Coincidence of active Crohn’s disease and florid endometriosis in the terminal ileum: A case report

Crohn’s disease (CD), a variant of chronic inflammatory bowel disease, frequently affects the terminal ileum and coecal region. The clinical symptoms are often subtle and depend on the inflammatory activity of disease. In women of child-bearing age, florid intestinal endometriosis can simulate CD. Moreover, current pathophysiological concepts include intestinal endometriosis as a putative founder lesion for consecutive CD establishment. The report summarizes clinical and histomorphological data of a 35-year-old woman with the rare coincidence of florid intestinal endometriosis and CD both affecting the terminal ileum. The patient was suffering over 10 years from strong abdominal disorders including constipation, diarrhea, weight loss, and diffuse abdominal pain. In magnetic resonance imaging-Sellink, strong inflammation and intestinal obstruction of the terminal ileum were found. The laparoscopy revealed further evidence for existence of an inflammatory disease like CD, but brownish spots on the peritoneum were found indicative for endometriosis. Surgical resection of the terminal ileum and the coecal segment was performed followed by histopathological investigations. In transmural sections of the terminal ileum, histomorphological features of florid endometriosis intermingled with florid CD was found. The diagnostic findings were substantiated with a panel of immunohistological stainings. In conclusion, the findings demonstrate that florid endometriosis persists in florid CD lesions and the putative link between intestinal endometriosis and CD is more complex than previously assumed.     

Muscle performance and fatigue in compensated chronic liver disease

Abstract

Background: A common and debilitating symptom in patients with chronic liver disease is fatigue (CLD). Muscle dysfunction has been suggested to be a key mechanism of fatigue in CLD.

Objective: We aimed to evaluate fatigue and the potential association with muscle performance and physical activity in outpatients with CLD.

Methods: Two-hundred seventy outpatients with CLD were included, (52?±?15 years, mean?±?SD; 151 females) with autoimmune hepatitis (n?=?49), primary biliary cholangitis (n?=?45), primary sclerosing cholangitis (n?=?46), chronic hepatitis B (n?=?57) or C (n?=?73). Patients with a Child-Pugh >6 were excluded. The questionnaire Fatigue Impact Scale (FIS) was used to evaluate fatigue, and physical activity was evaluated through a self-reported level of physical activity. Muscle function was assessed with four muscle tests, walking speed, handgrip strength, standing heel-rise test (SHT) and ‘Timed Up and Go’ test (TUG).

Results: The median total FIS score was 30 (40% had FIS > 40, considered high-fatigue). Diminished muscle performance was observed in the SHT (% of predicted value: 53?±?26%) and with maximum grip strength (85?±?20%). The FIS score was significantly different between groups of CLDs (p?=?.004). In multivariate analysis the TUG (p?=?.001), SHT (p?=?.005), antidepressants (p?p?=?.001) were associated with fatigue (R²?=?29%). Subjects with higher levels of physical activity had lower FIS (p?Conclusions: In patients with CLD, fatigue was associated with low muscle performance and reduced level of physical activity, which could be a potential therapeutic target.     

Metal ions control product specificity of isoprenyl diphosphate synthases in the insect terpenoid pathway

Isoprenyl diphosphate synthases (IDSs) produce the ubiquitous branched-chain diphosphates of different lengths that are precursors of all major classes of terpenes. Typically, individual short-chain IDSs (scIDSs) make the C₁₀, C₁₅, and C₂₀ isoprenyl diphosphates separately. Here, we report that the product length synthesized by a single scIDS shifts depending on the divalent metal cofactor present. This previously undescribed mechanism of carbon chain-length determination was discovered for a scIDS from juvenile horseradish leaf beetles, Phaedon cochleariae. The recombinant enzyme P. cochleariae isoprenyl diphosphate synthase 1 (PcIDS1) yields 96% C₁₀-geranyl diphosphate (GDP) and only 4% C₁₅-farnesyl diphosphate (FDP) in the presence of Co²⁺ or Mn²⁺ as a cofactor, whereas it yields only 18% C₁₀ GDP but 82% C₁₅ FDP in the presence of Mg²⁺. In reaction with Co²⁺, PcIDS1 has a K_m of 11.6 μM for dimethylallyl diphosphate as a cosubstrate and 24.3 μM for GDP. However, with Mg²⁺, PcIDS1 has a K_m of 1.18 μM for GDP, suggesting that this substrate is favored by the enzyme under such conditions. RNAi targeting PcIDS1 revealed the participation of this enzyme in the de novo synthesis of defensive monoterpenoids in the beetle larvae. As an FDP synthase, PcIDS1 could be associated with the formation of sesquiterpenes, such as juvenile hormones. Detection of Co²⁺, Mn²⁺, or Mg²⁺ in the beetle larvae suggests flux control into C₁₀ vs. C₁₅ isoprenoids could be accomplished by these ions in vivo. The dependence of product chain length of scIDSs on metal cofactor identity introduces an additional regulation for these branch point enzymes of terpene metabolism.     

Drug- and Herb-Induced Liver Injury in Clinical and Translational Hepatology: Causality Assessment Methods,Quo Vadis?

Drug-induced liver injury (DILI) and herb-induced liver injury (HILI) are typical diseases of clinical and translational hepatology. Their diagnosis is complex and requires an experienced clinician to translate basic science into clinical judgment and identify a valid causality algorithm. To prospectively assess causality starting on the day DILI or HILI is suspected, the best approach for physicians is to use the Council for International Organizations of Medical Sciences (CIOMS) scale in its original or preferably its updated version. The CIOMS scale is validated, liver-specific, structured, and quantitative, providing final causality grades based on scores of specific items for individual patients. These items include latency period, decline in liver values after treatment cessation, risk factors, co-medication, alternative diagnoses, hepatotoxicity track record of the suspected product, and unintentional re-exposure. Provided causality is established as probable or highly probable, data of the CIOMS scale with all individual items, a short clinical report, and complete raw data should be transmitted to the regulatory agencies, manufacturers, expert panels, and possibly to the scientific community for further refinement of the causality evaluation in a setting of retrospective expert opinion. Good-quality case data combined with thorough CIOMS-based assessment as a standardized approach should avert subsequent necessity for other complex causality assessment methods that may have inter-rater problems because of poor-quality data. In the future, the CIOMS scale will continue to be the preferred tool to assess causality of DILI and HILI cases and should be used consistently, both prospectively by physicians, and retrospectively for subsequent expert opinion if needed. For comparability and international harmonization, all parties assessing causality in DILI and HILI cases should attempt this standardized approach using the updated CIOMS scale.     

Differential contribution of frontal and temporal cortices to auditory change detection: fMRI and ERP results.

The present study addresses the functional role of the temporal and frontal lobes in auditory change detection. Prior event-related potential (ERP) research suggested that the mismatch negativity (MMN) reflects the involvement of a temporofrontal network subserving auditory change detection processes and the initiation of an involuntary attention switch. In the present study participants were presented with repetitive spectrally rich sounds. Infrequent changes of either small (10% change), medium (30% change), or large (100% change) magnitude were embedded in the stimulus train. ERPs and fMRI measures were obtained in the same subjects in subsequent sessions. Significant hemodynamic activation in the superior temporal gyri (STG) bilaterally and the opercular part of the right inferior frontal gyrus was observed for large and medium deviants only. ERPs showed that small deviants elicited MMN when presented in silence but not when presented with recorded MR background noise, indicating that small deviants were hardly detected under fMRI conditions. The MR signal change in temporal lobe regions was larger for large than for medium deviants. For the right fronto-opercular cortex the opposite pattern was observed. The strength of the temporal activation correlated with the amplitude of the change-related ERP at around 110 ms from stimulus onset while the frontal activation correlated with the change-related ERP at around 150 ms. These results suggest that the right fronto-opercular cortex is part of the neural network generating the MMN. Three alternative explanations of these findings are discussed.     

Adiponectin promotes the migration of circulating angiogenic cells through p38-mediated induction of the CXCR4 receptor

Aims

Adiponectin (adipo) and exercise training (ET) contribute to the maintenance of a normal vascular tone by influencing vascular NO bioavailability and concentration and function of circulating angiogenic cells (CAC). The molecular mechanisms are only partially understood. Aim of the present study was to elucidate the effects of adipo on CAC migration and the underlying signaling pathways. Furthermore, the impact of ET on adiponectin-mediated CAC migration was investigated.

Methods and results

CACs were isolated from peripheral blood and exposed to different adipo concentrations. Adipo (5 μg/ml) enhanced the ability of CACs to migrate following an SDF-1 gradient by 345%. This was associated with a significant increase in CXCR4 expression on the surface of CACs as compared to control (10.1 ± 1.5 vs. 33.2 ± 4.5% CXCR4 positive cells, p < 0.05). Adiponectin-induced CAC migration and CXCR4-upregulation were mediated through adipo-receptor 1 (AdipoR1) and blocked by an inhibitor of PI3-kinase, p38MAP kinase and NFκb. Adipo-stimulated migration of CACs, CXCR4 expression and p38MAPK-activation is impaired in patients with coronary artery disease (CAD). ET over 4 weeks partially corrects adiponectin-stimulated CAC migration and CXCR4 expression in patients with CAD (n = 10). No change was observed in the control group (n = 10).

Conclusion

Adipo improves the migratory capacity of CACs in response to SDF1, partially through an upregulation of CXCR4. This is mediated through a pathway that involves binding of adipo to the AdipoR1 and subsequent PI3kinase/p38MAPK/ NFκb activation. In addition ET corrects the adiponectin responsiveness of CACs, and thereby might promote endogenous repair of damaged endothelium.     

Dysphagia Due to Unilateral Infarction in the Vascular Territory of the Anterior Insula

We describe a patient who suddenly developed dysphagia for liquids as the sole manifestation of stroke. Magnetic resonance imaging (MRI) revealed a right-sided infarction of the superior part of the anterior insula and a small portion of the adjacent medial frontal operculum. These findings confirm the role of the anterior insula as a critical area in humans with regard to the origin of dysphagia.

Head-to-head comparison of bivalirudin versus heparin without glycoprotein IIb/IIIa inhibitors in patients with acute myocardial infarction undergoing primary angioplasty

BackgroundIn patients receiving primary percutaneous coronary intervention for ST elevation myocardial infarction (STEMI), bivalirudin with provisional glycoprotein (GP) IIb/IIIa inhibitors has been demonstrated to be noninferior to heparin plus systematic GP IIb/IIIa inhibitors in preventing recurrent ischemic events with improved safety in terms of bleeding. However, no study has been performed comparing head-to-head bivalirudin with heparin without GP IIb/IIIa inhibitor infusion in STEMI patients.MethodsWe retrospectively studied 899 consecutive patients who presented with STEMI treated by primary angioplasty within 12 h after symptoms. Among them, 566 received bivalirudin and 333 received unfractionated heparin. Their in-hospital outcome in terms of efficacy and safety was assessed using rates of major adverse cardiac events (MACE) and major bleeding, respectively. Clinical, angiographic and procedural characteristics were well matched between the two groups.ResultsPatients in the heparin group more frequently required intra-aortic balloon pumping (6.6% vs. 3.6%, P=.037). Regarding the safety end point, the MACE rate, including death, ischemic stroke and urgent repeated revascularization, was low and similar in both groups (2.7% bivalirudin vs. 1.2% heparin, P=.15). The rate of major bleeding, including major hematoma, gastrointestinal bleeding and hematocrit drop >15% during hospitalization, was high and identical in the two groups (4.1% bivalirudin vs. 4.2% heparin, P=.92).ConclusionThis study suggests that bivalirudin and heparin present similar safety and efficacy profiles when used without GP IIb/IIIa inhibitor infusion during primary angioplasty.     

Dose Dependency and Reversibility of Serotonin-Induced Valvular Heart Disease in Rats

Serotonergic drugs may lead to valvular heart disease in humans and more recently also in rats. Although clinical data suggest that dose dependency and reversibility after drug cessation might occur, proof of this is lacking. For that purpose, a total of 106 rats were prospectively enrolled: 22 control animals and 7 groups of 12 rats that received daily subcutaneous serotonin injections (5, 10, 20, 30, 40, 50 and 60 mg/kg respectively) for 12 weeks. At 12 weeks, half of the animals of each group were killed for histological analysis, whereas the remaining rats were further followed (without serotonin injections) for an additional 8 weeks. After 12 weeks of serotonin treatment, aortic and mitral regurgitation (AR, MR) were more frequently observed in the high dose groups (>30 mg/kg) compared to controls. Moreover, aortic and mitral valves were also thicker in the high dose groups compared to controls. After 8 weeks free of serotonin injections, AR and MR were no longer significantly higher than controls. Moreover, aortic and mitral valve thickness had normalized, returning to control levels. In conclusion, this study provides evidence for a dose-dependent valvular toxicity of serotonergic drugs, which appears to be reversible after drug withdrawal.