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CD19-specific chimeric antigen receptor (CD19-CAR) T-cell therapies mediate durable responses in late-stage B-cell malignancies, but can be complicated by a potentially severe immune effector cell-associated neurotoxicity syndrome (ICANS). Despite broad efforts, the precise mechanisms of ICANS are not entirely known, and resistance to current ICANSdirected therapies (especially corticosteroids) has been observed. Recent data suggest that inflammatory cytokines and/or targeting of cerebral CD19-expressing pericytes can disrupt the blood-brain barrier and facilitate influx of immune cells, including CAR T cells. However, specific tools for CD19-CAR T-cell analysis within often minute samples of cerebrospinal fluid (CSF) are not broadly available. Here, we applied our recently developed digital polymerase chain reaction assays to monitor CD19-CAR T-cell kinetics in CSF and blood in real-world patients with neurotoxicity. Consistently, we observed a CAR T-cell enrichment within CSF in ICANS patients with further progressive accumulation despite intense corticosteroid- containing immuno-chemotherapies in a subset of patients with prolonged and therapy-resistant grade 3-4 neurotoxicity. We used next-generation T-cell receptor-b sequencing to assess the repertoire of treatment-refractory cells. Longitudinal analysis revealed a profound skewing of the T-cell receptor repertoire, which at least partly reflected selective expansion of infused T-cell clones. Interestingly, a major fraction of eventually dominating hyperexpanded T-cell clones were of non-CAR T-cell derivation. These findings hint to a role of therapy-refractory T-cell clones in severe ICANS development and prompt future systematic research to determine if CAR T cells may serve as 'door openers' and to further characterize both CAR-positive and non-CAR T cells to interrogate the transcriptional signature of these possibly pathologic T cells.

Establishing a diagnosis in cases of fever of unknown origin (FUO) in immunocompromised patients can be difficult. In 25-35% infectious diseases are the underlying cause. This article reports the case of a 74-year-old woman with a 5-month history of fever. Through open biopsy of the femoral shaft and microbiological analysis, a diagnosis of neoehrlichiosis could be established. After initiation of treatment with doxycycline, the symptoms quickly resolved resulting in a complete recovery., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

High-dose chemotherapy (HD-Cx) in refractory germ cell cancer (GCC) is effective but limited data are available concerning the optimal approach for stem cell mobilization (SCM) in these patients. In this analysis 102 patients undergoing SCM during first (n = 25) or subsequent treatment lines (n = 77) were analyzed. Subcutaneous injections of granulocyte colony-stimulating factor (G-CSF) were given once daily (group 1) in 52 patients (51%), twice daily (group 2) in 39 patients (38%) or one injection Pegylated-G-CSF (PegG-CSF) (group 3) in eleven patients (11%) after one cycle of mobilization chemotherapy. Plerixafor was administered 13 times in group 1, seven times in group 2 and once in group 3. Overall, 77 (75%) patients achieved successful SCM defined as ≥8*10 6 CD34+ cells/kg body weight for three consecutive HD-Cx plus one backup dose. In group 1, 40 of 52 patients (77%) achieved successful SCM with a median of 11 G-CSF injections, in group 2, 27 of 39 patients (69%) with a median of 14 G-CSF injections and in group 3, 10 of 11 patients (91%) with one injection of PegG-CSF. SCM was more successful if conducted during first-line chemotherapy (p = 0.016) and associated with a beneficial outcome concerning overall survival (p = 0.02) if performed satisfactorily., (© 2022. The Author(s).)

Promoting hope was identified in our prior work as the top priority research question among patients and caregivers with diverse childhood-onset chronic conditions. Here, we aimed to construct a conceptual model to guide future research studies of interventions to improve hope. We conducted eight monthly virtual focus groups and one virtual workshop with patients, caregivers, and researchers to explore key constructs to inform the model. Discussions were facilitated by Patient Co-Investigators. Participants developed a definition of hope and identified promotors and inhibitors that influence the experience of hope. We utilized qualitative methods to analyze findings and organize the promotors and inhibitors of hope within three strata of the socio-ecologic framework: structural, interpersonal, and intrapersonal. Participants identified three types of interventions to promote hope: resources, navigation, and activities to promote social connection. The hope conceptual model can be used to inform the selection of interventions to assess in future research studies aimed at improving hope and the specification of outcome measures to include in hope research studies. Inclusion of the health care system in the model provides direction for identifying strategies for improving the system and places responsibility on the system to do better to promote hope among young patients with chronic illness and their caregivers.

Data on the association between chimeric antigen receptor (CAR)-T-cell kinetics and patient outcome in the nontrial setting are missing, mainly due to the lack of broadly available CAR-T-cell diagnostic quantification tools. We performed prospective quantification of axicabtagene ciloleucel (axi-cel) in 21 patients treated for aggressive B-cell lymphoma at our clinic. Median peak CAR-T-cell count was 16.14 CAR-T cells/µL. Patients with 16.14/μL or higher peak CAR-T cells (strong expanders) had more day-30 objective responses (91% vs 40%, P = .02). In univariate analysis, peak CAR-T cell ≥ 16.14 (P < .001), normal platelet counts at start of lymphodepletion (P < .001), no prior stem cell transplant (P = .04), and peak CAR-T cells as continuous variable (P = .03) were associated with better progression-free survival (PFS). After adjusting for platelet counts and prior stem cell transplantation, peak CAR-T cells below median was still associated with shorter PFS (relative risk, 0.15, 95% confidence interval, 0.04-0.59, P = .007). Low platelet counts also maintained significant impact on PFS. Our data demonstrate association of axi-cel levels and outcome in a nontrial setting and for the first time use a cutoff to segregate weak and strong expanders with respective outcomes., (© 2021 by The American Society of Hematology.)

Background: High-dose (HD) methotrexate (MTX) is an essential component of treatment protocols in acute lymphoblastic leukemia, aggressive lymphoma, and osteosarcoma. However, delayed MTX clearance may lead to life-threatening toxicities. Administration of supportive therapy for HD-MTX is complex, and insufficient supportive care increases the risk of MTX toxicity. To improve patient safety, we investigated the implementation of a checklist and urine alkalinization protocol in addition to standard supportive care during HD-MTX therapy., Materials and Methods: The intervention included individualized patient checklists for control of adequate supportive care for every HD-MTX treatment cycle and a urine alkalinization protocol for documentation and guidance during urine alkalinization therapy. The impact of these tools on the rate of adverse events (acute renal injury, delayed MTX clearance) was retrospectively assessed in patients treated from April 2017 to April 2019 (intervention group) and compared with patients treated from January 2015 to March 2017 who received standard supportive care for HD-MTX according to a standard operating procedure (SOP)., Results: In total, 118 patients received 414 HD-MTX cycles in the intervention group compared with 108 patients with 332 treatment cycles in the SOP group. Delayed MTX clearance was observed in 2.6% of treatment cycles in the intervention cohort opposed to 15.2% of cycles in the SOP group. The rate of acute kidney injury was also significantly reduced in the intervention group (6.2%. vs. 0.7%). The use of carboxypeptidase as rescue treatment for severe renal impairment and insufficient MTX clearance was necessary in five cases in the SOP group and in only two cycles within the intervention group., Conclusion: The use of standardized documentation for supportive care during HD-MTX therapy is recommended to minimize the risk of adverse events., Implications for Practice: High-dose methotrexate (HD-MTX) is a commonly used treatment in several cancer types. Distinct supportive measures are necessary to minimize the risk of HD-MTX side effects, which can be life-threatening. Supportive care consists of certain examinations and interventions before starting HD-MTX and permanent alkalinization of the urine, as this greatly increases the elimination of MTX and decreases the risk of kidney injury. After implementing a checklist for control of supportive care and a urine alkalinization protocol to optimize urine alkalinization, a significant decrease of side effects was observed in comparison to the standard of care; therefore, the use of a safety checklist and alkalinization protocol is recommended for all patients who receive HD-MTX., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Background: Aggressive non-Hodgkin lymphomas with secondary central nervous system (CNS) involvement bear a dismal prognosis. Optimal treatment remains so far unclear, and effective treatment options remain an unmet clinical need. Remission rates are in general low, resulting in rapid relapses and palliative care in the majority of patients. High-intensity treatment combining effective CNS-directed chemoimmunotherapy with autologous stem cell transplantation was shown in a recent phase 2 trial to induce durable remissions. Here, we report the outcome of the first real-world patient cohort treated according to the published protocol., Methods: We retrospectively identified 17 HIV-negative lymphoma patients with secondary CNS involvement, either at first diagnosis or at relapse of lymphoma, treated according to the study protocol published by Ferreri et al. [J Clin Oncol. 2015] at two university medical centers in Germany. Treatment consisted of four cycles of chemoimmunotherapy with a consolidating autologous stem cell transplantation. Adverse events and overall outcome were assessed., Results: Five patients had CNS involvement at first diagnosis and 12 patients at relapse of lymphoma. A complete response was achieved in 9 patients. Median survival was 11 months. Five patients died of septic complications and 4 patients succumbed to progression or relapse of disease., Conclusions: The outcome of our real-world cohort emphasizes the possible toxic character of the treatment protocol by Ferreri et al. [J Clin Oncol. 2015]. Further improvement in treatment regimens is still an unmet need., (© 2021 S. Karger AG, Basel.)

Objectives: Acute diplopia is a diagnostic challenge for clinicians, in particular in the emergency department. The most common cause of acute diplopia are ocular motor nerve palsies (OMP). In this prospective study, we focused on identifying the most crucial signs and symptoms for differentiating between peripheral and central OMP., Methods: We prospectively evaluated 56 non-consecutive patients who presented at our emergency department with acute binocular diplopia (≤ 10 days). The patient history was taken using a standardized questionnaire and patients underwent a neurological, neuro-ophthalmological and neuro-otological examination, including measurement of the subjective visual vertical (SVV), Harms tangent screen test, and cranial MRI., Results: Forty-six out of 56 patients were diagnosed with an ocular motor cranial nerve palsy (OMP), 21 of peripheral and 23 of central origin; in two patients, the etiology remained unknown. The following features were different in peripheral and central OMP: (1) the presence of vertigo/dizziness was more frequent in central (43.5%) than in peripheral (9.5%) OMP. (2) Central ocular motor signs, such as saccadic smooth pursuit, additional internuclear ophthalmoplegia, skew deviation, and saccade palsies, were also found more frequently in the central than in the peripheral group (86.7% vs. 33.3%). (3) Further, a pathological SVV deviation by monocular testing of the non-affected eye was also more common in central (77.3%) than in peripheral OMP (38.9%). The presence of all three factors has a positive predictive value of 100% (CI 50-100%) for the presence of a central lesion., Conclusions: In acute diplopia due to central OMP, the most important accompanying symptom is vertigo/dizziness, and the most important clinical signs are central ocular motor disorders (which require examination of the non-paretic eye) and an SVV deviation in the non-paretic eye.

The differential diagnosis of vertigo or dizziness as a result of cerebellar disorders can be difficult as many patients with a cerebellar pathology do not present with the full spectrum of cerebellar signs. The main goal of this study was to describe the typical clinical features of these patients with vertigo or dizziness of a cerebellar origin. We reviewed the medical records of 5400 patients with vertigo and dizziness from our tertiary outpatient clinic for vertigo and balance disorders. In 459 the diagnosis of "cerebellar vertigo or dizziness" was made; 90 patients were excluded from further analysis due to evident structural changes in MRI. Of the remaining 369 patients (67.0 ± 15.1, 54% female, symptom duration until diagnosis 5.5 ± 6.9 years), 81% suffered from persistent vertigo or dizziness, 31% from attacks of vertigo and dizziness and 21% from both. Neuro-ophthalmologically, 95% had saccadic smooth pursuit, 80% gaze-holding deficits, 64% a pathological fixation suppression of the VOR, 24% central fixation nystagmus (in 64% of these cases downbeat nystagmus (DBN)), 23% rebound nystagmus, and an ocular misalignment in 84% in near view and 50% in distance view. Eleven percent had isolated mild to moderate cerebellar ocular motor disturbances without any other typical cerebellar signs. The most common diagnoses were sporadic adult-onset degenerative ataxia in 26%; idiopathic DBN syndrome in 20%; cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in 10%; episodic ataxia type 2 in 7%; and multiple system atrophy cerebellar type in 6%. In posturography, a typical cerebellar 3-Hz sway was found in 16%. The diagnostic key to patients with cerebellar vertigo or dizziness is a careful examination of eye movements since practically all of them have cerebellar ocular disturbances.

Objectives: To evaluate the function of the oculomotor and vestibular systems and to correlate these findings with the clinical status of patients with Gaucher disease type 3 (GD3). The goal of this cross-sectional and longitudinal study was to find oculomotor biomarkers for future clinical trials., Methods: Twenty-six patients with GD3 were assessed for eligibility and 21 were able to perform at least one task. Horizontal and vertical reflexive saccades, smooth pursuit, gaze-holding, optokinetic nystagmus, and horizontal vestibulo-ocular reflex (VOR) were examined by video-oculography/video-head impulse test and compared concurrently with 33 healthy controls. The Scale for the Assessment and Rating of Ataxia (SARA), the modified Severity Scoring Tool (mSST), and Grooved Pegboard Test (GPT) were administered to assess overall neurological function. Eleven patients were also re-assessed after 1 year., Results: Nine out of 17 patients exhibited gaze-holding deficits. One patient had upbeat nystagmus. Three patients presented with bilateral abducens palsy in combination with central oculomotor disorders, suggesting a bilateral involvement of the abducens nucleus. Horizontal angular VOR gain was reduced in all patients (0.66 ± 0.37) compared with controls (1.1 ± 0.11, p  < 0.001). Most strongly correlated with clinical rating scales were peak velocity of downward saccades (SARA: ρ = -0.752, p  < 0.0005; mSST: ρ = -0.611, p  = 0.003; GPT: ρ = -0.649, p  = 0.005) and duration of vertical saccades (SARA: ρ = 0.806, p  < 0.001; mSST: ρ = 0.700, p  < 0.0005; GPT: ρ = 0.558, p  = 0.02) together with the VOR gain (SARA: ρ = -0.63, p  = 0.016; mSST: ρ = -0.725, p  = 0.003; GPT: ρ = -0.666, p  = 0.004). Vertical smooth pursuit gain decreased significantly at follow-up., Interpretation: This study shows neuronal degeneration of the brainstem and cerebellum with combined involvement of both supranuclear and nuclear oculomotor structures and the vestibular system in GD3. We also identified oculomotor parameters that correlate with the neurological status and can be used as biomarkers in future clinical trials.

Pregnancy-associated diffuse large B-cell lymphoma (DLBCL) is a rare event. Experience regarding fetal effects of maternal treatment during pregnancy is limited. Cardiotoxicity is a known adverse effect of some antineoplastic agents especially of doxorubicin. We report a case of pregnancy-associated DLBCL, which was treated between gestational week 26 and 33 with three cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone combined with rituximab). At gestational age 34 2/7 she delivered a male infant who was admitted to neonatal care due to cardiomyopathy. In the absence of other explanations it was interpreted as a direct toxic effect of maternal chemotherapy. At age 6 months the boy's cardiac output had normalized. This case report is the first presenting congenital cardiomyopathy after maternal R-CHOP during pregnancy. Since especially anthracyclines are known to cause acute and chronic cardiotoxicity in treated patients, the most probable explanation for neonatal cardiomyopathy in this case is doxorubicin., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Herb induced liver injury (HILI) and drug induced liver injury (DILI) share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body and need metabolic degradation to be eliminated. During this process, hepatotoxic metabolites may be generated causing liver injury in susceptible patients. There is uncertainty, whether risk factors such as high lipophilicity or high daily and cumulative doses play a pathogenetic role for HILI, as these are under discussion for DILI. It is also often unclear, whether a HILI case has an idiosyncratic or an intrinsic background. Treatment with herbs of Western medicine or traditional Chinese medicine (TCM) rarely causes elevated liver tests (LT). However, HILI can develop to acute liver failure requiring liver transplantation in single cases. HILI is a diagnosis of exclusion, because clinical features of HILI are not specific as they are also found in many other liver diseases unrelated to herbal use. In strikingly increased liver tests signifying severe liver injury, herbal use has to be stopped. To establish HILI as the cause of liver damage, RUCAM (Roussel Uclaf Causality Assessment Method) is a useful tool. Diagnostic problems may emerge when alternative causes were not carefully excluded and the correct therapy is withheld. Future strategies should focus on RUCAM based causality assessment in suspected HILI cases and more regulatory efforts to provide all herbal medicines and herbal dietary supplements used as medicine with strict regulatory surveillance, considering them as herbal drugs and ascertaining an appropriate risk benefit balance.

Objectives: The primary aim was to determine the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the bedside head-impulse test (bHIT) using the video HIT (vHIT) as the gold standard for quantifying the function of the vestibulo-ocular reflex (VOR). Secondary aims were to determine the bHIT inter-rater reliability and sensitivity in detecting unilateral and bilateral vestibulopathy., Methods: In this prospective study, 500 consecutive outpatients presenting to a tertiary neuro-otology clinic with vertigo or dizziness of various vestibular etiologies who did not have any of the pre-defined exclusion criteria were recruited. Bedside HITs were done by three experienced neuro-otology clinicians masked to the diagnosis, and the results were compared with the vHIT. The patients were likewise blinded to the bHIT and vHIT findings. Patients with VOR deficits were identified on the vHIT by referencing to the pre-selected "pathological" gain of <0.7. The data were then analyzed using standard statistical methods., Results: For the primary outcome (vHIT "pathological" VOR gain <0.7), the three-rater mean bHIT sensitivity = 66.0%, PPV = 44.3%, specificity = 86.2%, and NPV = 93.9%. Shifting the "pathological" threshold from 0.6 to 0.9 caused the bHIT sensitivity to decrease while the PPV increased. Specificity and NPV tended to remain stable. Inter-rater agreement was moderate (Krippendorff's alpha = 0.54). For unilateral vestibulopathy, overall bHIT sensitivity = 69.6%, reaching 86.67% for severely reduced unilateral gain. For VOR asymmetry <40% and >40%, the bHIT sensitivity = 51.7 and 83%, respectively. For bilateral vestibulopathy, overall bHIT sensitivity = 66.3%, reaching 86.84% for severely reduced bidirectional gains., Conclusion: For the primary outcome, the bHIT had moderate sensitivity and low PPV. While the study did not elucidate the best choice for vHIT reference, it demonstrated how the bHIT test properties varied with vHIT thresholds: selecting a lower threshold improved the sensitivity but diminished the PPV, while a higher threshold had the opposite effect. The VOR was most likely normal if the bHIT was negative due to its high NPV. The bHIT was moderately sensitive for detecting unilateral and bilateral vestibulopathy overall, but better for certain subgroups.

Background and Aim: In the fall of 2013, the US Centers for Disease Control and Prevention (CDC) published a preliminary report on a cluster of liver disease cases that emerged in Hawaii in the summer 2013. This report claimed a temporal association as sufficient evidence that OxyELITE Pro (OEP), a dietary supplement (DS) mainly for weight loss, was the cause of this mysterious cluster. However, the presented data were inconsistent and required a thorough reanalysis., Material and Methods: To further investigate the cause(s) of this cluster, we critically evaluated redacted raw clinical data of the cluster patients, as the CDC report received tremendous publicity in local and nationwide newspapers and television. This attention put regulators and physicians from the medical center in Honolulu that reported the cluster, under enormous pressure to succeed, risking biased evaluations and hasty conclusions., Results: We noted pervasive bias in the documentation, conclusions, and public statements, also poor quality of case management. Among the cases we reviewed, many causes unrelated to any DS were evident, including decompensated liver cirrhosis, acute liver failure by acetaminophen overdose, acute cholecystitis with gallstones, resolving acute hepatitis B, acute HSV and VZV hepatitis, hepatitis E suspected after consumption of wild hog meat, and hepatotoxicity by acetaminophen or ibuprofen. Causality assessments based on the updated CIOMS scale confirmed the lack of evidence for any DS including OEP as culprit for the cluster., Conclusions: Thus, the Hawaii liver disease cluster is now best explained by various liver diseases rather than any DS, including OEP.

Background: The optimal use of various therapeutic combinations for moderate/severe chronic obstructive pulmonary disease (COPD) is unclear. The GLISTEN trial compared the efficacy of two long-acting anti-muscarinic antagonists (LAMA), when combined with an inhaled corticosteroid (ICS) and a long-acting β2 agonist (LABA)., Methods: This randomised, blinded, placebo-controlled trial in moderate/severe COPD patients compared once-daily glycopyrronium (GLY) 50 µg, once-daily tiotropium (TIO) 18 µg or placebo (PLA), when combined with salmeterol/fluticasone propionate (SAL/FP) 50/500 µg twice daily. The primary objective was to determine the non-inferiority of GLY+SAL/FP versus TIO+SAL/FP on trough FEV1 after 12 weeks. An important secondary objective was whether addition of GLY to SAL/FP was better than SAL/FP alone., Results: 773 patients (mean FEV1 57.2% predicted) were randomised; 84.9% completed the trial. At week 12, GLY+SAL/FP demonstrated non-inferiority to TIO+SAL/FP for trough FEV1: least square mean treatment difference (LSMdiff) -7 mL (SE 17.4) with a lower limit for non-inferiority of -60 mL. There was significant increase in week 12 trough FEV1 with GLY+SAL/FP versus PLA+SAL/FP (LSMdiff 101 mL, p<0.001). At 12 weeks, GLY+SAL/FP produced significant improvement in St George's Respiratory Questionnaire total score versus PLA+SAL/FP (LSMdiff -2.154, p=0.02). GLY+SAL/FP demonstrated significant rescue medication reduction versus PLA+SAL/FP (LSMdiff -0.72 puffs/day, p<0.001). Serious adverse events were similar for GLY+SAL/FP, TIO+SAL/FP and PLA+SAL/FP with an incidence of 5.8%, 8.5% and 5.8%, respectively., Conclusions: GLY+SAL/FP showed comparable improvements in lung function, health status and rescue medication to TIO+SAL/FP. Importantly, addition of GLY to SAL/FP demonstrated significant improvements in lung function, health status and rescue medication compared to SAL/FP., Trial Registration Number: NCT01513460., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Herbal traditional Chinese medicine (TCM) is used to treat several ailments, but its efficiency is poorly documented and hence debated, as opposed to modern medicine commonly providing effective therapies. The aim of this review article is to present a practical reference guide on the role of herbal TCM in managing gastrointestinal disorders, supported by systematic reviews and evidence based trials. A literature search using herbal TCM combined with terms for gastrointestinal disorders in PubMed and the Cochrane database identified publications of herbal TCM trials. Results were analyzed for study type, inclusion criteria, and outcome parameters. Quality of placebo controlled, randomized, double-blind clinical trials was poor, mostly neglecting stringent evidence based diagnostic and therapeutic criteria. Accordingly, appropriate Cochrane reviews and meta-analyses were limited and failed to support valid, clinically relevant evidence based efficiency of herbal TCM in gastrointestinal diseases, including gastroesophageal reflux disease, gastric or duodenal ulcer, dyspepsia, irritable bowel syndrome, ulcerative colitis, and Crohn's disease. In conclusion, the use of herbal TCM to treat various diseases has an interesting philosophical background with a long history, but it received increasing skepticism due to the lack of evidence based efficiency as shown by high quality trials; this has now been summarized for gastrointestinal disorders, with TCM not recommended for most gastrointestinal diseases. Future studies should focus on placebo controlled, randomized, double-blind clinical trials, herbal product quality and standard criteria for diagnosis, treatment, outcome, and assessment of adverse herb reactions. This approach will provide figures of risk/benefit profiles that hopefully are positive for at least some treatment modalities of herbal TCM. Proponents of modern herbal TCM best face these promising challenges of pragmatic modern medicine by bridging the gap between the two medicinal cultures.

Convergent strabismus is a common diagnosis in early childhood, when it is mostly considered benign. If it develops later in life, strabismus can, however, be a sign of neurological disease. In these cases the underlying pathophysiological mechanisms are largely unknown. In this retrospective case-control study we analyzed the neuro-ophthalmological examination reports of 400 adult patients who presented at the German Center for Vertigo and Balance Disorders to determine an association between ocular misalignment and cerebellar dysfunction. Patients with cerebellar signs (i.e., cerebellar ataxia and/or cerebellar ocular motor signs) had a 4.49 (95 % CI [1.60; 13.78]) times higher frequency of ocular misalignment and specifically a 13.3 (95 % CI [3.80; 55.73]) times increased frequency of esophoria/esotropia (ESO) during distant gaze than patients without cerebellar dysfunction. ESO when looking into the distance was associated with saccadic smooth pursuit, dysmetria of saccades, and downbeat nystagmus (DBN) (χ (2) test, p < 0.0001 for all associations). Patients with cerebellar dysfunction also showed mildly impaired eye abduction (χ (2) test, left eye and right eye: p < 0.0001), associated with horizontal gaze-evoked nystagmus (χ (2) test, p < 0.0001). The association of ESO and DBN implicates a pathophysiological involvement of the cerebellar flocculus, while the association with dysmetric saccades suggests involvement of the oculomotor vermis. This is compatible with animal studies showing that the pathways of the flocculus/posterior interposed nucleus and vermis/nucleus fastigii are both involved in vergence movements and static binocular alignment. From a clinical point of view, a newly diagnosed esophoria/esotropia only during distant gaze may be a sign of a cerebellar disease.

Traditional Chinese Medicine (TCM) with its focus on herbal use became popular worldwide. Treatment was perceived as safe, with neglect of rare adverse reactions including liver injury. To compile worldwide cases of liver injury by herbal TCM, we undertook a selective literature search in the PubMed database and searched for the items Traditional Chinese Medicine, TCM, Traditional Asian Medicine, and Traditional Oriental Medicine, also combined with the terms herbal hepatotoxicity or herb induced liver injury. The search focused primarily on English-language case reports, case series, and clinical reviews. We identified reported hepatotoxicity cases in 77 relevant publications with 57 different herbs and herbal mixtures of TCM, which were further analyzed for causality by the Council for International Organizations of Medical Sciences (CIOMS) scale, positive reexposure test results, or both. Causality was established for 28/57 different herbs or herbal mixtures, Bai Xian Pi, Bo He, Ci Wu Jia, Chuan Lian Zi, Da Huang, Gan Cao, Ge Gen, Ho Shou Wu, Huang Qin, Hwang Geun Cho, Ji Gu Cao, Ji Xue Cao, Jin Bu Huan, Jue Ming Zi, Jiguja, Kudzu, Ling Yang Qing Fei Keli, Lu Cha, Rhen Shen, Ma Huang, Shou Wu Pian, Shan Chi, Shen Min, Syo Saiko To, Xiao Chai Hu Tang, Yin Chen Hao, Zexie, and Zhen Chu Cao. In conclusion, this compilation of liver injury cases establishes causality for 28/57 different TCM herbs and herbal mixtures, aiding diagnosis for physicians who care for patients with liver disease possibly related to herbal TCM.

Mutations in the merlin tumor suppressor gene cause Neurofibromatosis type 2 (NF2), which is a disease characterized by development of multiple benign tumors in the nervous system. The current standard of care for NF2 calls for surgical resection of the characteristic tumors, often with devastating neurological consequences. There are currently no approved non-surgical therapies for NF2. In an attempt to identify much needed targets and therapeutically active compounds for NF2 treatment, we employed a chemical biology approach using ultra-high-throughput screening. To support this goal, we created a merlin-null mouse Schwann cell (MSC) line to screen for compounds that selectively decrease their viability and proliferation. We optimized conditions for 384-well plate assays and executed a proof-of-concept screen of the Library of Pharmacologically Active Compounds. Further confirmatory and selectivity assays identified phosphatidylinositol 3-kinase (PI3K) as a potential NF2 drug target. Notably, loss of merlin function is associated with activation of the PI3K/Akt pathway in human schwannomas. We report that AS605240, a PI3K inhibitor, decreased merlin-null MSC viability in a dose-dependent manner without significantly decreasing viability of control Schwann cells. AS605240 exerted its action on merlin-null MSCs by promoting caspase-dependent apoptosis and inducing autophagy. Additional PI3K inhibitors tested also decreased viability of merlin-null MSCs in a dose-dependent manner. In summary, our chemical genomic screen and subsequent hit validation studies have identified PI3K as potential target for NF2 therapy.

The diagnosis of drug induced liver injury (DILI) is based primarily on the exclusion of alternative causes. To assess the frequency of alternative causes in initially suspected DILI cases, we searched the Medline database with the following terms: drug hepatotoxicity, drug induced liver injury, and hepatotoxic drugs. For each term, we used the first 100 publications. We reviewed references, selected those reports relevant to our study, and retrieved finally 15 publications related to DILI and alternative causes. A total of 2,906 cases of initially assumed DILI were analyzed in these 15 publications, with diagnoses missed in 14% of the cases due to overt alternative causes. In another 11%, the diagnosis of DILI could not be established because of confounding variables. Alternative diagnoses included hepatitis B, C, and E, CMV, EBV, ischemic hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, Wilson's disease, Gilbert's syndrome, fatty liver, non alcoholic steatohepatitis, alcoholic liver diseases, cardiac and thyroid causes, rhabdomyolysis, polymyositis, postictal state, tumors, lymphomas, chlamydial and HIV infections. Causality assessment methods applied in these 15 publications were the CIOMS (Council for International Organizations of Medical Sciences) scale alone (n = 5) or combined with the Maria and Victorino (MV) scale (n = 1), the DILIN (Drug-Induced Liver Injury Network) method (n = 4), or the Naranjo scale (n = 1); the qualitative CIOMS method alone (n = 3) or combined with the MV scale (n = 1). In conclusion, alternative diagnoses are common in primarily suspected DILI cases and should be excluded early in future cases, requiring a thorough clinical and causality assessment.

Background: Positive re-exposure tests are diagnostic hallmarks for hepatotoxicity., Objective: To test validity of positive re-exposures in herb induced liver injury., Methods: We searched Medline database for cases of herb induced liver injury with positive re-exposures and analysed 34 cases for positive re-exposure test criteria of baseline alanine aminotransferase< 5N before re-exposure, and re-exposure alanine aminotransferase ≥ 2× baseline alanine aminotransferase. Re-exposure test was negative, if baseline alanine aminotransferase< 5N combined with re-exposure alanine aminotransferase< 2× baseline alanine aminotransferase, or if baseline alanine aminotransferase≥ 5N regardless of the re-exposure alanine aminotransferase including no available re-exposure alanine aminotransferase result., Results: In 21/34 cases (61.8%), criteria for a positive re-exposure were fulfilled, with negative tests in 6/34 cases (17.6%) or uninterpretable ones in 7/34 cases (20.6%). Confirmed positive re-exposure tests established potential of herb induced liver injury for Aloe, Chaparral, Chinese herbal mixtures, Chinese Jin Bu Huan, Chinese Syo Saiko To, Germander, Greater Celandine, Green tea, Kava, Mistletoe, Polygonum multiflorum, and Senna, with up to 4 case reports per herb., Conclusions: Among 34 cases of herb-induced liver injury with initially reported positive re-exposure tests, 61.8% of the cases actually fulfilled established test criteria and provided firm diagnoses of herb induced liver injury by various herbs., (Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Causality assessment of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI) is hampered by the lack of a standardized approach to be used by attending physicians and at various subsequent evaluating levels. The aim of this review was to analyze the suitability of the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale as a standard tool for causality assessment in DILI and HILI cases. PubMed database was searched for the following terms: drug induced liver injury; herb induced liver injury; DILI causality assessment; and HILI causality assessment. The strength of the CIOMS lies in its potential as a standardized scale for DILI and HILI causality assessment. Other advantages include its liver specificity and its validation for hepatotoxicity with excellent sensitivity, specificity and predictive validity, based on cases with a positive reexposure test. This scale allows prospective collection of all relevant data required for a valid causality assessment. It does not require expert knowledge in hepatotoxicity and its results may subsequently be refined. Weaknesses of the CIOMS scale include the limited exclusion of alternative causes and qualitatively graded risk factors. In conclusion, CIOMS appears to be suitable as a standard scale for attending physicians, regulatory agencies, expert panels and other scientists to provide a standardized, reproducible causality assessment in suspected DILI and HILI cases, applicable primarily at all assessing levels involved.

We present Activity Analysis as a new method for the quantification of subjective reports of altered states of consciousness with regard to the indicated level of simulated motor activity. Empirical linguistic activity analysis was conducted with dream reports conceived immediately after EEG-controlled periods of hypnagogic hallucinations and REM-sleep in the sleep laboratory. Reports of REM-dreams exhibited a significantly higher level of simulated physical dreamer activity, while hypnagogic hallucinations appear to be experienced mostly from the point of passive observer. This study lays the groundwork for clinical research on the level of simulated activity in pathologically altered states of subjective experience, for example in the REM-dreams of clinically depressed patients, or in intrusions and dreams of patients diagnosed with PTSD., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background and Objectives: Alternative explanations are common in suspected drug-induced liver injury (DILI) and account for up to 47.1% of analyzed cases. This raised the question of whether a similar frequency may prevail in cases of assumed herb-induced liver injury (HILI)., Methods: We searched the Medline database for the following terms: herbs, herbal drugs, herbal dietary supplements, hepatotoxic herbs, herbal hepatotoxicity, and herb-induced liver injury. Additional terms specifically addressed single herbs and herbal products: black cohosh, Greater Celandine, green tea, Herbalife products, Hydroxycut, kava, and Pelargonium sidoides. We retrieved 23 published case series and regulatory assessments related to hepatotoxicity by herbs and herbal dietary supplements with alternative causes., Results: The 23 publications comprised 573 cases of initially suspected HILI; alternative causes were evident in 278/573 cases (48.5%). Among them were hepatitis by various viruses (9.7%), autoimmune diseases (10.4%), nonalcoholic and alcoholic liver diseases (5.4%), liver injury by comedication (DILI and other HILI) (43.9%), and liver involvement in infectious diseases (4.7%). Biliary and pancreatic diseases were frequent alternative diagnoses (11.5%), raising therapeutic problems if specific treatment is withheld; pre-existing liver diseases including cirrhosis (9.7%) were additional confounding variables. Other diagnoses were rare, but possibly relevant for the individual patient., Conclusion: In 573 cases of initially assumed HILI, 48.5% showed alternative causes unrelated to the initially incriminated herb, herbal drug, or herbal dietary supplement, calling for thorough clinical evaluations and appropriate causality assessments in future cases of suspected HILI.

Background: The oxygen reactivity index (ORx) has been introduced to assess the status of cerebral autoregulation after traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH). Currently, there is some controversy about whether the ORx depends on the type of PbrO2-sensor technology used for its calculation. To examine if the probe technology does matter, we compared the ORx and the resulting optimal cerebral perfusion pressures (CPPopt) of simultaneously implanted Licox (CC1.SB, Integra Neuroscience, France) and Neurovent-PTO (Raumedic, Germany) probes in patients after aneurysmal SAH or severe TBI., Methods: Licox and Raumedic probes were implanted side by side in 11 patients after TBI or SAH. ORx and CPPopt were recorded continuously. The equivalence of both probes was examined using Bland-Altman analyses., Results: The mean difference in ORx was 0.1, with Licox producing higher values. The limits of agreement regarding ORx ranged from -0.6 to +0.7. When both probes' ORx values were compared in each patient, no specific pattern in their relationship was seen. The mean difference in CPPopt was 0 mmHg with limits of agreement between -16.5 and +16.4 mmHg., Conclusions: Owing to the rather limited number of patients, we view the results of this study as preliminary. The main result is that Licox and Raumedic showed consistent differences in ORx and CPPopt. Therefore, ORx values of both probes cannot be interchanged and should not be viewed as equivalent. This should be taken into consideration when discussing ORx data generated by different PbrO2 probe types.

Aim: To analyze the validity of applied test criteria and causality assessment methods in assumed Herbalife hepatotoxicity with positive reexposure tests., Methods: We searched the Medline database for suspected cases of Herbalife hepatotoxicity and retrieved 53 cases including eight cases with a positive unintentional reexposure and a high causality level for Herbalife. First, analysis of these eight cases focused on the data quality of the positive reexposure cases, requiring a baseline value of alanine aminotransferase (ALT) < 5 upper limit of normal (N) before reexposure, with N as the upper limit of normal, and a doubling of the ALT value at reexposure as compared to the ALT value at baseline prior to reexposure. Second, reported methods to assess causality in the eight cases were evaluated, and then the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale validated for hepatotoxicity cases was used for quantitative causality reevaluation. This scale consists of various specific elements with scores provided through the respective case data, and the sum of the scores yields a causality grading for each individual case of initially suspected hepatotoxicity., Results: Details of positive reexposure test conditions and their individual results were scattered in virtually all cases, since reexposures were unintentional and allowed only retrospective rather than prospective assessments. In 1/8 cases, criteria for a positive reexposure were fulfilled, whereas in the remaining cases the reexposure test was classified as negative (n = 1), or the data were considered as uninterpretable due to missing information to comply adequately with the criteria (n = 6). In virtually all assessed cases, liver unspecific causality assessment methods were applied rather than a liver specific method such as the CIOMS scale. Using this scale, causality gradings for Herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n = 3). Confounding variables included low data quality, alternative diagnoses, poor exclusion of important other causes, and comedication by drugs and herbs in 6/8 cases. More specifically, problems were evident in some cases regarding temporal association, daily doses, exact start and end dates of product use, actual data of laboratory parameters such as ALT, and exact dechallenge characteristics. Shortcomings included scattered exclusion of hepatitis A-C, cytomegalovirus and Epstein Barr virus infection with only globally presented or lacking parameters. Hepatitis E virus infection was considered in one single patient and found positive, infections by herpes simplex virus and varicella zoster virus were excluded in none., Conclusion: Only one case fulfilled positive reexposure test criteria in initially assumed Herbalife hepatotoxicity, with lower CIOMS based causality gradings for the other cases than hitherto proposed.

The diagnosis of herbal hepatotoxicity or herb induced liver injury (HILI) represents a particular clinical and regulatory challenge with major pitfalls for the causality evaluation. At the day HILI is suspected in a patient, physicians should start assessing the quality of the used herbal product, optimizing the clinical data for completeness, and applying the Council for International Organizations of Medical Sciences (CIOMS) scale for initial causality assessment. This scale is structured, quantitative, liver specific, and validated for hepatotoxicity cases. Its items provide individual scores, which together yield causality levels of highly probable, probable, possible, unlikely, and excluded. After completion by additional information including raw data, this scale with all items should be reported to regulatory agencies and manufacturers for further evaluation. The CIOMS scale is preferred as tool for assessing causality in hepatotoxicity cases, compared to numerous other causality assessment methods, which are inferior on various grounds. Among these disputed methods are the Maria and Victorino scale, an insufficiently qualified, shortened version of the CIOMS scale, as well as various liver unspecific methods such as the ad hoc causality approach, the Naranjo scale, the World Health Organization (WHO) method, and the Karch and Lasagna method. An expert panel is required for the Drug Induced Liver Injury Network method, the WHO method, and other approaches based on expert opinion, which provide retrospective analyses with a long delay and thereby prevent a timely assessment of the illness in question by the physician. In conclusion, HILI causality assessment is challenging and is best achieved by the liver specific CIOMS scale, avoiding pitfalls commonly observed with other approaches.

Introduction: Herbal hepatotoxicity represents a poorly understood, neglected and multifaceted disease with numerous confounding variables and missing established causality in the majority of cases. This review discusses overt shortcomings in its clinical and causality assessment and suggests improvements., Areas Covered: A selective literature search of PubMed using the terms herbal hepatotoxicity, herb-induced liver injury, drug hepatotoxicity and drug-induced liver injury was performed to identify published case reports, spontaneous case reports, case series and review articles regarding hepatotoxicity due to herbs, herbal drugs and herbal dietary supplements. Covered areas focused on confounding variables related to the documentation of the herbal product and the clinical course, hepatotoxicity and reexposure criteria, temporal association, comedication and alternative causes with special attention to preexisting diseases of the liver, bile ducts and the pancreas. Of particular interest were recent discussions of approaches designed and validated for hepatotoxicity causality, such as the scale of CIOMS (Council for International Organizations of Medical Sciences)., Expert Opinion: The authors call for substantial improvements in data quality of herbal products and case characteristics and strongly recommend using the CIOMS scale to assess causality in suspected herbal hepatotoxicity.

This review deals with herbal hepatotoxicity, identical to herb induced liver injury (HILI), and critically summarizes the pitfalls associated with the evaluation of assumed HILI cases. Analysis of the relevant publications reveals that several dozens of different herbs and herbal products have been implicated to cause toxic liver disease, but major quality issues limit the validity of causality attribution. In most of these reports, discussions around quality specifications regarding herbal products, case data presentations and causality assessment methods prevail. Though the production of herbal drugs is under regulatory surveillance and quality aspects are normally not a matter of concern, low quality of the less regulated herbal supplements may be a critical issue considering product batch variability, impurities, adulterants and herb misidentifications. Regarding case data presentation, essential diagnostic information is often lacking, as is the use of valid and liver specific causality assessment methods that also consider alternative diseases. At present, causality is best assessed by using the Council for International Organizations of Medical Sciences scale ( CIOMS) in its original or updated form, which should primarily be applied prospectively by the treating physician when evaluating a patient rather than retrospectively by regulatory agencies. To cope with these problems, a common quality approach by manufacturers, physicians and regulatory agencies should strive for the best quality. We propose steps for improvements with impact on future cases of liver injury by herbs, herbal drugs and herbal supplements., (© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

In this article, we present results from an interdisciplinary research project aimed at assessing consciousness in dreams. For this purpose, we compared lucid dreams with normal non-lucid dreams from REM sleep. Both lucid and non-lucid dreams are an important contrast condition for theories of waking consciousness, giving valuable insights into the structure of conscious experience and its neural correlates during sleep. However, the precise differences between lucid and non-lucid dreams remain poorly understood. The construction of the Lucidity and Consciousness in Dreams scale (LuCiD) was based on theoretical considerations and empirical observations. Exploratory factor analysis of the data from the first survey identified eight factors that were validated in a second survey using confirmatory factor analysis: INSIGHT, CONTROL, THOUGHT, REALISM, MEMORY, DISSOCIATION, NEGATIVE EMOTION, and POSITIVE EMOTION. While all factors are involved in dream consciousness, realism and negative emotion do not differentiate between lucid and non-lucid dreams, suggesting that lucid insight is separable from both bizarreness in dreams and a change in the subjectively experienced realism of the dream., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Herbal hepatotoxicity is a rare but highly disputed disease because numerous confounding variables may complicate accurate causality assessment. Case evaluation is even more difficult when the WHO global introspection method (WHO method) is applied as diagnostic algorithm. This method lacks liver specificity, hepatotoxicity validation, and quantitative items, basic qualifications required for a sound evaluation of hepatotoxicity cases. Consequently, there are no data available for reliability, sensitivity, specificity, positive and negative predictive value. Its scope is also limited by the fact that it cannot discriminate between a positive and a negative causality attribution, thereby stimulating case overdiagnosing and overreporting. The WHO method ignores uncertainties regarding daily dose, temporal association, start, duration, and end of herbal use, time to onset of the adverse reaction, and course of liver values after herb discontinuation. Insufficiently considered or ignored are comedications, preexisting liver diseases, alternative explanations upon clinical assessment, and exclusion of infections by hepatitis A-C, cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), and varicella zoster virus (VZV). We clearly prefer as alternative the scale of CIOMS (Council for International Organizations of Medical Sciences) which is structured, quantitative, liver specific, and validated for hepatotoxicity. In conclusion, causality of herbal hepatotoxicity is best assessed by the liver specific CIOMS scale validated for hepatotoxicity rather than the obsolete WHO method that is liver unspecific and not validated for hepatotoxicity. CIOMS based assessments will ensure the correct diagnosis and exclude alternative diagnosis that may require other specific therapies.

For the pathologist, the diagnosis of drug induced liver injury (DILI) is challenging, because histopathological features mimic all primary hepatic and biliary diseases, lacking changes that are specific for DILI. Therefore, in any patient of suspected DILI who underwent liver biopsy, the pathologist will assure the clinician that the observed hepatic changes are compatible with DILI, but this information is less helpful due to lack of specificity. Rather, the pathologist should assess liver biopsies blindly, without knowledge of prior treatment by drugs. This will result in a detailed description of the histological findings, associated with suggestions for potential causes of these hepatic changes. Then, it is up to the physician to reassess carefully the differential diagnoses, if not done before. At present, liver histology is of little impact establishing the diagnosis of DILI with the required degree of certainty, and this shortcoming also applies to herb induced liver injury (HILI). To reach at the correct diagnoses of DILI and HILI, clinical and structured causality assessments are therefore better approaches than liver histology results obtained through liver biopsy, an invasive procedure with a low complication rate.

Background & Aims: The liver can mitigate the inflammatory activity of infiltrating T cells by mechanisms that are not entirely clear. Here we investigated the role of liver sinusoidal endothelial cells (LSECs) in regulating the activity of inflammatory CD4 T cells., Methods: Interactions between T helper (Th) 1 or Th17 cells and LSEC were studied by intravital microscopy and by in vitro stimulation assays., Results: Circulating CD4 T cells established lasting and repeated interactions with liver endothelium in vivo. Stimulation of Th1 and Th17 cells by LSEC greatly inhibited their capacity to secrete interferon-γ or interleukin-17 in vitro; in contrast, stimulation by dendritic cells (DCs) resulted in considerable secretion of both cytokines. Cytokine release by Th1 or Th17 cells seemed to be actively suppressed by LSEC, as indicated by the inhibition of cytokine secretion even in the presence of Th1- and Th17-promoting DC. This inhibition of CD4 T cell effector function seemed to depend on the dominance of inhibitory over activating co-stimulatory signals on LSEC, since (1) cytokine secretion could be restored by increased CD28 co-activation; (2) LSEC from interleukin-10(-/-) mice, which manifest increased activating signals, such as MHC II, and decreased inhibitory signals, such as PD-L1, failed to suppress cytokine secretion; and (3) cytokine secretion by Th1 or Th17 cells that lacked PD-1, the ligand for inhibitory PD-L1, could not be suppressed by LSEC., Conclusions: LSEC inhibit inflammatory cytokine secretion of Th1 and Th17 effector CD4 T cells in dependence of interleukin-10 and PD-1., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The current study focused on the distribution of lucid dreams in school children and young adults. The survey was conducted on a large sample of students aged 6-19 years. Questions distinguished between past and current experience with lucid dreams. Results suggest that lucid dreaming is quite pronounced in young children, its incidence rate drops at about age 16 years. Increased lucidity was found in those attending higher level compared with lower level schools. Taking methodological issues into account, we feel confident to propose a link between the natural occurrence of lucid dreaming and brain maturation., (© 2012 European Sleep Research Society.)

Background: Herbal hepatotoxicity is a field that has rapidly grown over the last few years along with increased use of herbal products worldwide., Aims: To summarize the various facets of this disease, we undertook a literature search for herbs, herbal drugs and herbal supplements with reported cases of herbal hepatotoxicity., Methods: A selective literature search was performed to identify published case reports, spontaneous case reports, case series and review articles regarding herbal hepatotoxicity., Results: A total of 185 publications were identified and the results compiled. They show 60 different herbs, herbal drugs and herbal supplements with reported potential hepatotoxicity, additional information including synonyms of individual herbs, botanical names and cross references are provided. If known, details are presented for specific ingredients and chemicals in herbal products, and for references with authors that can be matched to each herbal product and to its effect on the liver. Based on stringent causality assessment methods and/or positive re-exposure tests, causality was highly probable or probable for Ayurvedic herbs, Chaparral, Chinese herbal mixture, Germander, Greater Celandine, green tea, few Herbalife products, Jin Bu Huan, Kava, Ma Huang, Mistletoe, Senna, Syo Saiko To and Venencapsan(®). In many other publications, however, causality was not properly evaluated by a liver-specific and for hepatotoxicity-validated causality assessment method such as the scale of CIOMS (Council for International Organizations of Medical Sciences)., Conclusions: This compilation presents details of herbal hepatotoxicity, assisting thereby clinical assessment of involved physicians in the future., (© 2012 John Wiley & Sons A/S.)

Herbal hepatotoxicity is a rare and poorly described disease because reported cases are mostly scattered and lack an appropriate causality assessment. We now describe in detail the clinical picture of herbal hepatotoxicity by extracts of Greater Celandine (GC), syn. Chelidonium majus L. from the Papaveraceae family, which contain more than 20 ingredients including various biologically active isoquinoline alkaloids. For this purpose, we analyzed and reviewed published cases of 16 patients from various European countries. In all patients, herbal hepatotoxicity was of probable and highly probable causality for GC, using the original and updated scale of CIOMS (Council for International Organizations of Medical Sciences). GC associated hepatotoxicity usually has an acute clinical course exhibiting a hepatocellular pattern of injury and is correlated to an idiosyncratic reaction with its metabolic subtype. Jaundice combined with high values of serum aminotransferases was present in virtually all cases with favourable outcome despite severe clinical course. In conclusion, GC hepatotoxicity is a typical herbal hepatotoxicity with a sound causality track for GC, but there is uncertainty regarding the respective causative compound(s). The present detailed review of GC hepatotoxicity may serve as an example for clinical causality assessments of future cases of liver injury due to other herbs.

Background: Minilaparoscopy is an accepted method for liver biopsy. We report our experience with minilaparoscopy for splenic biopsy., Methods: We reviewed the records of all minilaparoscopy procedures performed from 1996 to 2004 at the University of Mainz Medical Center and from 2005 to mid-2011 at the University of Hamburg Medical Center to identify patients who underwent a minilaparoscopy-guided splenic biopsy. All procedures were performed using the previously described method (2.75-mm trocar, 2.3-mm Veress needle, 1.9-mm laparoscope) with the patient under conscious sedation (midazolam/meperidine/propofol). Splenic biopsies were performed using a second trocar with an 18-G Tru-Cut needle. Argon plasma coagulation (APC) and/or fibrin glue (FG) were used to control postbiopsy bleeding., Results: Fifty-seven patients underwent minilaparoscopy-guided biopsy of the spleen (27 females, 30 males; median age = 41 years, range = 16-76). A specimen suitable for histopathologic evaluation was obtained in all patients. Grouped by preprocedure indication, a definitive diagnosis was obtained in 70% (7/10) of patients who had splenic mass lesions in prior imaging (3 B-NHL, 2 hemangioma, 1 tuberculosis, 1 sarcoidosis; p < 0.01) compared to 29% (10/34) in the group with unexplained fever or suspected lymphoma (3 tuberculosis, 2 B-NHL, 1 hepatosplenic T-cell lymphoma, 1 sarcoidosis, 1 Still's disease, 1 EBV, 1 Q-fever) and 0/13 with unexplained splenomegaly. Focal lesions noted at laparoscopy yielded to a histologic diagnosis in 38% (11/29) of 42 patients compared to 21% (6/28) without laparoscopic abnormality (p = 0.25). Bleeding from the biopsy site was noted in 96.5% (55/57) and was classified as brisk in 9. Control of hemorrhage was achieved in all patients (APC: 47, FG: 1, APC/FG: 7). There was no postprocedure bleeding or other complications., Conclusion: Splenic biopsy guided by minilaparoscopy can be performed safely. Postprocedure bleeding is readily controlled with APC with or without fibrin glue. The highest diagnostic yield is in patients with focal splenic lesions.

Background: Spontaneous reports of herb induced liver injury (HILI) represent a major regulatory issue, and it is in the interest of pharmacovigilance to identify and quantify previously unrecognized adverse reactions and to confirm or refute false positive signals of safety concerns. In a total of 13 spontaneous cases, liver disease has initially been attributed to the use of Pelargonium sidoides (PS), a plant from the South African region. Water/ethanol extracts derived from its roots are available as registered herbal drugs for the treatment of upper respiratory tract infections including acute bronchitis., Objectives: The present study examines whether and to what extent treatment by PS was associated with the risk of liver injury in these spontaneous cases., Study Design: Overall, 13 spontaneous cases with primarily suspected PS hepatotoxicity were included in the study. Their data were submitted to a thorough clinical evaluation that included the use of the original and updated scale of CIOMS (Council for International Organizations of Medical Sciences) to assess causality levels. These scales are liver specific, validated for liver toxicity, structured and quantitative., Results: None of the 13 spontaneous cases of liver disease generated a positive signal of safety concern, since causality for PS could not be established on the basis of the applied CIOMS scales in any of the assessed patients. Confounding variables included comedication with synthetic drugs, major comorbidities, low data quality, lack of appropriate consideration of differential diagnoses, and multiple alternative diagnoses. Among these were liver injury due to comedication, acute pancreatitis and cholangitis, acute cholecystitis, hepatic involvement following lung contusion, hepatitis in the course of virus and bacterial infections, ANA positive autoimmune hepatitis, and other preexisting liver diseases. In the course of the case assessments and under pharmacovigilance aspects, data and interpretation deficits became evident. Possible improvements include appropriate data quality of cases in spontaneous reports, case assessment by skilled specialists, use of a validated liver specific causality assessment method, and inclusion only of confirmed cases into the final regulatory case database., Conclusions: This study shows lack of hepatotoxicity by PS in all 13 spontaneous cases as opposed to initial judgment that suggested a toxic potential of PS. Major shortcomings emerged in the pharmacovigilance section that require urgent improvements.

Background/aims: Mini-laparoscopy (ML) allows macroscopic assessment and biopsy under direct vision and therefore is a valuable technique in the diagnosis of liver disease. Herein we report procedure-related complications and risk factors., Methods: A total of 2731 consecutive patients underwent diagnostic ML at two university hospitals (June 1996-December 2007). ML was performed using standard technique with a 1.9mm optical instrument. Coagulation of the liver biopsy site was performed with APC. The following variables were analysed as risk factors for complications: platelet count (<50/nL), international normalized ratio (INR) (>1.5), Cirrhosis, signs of portal hypertension, prior abdominal surgery., Results: Major complications occurred in 1.0% (n=27) of patients and these were, delayed bleeding from the liver biopsy site or abdominal wall (in 0.7% of patients) and intestinal perforation (in 0.3% of patients). Two patients died after severe haemorrhage (mortality 0.07%); the other patients recovered without sequelae. Bleeding risk was increased in patients with low platelets (OR=6.1), increased INR (OR=8.9), cirrhosis (OR=1.9) and portal hypertension (OR=2.1). Logistic regression showed a significant correlation only for the concurrence of low platelets and increased INR (P = 0.001; OR=14.1); bootstrap analysis identified INR >1.5 as significant predictor (P = 0.0002). Prior abdominal surgery did not carry a significant risk for intestinal perforation (OR=1.1; P = 0.142), unless abdominal adhesions were present (OR=9.5; P = 0.0002). None of the patients required surgery for intestinal perforation., Conclusion: Mini-laparoscopy is a diagnostic technique with a low complication rate. However, in patients with increased INR, low platelets or after extensive abdominal surgery, complications may occur in up to 5%., (© 2012 John Wiley & Sons A/S.)