark | Martinelli, Vittorio | Mason, Deborah | McCauley, Jacob L. | Mentch, Frank | Mero, Inger-Lise | Mihalova, Tania | Montalban, Xavier | Mottershead, John | Myhr, Kjell-Morten | Naldi, Paola | Ollier, William | Page, Alison | Palotie, Aarno | Pelletier, Jean | Piccio, Laura | Pickersgill, Trevor | Piehl, Fredrik | Pobywajlo, Susan | Quach, Hong L. | Ramsay, Patricia P. | Reunanen, Mauri | Reynolds, Richard | Rioux, John D. | Rodegher, Mariaemma | Roesner, Sabine | Rubio, Justin P. | Rückert, Ina-Maria | Salvetti, Marco | Salvi, Erika | Santaniello, Adam | Schaefer, Catherine A. | Schreiber, Stefan | Schulze, Christian | Scott, Rodney J. | Sellebjerg, Finn | Selmaj, Krzysztof W. | Sexton, David | Shen, Ling | Simms-Acuna, Brigid | Skidmore, Sheila | Sleiman, Patrick M.A. | Smestad, Cathrine | Sørensen, Per Soelberg | Søndergaard, Helle Bach | Stankovich, Jim | Strange, Richard C. | Sulonen, Anna-Maija | Sundqvist, Emilie | Syvänen, Ann-Christine | Taddeo, Francesca | Taylor, Bruce | Blackwell, Jenefer M. | Tienari, Pentti | Bramon, Elvira | Tourbah, Ayman | Brown, Matthew A. | Tronczynska, Ewa | Casas, Juan P. | Tubridy, Niall | Corvin, Aiden | Vickery, Jane | Jankowski, Janusz | Villoslada, Pablo | Markus, Hugh S. | Wang, Kai | Mathew, Christopher G. | Wason, James | Palmer, Colin N.A. | Wichmann, H-Erich | Plomin, Robert | Willoughby, Ernest | Rautanen, Anna | Winkelmann, Juliane | Wittig, Michael | Trembath, Richard C. | Yaouanq, Jacqueline | Viswanathan, Ananth C. | Zhang, Haitao | Wood, Nicholas W. | Zuvich, Rebecca | Deloukas, Panos | Langford, Cordelia | Duncanson, Audrey | Oksenberg, Jorge R. | Pericak-Vance, Margaret A. | Haines, Jonathan L. | Olsson, Tomas | Hillert, Jan | Ivinson, Adrian J. | De Jager, Philip L. | Peltonen, Leena | Stewart, Graeme J. | Hafler, David A. | Hauser, Stephen L. | McVean, Gil | Donnelly, Peter | Compston, Alastair
Nature  2011;476(7359):214-219.
Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region. Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.
doi:10.1038/nature10251
PMCID: PMC3182531  PMID: 21833088
multiple sclerosis; GWAS; genetics
17.  Chronic cerebrospinal venous insufficiency in multiple sclerosis: clinical correlates from a multicentre study 
BMC Neurology  2011;11:132.
Background
Chronic cerebrospinal venous insufficiency (CCSVI) has recently been reported to be associated with multiple sclerosis (MS). However, its actual prevalence, possible association with specific MS phenotypes, and potential pathophysiological role are debated.
Method
We analysed the clinical data of 710 MS patients attending six centres (five Italian and one Canadian). All were submitted to venous Doppler sonography and diagnosed as having or not having CCSVI according to the criteria of Zamboni et al.
Results
Overall, CCSVI was diagnosed in 86% of the patients, but the frequency varied greatly between the centres. Even greater differences were found when considering singly the five diagnostic criteria proposed by Zamboni et al. Despite these differences, significant associations with clinical data were found, the most striking being age at disease onset (about five years greater in CCSVI-positive patients) and clinical severity (mean EDSS score about one point higher in CCSVI-positive patients). Patients with progressive MS were more likely to have CCSVI than those with relapsing-remitting MS.
Conclusion
The methods for diagnosing CCSVI need to be refined, as the between-centre differences, particularly in single criteria, were excessively high. Despite these discrepancies, the strong associations between CCSVI and MS phenotype suggest that the presence of CCSVI may favour a later development of MS in patients with a lower susceptibility to autoimmune diseases and may increase its severity.
doi:10.1186/1471-2377-11-132
PMCID: PMC3221625  PMID: 22029656
18.  Are nonintestinal inflammatory diseases and celiac disease linked? 
Hepatitis Monthly  2011;11(1):40.
PMCID: PMC3206658  PMID: 22087116
Celiac; Virus Hepatitis
19.  Cerebrospinal fluid antibodies to aquaporin-4 in neuromyelitis optica and related disorders: frequency, origin, and diagnostic relevance 
Background
In 70-80% of cases, neuromyelitis optica (NMO) is associated with highly specific serum auto-antibodies to aquaporin-4 (termed AQP4-Ab or NMO-IgG). Recent evidence strongly suggests that AQP4-Ab are directly involved in the immunopathogenesis of NMO.
Objective
To assess the frequency, syndrome specificity, diagnostic relevance, and origin of cerebrospinal fluid (CSF) AQP4-Ab in patients with NMO spectrum disorders (NMOSD).
Methods
87 CSF samples from 37 patients with NMOSD and 42 controls with other neurological diseases were tested for AQP4-Ab in a cell based assay using recombinant human AQP4. Twenty-three paired CSF and serum samples from AQP4-Ab seropositive NMOSD patients were further analysed for intrathecal IgG synthesis to AQP4.
Results
AQP4-Ab were detectable in 68% of CSF samples from AQP4-Ab seropositive patients with NMOSD, but in none of the CSF samples from AQP4-Ab seronegative patients with NMOSD and in none of the control samples. Acute disease relapse within 30 days prior to lumbar puncture, AQP4-Ab serum titres >1:250, and blood-CSF barrier dysfunction, but not treatment status, predicted CSF AQP4-Ab positivity. A positive AQP4-specific antibody index was present in 1/23 samples analysed.
Conclusions
AQP4-Ab are detectable in the CSF of most patients with NMOSD, mainly during relapse, and are highly specific for this condition. In the cohort analysed in this study, testing for CSF AQP4-Ab did not improve the sensitivity and specificity of the current diagnostic criteria for NMO. The substantial lack of intrathecal AQP4-Ab synthesis in patients with NMOSD may reflect the unique localisation of the target antigen at the blood brain barrier, and is important for our understanding of the immunopathogenesis of the disease.
doi:10.1186/1742-2094-7-52
PMCID: PMC2945323  PMID: 20825655
20.  Early prediction of the long term evolution of multiple sclerosis: the Bayesian Risk Estimate for Multiple Sclerosis (BREMS) score 
Aim
To propose a simple tool for early prediction of unfavourable long term evolution of multiple sclerosis (MS).
Methods
A Bayesian model allowed us to calculate, within the first year of disease and for each patient, the Bayesian Risk Estimate for MS (BREMS) score that represents the risk of reaching secondary progression (SP).
Results
The median BREMS scores were higher in 158 patients who reached SP within 10 years compared with 1087 progression free patients (0.69 vs 0.30; p<0.0001). The BREMS value was related to SP risk in the whole cohort (p<0.0001) and in the subgroup of 535 patients who had never been treated with immune therapies, thus reasonably representing the natural history of the disease (p<0.000001).
Conclusions
The BREMS score may be useful both to identify patients who are candidates for early or for more aggressive therapies and to improve the design and analysis of clinical therapeutic trials and of observational studies.
doi:10.1136/jnnp.2006.107052
PMCID: PMC2117665  PMID: 17220286
21.  The Sigma-trial protocol: a prospective double-blind multi-centre comparison of laparoscopic versus open elective sigmoid resection in patients with symptomatic diverticulitis 
BMC Surgery  2007;7:16.
Backround
Diverticulosis is a common disease in the western society with an incidence of 33–66%. 10–25% of these patients will develop diverticulitis. In order to prevent a high-risk acute operation it is advised to perform elective sigmoid resection after two episodes of diverticulitis in the elderly patient or after one episode in the younger (< 50 years) patient. Open sigmoid resection is still the gold standard, but laparoscopic colon resections seem to have certain advantages over open procedures. On the other hand, a double blind investigation has never been performed. The Sigma-trial is designed to evaluate the presumed advantages of laparoscopic over open sigmoid resections in patients with symptomatic diverticulitis.
Method
Indication for elective resection is one episode of diverticulitis in patients < 50 years and two episodes in patient > 50 years or in case of progressive abdominal complaints due to strictures caused by a previous episode of diverticulits. The diagnosis is confirmed by CT-scan, barium enema and/or coloscopy.
It is required that the participating surgeons have performed at least 15 laparoscopic and open sigmoid resections. Open resection is performed by median laparotomy, laparoscopic resection is approached by 4 or 5 cannula. Sigmoid and colon which contain serosal changes or induration are removed and a tension free anastomosis is created. After completion of either surgical procedure an opaque dressing will be used, covering from 10 cm above the umbilicus to the pubic bone. Surgery details will be kept separate from the patient's notes.
Primary endpoints are the postoperative morbidity and mortality. We divided morbidity in minor (e.g. wound infection), major (e.g. anastomotic leakage) and late (e.g. incisional hernias) complications, data will be collected during hospital stay and after six weeks and six months postoperative. Secondary endpoints are the operative and the postoperative recovery data. Operative data include duration of the operation, blood loss and conversion to laparotomy. Post operative recovery consists of return to normal diet, pain, analgesics, general health (SF-36 questionnaire) and duration of hospital stay.
Discussion
The Sigma-trial is a prospective, multi-center, double-blind, randomized study to define the role of laparoscopic sigmoid resection in patients with symptomatic diverticulitis.
doi:10.1186/1471-2482-7-16
PMCID: PMC1955435  PMID: 17683563
22.  Antibody to Aquaporin 4 in the Diagnosis of Neuromyelitis Optica 
PLoS Medicine  2007;4(4):e133.
Background
Neuromyelitis optica (NMO) is a demyelinating disease of the central nervous system (CNS) of putative autoimmune aetiology. Early discrimination between multiple sclerosis (MS) and NMO is important, as optimum treatment for both diseases may differ considerably. Recently, using indirect immunofluorescence analysis, a new serum autoantibody (NMO-IgG) has been detected in NMO patients. The binding sites of this autoantibody were reported to colocalize with aquaporin 4 (AQP4) water channels. Thus we hypothesized that AQP4 antibodies in fact characterize NMO patients.
Methods and Findings
Based on these observations we cloned human water channel AQP4, expressed the protein in a eukaryotic transcription/translation system, and employed the recombinant AQP4 to establish a new radioimmunoprecipitation assay (RIPA). Indeed, application of this RIPA showed that antibodies against AQP4 exist in the majority of patients with NMO (n = 37; 21 positive) as well as in patients with isolated longitudinally extensive transverse myelitis (n = 6; six positive), corresponding to a sensitivity of 62.8% and a specificity of 98.3%. By contrast, AQP4 antibodies were virtually absent in 291 other participants, which included patients with MS (n = 144; four positive), patients with other inflammatory and noninflammatory neurological diseases (n = 73; one positive), patients with systemic autoimmune diseases (n = 45; 0 positive), and healthy participants (n = 29; 0 positive).
Conclusions
In the largest series reported so far to our knowledge, we quantified AQP4 antibodies in patients with NMO versus various other diseases, and showed that the aquaporin 4 water channel is a target antigen in a majority of patients with NMO. The newly developed assay represents a highly specific, observer-independent, and easily reproducible detection method facilitating clinically relevant discrimination between NMO, MS, and other inflammatory diseases.
A newly developed method to detect antibodies to the aquaporin 4 water channel can help discriminate between neuromyelitis optica, multiple sclerosis, and other inflammatory diseases.
Editors' Summary
Background.
Neuromyelitis optica (NMO or Devic syndrome) is a rare disease in which the immune system destroys the myelin (fatty material that insulates nerve fibers so that the body and the brain can communicate using electrical messages) in the optic nerve and spinal cord. Myelin destruction (demyelination) in these parts of the central nervous system (CNS) causes pain and swelling (inflammation) of the optic nerve (optic neuritis) and spinal cord (myelitis). The resultant disruption of communication along these nerves means that patients with NMO experience temporary or permanent blindness in one or both eyes that is preceded or followed by limb weakness or paralysis and loss of bladder and bowel control. These two sets of symptoms can occur many months apart and may happen once during a person's lifetime or recur at intervals. There is no cure for NMO, but corticosteroids or plasmapheresis reduce inflammation during acute attacks and, because NMO is an autoimmune disease (one in which the immune system attacks the body's own tissues instead of foreign organisms), long-term immunosuppression may prevent further attacks.
Why Was This Study Done?
There are many inflammatory/demyelinating diseases of the CNS with clinical symptoms similar to those of NMO. It is particularly hard to distinguish between NMO and multiple sclerosis, an autoimmune disease that involves widespread demyelination. Neurologists need to make a correct diagnosis before starting any treatment and usually use clinical examination and magnetic resonance imaging (to detect sites of inflammation) to help them in this task. Recently, however, a biomarker for NMO was identified. Many patients with NMO make autoantibodies (proteins that recognize a component of a person's own tissues) called NMO-IgGs. These recognize aquaporin 4 (AQP4), a protein that allows water to move through cell membranes. It is not known how often patients with NMO or other demyelinating diseases make antibodies to AQP4, so it is unclear whether testing for these antibodies would help in the diagnosis of NMO. In this study, the researchers have developed a new assay for antibodies to AQP4 and then quantified the antibodies in patients with NMO and other demyelinating diseases.
What Did the Researchers Do and Find?
The researchers made radioactively labeled AQP4 in a test tube, then incubated samples of this with serum (the liquid portion of blood), added small beads coated with protein A (a bacterial protein that binds to antibodies) and allowed the beads to settle. The amount of radioactivity attached to the beads indicates the amount of antibody to AQP4 in the original serum. The researchers used this radioimmunoprecipitation assay to measure antibodies to AQP4 in sera from 37 patients with NMO and from six with another neurological condition, longitudinally extensive transverse myelitis (LETM), which is characterized by large demyelinated lesions across the width of the spinal cord but no optic neuritis; these patients often develop NMO. They also measured antibodies to AQP4 in the sera of nearly 300 other people including patients with multiple sclerosis, other neurological conditions, various autoimmune diseases, and healthy individuals. Nearly two-thirds of the patients with NMO and all those with LETM made antibodies against AQP4; very few of the other study participants made these antibodies. In particular, only four of the 144 patients with multiple sclerosis made AQP4 antibodies.
What Do These Findings Mean?
These findings indicate that testing for antibodies to AQP4 could help neurologists distinguish between NMO and multiple sclerosis and between NMO and other demyelinating diseases of the CNS. In addition, the new radioimmunoprecipitation assay provides a standardized, high-throughput way to quantitatively test for these antibodies, whereas the indirect immune fluorescence assay for measurement of unspecific NMO-IgG is observer-dependent and nonquantitative. Although these findings need to be confirmed in more patients and the assay's reliability demonstrated in different settings, the measurement of antibodies to AQP4 by radioimmunoprecipitation may become a standard part of the differential diagnosis of NMO. Additional research will determine whether AQP4 is the only protein targeted by autoantibodies in NMO and whether this targeting is a critical part of the disease process.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040133.
US National Institute of Neurological Disorders and Stroke has information for patients who have neuromyelitis optica, transverse myelitis, and multiple sclerosis
The Transverse Myelitis Association offers information and useful links for patients and their carers about transverse myelitis and neuromyelitis optica (in several languages, including English and Spanish)
Mayo Clinic information for patients on Devic's syndrome
Medline Plus encyclopedia pages discuss autoimmune disorders (in English and Spanish)
A brief overview of aquaporins is available from the University of Miami
The American MS Society has information on MS
doi:10.1371/journal.pmed.0040133
PMCID: PMC1852124  PMID: 17439296
23.  Laparoscopic Bowel Resection: A Comparison of Three Ultrasonically Activated Devices 
Background and Objectives:
To compare resection time and collateral thermal damage of 3 currently available ultrasonically activated devices in laparoscopic small bowel surgery.
Methods:
AutoSonix®, SonoSurg®, and UltraCision® were compared in laparoscopic small bowel mesentery resection in a porcine model. A resection was defined as 12 endarcade arteries supplying the intended bowel segment. Vessels were divided 1 cm off the bowel wall. AutoSonix®, SonoSurg®, and UltraCision® were comparable for blade length and type, cutting mechanism, handle ergonomics, and vibration amplitude, but not well matched for vibration frequency (55.5;23.5;55.5 kHz), working shaft diameter (5;11;10mm) and length (29;33;34cm), respectively. A sample size of 114 was calculated to detect a 25% difference with 90% power at a 5% significance level. Resections were allocated to devices by block randomization. Analysis of variance and pairwise Scheffe tests were used for multiple comparisons, and a Kaplan-Meier plot was drawn to confirm differences in resection time with each device. A pathologist blind to the devices evaluated bowel wall biopsies for thermal damage.
Results:
Procedures as allocated comprised 114 resections (38 with each device). UltraCision® median resection time of 5160 (range 2340-7860) seconds was significantly longer (P=0.0001). The difference in resection time between AutoSonix® (median 3420, range 1860-8760 s) and SonoSurg® (median 3660, range 1800-6900 s) did not reach statistical significance. A microscopy revealed no thermal damage.
Conclusions:
Laparoscopic resection time for porcine bowel mesentery was shorter with AutoSonix® or SonoSurg® than with UltraCision®, and no thermal damage to the bowel wall was found.
PMCID: PMC3015463  PMID: 12722994
Laparoscopic colorectal surgery; Laparoscopic intracorporeal bowel surgery; Thermal damage; Ultrasonically activated devices; Ultrasonic dissection
24.  Laparoscopic Intracorporeal Bowel Resection with Ultrasound versus Electrosurgical Dissection 
Background and Objectives:
We assessed resection time and collateral thermal tissue damage of ultrasonically activated surgery (UAS) and high-frequency blade-enhanced bipolar electrosurgery (BE) in laparoscopic bowel surgery.
Methods:
We compared UAS laparoscopic intracorporeal small bowel mesentery re-section with an equivalent procedure performed with BE in a porcine model. Resection was defined as 12 end-arcade arteries supplying the intended bowel segment. Vessels were divided one cm off the bowel wall. Aside from shaft diameter, jaws gaping pattern, and cutting blade length, UAS and BE devices were well matched for handle ergonomics, jaws gaping extent, power setting, type of use, working shaft axial rotation, and length. A pathologist blind to the method used assessed the collateral thermal damage. Resections were allocated to either method by computer-generated block randomization. The study design was sequential triangular with a 5% significance level and 90% power.
Results:
No significant differences occurred in intraoperative blood pressure and heart rate variations in pigs undergoing UAS or BE. Median operating time (measured after 10, 20, and 30 resections in each study arm) was significantly shorter in UAS than in BS (0.57 vs. 2.01 min P < 0.001). Histology of small bowel wall specimens revealed no collateral thermal damage.
Conclusions:
UAS laparoscopic bowel surgery offers reduced resection time as com-pared with its BE counterpart in a porcine model.
PMCID: PMC3015418  PMID: 11303990
Bipolar coagulation; Electrosurgery; Laparoscopy; Thermal damage; Ultrasonic dissection
25.  Facilitating Intracorporeal Colorectal Anastomoses 
Background and Objectives:
An experimental study was undertaken to evaluate whether a previously described technique for laparoscopic sigmoid resection with intracorporeal resection-anastomosis and specimen removal via a suprapubic incision could be facilitated and applied to the rectum.
Methods:
Ten domestic pigs (median weight 41 kg) underwent low anterior resection of the rectum, which was transected with an articulating endoscopic stapler. Pursestring sutures were fashioned intracorporeally with a laparoscopic pursestring clamp. The anvil of a circular stapler was inserted through a 33 mm port into the colon and pursestring tied intracorporeally. A circular gun with a spike fixed to its shaft was introduced per anum and a double-stapled anastomosis performed.
Results:
Complete doughnuts were obtained in all cases and anastomoses were all methylene blue tight. All porcine subjects had an uneventful 5-week postoperative course. The median anastomotic level from the anal verge was 5.2 cm. Histology of colorectal anastomoses revealed healing mucosa.
Conclusions:
The use of articulating endoscopic stapler, laparoscopic pursestring clamp, and circular stapler with a spike fixed to its shaft seems to facilitate a previously described intracorporeal approach to sigmoid resection which was safely applied to the rectum in a porcine model.
PMCID: PMC3015262  PMID: 9876710
Anastomosis; Colorectal surgery; Laparoscopy; Surgical technique

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