Association between self-rated depressive symptoms and mucosal expression of NF-κ B in patients with upper gastrointestinal symptoms.

BACKGROUND: Previous clinical studies have reported elevated levels of depressive symptoms in selected samples of patients with gastritis. The objective of this study was to examine the associations of specific biomarkers of inflammation expressed in mucosal tissue from the stomach with mood and anxiety symptoms in adult patients with upper gastrointestinal symptoms. METHODS: In this monocentric, observational study, a total of 32 study participants were included who were referred for a routine diagnostic upper endoscopic assessment based on the suspected clinical diagnosis of gastritis. All participants completed the Hospital Anxiety and Depression Scale (HADS) before undergoing gastroscopy. Immunohistochemical stainings from biopsy sections were performed to evaluate the expression level of nuclear factor kappa B (NF-κ B), myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS). RESULTS: Our findings confirmed that nearly half of the study cohort (n = 13; 41%) displayed positive HADS depression scores above the clinically relevant cut-off level of ≥ 8. Regression models demonstrated that depressive symptoms were significantly and positively associated with the expression level of NF-κ B in biopsies from the upper gastrointestinal tract. CONCLUSIONS: In summary, our study showed a significant association between NF-κ B expression and clinically relevant depressive symptoms in patients with gastritis, as assessed by a self-rated psychometric questionnaire. Further investigations are needed to confirm this relationship and to identify the pathophysiological mechanisms involved.

Budesonide with Low-Dose 6-Mercaptopurine as a Possible New Treatment for IgG4-Related Sclerosing Cholangitis and Systemic IgG4-Related Disease: A Case Report.

BACKGROUND Systemic IgG4-related disease is a rare disease that can affect the hepatobiliary system and may lead to tissue fibrosis and organ failure. Diagnostic criteria for IgG4-related disease are well established, and systemic glucocorticoids are recommended for initiation of treatment. Besides the beneficial properties of glucocorticoids, the long-term treatment with systemic steroids carries the risk of toxicity, especially in elderly patients, in whom IgG4-related disease is more common. Furthermore, disease relapses may occur during the tapering of steroids. Overall, the optimal treatment approach for maintenance therapy has not been clarified yet and is an area of current clinical research. CASE REPORT We present a patient with IgG4-related sclerosing cholangitis and histologically confirmed systemic (multi-organ) IgG4-related disease who was at increased risk of disease recurrence. The effects of immunosuppressants (prednisolone, 6-mercaptopurine, budesonide) on clinical symptoms, laboratory parameters (AST, ALT, AP, γGT, bilirubin), and imaging examinations (magnetic resonance cholangiography) were documented over 56 months. Control of IgG4-related sclerosing cholangitis was achieved - without systemic prednisolone - with the locally acting glucocorticoid budesonide in combination with low-dose 6-mercaptopurine. During treatment with 6-mercaptopurine, transient hepatotoxicity occurred, which was reversed by intermittent pausing and subsequent dose reduction. In addition, gangrenous cholecystitis occurred as a complication of immunosuppression and was treated by emergency cholecystectomy. CONCLUSIONS Budesonide could be a new treatment modality for IgG4-related sclerosing cholangitis. Systemic manifestations of immunoglobulin G4-related disease can be controlled with low-dose 6-mercaptopurine. Gangrenous cholecystitis may occur as a complication of immunosuppressive treatment.

Case report: Kinetics of human leukocyte antigen receptor HLA-DR during liver injury induced by potassium para-aminobenzoate as assessed for causality using the updated RUCAM.

Potassium para-aminobenzoate (POTABA) is used to treat Peyronie's disease by decreasing fibrosis and plaque size progression. Among potential side effects, drug-induced liver injury (DILI) attributed to POTABA administration has been reported in a few cases and inferred to immune hypersensitivity. In the present case, we investigated clinical, biochemical, and serological features as well as searched for non-drug-related causes, and applied the updated Roussel Uclaf Causality Assessment Method (RUCAM) confirming a highly probable causality of POTABA-induced liver injury. Moreover, we here observed specific activated CD3+ T lymphocytes during the acute phase of liver injury by monitoring of human leukocyte antigen receptor (HLA-DR) expression. Furthermore, improvement of biochemical markers of liver injury after POTABA withdrawal was associated with a rapid decline of CD3+ HLA-DR+ immune cells. In contrast, CD14+ monocytes expressing HLA-DR remained stable during recovery from liver injury. These observations implicate a specific involvement of activated T lymphocytes in liver injury mediated by POTABA. Clinicians should be aware of POTABA-induced liver injury, and measurement of activated immune cells by assessment of HLA-DR could provide pathomechanistic insights enabling biomonitoring of recovery from DILI.

Systemic IgG4-Related Disease Masquerading as Cholangiocarcinoma: A Case Report Underscoring the Importance of Medical History.

BACKGROUND Immunoglobulin (Ig) G4-related disease is a rare disease of unknown pathophysiology, which can affect multiple organs leading to tissue fibrosis and organ failure. The present case report describes a patient with systemic IgG4-related disease (IgG4-RD) that occurred over a 1-year period and affected multiple organs at different times. Imaging studies, interventional procedures, changes in laboratory parameters, and histopathology demonstrate the novel and known aspects of this disease before and during prednisolone monotherapy and in combination with azathioprine. CASE REPORT A 64-year-old man presented with weight loss and painless jaundice, which was highly suspicious for cholangiocarcinoma. A thorough medical history together with laboratory tests, imaging procedures, and endoscopic interventions confirmed that surgery was not needed and led to the final diagnosis of histologically-confirmed, IgG4-related sclerosing cholangitis and autoimmune pancreatitis type 1. Other typical organ manifestations of systemic IgG4-RD were diagnosed through a thorough medical review, which led to immunohistochemical reevaluation of past surgical specimens. Besides the IgG4-related organ manifestations, which can include periorbital xanthelasmas, our patient developed a pulmonary adenocarcinoma 6 years after the initial clinical onset of IgG4-RD. After immunosuppressive treatment with prednisolone alone and subsequently in combination with azathioprine, the patient's IgG4-RD resolved. CONCLUSIONS Interdisciplinary collaboration is required to diagnose IgG4-RD that involves multiple organs. Patient medical history remains crucial for diagnosis and attention should be paid to avoiding unnecessary surgery. Tumors (lung adenocarcinomas) and xanthelasmas can develop because of IgG4-RD. Glucocorticoids and additional azathioprine may be advisable for maintenance treatment.

Severe drug-induced liver injury in patients under treatment with antipsychotic drugs: Data from the AMSP study.

OBJECTIVES: Drug-induced liver injury (DILI) has been associated with various antipsychotic drugs (APDs). Comparative studies between individual APDs are largely not available. METHODS: Antipsychotic drug utilisation data and reports of severe antipsychotic DILI were assessed by using data from an observational pharmacovigilance programme-Arzneimittelsicherheit in der Psychiatrie (AMSP)-during the period 1993-2016. RESULTS: Of the 333,175 patients treated with APDs, a total of 246 (0.07%) events of severe DILI were identified. Phenothiazines were associated with significantly higher rates of severe DILI (0.03%, 95% CI = 0.02-0.04) than thioxanthenes (0.01%, 95% CI = 0.00-0.02) or butyrophenones (0.01%, 95% CI = 0.00-0.01). Among individual drugs, olanzapine (0.12%, 95% CI = 0.10-0.16), perazine (0.09%, 95% CI = 0.05-0.15) and clozapine (0.09%, 95% CI = 0.10-0.12 ranked highest. In 78 cases (31.7%), combination therapies with antipsychotic and antidepressant drugs or with two or more APDs were considered responsible. Male sex and a diagnosis of mania were associated with significantly higher rates of severe DILI while older patients (≥65 years old) were significantly less often affected. CONCLUSIONS: In the present analysis of a representative psychiatric inpatient cohort, olanzapine, perazine, and clozapine were the most common individual APDs associated with severe DILI.

[Food poisoning by cucurbitacines]. / Lebensmittelvergiftung durch Cucurbitacine.

MEDICAL HISTORY AND CLINICAL PRESENTATION: A 66-year-old female patient was admitted to the emergency department following bitter zucchini ingestion. Clinical symptoms were tachycardia, hypotension, somnolence, diarrhea, hematochezia as well as exsiccosis, nausea and emesis. EXAMINATION AND DIAGNOSIS: Laboratory results showed leukocytosis and signs of exsiccosis. Ultrasound revealed thickening of the sigmoid colon wall, interpretable as acute colitis. Poisoning with cucurbitacin containing zucchini was diagnosed. THERAPY: The patient improved after intravenous fluid administration. Hemorrhagic colitis with diarrhea was self limiting. After 2 days, the patient was able to eat again. CONCLUSION: Acute food poisoning due to cucurbitacin - containing pumpkin is rare but can occur in small gardening units in association with higher outside temperatures. Cucurbitacin poisoning has to be taken into account for differential diagnosis in food poisoning. Bitter taste is essential to diagnose cucurbitacin intoxications.

Pantoprazole Does not Affect Serum Trough Levels of Tacrolimus and Everolimus in Liver Transplant Recipients.

Background: Liver transplant recipients are frequently treated with proton pump inhibitors. Drug interactions have been described especially with respect to omeprazole. Due to the lower binding capacity of pantoprazole to CYP2C19 this drug became preferred and became the most used proton pump inhibitor in Germany. The data on the influence of pantoprazole on immunosuppressive drugs in liver transplant recipients a very scarce. Methods: The authors performed a single center analysis in liver transplant recipients on the effect of pantoprazole on the serum trough levels of different immunosuppressants. The trough levels were compared over a period of 1 year before and after start or stop of a continuous oral co-administration of 40 mg pantoprazole once daily. Results: The serum trough levels of tacrolimus (n = 30), everolimus (n = 7), or sirolimus (n = 3) remain constant during an observation period of at least 1 year before and after co-administration of pantoprazole. None of the included patients needed a change of dosage of the observed immunosuppressants during the observation period. Conclusions: The oral co-administration of pantoprazole is safe in immunosuppressed liver transplant recipients according to the serum trough levels of tacrolimus, everolimus, and sirolimus. This analysis provides first data on the influence of pantoprazole on immunosuppressive drugs in liver transplant recipients.

[Severe hypoglycemia following tramadol intake in a 79 year old non-diabetic patient]. / Schwere Hypoglykämie nach Tramadol-Einnahme bei einer nicht-diabetischen Patientin.

History and clinical findings | We report about a 79 year old non-diabetic patient who was admitted to the emergency room with severe hypoglycemia (blood glucose level: 36 mg / dl and Glasgow Coma Scale Score: 3). After the infusion of G40 % her blood glucose level stabilised. The patient reported to have taken 50 mg of Tramadol during the night to treat her headache. Investigations and diagnosis | No other differential diagnosis for hypoglycemia (i.e. diabetes, insulinoma, severe liver or kidney disease) could be established. Therefore, we suspected a tramadol induced hypoglycemia. The mechanisms and the risk factors for this potential side effect remain unclear. The patient showed no abnormality in metabolism (CYP2D6) or membrane transport (OCT1) of tramadol. Treatment and course | No further treatment for hypoglycemic episodes was needed. The patient was discharged after the differential diagnosis and pharmacogenetic testing was completed. Conclusions | Hypoglycemia is a little known adverse effect after tramadol intake, which has only been published in few cases. Tramadol, a weak opioid analgesic classified as step 2 of the WHO cancer pain ladder, is used in moderate pain. Given the continuous rise in tramadol prescription due to better management of chronic pain, further investigation of this issue seems needed as well as an increased awareness amongst physicians.

Long-lasting complete response of metastatic melanoma to ipilimumab with analysis of the resident immune cells.

Even though ipilimumab is a promising antibody used for stage IV melanoma therapy, the response varies and is difficult to predict. We here report on a case of successful treatment with ipilimumab in dacarbazine-resistant metastatic malignant melanoma, including a review of the literature on the long-term treatment results. A 62-year-old patient with a history of a resected lentigo-maligna melanoma 5 years earlier and parotideal metastasis 1 year before was admitted with a newly detected 3.5 cm liver metastasis. Atypical liver resection was performed (R1). Immunohistochemically, CD3+ T-lymphocytes and CD68+ macrophages were detected at the tumour margins and within the parotideal and hepatic melanoma metastases. A sub-analysis of the liver metastasis showed scattered FOX-P3+ regulatory T-lymphocytes as well as multiple CD8+ effector T-cells. Chemotherapy with dacarbazine 1,000 mg/m(2)/day was administered at 4-weeks intervals for 3 months. A follow-up positron-emission computed tomography and liver biopsy revealed melanoma metastases in the liver, lungs, and mediastinum. Compassionate use of ipilimumab was administered at 3 mg/kg every 3 weeks for a total of four doses. After an initial increase in tumour size, most lesions responded, but progressive axillary and cervical lymphadenopathy was observed before complete remission was achieved. Side effects included fatigue, dyspnoea, cough, upper abdominal pain with diarrhoea, and gingival hyperplasia. Now, 36 months after ipilimumab therapy and 8 years after the initial melanoma diagnosis, the tumour did not recur. It would be challenging to hypothesize that long intervals between diagnosis and need for treatment, clinical side effects, an initial increase in tumour size and the presence of intra-tumoural T-cells and macrophages might predict tumour response.

Pharmacokinetics of meropenem in critically ill patients with severe infections.

BACKGROUND: Meropenem is an effective ß-lactam antibiotic that is frequently used to treat serious infections in both intensive care unit (ICU) and febrile neutropenic hematology/oncology (Hem/Onc) patients. Studies suggest that to be effective, meropenem concentrations must be maintained above the inhibitory concentrations for the majority of a dosing interval. However, the pharmacokinetics (PK) of meropenem seem to differ in critically ill patients compared with healthy or less ill subjects used to select labeled dosing regimens. OBJECTIVES: This study was designed to investigate meropenem PK in critically ill patients and to see how often standard dosing regimens produced adequate plasma concentrations. A secondary objective was to investigate how achieved concentrations were related to outcomes (morbidity and mortality) in these patients. METHODS: Meropenem plasma concentrations over time were measured using a high pressure liquid chromatography assay in febrile Hem/Onc and ICU patients who were treated with standard meropenem dosing schedules. Outcomes such as fever control and survival were assessed in these patients and compared with individual meropenem PK data and with recommended target concentrations. RESULTS: A total of 25 subjects including 10 febrile Hem/Onc and 15 ICU patients with a variety of serious illnesses and baseline renal function were studied. Mean peak concentrations were less variable than were pre-dose concentrations. Post peak and trough concentrations were often below recommended minimum inhibitory concentrations. Both clearance and volumes of distribution were greater than reported in less ill subjects, only in part explained by increased renal clearance. Therefore, serum concentrations often did not exceed recommended concentration targets even for moderately sensitive organisms. Inadequate concentrations were especially common in the mostly ill, febrile neutropenic Hem/Onc subjects and seemed to explain at least some therapeutic failures. Conversely, drug accumulation occurred in ICU subjects with decreased renal function. CONCLUSIONS: Standard meropenem dosing regimens were inadequate in many critically ill febrile, neutropenic Hem/Onc, and septic ICU patients. These data suggest a role for meropenem concentration monitoring in such patients.

Pyloric gland adenoma of the cystic duct with malignant transformation: report of a case with a review of the literature.

BACKGROUND: Pyloric gland adenoma consists of closely packed pyloric-type glands lined by mucus-secreting cells. To date, approximately 230 cases have been reported, mostly of gastric localization with a tumour size up to 3.5 cm and a mean age of occurrence around 70 years. Adenocarcinoma develops in about 40% of cases and may be difficult to detect due to relatively mild nuclear atypia. CASE PRESENTATION: We present the first case of a pyloric gland adenoma of the cystic duct in a 62-year-old male patient and demonstrate the clinicopathologic characteristics, including radiographic, molecular, and cytogenetic findings. The 2 cm-tumour developed in the cystic duct and protruded into the hepatic and common bile duct. On microscopic examination, it displayed closely packed pyloric-type glands, and focal architectural distortion with mild nuclear atypia. Immunohistochemically, it expressed MUC1, MUC5AC, MUC6 and p53, but not MUC2 and CD10. The Ki67-proliferation index was 25%. Furthermore, high-grade intraepithelial neoplasia was observed in the surrounding bile duct. We detected chromosomal gains at 7p, 7q11q21, 15q, 16p, 20, losses at 6p23pter, 6q, 18, and amplifications at 1q and 6p21p22 in the pyloric gland adenoma by comparative genomic hybridization. A KRAS codon 12 mutation (c.35G>T; p.G12V) was detected in the pyloric gland adenoma and in the adjacent dysplasia by sequencing analysis. The diagnosis of pyloric gland adenoma was established with transition into well-differentiated adenocarcinoma and high-grade biliary intraepithelial neoplasia. CONCLUSION: Pyloric gland adenoma evolving in the cystic duct is a rare differential diagnosis of obstructive bile duct tumours. Other premalignant bile duct lesions may be associated. Due to the risk of developing adenocarcinoma, surgical resection should be performed.

A case report of a patient with hereditary hemorrhagic telangiectasia treated successively with thalidomide and bevacizumab.

Hereditary hemorrhagic telangiectasia is characterized by mucocutaneous and visceral telangiectasia and involves several organs with vascular malformations. It is an autosomal dominant disease and is distinguished into three types, which are due to mutations in different genes. The common symptom is anemia, causing a continous need of blood transfusion. Depending on the severity and disease manifestation, there are various forms of therapy ranging from local therapy activities to operations or drug therapy. Here we describe a dramatic improvement of a patient with a high transfusion frequency due to severe recurrent anemia successively treated with thalidomide and bevacizumab.

Response of the primary tumor in symptomatic and asymptomatic stage IV colorectal cancer to combined interventional endoscopy and palliative chemotherapy.

BACKGROUND: The treatment of the primary tumor in advanced metastatic colorectal cancer (CRC) is still a matter of discussion. Little attention has thus far been paid to the endoscopically observable changes of the primary in non-curatively resectable stage IV disease. METHODS: 20 patients [14 men, 6 women, median age 67 (39-82) years] were observed after initial diagnosis of non-curatively resectable metastasized symptomatic (83%) or asymptomatic (17%) CRC, from June 2002 to April 2009. If necessary, endoscopic tumor debulking was performed. 5-FU based chemotherapy was given immediately thereafter. In 10 patients, chemotherapy was combined with antibody therapy. RESULTS: Response of the primary was observed in all patients. Local symptoms were treated endoscopically whenever necessary (obstruction or bleeding), and further improved after chemotherapy was started: Four patients showed initial complete endoscopic disappearance of the primary. In an additional 6 patients, only adenomatous tissue was histologically detected. In both these groups, two patients revealed local tumor relapse after interruption of therapy. Local tumor regression or stable disease was achieved in the remaining 10 patients. 15 patients died during the observation time. In 13 cases, death was related to metastatic disease progression. The mean overall survival time was 19.6 (3-71) months. No complications due to the primary were observed. CONCLUSION: This study shows that modern anti-cancer drugs combined with endoscopic therapy are an effective and safe treatment of the symptomatic primary and ameliorate local complaints without the need for surgical intervention in advanced UICC stage IV CRC.

Recent in vitro findings of negative inotropy of pantoprazole did not translate into clinically relevant effects on left ventricular function in healthy volunteers.

PURPOSE: Reports on cardiac problems with oral proton pump inhibitors have caused extensive safety reviews by the US Food and Drug Administration. We provide additional data on acute cardiac effects of an intravenous application. METHODS: Echocardiography was performed in 18 healthy volunteers after administration of a common high-dose regimen of pantoprazole (80 mg i.v. bolus followed by 8 mg/h for 1 h) or placebo. DESIGN: The design included a randomized, double-blind, placebo-controlled cross-over trial. RESULTS: Ejection fraction (%, mean +/- SE) in the treatment group (placebo group) was 60.7 +/- 1.1 (61.2 +/- 1.7) at baseline, and 62.6 +/- 1.1 (62.1 +/- 1.9), 64.7 +/- 1.6 (63.5 +/- 1.3), 62.6 +/- 1.6 (61.0 +/- 1.6) and 63.0 +/- 1.4 (61.8 +/- 1.5) at 7.5, 15, 30 and 60 min after bolus application, respectively (p = n.s.). Similarly, no significant changes were found for cardiac output, cardiac index, blood pressure and heart rate. In contrast, gastric pH that was used as a treatment control was significantly increased 60 min after the application of pantoprazole as compared to baseline and to placebo. CONCLUSIONS: Pantoprazole as injection is safe in healthy subjects with respect to cardiac contractile function. However, in view of recent reports of negative inotropy of the drug, further studies in heart failure patients are required.

Negative inotropy of the gastric proton pump inhibitor pantoprazole in myocardium from humans and rabbits: evaluation of mechanisms.

BACKGROUND: Proton pump inhibitors are used extensively for acid-related gastrointestinal diseases. Their effect on cardiac contractility has not been assessed directly. METHODS AND RESULTS: Under physiological conditions (37 degrees C, pH 7.35, 1.25 mmol/L Ca2+), there was a dose-dependent decrease in contractile force in ventricular trabeculae isolated from end-stage failing human hearts superfused with pantoprazole. The concentration leading to 50% maximal response was 17.3+/-1.3 microg/mL. Similar observations were made in trabeculae from human atria, normal rabbit ventricles, and isolated rabbit ventricular myocytes. Real-time polymerase chain reaction demonstrated the expression of gastric H+/K+-adenosine triphosphatase in human and rabbit myocardium. However, measurements with BCECF-loaded rabbit trabeculae did not reveal any significant pantoprazole-dependent changes of pH(i). Ca2+ transients recorded from field-stimulated fluo 3-loaded myocytes (F/F0) were significantly depressed by 10.4+/-2.1% at 40 microg/mL. Intracellular Ca2+ fluxes were assessed in fura 2-loaded, voltage-clamped rabbit ventricular myocytes. Pantoprazole (40 microg/mL) caused an increase in diastolic [Ca2+]i by 33+/-12%, but peak systolic [Ca2+]i was unchanged, resulting in a decreased Ca2+ transient amplitude by 25+/-8%. The amplitude of the L-type Ca2+ current (I(Ca,L)) was reduced by 35+/-5%, and sarcoplasmic reticulum Ca2+ content was reduced by 18+/-6%. Measurements of oxalate-supported sarcoplasmic reticulum Ca2+ uptake in permeabilized cardiomyocytes indicated that pantoprazole decreased Ca2+ sensitivity (Kd) of sarcoplasmic reticulum Ca2+ adenosine triphosphatase: control, Kd=358+/-15 nmol/L; 40 microg/mL pantoprazole, Kd=395+/-12 nmol/L (P<0.05). Pantoprazole also acted on cardiac myofilaments to reduced Ca2+-activated force. CONCLUSIONS: Pantoprazole depresses cardiac contractility in vitro by depression of Ca2+ signaling and myofilament activity. In view of the extensive use of this agent, the effects should be evaluated in vivo.

Relief of cholestatic pruritus by a novel class of drugs: 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists: effectiveness of ondansetron.

The objective of the present study was to determine whether ondansetron, a specific serotonin type 3 receptor antagonist (5-HT3), relieves cholestatic pruritus in patients resistant to conventional antipruritic therapy (antihistamines and cholestyramine). In a placebo-controlled study the acute effect of an intravenous injection of ondansetron (4 mg, 8 mg) or placebo (NaCl solution) was tested in 10 patients (41-66 years of age; 4 men, 6 women) with cholestatic itch. A successful treatment was assessed when the intensity of itch was reduced by 50% or more within 2 h after injection of ondansetron. Intensity of itch was determined by the patients on a visual rating scale from 0 to 10. Ondansetron reduced or abolished pruritus within 30-60 min after injection. A 50% reduction of the intensity of itch was observed up to 6 h after injection of 8 mg. The effect was reproducible in the same patient. In conclusion ondansetron is effective in the treatment of cholestatic itch. Serotonin may participate in the generation and/or sensation of cholestatic pruritus.