The change of working alliance and the association to treatment outcome in an internet-based therapy after pregnancy loss.

BACKGROUND: Working alliance is a prominent non-specific factor for treatment outcomes in face-to-face and internet-based interventions. The association between working alliance and therapy outcome appears to be time- and disorder-specific, but less is known about the change of working alliance during the intervention and the impact of working alliance in grief-specific interventions. The present study examines the association between the change of working alliance and treatment outcomes in an internet-based intervention for parents who experienced pregnancy loss. METHODS: 228 participants received a grief intervention based on cognitive behavioral therapy with asynchronous text-based therapist feedback. Prolonged grief and related symptoms of traumatic stress, depression, anxiety, and general psychopathology were assessed with validated instruments before and after the intervention. The change of working alliance was assessed using the short version of the Working Alliance Inventory at mid-treatment (session 4) and the end of the treatment (session 10). RESULTS: Data for N = 146 persons was analyzed. Working alliance in total and all subscales increased significantly from sessions 4 to 10. This change in working alliance correlated significantly with a reduction in prolonged grief. Changes in subscales of working alliance also correlated with symptoms of depression and general psychopathology. Regression analysis showed that a change in working alliance predicted a reduction in prolonged grief but did not predict improvements in other grief-related symptoms. CONCLUSION: The results examine the change of working alliance during an internet-based intervention and the association with treatment outcome. A small impact of change in working alliance on treatment outcome of prolonged grief was confirmed, but not on related symptoms. Further research is needed to assess moderators of the alliance-outcome association to improve internet-based interventions. TRIAL REGISTRATION: Not applicable.

Linguistic predictors of symptom change in an internet-based cognitive behavioural intervention for prolonged grief symptoms.

This study investigates linguistic predictors of reduction in prolonged grief symptoms following a writing intervention in an internet-based cognitive behavioural therapy for people bereaved by cancer. Data stem from a randomized control clinical trial with 70 people. The Linguistic Inquiry and Word Count program was used to analyse patient language. Absolute change scores and reliable change index were used to calculate reduction in grief symptoms and clinical significant change. Best subset regression and Mann-Whitney U tests were conducted. A higher reduction of prolonged grief symptoms was correlated with more social words in the first module (ß = -.22, p = .042), less risk (ß = .33, p = .002) and body words (ß = .22, p = .048) in the second module and more time words in the third module (ß = -.26, p = .018). Patients with clinically significant change showed a higher median in function words in the first module (p = .019), a lower median in risk words in the second module (p = .019) and a higher median in assent words in the last module (p = .014) compared to patients without clinically significant change. Findings suggest that it may be beneficial for therapists to encourage a more detailed description of patients' relationship with their deceased relative during the first module, a change in perspective during the second module and a summary of past, present and future aspects at the end of therapy. Future studies should include mediation analyses to allow causal attribution of the studied effects.

Factors Associated With Treatment Response in an Internet-Based Intervention for Prolonged Grief Disorder After Cancer Bereavement.

Internet-based psychological interventions have proven effective in the treatment of prolonged grief disorder (PGD). Yet, some patients do not benefit from treatment in a clinically significant way. We aimed to examine predictors of symptom reduction in an Internet-based intervention for PGD after cancer bereavement, in order to identify possible treatment mechanisms and discern directions for future intervention design. A secondary analysis of data from a randomized wait-list controlled trial on an Internet-based intervention for PGD after cancer bereavement was conducted. Multiple regression models were used (1) to test for the influence of pretreatment PGD, working alliance, avoidance and gender on PGD symptom reduction; and (2) to explore further predictors of treatment success with a best subset selection protocol. The regression models explained 18% (Model 1) and 34% (Model 2) of variance in symptom reduction. Participants with more favorable symptom change had more severe pretreatment PGD scores and better working alliance. Those with lower social support and less posttraumatic growth experienced more PGD symptom change. In conclusion, therapeutic alliance is an important factor that should be monitored and fostered. Findings regarding social support and posttraumatic growth need further replication and clarification.

Human biodistribution and radiation dosimetry of the demyelination tracer [18F]3F4AP.

PURPOSE: [18F]3F4AP is a novel PET radiotracer that targets voltage-gated potassium (K+) channels and has shown promise for imaging demyelinated lesions in animal models of neurological diseases. This study aimed to evaluate the biodistribution, safety, and radiation dosimetry of [18F]3F4AP in healthy human volunteers. METHODS: Four healthy volunteers (2 females) underwent a 4-h dynamic PET scan from the cranial vertex to mid-thigh using multiple bed positions after administration of 368 ± 17.9 MBq (9.94 ± 0.48 mCi) of [18F]3F4AP. Volumes of interest for relevant organs were manually drawn guided by the CT, and PET images and time-activity curves (TACs) were extracted. Radiation dosimetry was estimated from the integrated TACs using OLINDA software. Safety assessments included measuring vital signs immediately before and after the scan, monitoring for adverse events, and obtaining a comprehensive metabolic panel and electrocardiogram within 30 days before and after the scan. RESULTS: [18F]3F4AP distributed throughout the body with the highest levels of activity in the kidneys, urinary bladder, stomach, liver, spleen, and brain and with low accumulation in muscle and fat. The tracer cleared quickly from circulation and from most organs. The clearance of the tracer was noticeably faster than previously reported in nonhuman primates (NHPs). The average effective dose (ED) across all subjects was 12.1 ± 2.2 µSv/MBq, which is lower than the estimated ED from the NHP studies (21.6 ± 0.6 µSv/MBq) as well as the ED of other fluorine-18 radiotracers such as [18F]FDG (~ 20 µSv/MBq). No differences in ED between males and females were observed. No substantial changes in safety assessments or adverse events were recorded. CONCLUSION: The biodistribution and radiation dosimetry of [18F]3F4AP in humans are reported for the first time. The average total ED across four subjects was lower than most 18F-labeled PET tracers. The tracer and study procedures were well tolerated, and no adverse events occurred.

Risk and course of COVID-19 in immunosuppressed patients with myasthenia gravis.

BACKGROUND: Patients with myasthenia gravis (MG) are potentially prone for a severe COVID-19 course, but there are limited real-world data available on the risk associated with COVID-19 for patients with MG. Here, we investigate whether current immunosuppressive therapy (IST) influences the risk of SARS-CoV-2 infection and COVID-19 severity. METHODS: Data from the German myasthenia gravis registry were analyzed from May 2020 until June 2021 and included patient demographics, MG disease duration, comorbidities, current IST use, COVID-19 characteristics, and outcomes. Propensity score matching was employed to match MG patients with IST to those without, and multivariable binary logistic regression models were used to determine associations between IST with (1) symptomatic SARS-CoV-2 infection and (2) severe COVID-19 course, as measured by hospitalization or death. RESULTS: Of 1379 patients with MG, 95 (7%) patients (mean age 58 (standard deviation [SD] 18) presented with COVID-19, of which 76 (80%) received IST at time of infection. 32 patients (34%) were hospitalized due to COVID-19; a total of 11 patients (12%) died. IST was a risk factor for hospitalization or death in the group of COVID-19-affected MG patients (odds ratio [OR] 3.04, 95% confidence interval [CI] = 1.02-9.06, p = 0.046), but current IST was not associated with a higher risk for SARS-CoV-2 infection itself. DISCUSSION: In this national MG cohort study, current IST use was a risk factor for a severe disease course of COVID-19 but not for SARS-CoV-2 infection itself. These data support the consequent implementation of effective strategies to prevent COVID-19 in this high-risk group. TRIAL REGISTRATION INFORMATION: German clinical trial registry ( https://www.drks.de ), DRKS00024099, first patient enrolled: February 4th, 2019.

Factors associated with pre-loss grief and preparedness in relatives of people with cancer during the COVID-19 pandemic: A cross-sectional study.

OBJECTIVES: Before the loss of a loved one to cancer, relatives have time to adapt to the impending death. However, due to the current COVID-19 pandemic, adjustment to an imminent death may be more difficult. This study investigates factors related to pre-loss grief and preparedness during the COVID-19 pandemic and their relationship with COVID-19 related fears. METHODS: Data of 299 participants from a cross-sectional study was used. Participants were included if they were relatives of people with cancer, spoke German and were at least 18 years. Multivariate linear regression analyses were conducted to measure the relationship between predictors (dysfunctional coping, emotion-focused coping, problem-focused coping, attachment anxiety, attachment avoidance, COVID-19 related fears, prognosis, perceived depth of the relationship, perceived conflict in the relationship, health status) and pre-loss grief, preparedness for caregiving and preparedness for death as the dependent variables. RESULTS: Perceived depth (ß = .365, p < .001), COVID-19 related fears (ß = .141, p = .002), prognosis for death (ß = .241, p < .001), dysfunctional coping strategies (ß = .281, p < .001) and emotion-focused coping strategies (ß = -.320, p < .001) significantly predicted pre-loss grief. Prognosis for death (ß = .347, p < .001), dysfunctional coping strategies (ß = -.229, p < .001), emotion-focused coping strategies (ß = .242, p < .001), COVID-19 related fears (ß = -.112, p = .037) and health status (ß = .123, p = .025) significantly predicted preparedness for death. Dysfunctional coping (ß = -.147, p = .009), problem-focused coping (ß = .162, p = .009), emotion-focused coping (ß = .148, p = .017), COVID-19 related fears (ß = -.151, p = .006), attachment anxiety (ß = -.169, p = .003), perceived conflict in the relationship with the patient with cancer (ß = -.164, p = .004), perceived depth in the relationship (ß = .116, p = .048) and health status (ß = .157, p = .003) significantly predicted preparedness for caregiving. CONCLUSIONS: This study shows COVID-19 pandemic impacts on the grieving process of relatives of patients with cancer. Consequently, screening for pre-loss grief, preparedness and their associated factors may help provide early support for relatives of people with cancer at need. However, further research is needed to help understand the stability of pre-loss grief and preparedness.

Eating behavior in patients with smell loss.

Background: The objective of this study was to determine how clinical characteristics and validated quality of life (QoL)-measures are associated with eating behavior in patients with olfactory dysfunction (OD). Methods: For this cross-sectional study, 150 OD patients of different causes were retrospectively recruited. Olfactory function was measured using the Sniffin' Sticks (TDI), while olfactory-related QoL was evaluated with the Questionnaire of OD negative and positive statements (QOD-NS and QOD-PS). The importance of olfaction was measured using the Importance of Olfaction Questionnaire (IOQ). The Dutch Eating Behavior Questionnaire (DEBQ) assessed eating behavior based on emotional, external, and restrained eating. Associations were sought between eating behavior metrics (as dependent variables) with clinical characteristics and olfactory-related outcome measures. Results: Emotional, external, and restrained eating behavior deviating from normative standards were reported in 54%, 71.3%, and 68% of patients, respectively. Multivariate regression modeling revealed that emotional eating was associated with age (ß = -0.227, p = 0.032), the body mass index (BMI, ß = 0.253, p = 0.005), the TDI (ß = 0.190, p = 0.046), and the QOD-NS (ß = 0.203, p = 0.049). External eating was associated with OD duration (ß = 0.291, p = 0.005), the TDI (ß = 0.225, p = 0.018), the QOD-PS (ß = -0.282, p = 0.008), and the IOQ (ß = 0.277, p = 0.004). Restrained eating was associated with age (ß = 0.216, p = 0.033), the BMI (ß = 0.257, p = 0.003), male gender (ß = -0.263, p = 0.002), and the IOQ (ß = 0.332, p < 0.001). Conclusion: Clinical characteristics and olfactory outcome measures differentially impact eating styles in OD patients. Our study's results highlight the importance of considering unfavorable changes in eating behavior during clinical counseling.

The Relationship Between Pre-Loss Grief, Preparedness and Psychological Health Outcomes in Relatives of People With Cancer.

The aim of this study was to examine the simultaneous effects of pre-loss grief, preparedness for death and preparedness for caregiving on different psychological health outcomes in relatives of people with cancer. Two hundred ninety-nine relatives of people with cancer participated in a cross-sectional online survey. Participants were included if they spoke German and were 18 years or older. Multivariate regression analysis was conducted. Pre-loss grief was significantly associated with depression (ß = .388, p < .001), anxiety (ß = .429, p < .001), somatization (ß = .221, p < .001) and satisfaction with life (ß = -.205, p < .001). Preparedness for death was significantly associated with somatization (ß = -.247, p < .001). Results suggest that people with high scores in pre-loss grief and low scores in preparedness for death are in need of early support. Interventions should address pre-loss grief and the various aspects of preparedness for death and take into account the psychological health in relatives of people with cancer. Future studies should investigate underlying mechanisms.

Deep learning-based behavioral profiling of rodent stroke recovery.

BACKGROUND: Stroke research heavily relies on rodent behavior when assessing underlying disease mechanisms and treatment efficacy. Although functional motor recovery is considered the primary targeted outcome, tests in rodents are still poorly reproducible and often unsuitable for unraveling the complex behavior after injury. RESULTS: Here, we provide a comprehensive 3D gait analysis of mice after focal cerebral ischemia based on the new deep learning-based software (DeepLabCut, DLC) that only requires basic behavioral equipment. We demonstrate a high precision 3D tracking of 10 body parts (including all relevant joints and reference landmarks) in several mouse strains. Building on this rigor motion tracking, a comprehensive post-analysis (with >100 parameters) unveils biologically relevant differences in locomotor profiles after a stroke over a time course of 3 weeks. We further refine the widely used ladder rung test using deep learning and compare its performance to human annotators. The generated DLC-assisted tests were then benchmarked to five widely used conventional behavioral set-ups (neurological scoring, rotarod, ladder rung walk, cylinder test, and single-pellet grasping) regarding sensitivity, accuracy, time use, and costs. CONCLUSIONS: We conclude that deep learning-based motion tracking with comprehensive post-analysis provides accurate and sensitive data to describe the complex recovery of rodents following a stroke. The experimental set-up and analysis can also benefit a range of other neurological injuries that affect locomotion.

Depression Symptoms and Olfactory-related Quality of Life.

OBJECTIVES: Patients with olfactory dysfunction (OD) frequently report symptoms of depression. The objective of this study was to determine how clinical characteristics and olfactory-related quality of life (QoL) measures associate with the likelihood for major depressive disorders (MDDs). METHODS: A total of 192 OD patients were included. Olfactory function was measured using all three subtests of the Sniffn' Sticks test. Olfactory-related quality of life (QoL) was evaluated using the Questionnaires of Olfactory Dysfunction (QOD)-negative (NS) and -positive statement (PS). The likelihood for MDD was assessed using the Patients Health Questionnaire-2 (PHQ-2). Demographics and disease-specific variables (etiology and duration of OD) were collected. Univariate and multivariable analyses were used to associate disease-specific variables and the QOD with the outcome of the PHQ-2. Additionally, the predictive ability of the QOD-NS to predict depressive symptoms was calculated. RESULTS: In univariate analysis, COVID-19 related smell loss, the QOD-NS, and the QOD-PS were significantly associated with the PHQ-2. In multivariable analyses adjusting for QoL measures, the QOD-NS (ß = 0.532, p < 0.001) and sinonasal OD (compared with postinfectious OD) were significantly associated with the PHQ-2 (ß = 0.146, p = 0.047). When omitting QoL measures from multivariable analyses, only COVID-19 related OD (compared with postinfectious OD) was significantly associated with the PHQ-2 (ß = 0.287, p = 0.009). A QOD-NS score > 20.5 had 70.13% sensitivity and 76.32% specificity for detecting symptoms of depression. CONCLUSION: Our results suggest that COVID-19 related OD might be associated with a higher likelihood for MDD. Furthermore, we showed that the QOD-NS score might be helpful to predict symptoms of depression in OD patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:1829-1834, 2022.

Therapist-Assisted Web-Based Intervention for Prolonged Grief Disorder After Cancer Bereavement: Randomized Controlled Trial.

BACKGROUND: Bereavement due to cancer increases the risk of prolonged grief disorder. However, specialized treatment options for prolonged grief after a loss due to illness are still scarce. OBJECTIVE: The aim of this study is to extend previous findings by evaluating a web-based cognitive behavioral intervention with asynchronous therapist support, consisting of structured writing tasks adapted specifically for prolonged grief after cancer bereavement. METHODS: The intervention was evaluated in a purely web-based randomized waitlist-controlled trial. Open-access recruitment of participants was conducted on the web. Prolonged grief (Inventory of Complicated Grief), depression, anxiety, posttraumatic stress, posttraumatic growth, somatization, sleep quality, and mental and physical health were assessed on the web via validated self-report measures. RESULTS: A total of 87 participants were randomized into the intervention group (IG; 44/87, 51%) or the waitlist control group (43/87, 49%). Of the participants, 7% (6/87) dropped out of the study (5/44, 11%, in the IG). Of the 39 completers in the IG, 37 (95%) completed all intervention tasks. The intervention reduced symptoms of prolonged grief (intention-to-treat: P<.001; η2=0.34; Cohen d=0.80) to a clinically significant extent. It had favorable effects on depression, anxiety, posttraumatic stress, posttraumatic growth, and overall mental health but not on somatization, sleep quality, or physical health. CONCLUSIONS: The web-based intervention for prolonged grief after cancer bereavement is effective in reducing symptoms of prolonged grief disorder and accompanying syndromes in a timely, easily realizable manner and addresses specific challenges of bereavement to illness. Considering web-based approaches in future mental health care policy and practice can reduce health care gaps for those who are bereaved to cancer. TRIAL REGISTRATION: German Clinical Trial Register U1111-1186-6255; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011001.

[Traumatization in the Medical Profession: Initiating Events, Roles and Process Factors]. / Traumatisierung im Arztberuf: Auslöser, Rollen und Prozessfaktoren.

BACKGROUND: Physicians show an increased prevalence of post-traumatic stress disorder (PTSD). Potentially traumatic events in the medical profession include confrontation with suffering, death, violent experiences, and medical errors. The aim of the present analysis is to record traumatic events (TE) in physicians seeking help and to qualitatively analyze the roles and process factors involved. METHOD: Using an online questionnaire, physicians who had experienced a traumatic event (TE) were surveyed regarding posttraumatic stress (PCL-5), depression (PHQ-9), alcohol abuse (CAGE test), and suicidality (BSIS). Reports of TEs were qualitatively analyzed using structured content analysis. RESULTS: N=41 physicians described at least one TE. K=54 descriptions of TEs were qualitatively analyzed. In some cases, the physicians were victims of e. g., accidents or violence; in other cases, they were involved as witnesses or helpers. The following themes could be identified: Accompaniment of and confrontation with suffering and dying, negative courses of treatment (especially complications and medical errors), and lack of support (especially lack of error management). 53,7% of physicians had PTSD, and 36,6% showed symptoms of posttraumatic stress. Harmful alcohol use was observed in 24,4% of the sample. Psychotropic medication was taken by 31,7% of the respondents. DISCUSSION: The results show a high burden of TE in the medical profession. In this context, physicians are affected by traumatization in their role as victims, witnesses, or treatment providers and confronted with the death or dying process of others. Residency presumably represents a particularly vulnerable phase. CONCLUSION: Easily accessible forms of therapy (e. g., online therapy), structural changes (e. g., adequate support for residents), and programs for functional error management in hospitals could have a positive effect on the mental health of physicians.

Re-Irradiation for Locally Recurrent Lung Cancer: A Single Center Retrospective Analysis.

The treatment of locally recurrent lung cancer is a major challenge for radiation-oncologists, especially with data on high-dose reirradiation being limited to small retrospective studies. The aim of the present study is to assess overall survival (OS) for patients with locally recurrent lung cancer after high-dose thoracic reirradiation. Thirty-nine patients who were re-irradiated for lung cancer relapse between October 2013 and February 2019 were eligible for the current retrospective analysis. All patients were re-irradiated with curative intent for in-field tumor recurrence. The diagnostic work-up included a mandatory 18F-FDG-PET-CT scan and-if possible-histological verification. The ECOG was ≤2, and the interval between initial and second radiation was at least nine months. Thirty patients (77%) had non-small cell lung cancer (NSCLC), eight (20%) had small cell lung cancer (SCLC), and in one patient (3%) histological confirmation could not be obtained. More than half of the patients (20/39, 51%) received re-treatment with dose differentiated accelerated re-irradiation (DART) at a median interval of 20.5 months (range: 6-145.3 months) after the initial radiation course. A cumulative EQD2 of 131 Gy (range: 77-211 Gy) in a median PTV of 46 mL (range: 4-541 mL) was delivered. Patients with SCLC had a 3 mL larger median re-irradiation volume (48 mL, range: 9-541) compared to NSCLC patients (45 mL, range: 4-239). The median cumulative EQD2 delivered in SCLC patients was 84 Gy (range: 77-193 Gy), while NSCLC patients received a median cumulative EQD2 of 135 Gy (range: 98-211 Gy). The median OS was 18.4 months (range: 0.6-64 months), with tumor volume being the only predictor (p < 0.000; HR 1.007; 95%-CI: 1.003-1.012). In terms of toxicity, 17.9% acute and 2.6% late side effects were observed, with a toxicity grade >3 occurring in only one patient. Thoracic high dose reirradiation plays a significant role in prolonging survival, especially in patients with small tumor volume at recurrence.

A Sum Score to Define Therapy-Refractory Myasthenia Gravis: A German Consensus.

BACKGROUND AND PURPOSE: In 2017, eculizumab has been approved for treatment-refractory generalised myasthenia gravis (TRgMG). The German Myasthenia Foundation has published a consensus statement on the use of eculizumab, with a recent update. However, a treatment-refractory state is still ill-defined and the term warrants further clarification. We aimed at developing a sum score to operationalise the definition of a TRgMG status, which is easy- to-handle in clinical decision making. METHODS: We established a structured consensus process according to the Delphi consensus methodology, with 12 members of the medical advisory board of the German Myasthenia Foundation. Accordingly, 4 consensus rounds were accomplished. Additionally, a literature survey covering the years 2004-2020 was done and relevant information offered to the consensus group. Consensus criteria were predefined. In the consensus process the relative importance of scoring items were to be consented, with a sum score of 20 and above indicating a TRgMG status. RESULTS: The sum score considers the categories disease severity, inefficiency of antecedent therapies, cessation of therapies due to side effects, and long term stay on the intensive care unit. Categories were specified by a total of 13 scoring items. Eventually, the Delphi process developed an unanimous scoring consensus. CONCLUSION: We suggest a sum score to define treatment refractory state in generalised myasthenia gravis. Beyond clarifying the indication of eculizumab, this easy-to-handle score facilitates clinical decision making and offers new inclusion criteria for clinical studies that explore new therapeutic perspectives in myasthenia gravis treatment.

Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2.

Recent studies suggest that synaptic lysophosphatidic acids (LPAs) augment glutamate-dependent cortical excitability and sensory information processing in mice and humans via presynaptic LPAR2 activation. Here, we studied the consequences of LPAR2 deletion or antagonism on various aspects of cognition using a set of behavioral and electrophysiological analyses. Hippocampal neuronal network activity was decreased in middle-aged LPAR2-/- mice, whereas hippocampal long-term potentiation (LTP) was increased suggesting cognitive advantages of LPAR2-/- mice. In line with the lower excitability, RNAseq studies revealed reduced transcription of neuronal activity markers in the dentate gyrus of the hippocampus in naïve LPAR2-/- mice, including ARC, FOS, FOSB, NR4A, NPAS4 and EGR2. LPAR2-/- mice behaved similarly to wild-type controls in maze tests of spatial or social learning and memory but showed faster and accurate responses in a 5-choice serial reaction touchscreen task requiring high attention and fast spatial discrimination. In IntelliCage learning experiments, LPAR2-/- were less active during daytime but normally active at night, and showed higher accuracy and attention to LED cues during active times. Overall, they maintained equal or superior licking success with fewer trials. Pharmacological block of the LPAR2 receptor recapitulated the LPAR2-/- phenotype, which was characterized by economic corner usage, stronger daytime resting behavior and higher proportions of correct trials. We conclude that LPAR2 stabilizes neuronal network excitability upon aging and allows for more efficient use of resting periods, better memory consolidation and better  performance in tasks requiring high selective attention. Therapeutic LPAR2 antagonism may alleviate aging-associated cognitive dysfunctions.

Acyl-Ghrelin Influences Pancreatic ß-Cell Function by Interference with KATP Channels.

The aim for this study was to elucidate how the hypothalamic hunger-inducing hormone acyl-ghrelin (AG), which is also produced in the pancreas, affects ß-cell function, with particular attention to the role of ATP-sensitive K+ (KATP) channels and the exact site of action of the hormone. AG hyperpolarized the membrane potential and decreased cytoplasmic calcium concentration [Ca2+]c and glucose-stimulated insulin secretion (GSIS). These effects were abolished in ß-cells from SUR1-knockout (KO) mice. AG increased KATP current but only in a configuration with intact metabolism. Unacylated ghrelin counteracted the effects of AG. The influence of AG on membrane potential and GSIS could only be averted in the combined presence of a ghrelin receptor (GHSR1a) antagonist and an inverse agonist. The inhibition of GSIS by AG could be prevented by dibutyryl cyclic-cAMP or 3-isobutyl-1-methylxanthine and the somatostatin (SST) receptor 2-5 antagonist H6056. These data indicate that AG indirectly opens KATP channels probably by interference with the cAMP/cAMP-dependent protein kinase pathway, resulting in a decrease of [Ca2+]c and GSIS. The experiments with SUR1-KO ß-cells point to a direct effect of AG on ß-cells and not, as earlier suggested, to an exclusive effect by AG-induced SST release from δ-cells. Nevertheless, SST receptors may be involved in the effect of AG, possibly by heteromerization of AG and SST receptors.

Possible New Strategies for the Treatment of Congenital Hyperinsulinism.

Objective: Congenital hyperinsulinism (CHI) is a rare disease characterized by persistent hypoglycemia as a result of inappropriate insulin secretion, which can lead to irreversible neurological defects in infants. Poor efficacy and strong adverse effects of the current medications impede successful treatment. The aim of the study was to investigate new approaches to silence ß-cells and thus attenuate insulin secretion. Research Design and Methods: In the scope of our research, we tested substances more selective and more potent than the gold standard diazoxide that also interact with neuroendocrine ATP-sensitive K+ (KATP) channels. Additionally, KATP channel-independent targets as Ca2+-activated K+ channels of intermediate conductance (KCa3.1) and L-type Ca2+ channels were investigated. Experiments were performed using human islet cell clusters isolated from tissue of CHI patients (histologically classified as pathological) and islet cell clusters obtained from C57BL/6N (WT) or SUR1 knockout (SUR1-/-) mice. The cytosolic Ca2+ concentration ([Ca2+]c) was used as a parameter for the pathway regulated by electrical activity and was determined by fura-2 fluorescence. The mitochondrial membrane potential (ΔΨ) was determined by rhodamine 123 fluorescence and single channel currents were measured by the patch-clamp technique. Results: The selective KATP channel opener NN414 (5 µM) diminished [Ca2+]c in isolated human CHI islet cell clusters and WT mouse islet cell clusters stimulated with 10 mM glucose. In islet cell clusters lacking functional KATP channels (SUR1-/-) the drug was without effect. VU0071063 (30 µM), another KATP channel opener considered to be selective, lowered [Ca2+]c in human CHI islet cell clusters. The compound was also effective in islet cell clusters from SUR1-/- mice, showing that [Ca2+]c is influenced by additional effects besides KATP channels. Contrasting to NN414, the drug depolarized ΔΨ in murine islet cell clusters pointing to severe interference with mitochondrial metabolism. An opener of KCa3.1 channels, DCEBIO (100 µM), significantly decreased [Ca2+]c in SUR1-/- and human CHI islet cell clusters. To target L-type Ca2+ channels we tested two already approved drugs, dextromethorphan (DXM) and simvastatin. DXM (100 µM) efficiently diminished [Ca2+]c in stimulated human CHI islet cell clusters as well as in stimulated SUR1-/- islet cell clusters. Similar effects on [Ca2+]c were observed in experiments with simvastatin (7.2 µM). Conclusions: NN414 seems to provide a good alternative to the currently used KATP channel opener diazoxide. Targeting KCa3.1 channels by channel openers or L-type Ca2+ channels by DXM or simvastatin might be valuable approaches for treatment of CHI caused by mutations of KATP channels not sensitive to KATP channel openers.

Report of rare case of intense parasitism by 34 specimens of Dioctophyme renale in a dog.

Dioctophymosis is caused by Dioctophyme renale, a nematode that usually affects the right kidney of carnivores. The aim of this study was to report on a case of a dog with progressive weight loss and swollen abdomen that was diagnosed as presenting dioctophymosis. The patient underwent surgical treatment through which 34 nematodes were found, of which 18 were female and 16 were male, with a maximum length of 74 centimeters. The parasites were free in the abdominal cavity and inside the right kidney, and had caused peritonitis, free fluid, severe adherences between the abdominal organs and renal perforation. Parasitic diseases with a high number of specimens of this species are uncommon in dogs. The disease progresses with an inflammatory reaction and consequent formation of adherences and granulomatous tissue. This surrounds the eggs that were eliminated in the abdominal cavity by the free parasites. This disease occurs frequently in the city of Pelotas, Rio Grande do Sul, Brazil, where the patient of this report was living. To the best of authors' knowledge, this is the case with the largest number of specimens of D. renale removed from a single dog in vivo.

TGFß1 Induces Axonal Outgrowth via ALK5/PKA/SMURF1-Mediated Degradation of RhoA and Stabilization of PAR6.

Transforming growth factor (TGF)ß1 has repeatedly been associated with axonal regeneration and recovery after injury to the CNS. We found TGFß1 upregulated in the stroke-denervated mouse spinal cord after ischemic injury to the motor cortex as early as 4 d postinjury (dpi) and persisting up to 28 dpi. Given the potential role of TGFß1 in structural plasticity and functional recovery after stroke highlighted in several published studies, we investigated its downstream signaling in an in vitro model of neurite outgrowth. We found that in this model, TGFß1 rescues neurite outgrowth under growth inhibitory conditions via the canonical TGFßR2/ALK5 signaling axis. Thereby, protein kinase A (PKA)-mediated phosphorylation of the E3 ubiquitin ligase SMURF1 induces a switch of its substrate preference from PAR6 to the Ras homolog A (RhoA), in this way enhancing outgrowth on the level of the cytoskeleton. This proposed mechanism of TGFß1 signaling could underly the observed increase in structural plasticity after stroke in vivo as suggested by the temporal and spatial expression of TGFß1. In accordance with previous publications, this study corroborates the potential of TGFß1 and associated signaling cascades as a target for future therapeutic interventions to enhance structural plasticity and functional recovery for stroke patients.

Assessing prolonged grief disorder: A systematic review of assessment instruments.

BACKGROUND: Grief reactions that become abnormally persistent and cause significant impairment in functioning have been introduced as new diagnostic entities within the classification systems DSM-5 and ICD-11 termed persistent complex bereavement disorder (PCBDDSM-5) and prolonged grief disorder (PGDICD-11), respectively. In order to assess these conditions, reliable and valid assessment instruments are indispensable. This systematic review examines available assessment tools for disordered grief, reviews their psychometric properties and assesses the extent to which they reflect the diagnostic entities. METHODS: A systematic search of PubMed, PsycINFO and Web of Science databases was conducted. English language articles describing either the development of a measure for assessing PGD in adults or the validation of such a measure were included. RESULTS: Overall 2215 publications were screened, 29 of which met the eligibility criteria. Three of the eleven described assessment tools are structured clinical interviews, one tool is a carer-based assessment and the remaining tools are self-report questionnaires. Most instruments demonstrate excellent or good reliability and validity. No tool assesses the current diagnostic criteria for PGDICD-11 fully. While three tools cover all diagnostic criteria for PCBDDSM-5, only one (TGI-SR) provides an adequate, empirically tested diagnostic algorithm. LIMITATIONS: The inclusion of only English-language publications may have led to omission of relevant measurement tools and/or validation studies in different languages. CONCLUSIONS: The newly released ICD-11 criteria for PGD could serve as a gold standard for diagnosis and build a foundation for the development of more precise assessment tools. Recommendations for clinical practice and future research are provided.