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1.  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
2.  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 | Derfuss, Tobias
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
3.  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
4.  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
5.  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
6.  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
7.  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
9.  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
10.  Are nonintestinal inflammatory diseases and celiac disease linked? 
Hepatitis Monthly  2011;11(1):40.
PMCID: PMC3206658  PMID: 22087116
Celiac; Virus Hepatitis
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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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