Patricia L. Kozuch

THE ROLE OF THE ANTERIOR CINGULATE IN AUTOMATIC AND CONTROLLED PROCESSES :A DEVELOPMENTAL NEUROANATOMICAL STUDY

This study examines the role of the anterior cingulate in the development of attention. Task performance relying predominantly on either automatic or controlled processes was correlated with magnetic resonance imaging based measures of the anterior cingulate in 26 normal children ages 5 to 16 years. Attentional measures were assessed with a visual discrimination paradigm. Parasagittal slices from a 3-D, T1-weighted volume data set were used to obtain area measurements of the anterior cingulate. Response latencies decreased with age for both tasks. There were significant correlations between attentional performance and right, but not left, anterior cingulate measures. Performance was faster and more accurate during trials requiring predominantly controlled processes for those children with larger right anterior cingulate measures. The results are consistent with adult neuroimaging findings of activation in the right anterior cingulate during attention tasks and with lesion studies implicating greater right hemisphere involvement in attentional processes.

Sydenham's chorea Magnetic resonance imaging of the basal ganglia

Analysis of cerebral magnetic resonance images of 24 subjects with Sydenhams chorea and 48 age-, height-, weight-, gender-, and handedness-matched controls demonstrated increased sizes of the caudate, putamen, and globus pallidus in the Sydenhams chorea group. In contrast, neither total cerebral, prefrontal, or midfrontal volumes or thalamic area were increased. These results indicate the selective involvement of the basal ganglia in Sydenhams chorea. NEUROLOGY 1995;45: 2199-2203

Review article: diagnosis and management of mesenteric ischaemia with an emphasis on pharmacotherapy.

Mesenteric ischaemia results from decreased blood flow to the bowel, causing cellular injury from lack of oxygen and nutrients. Acute mesenteric ischaemia (AMI) is an uncommon disorder with high morbidity and mortality, but outcomes are improved with prompt recognition and aggressive treatment. Five subgroups of AMI have been identified, with superior mesenteric artery embolism (SMAE) the most common. Older age and cardiovascular disease are common risk factors for AMI, excepting acute mesenteric venous thrombosis (AMVT), which affects younger patients with hypercoaguable states. AMI is characterized by sudden onset of abdominal pain; a benign abdominal exam may be observed prior to bowel infarction. Conventional angiography and more recently, computed tomography angiography, are the cornerstones of diagnosis. Correction of predisposing conditions, volume resuscitation and antibiotic treatment are standard treatments for AMI, and surgery is mandated in the setting of peritoneal signs. Intra‐arterial vasodilators are used routinely in the treatment of non‐occlusive mesenteric ischaemia (NOMI) and also are advocated in the treatment of occlusive AMI to decrease associated vasospasm. Thrombolytics have been used on a limited basis to treat occlusive AMI. A variety of agents have been studied in animal models to treat reperfusion injury, which sometimes can be more harmful than ischaemic injury. Chronic mesenteric ischaemia (CMI) usually is caused by severe obstructive atherosclerotic disease of two or more splanchnic vessels, presents with post‐prandial pain and weight loss, and is treated by either surgical revascularization or percutaneous angioplasty and stenting.

Effects of Concomitant Immunomodulator Therapy on Efficacy and Safety of Anti–Tumor Necrosis Factor Therapy for Crohn’s Disease: A Meta-analysis of Placebo-controlled Trials

BACKGROUND & AIMS There is debate over whether patients with Crohns disease who start anti-tumor necrosis factor (TNF) therapy after failed immunomodulator therapy should continue to receive concomitant immunomodulators. We conducted a meta-analysis of subgroups from randomized controlled trials (RCTs) of anti-TNF agents to compare the efficacy and safety of concomitant immunomodulator therapy vs anti-TNF monotherapy. METHODS We performed a systematic review of literature published from 1980 through 2008 and identified 11 RCTs of anti-TNF agents in patients with luminal or fistulizing Crohns disease. We excluded RCTs of patients who were naive to anti-TNF and immunomodulator therapy. The primary end points were clinical response at weeks 4-14 and 24-30 and remission at weeks 24-30. Secondary end points included infusion site or injection site reactions and selected adverse events. A priori subgroup analyses were performed to evaluate fistula closure and the efficacy and safety of combination therapy with different anti-TNF agents. RESULTS Overall, combination therapy was no more effective than monotherapy in inducing 6-month remission (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.80-1.31), inducing a response (OR, 1.08; 95% CI, 0.79-1.48), maintaining a response (OR, 1.53; 95% CI, 0.67-3.49), or inducing partial (OR, 1.25; 95% CI, 0.84-1.88) or complete fistula closure (OR, 1.10; 95% CI, 0.68-1.78). In subgroup analyses of individual anti-TNF agents, combination therapy was not more effective than monotherapy in inducing 6-month remission in those treated with infliximab (OR, 1.73; 95% CI, 0.97-3.07), adalimumab (OR, 0.88; 95% CI, 0.58-1.35), or certolizumab (OR, 0.93; 95% CI, 0.65-1.34). Overall, combination therapy was not associated with an increase in adverse events, but inclusion of infliximab was associated with fewer injection site reactions (OR, 0.46; 95% CI, 0.26-0.79.) CONCLUSIONS On the basis of a meta-analysis, continued use of immunomodulator therapy after starting anti-TNF therapy is no more effective than anti-TNF monotherapy in inducing or maintaining response or remission. RCTs are needed to adequately assess the efficacy of continued immunomodulator therapy after anti-TNF therapy is initiated.

Pharmacologically mediated colon ischemia.

Colon ischemia (CI) is the most common form of ischemic injury of the gastrointestinal tract. Determining the precise incidence of CI is a challenging task, because of its often brief, mild nature, and frequent spontaneous resolution, as well as its misdiagnosis as other diseases. While many underlying disease conditions may predispose patients to CI, an important and possibly overlooked etiology is that of pharmacologically induced alterations of colonic blood flow. This review details the pharmacologic agents known to be associated with CI; when possible, their mechanisms of action are described. The aim of this paper is to highlight this often unrecognized cause of CI, thereby helping physicians to be aware of the association, to recognize its occurrence promptly, and to possibly reduce morbidity and mortality.

The Appropriateness of Concomitant Immunomodulators With Anti–Tumor Necrosis Factor Agents for Crohn's Disease: One Size Does Not Fit All

BACKGROUND & AIMS There is no consensus on the appropriateness of concomitant immunomodulators with anti-tumor necrosis factor (TNF) therapy for Crohns disease. Some patients benefit from concomitant immunomodulators, but concerns related to infections and lymphoma risk have dampened enthusiasm for this approach. We applied the RAND/University of California Los Angeles Appropriateness Method toward establishing appropriateness of concomitant immunomodulators and anti-TNF therapies for Crohns disease. METHODS A literature review was conducted regarding efficacy and safety of concomitant immunomodulators in the setting of anti-TNF therapy for Crohns disease and presented to the Building Research in Inflammatory Bowel Disease Globally group, a globally diverse panel of 13 gastroenterologists clinically experienced in inflammatory bowel disease. A total of 134 scenarios were constructed using several clinical variables. Panelists used a modified Delphi method to rate the appropriateness of concomitant immunomodulators, and met to discuss and re-rate appropriateness. Disagreement was assessed using a validated index. RESULTS Concomitant immunomodulators were generally rated appropriate for 63 scenarios, uncertain for 60 scenarios, and inappropriate for 11 scenarios. In general, concomitant immunomodulators were appropriate for those with extensive disease, shorter duration of disease, perianal involvement, prior surgery, females, and older patients (>26 y). Concomitant immunomodulators were generally rated inappropriate for young males, and in some scenarios involving uncomplicated disease. Smoking and the particular anti-TNF medication did not influence ratings. Disagreement was observed in 6 of 134 scenarios. CONCLUSIONS The appropriateness of concomitant immunomodulators with anti-TNF therapy for Crohns disease was determined through a modified Delphi panel approach based on expert interpretation of the available literature. Clinicians should consider multiple factors when considering concomitant immunomodulators with anti-TNF treatment.

Reliability of cerebral measures in repeated examinations with magnetic resonance imaging

This study examined the reliability of quantitative measures of cerebral magnetic resonance images (MRI) in repeated scans. Ten subjects were scanned twice, at 2- to 4-week intervals. Volumetric data from 14 regions of the cerebrum, the caudate nucleus, and the lateral ventricles and area measures of the corpus callosum were acquired. Intrarater and scan-rescan reliabilities, including the relative percent error from each of these two sources, were determined for each structure. Intraclass correlations ranged from 0.88 for the head of the caudate nucleus to 0.99 for the ventricular volume. Quantitative cerebral MRI measures of these structures are stable over time intervals of 2-4 weeks.

979 Impact of Concomitant Immunomodulator Treatment on Efficacy and Safety of Anti-TNF Therapy in Crohn's Disease: A Meta-Analysis of Placebo Controlled Trials With Individual Patient-Level Data

Background: Objective markers of Crohns Disease (CD) activity have been sought as diagnostic, phenotypic, prognostic and disease activity markers. Complications such as stricture and fistula and characteristics such as TNF-antagonist responsiveness have been suggested as discreet mechanistic CD subtypes. This study explored the ability of genome wide expression profiling in whole blood to differentiate CD sub-populations. Methods: In the previously reported Phase 2b ustekinumab CERTIFI study of patients with moderate to severely active CDwho had failed or were intolerant to TNF-antagonists, whole blood samples were collected from a subset for mRNA expression profiling using Affymetrix HG-U133+ PM arrays. Baseline expression profiles were compared between patient sub-groups characterized by defined baseline disease attributes; and compared with those from samples obtained independently from healthy subjects. Expression modulations of .+/-1.5x and false discovery rate (FDR) p-value , 0.05 were considered significant. Results: Patients (n=204) with moderate to severe CD had significant expression modulations in 1725 transcripts in the whole blood compared with healthy subjects (n=49), including genes involved in inflammatory response and connective tissue disorders. A panel of 20 transcripts (including GAB2 and IL18R1) discriminated patients with only colonic (n=49) vs. strictly ileal (n=60) disease involvement. Significantly different expression modulations of 169, 321, and 151 transcripts, respectively, were identified in patients with high baseline CRP ( ≥10 mg/dL, n=97), fecal calprotectin (≥850 mg/g, n=80) or lactoferrin (. 100 mg/g, n=89) compared with patients with low baseline CRP ( ≤3 mg/dL, n=45), fecal calprotectin (≤250 mg/g, n=58), or lactoferrin (≤100 mg/g, n=107). As expected, patients with high baseline CRP, fecal calprotectin, or lactoferrin had elevated gene expressions in inflammatory pathways such as IL-6 and acute phase response signaling. In contrast, gene expression profiles did not differentiate between patients with different durations of disease (long [≥15yrs] vs. short [≤5yrs]); prior treatment response (Primary responder vs. non-responder) and treatment history (number of TNFs failed); and the presence or absence of complications (stricture/stenosis, fistula). Conclusion: Genomewide expression profiling of peripheral blood samples provides the understanding of CD at the molecular level in circulation. This is a new, non-invasive method that can be used to identify systemic markers of local pathological alterations in CD and to discriminate clinically between different CD sub-types. Table: Number of significant expression modulations between CD sub-populations

Appropriateness of Testing for Anti–Tumor Necrosis Factor Agent and Antibody Concentrations, and Interpretation of Results

BACKGROUND & AIMS The availability of tests for blood concentrations of anti-tumor necrosis factor (TNF) agents and antibodies against these drugs could improve dose selection for patients with inflammatory bowel disease (IBD). However, there is little consensus on when to test and how to interpret test results. We used the RAND/UCLA Appropriateness Method to determine when these tests are appropriate and how to clinically interpret their results. METHODS We conducted a systematic literature search in November 2013 to identify observational or experimental studies of the measurement of anti-TNF drug and antibody concentrations in patients with IBD and interpretation of their results. We developed 35 scenarios that assessed the appropriateness of testing and 143 scenarios that addressed clinical strategies in response to test results, and presented the findings to an expert panel. The appropriateness of each scenario was rated before and after an in-person meeting with the panel. Panelists rated the appropriateness of various clinical management options including changing therapy within class, switching out of class, adjusting drug dose or interval, adding or adjusting concomitant immune modulators, and doing nothing for each of 6 permutations of high versus low drug concentrations and high, low, or undetectable antibody concentrations. Disagreement was assessed using a validated index. RESULTS Assessment of anti-TNF drug and antibody concentrations was rated appropriate at the end of induction therapy in primary nonresponders, in secondary nonresponders, at least once during the first year of maintenance therapy, and following a drug holiday. Routine assessment in responders at the end of induction was rated uncertain. In nearly all scenarios, escalation of drug dosing was rated appropriate when drug concentration was low in the absence of antibodies, and switching within class was rated appropriate when antibodies were present. Other recommendations depended on the specific clinical scenario for which the test was obtained. CONCLUSIONS Based on the RAND/UCLA Appropriateness Method of analysis, an expert panel recommends testing for drug and antibody concentrations in many clinical scenarios. The appropriate timing and best way to respond to anti-TNF drug and antibody testing for IBD depends on the specific clinical scenario. These recommendations can help guide clinicians to best optimize anti-TNF therapy.

Setting priorities for comparative effectiveness research in inflammatory bowel disease: Results of an international provider survey, expert rand panel, and patient focus groups†

Background: Comparative effectiveness research (CER) is an emerging field that compares the relative effectiveness of alternative strategies to prevent, diagnose, or treat patients who are typical of day‐to‐day practice. We developed a priority list of CER topics for inflammatory bowel disease (IBD). Methods: Following the Institute of Medicines approach, we developed and administered a survey to gastroenterologists asking for important CER topics in IBD. Two patient focus groups were convened to solicit additional CER studies. CER topics were presented to the expert panel using the RAND/UCLA methodology. Following initial ratings, the panel met to discuss and re‐rate priorities. The top 10 CER topics were identified using a point‐allocation system. Results: Responses were collated into 234 CER topics across 21 categories, of which 87 were prioritized for discussion and re‐rated. Disagreement regarding priorities was observed in 5 of 87 studies. We utilized a point‐allocation system to prioritize the top‐10 CER topics. These related to comparing the effectiveness of: biomarkers in IBD; withdrawal of anti‐tumor necrosis factor (TNF) or immunomodulators for Crohns disease in remission; mucosal healing as an endpoint of treatment; infliximab levels versus standard infliximab dosing; anti‐TNF monotherapy versus combination therapy in patients failing thiopurines; safety of long‐term treatment options; anti‐TNF versus thiopurines for prevention of postoperative recurrence; and treatment options for steroid‐refractory UC. Conclusions: We systematically developed a list of high‐priority IBD topics for CER based on a survey of gastroenterologists, expert review, and patient input. This list may guide IBD research toward the most important CER studies. (Inflamm Bowel Dis 2012;)