Publications by authors named "Frank Weber"

255 Publications

Effect of High Dose Active Vitamin D Therapy on the Development of Hypocalcemia After Subtotal Parathyroidectomy in Patients on Chronic Dialysis.

Int J Nephrol Renovasc Dis 2021 11;14:399-410. Epub 2021 Nov 11.

Department of Nephrology, University Hospital Essen, Essen, Germany.

Background: The period after parathyroidectomy (PTx) in dialysis patients is characterized by periods of severe hypocalcemia. This study aims to investigate the effect of high doses of active vitamin D immediately after PTx on the development of hypocalcemia.

Materials And Methods: We retrospectively reviewed 111 patients with secondary hyperparathyroidism receiving subtotal PTx between 2010 and 2019. A high dose group "HDG" (n = 67) receiving 12 µg alfacalcidol in combination with 8.550 mg calcium acetate per day, which was then adapted according to lab values, was compared with a low dose group "LDG" (n = 44) receiving up to 4 µg alfacalcidol per day. The laboratory values were recorded up to ten weeks postoperatively.

Results: The assumed drops in parathyroid hormone (PTH) and calcium were observed in both groups after PTx. We observed significantly lower calcium values in the LDG between days 4 and 18 postoperatively than in the HDG ( < 0.001). The proportion of severe hypocalcemia after PTx (total calcium <1.5 mmol/l) in the HDG was 8.5% on day 1 and 47% on day 4 in the LDG. Intravenous calcium requirements were significantly lower in the HDG (7.6%) than in the LDG (45.7%; = 0.001).

Conclusion: The period after PTx in dialysis patients is characterized by an expected drop in PTH and calcium within the first days. Ongoing high turnover is observed in the 2nd and 3rd week after PTx. Administering high doses of alfacalcidol combined with calcium acetate diminishes the episodes of severe hypocalcemia and the need for intravenous calcium.
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http://dx.doi.org/10.2147/IJNRD.S334227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594789PMC
November 2021

Risk Patterns of Distant Metastases in Follicular, Papillary and Medullary Thyroid Cancer.

Horm Metab Res 2021 Nov 10. Epub 2021 Nov 10.

Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.

This study of 542 patients with follicular thyroid cancer, 366 patients with the follicular variant and 1452 patients with the classical variant of papillary thyroid cancer, and 819 patients with sporadic medullary thyroid cancer operated at a tertiary referral center aimed to determine risk patterns of distant metastasis for each tumor entity, which are ill-defined. On multivariable logistic regression analyses, lymph node metastasis consistently emerged as an independent risk factor of distant metastasis, yielding odds ratios (ORs) of 2.4 and 2.8 for follicular thyroid cancer and the follicular variant of papillary thyroid cancer, and ORs of 5.9 and 6.4 for the classical variant of papillary thyroid cancer and sporadic medullary thyroid cancer. Another independent risk factor consistently associated with distant metastasis, most strongly in follicular thyroid cancer and the follicular variant of papillary thyroid cancer (OR 3.5 and 4.0), was patient age >60 years. Altogether, 2 distinct risk patterns of distant metastasis were identified, which were modulated by other cancer type-dependent risk factors: one with lymph node metastasis as leading component (classical variant of papillary thyroid cancer and sporadic medullary thyroid cancer), and another one with age as leading component (follicular thyroid cancer and the follicular variant of papillary thyroid cancer). Distant metastasis was exceptional in node-negative patients with sporadic medullary thyroid cancer (1.7%) and the classical variant of papillary thyroid cancer (1.4%), and infrequent in node-negative patients with the follicular variant of papillary thyroid cancer (4.4%). These findings delineate windows of opportunity for early surgical intervention before distant metastasis has occurred.
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http://dx.doi.org/10.1055/a-1668-0094DOI Listing
November 2021

Medullary thyroid cancer and pheochromocytoma in MEN2A: are there parent of origin effects on disease expression?

Fam Cancer 2021 Oct 22. Epub 2021 Oct 22.

Medical Faculty, Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, 06097, Halle (Saale), Germany.

There are no data on the impact of parent-of-origin effects on the expression of multiple endocrine neoplasia type 2A (MEN2A). The present study aimed to explore effects of parent-of-origin and offspring gender in MEN2A. In total, 224 carriers harbored heterozygous RET (REarranged during Transfection) p.Cys634 missense variants, for 169 of whom information on parent-of-origin gender was available. Altogether, offspring from affected fathers harbored more often node metastases from medullary thyroid cancer (45 vs. 19%; P = 0.006) and bilateral pheochromocytoma (24 vs. 10%; P = 0.021) than offspring from affected mothers. The former also also tended to be older at most recent follow-up (medians of 21 vs. 14 years; P = 0.056) and tended to have more often pheochromocytoma (33 vs. 19 yrs.; P = 0.051) and primary hyperparathyroidism (13 vs. 4%; P = 0.090) than the latter. Daughters from affected fathers harbored more often node metastases (39 vs. 15%; P = 0.043) than daughters from affected mothers. This difference decreased in male offspring when sons from affected fathers were compared with sons from affected mothers (52 vs. 40%; P = 0.111). There was also a slight deficit of male offspring: 1.1 sons each per affected mother and father vs. 1.2 daughters per affected mother and 1.4 daughters per affected father. These data suggest a parent-of-origin effect in MEN2A, warranting international collaborative research.
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http://dx.doi.org/10.1007/s10689-021-00282-wDOI Listing
October 2021

Continued Discontinuation of TKI Treatment in Medullary Thyroid Carcinoma - Lessons From Individual Cases With Long-Term Follow-Up.

Front Endocrinol (Lausanne) 2021 29;12:718418. Epub 2021 Sep 29.

Department of Endocrinology, Diabetology and Metabolism, Endocrine Tumour Center at West German Cancer Center, University of Duisburg-Essen, Essen, Germany.

Background: The tyrosine kinase inhibitors (TKI) vandetanib and cabozantinib are approved as targeted therapies in advanced medullary thyroid carcinoma (MTC) with symptoms or high tumour burden. Only recently, toxicity in long-time TKI usage was analysed. However, little is known about the impact of TKI discontinuation on MTC disease course after longer-term therapy. Here, we report our experience in a series of 7 MTC patients with vandetanib treatment of up to 87 months followed by discontinuation for concerns of toxicity or due to side-effects. The discontinuation of TKI therapy is a relevant clinical scenario. To our knowledge we present the largest single center series on an important aspect of TKI management.

Methods: Retrospective analysis of MTC patients with continued discontinuation of vandetanib treatment in a tertiary referral endocrine tumour centre. Analysis included a review of patients' records for TKI indication, and treatment response as well indications for continued TKI discontinuation and follow-up by clinical assessment, calcitonin and CEA doubling times as well as imaging (ultrasound, CT).

Results: Seven MTC patients [6 sporadic MTC, 1 Multiple Endocrine Neplasie Type 2a (MEN2a)] with previous vandetanib treatment (median: 41 months; range 7-87 months) and continued TKI discontinuation were identified out of 161 analysed MTC files. TKI treatment was initiated due to high tumour burden and symptoms or RECIST (Response Evaluation Criteria In Solid Tumors) progression in all patients. Two patients (29%) remained stable after discontinuation of vandetanib until now (follow-up of 47 and 61 months). Both patients had been on TKI therapy for 73 and 58 months. Five patients (71%) developed progressive disease after TKI discontinuation. In 2 patients, vandetanib was restarted after 45 and 52 months resulting again in disease control. One patient was enrolled in a new RET kinase inhibitor trial after 45 months of vandetanib discontinuation. Two patients declined restart of treatment due to mental health issues leading to discontinuation of vandetanib in the first place (after 7 and 38 months of treatment) and both patients died of rapidly progressive disease. At time points of tumour progression, calcitonin-doubling time (CDT) was < 2 years in all patients.

Conclusion: This case series suggests that discontinuation of long-term vandetanib treatment with documented stable disease does not automatically result in rapid disease progression but may be followed by prolonged "TKI free" stable disease in individual patients. Analysis of calcitonin and CDT during discontinuation is indicated as it will unmask tumour progression earlier than imaging. Restart with the same TKI is possible in case of progression.
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http://dx.doi.org/10.3389/fendo.2021.718418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511790PMC
September 2021

Distinct Late-Night Salivary Cortisol Cut-Off Values for the Diagnosis of Hypercortisolism.

Horm Metab Res 2021 Oct 4;53(10):662-671. Epub 2021 Oct 4.

Department of Endocrinology, Diabetes and Metabolism, University Duisburg-Essen, Essen, Germany.

Due to high morbidity and mortality of untreated hypercortisolism, a prompt diagnosis is essential. Measurement of late-night salivary cortisol provides a simple and non-invasive method. However, thresholds and reference ranges differ among studies. The goal of this study was to define a threshold of late-night salivary cortisol for the diagnosis of hypercortisolism based on the used assay. Moreover, the influence of different aetiologies of hypercortisolism and individual comorbidities were investigated. Prospective analyses of 217 patients, including 36 patients with proven hypercortisolism were carried out. A sum of 149 patients with suspicion of hypercortisolism but negative endocrine testing and 32 patients with hypercortisolism in remission served as control group. Late-night salivary cortisol was measured using an automated chemiluminescence immunoassay. Cut-off values were calculated by ROC analysis. The calculated cut-off value for the diagnosis of hypercortisolism was 10.1 nmol/l (sensitivity 94%; specificity 84%). Only slightly lower thresholds were obtained in patients with suspected hypercortisolism due to weight gain/obesity (9.1 nmol/l), hypertension or adrenal tumours (both 9.8 nmol/l) or pituitary adenomas (9.5 nmol/l). The late-night salivary cortisol threshold to distinguish between Cushing's disease and Cushing's disease in remission was 9.2 nmol/l. The cut-off value for the diagnosis of ectopic ACTH-production was 109.0 nmol/l (sensitivity 50%, specificity 92%). Late-night salivary cortisol is a convenient and reliable parameter for the diagnosis of hypercortisolism. Except for ectopic ACTH-production, thresholds considering different indications for evaluation of hypercortisolism were only slightly different. Therefore, they might only be useful if late-night salivary cortisol results near the established cut-off value are present.
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http://dx.doi.org/10.1055/a-1608-1720DOI Listing
October 2021

Diagnostic performance of [I]m-iodobenzylguanidine PET/CT in patients with pheochromocytoma.

J Nucl Med 2021 Sep 23. Epub 2021 Sep 23.

University Clinic Essen.

I-MIBG scintigraphy has shown a high specificity for imaging pheochromocytoma and paraganglioma however with low sensitivity due to low spatial resolution. I-MIBG PET may overcome this limitation to improve the staging of patients with (suspected) pheochromocytoma. We analyzed the sensitivity, specificity, positive and negative predictive values (PPV, NPV) of I-MIBG PET in 43 consecutive patients with suspected (recurrence of) pheochromocytoma using histopathological ( = 25) and clinical validation ( = 18) as standard of truth. Furthermore, we compared I-MIBG PET versus contrast enhanced CT (CE-CT) per-patient and per-lesion detection rate of I-MIBG PET in 13 additional patients with known metastatic malignant pheochromocytoma (MMP). I-MIBG PET/CT was positive in 19/43 (44%) patients with suspected pheochromocytoma. Presence of pheochromocytoma was confirmed in 22/43 (51%). I-MIBG PET/CT sensitivity, specificity, PPV, NPV were 86%, 100%, 100%, 88%, respectively. I-MIBG PET was positive in 11/13 (85%) MMP patients. Combined I-MIBG PET and CE-CT detected 173 lesions, of which 166 (96%) and 118 (68%) were visible on I-MIBG PET and CE-CT, respectively. I-MIBG PET detects pheochromocytoma with high accuracy at initial staging and high detection rate at re-staging. Superior diagnostic performance aids guidance of surgical and medical management including personalized I-MIBG therapy.
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http://dx.doi.org/10.2967/jnumed.121.262797DOI Listing
September 2021

Clinical Significance of Coexistence of Hashimoto Thyroiditis and Graves' Disease with Differentiated and Medullary Thyroid Cancer.

Exp Clin Endocrinol Diabetes 2021 Sep 13. Epub 2021 Sep 13.

Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.

The association of Hashimoto thyroiditis and Graves' disease with papillary, follicular, and medullary thyroid cancer has not been comprehensively investigated until now. This comparative clinicopathological study of consecutive patients thyroidectomized at a surgical referral center aimed to explore interdependencies between chronic autoimmune thyroiditis and thyroid cancer. Altogether, there were 852 (58.4%) patients with papillary thyroid cancer, 181 (12.4%) patients with follicular thyroid cancer, and 426 (29.2%) patients with sporadic medullary thyroid cancer, of whom 75 (5.1%) patients also had Hashimoto thyroiditis and 40 (2.7%) patients also had Graves' disease. Patients with papillary (medians of 42 vs. 48 years;  =0.008) and follicular (medians of 33 vs. 63 years; =0.022) thyroid cancer, unlike patients with medullary thyroid cancer (medians of 57.5 vs. 57 years; =0.989), were younger at thyroidectomy when they had Hashimoto thyroiditis concomitantly. No such associations were seen with Graves' disease. Primary thyroid cancers tended to be more localized in conjunction with Hashimoto thyroiditis, and less so with Graves' disease, although patterns were not consistent across tumor types. In conclusion, Hashimoto thyroiditis, but not Graves' disease, may be associated with differentiated (papillary and follicular) thyroid cancer but not with medullary thyroid cancer.
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http://dx.doi.org/10.1055/a-1562-3455DOI Listing
September 2021

Metastatic Risk Profile of Microscopic Lymphatic and Venous Invasion in Medullary Thyroid Cancer.

Horm Metab Res 2021 Sep 8;53(9):588-593. Epub 2021 Sep 8.

Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.

The metastatic risk profile of microscopic lymphatic and venous invasion in medullary thyroid cancer is ill-defined. This evidence gap calls for evaluation of the suitability of microscopic lymphatic and venous invasion at thyroidectomy for prediction of lymph node and distant metastases in medullary thyroid cancer. In this study of 484 patients with medullary thyroid cancer who had≥5 lymph nodes removed at initial thyroidectomy, microscopic lymphatic and venous invasion were significantly associated with greater primary tumor size (27.6 vs. 14.5 mm, and 30.8 vs. 16.2 mm) and more frequent lymph node metastasis (97.0 vs. 25.9%, and 85.2 vs. 39.5%) and distant metastasis (25.0 vs. 5.1%, and 32.8 vs. 7.3%). Prediction of lymph node metastases by microscopic lymphatic invasion was better than prediction of distant metastases by microscopic venous invasion regarding sensitivity (97.0 vs. 32.8%) and positive predictive value (58.4 vs. 39.2%); comparable regarding negative predictive value (98.5 vs. 90.5%) and accuracy (80.4 vs. 85.1%); and worse regarding specificity (74.1 vs. 92.7%). On multivariable logistic regression, microscopic lymphatic invasion predicted lymph node metastasis better (odds ratio [OR] 65.6) than primary tumor size (OR 4.6 for tumors>40 mm and OR 2.7 for tumors 21-40 mm, relative to tumors≤20 mm), whereas primary tumor size was better in predicting distant metastasis (OR 8.3 for tumors>40 mm and OR 3.9 for tumors 21-40 mm, relative to tumors≤20 mm) than microscopic venous invasion (OR 3.2). These data show that lymphatic invasion predicts lymph node metastases better in medullary thyroid cancer than venous invasion heralds distant metastases.
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http://dx.doi.org/10.1055/a-1559-3424DOI Listing
September 2021

Multiple Sclerosis Therapy Consensus Group (MSTCG): position statement on disease-modifying therapies for multiple sclerosis (white paper).

Ther Adv Neurol Disord 2021 18;14:17562864211039648. Epub 2021 Aug 18.

Neurologie in Meerbusch, MS-Zentrum, Meerbusch, Germany.

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, and Switzerland).
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http://dx.doi.org/10.1177/17562864211039648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377320PMC
August 2021

Analysis of risk factors and prognosis in differentiated thyroid cancer with focus on minimal extrathyroidal extension.

BMC Endocr Disord 2021 Aug 10;21(1):161. Epub 2021 Aug 10.

Clinic for Nuclear Medicine, University Hospital Essen, Essen, Germany.

Aims: In contrast to all prior AJCC/TNM classifications for differentiated thyroid cancer (DTC) the 8th edition does not take minimal extrathyroidal extension (M-ETE) into consideration for local tumor staging. We therefore aimed to retrospectively assess the specific impact of M-ETE on the outcome of M-ETE patients treated in our clinic.

Methods: DTC patients with M-ETE and a follow-up time of ≥ 5 years were included and matched with an identical number of patients without M-ETE, but with equal histopathological tumor subtype and size. The frequency of initially metastatic disease among groups was compared using Fisher's exact test, the recurrence rate by virtue of log-rank test. Fisher's exact test and multivariate analysis were used to account for the presence of confounding risk factors.

Results: One hundred sixty patients (80 matching pairs) were eligible. With other confounding risk factors being equal, the prevalence of N1-/M1-disease at initial diagnosis was comparable among groups (M-ETE: 42.5 %; no M-ETE: 32.5 %; p = 0.25). No differences with regard to the recurrence rate were shown. However, M-ETE patients were treated with external beam radiation therapy more often (16.3 % vs. 1.3 %; p = 0.004) and received higher median cumulative activities of I (10.0 vs. 8.0 GBq; p < 0.001).

Discussion: Although having played a pivotal role for local tumor staging of DTC for decades M-ETE did not increase the risk for metastases at initial diagnosis and the recurrence rate in our cohort. Patients with M-ETE had undergone intensified treatment, which entails a possible confounding factor that warrants further investigation in randomized controlled trials.
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http://dx.doi.org/10.1186/s12902-021-00826-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353758PMC
August 2021

The Response and Tolerability of a Novel Cold Atmospheric Plasma Wound Dressing for the Healing of Split Skin Graft Donor Sites: A Controlled Pilot Study.

Skin Pharmacol Physiol 2021 6;34(6):328-336. Epub 2021 Aug 6.

Clinic and Policlinic for Dermatology and Venereology, University Medical Center Rostock, Rostock, Germany.

Introduction: Cold atmospheric plasma (CAP) has positive effects on wound healing and antimicrobial properties. However, an ongoing challenge is the development of specific modes of application for different clinical indications.

Objectives: We investigated in a prospective pilot study the response and tolerability of a newly developed CAP wound dressing for the acute healing of split skin graft donor sites compared to conventional therapy.

Methods: We applied both treatments to each patient (n = 10) for 7 days and measured 4 parameters of wound healing every other day (i.e., 1,440 measurements) using a hyperspectral imaging camera. Additionally, we evaluated the clinical appearance and pain levels reported by the patients.

Results: The CAP wound dressing was superior to the control (p < 0.001) in the improvement of 3 wound parameters, that is, deep tissue oxygen saturation, hemoglobin distribution, and tissue water distribution. CAP was well tolerated, and pain levels were lower in CAP-treated wound areas.

Conclusion: CAP wound dressing is a promising new tool for acute wound healing.
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http://dx.doi.org/10.1159/000517524DOI Listing
August 2021

Statistical Methods to Support Difficult Diagnoses.

Diagnostics (Basel) 2021 Jul 20;11(7). Epub 2021 Jul 20.

Center for Undiagnosed and Rare Diseases (ZusE), Philipps University, 35043 Marburg, Germany.

Far too often, one meets patients who went for years or even decades from doctor to doctor without obtaining a valid diagnosis. This brings pain to millions of patients and their families, not to speak of the enormous costs. Often patients cannot tell precisely enough which factors (or combinations thereof) trigger their problems. If conventional methods fail, we propose the use of statistics and algebra to provide doctors much more useful inputs from patients. We use statistical regression for triggering factors of medical problems, and in particular, "balanced incomplete block designs" for factors detection. These methods can supply doctors with much more valuable inputs and can also find combinations of multiple factors through very few tests. In order to show that these methods do work, we briefly describe a case in which these methods helped to solve a 60-year-old problem in a patient and provide some more examples where these methods might be particularly useful. As a conclusion, while regression is used in clinical medicine, it seems to be widely unknown in diagnosing. Statistics and algebra can save the health systems much money, as well as the patients a lot of pain.
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http://dx.doi.org/10.3390/diagnostics11071300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305132PMC
July 2021

[Multiple sclerosis treatment consensus group (MSTCG): position paper on disease-modifying treatment of multiple sclerosis 2021 (white paper)].

Nervenarzt 2021 Aug 23;92(8):773-801. Epub 2021 Jul 23.

Multiple Sklerose Therapie Konsensus Gruppe (MSTKG), Münster, Deutschland.

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, Switzerland).
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http://dx.doi.org/10.1007/s00115-021-01157-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300076PMC
August 2021

Training Courses in Laryngeal Nerve Monitoring in Thyroid and Parathyroid Surgery- The INMSG Consensus Statement.

Front Endocrinol (Lausanne) 2021 18;12:705346. Epub 2021 Jun 18.

Department of Human Pathology in Adulthood and Childhood "G. Barresi", University Hospital G. Martino, University of Messina, Messina, Italy.

Intraoperative neural monitoring (IONM) is now an integral aspect of thyroid surgery in many centers. Interest in IONM and the number of institutions that perform monitored thyroidectomies have increased throughout the world in recent years. For surgeons considering the introduction of IONM in their practice, specific training in IONM devices and procedures can substantially shorten the learning curve. The International Neural Monitoring Study Group (INMSG) has been at the forefront of IONM technology and procedural adoption since the introduction of neural monitoring in thyroid and parathyroid surgery. The purpose of this document is to define the INMSG consensus on essential elements of IONM training courses. Specifically, this document describes the minimum training required for teaching practical application of IONM and consensus views on key issues that must be addressed for the safe and reliable introduction of IONM in surgical practice. The intent of this publication is to provide societies, course directors, teaching institutions, and national organizations with a practical reference for developing IONM training programs. With these guidelines, IONM will be implemented optimally, to the ultimate benefit of the thyroid and parathyroid surgical patients.
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http://dx.doi.org/10.3389/fendo.2021.705346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253252PMC
June 2021

Midlatency auditory evoked potentials during anesthesia in children: A narrative review.

Paediatr Anaesth 2021 Oct 18;31(10):1031-1039. Epub 2021 Jul 18.

Department of Anesthesiology, Erasmus MC Sophia Childrens Hospital, Rotterdam, The Netherlands.

The brain is considered as the major target organ of anesthetic agents. Despite that, a reliable means to monitor its function during anesthesia is lacking. Mid latency auditory evoked potentials are known to be sensitive to anesthetic agents and might therefore be a measure of hypnotic state in pediatric patients. This review investigates the available literature describing various aspects of mid latency auditory evoked potential monitoring in pediatric anesthesia.
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http://dx.doi.org/10.1111/pan.14252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518658PMC
October 2021

Simulated Gastric Digestion and In Vivo Intestinal Uptake of Orally Administered CuO Nanoparticles and TiO E171 in Male and Female Rat Pups.

Nanomaterials (Basel) 2021 Jun 4;11(6). Epub 2021 Jun 4.

RTI International, 3040 E Cornwallis Road, Research Triangle Park, NC 27709, USA.

Oral exposure to nanoparticles (NPs) during early life is an understudied area. The goals of this study were to evaluate the effect of pre-weaned rat gastric fluids on 50 nm CuO NPs and TiO E171 in vitro, and to evaluate uptake in vivo. The NP uptake was studied in vivo in male and female Sprague-Dawley rat pups following oral administration of four consecutive daily doses of 10 mg/kg CuO NPs, TiO E171, or vehicle control (water) between postnatal day (PND) 7-10. Rat pups were sacrificed on either PND10 or PND21. Simulated digestion led to dissolution of CuO NPs at the later ages tested (PND14 and PND21, but not PND7). In vivo intestinal uptake of CuO NPs and TiO E171 was observed by hyperspectral imaging of intestinal cross sections. Brightfield microscopy showed that the number of immune cells increased in the intestinal tissue following NP administration. Orally administered NPs led to low intestinal uptake of NPs and an increase in immune cells in the small and large intestine, suggesting that oral exposure to NPs during early life may lead to irritation or a low-grade inflammation. The long-term impact of increased immune cells in the intestinal tract during early life is unknown.
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http://dx.doi.org/10.3390/nano11061487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230348PMC
June 2021

Predictive Factors for RAI-Refractory Disease and Short Overall Survival in PDTC.

Cancers (Basel) 2021 Apr 6;13(7). Epub 2021 Apr 6.

Department of Nuclear Medicine, University Hospital Essen, University Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany.

Background: The clinical phenotype of poorly differentiated thyroid cancer (PDTC) can vary substantially. We aim to evaluate risk factors for radioiodine refractory (RAI-R) disease and reduced overall survival (OS).

Methods: We retrospectively screened our institutional database for PDTC patients. For the assessment of RAI-R disease, we included patients who underwent dual imaging with F-FDG-PET and I-PET/I scintigraphy that met the internal standard of care. We tested primary size, extrathyroidal extension (ETE), and age >55 years as risk factors for RAI-R disease at initial diagnosis and during the disease course using uni- and multivariate analyses. We tested metabolic tumor volume (MTV), total lesion glycolysis (TLG) on F-FDG-PET, and the progression of stimulated thyroglobulin within 4-6 months of initial radioiodine therapy as prognostic markers for OS.

Results: Size of primary >40 mm and ETE were significant predictors of RAI-R disease in the course of disease in univariate (81% vs. 27%, = 0.001; 89% vs. 33%, < 0.001) and multivariate analyses. Primary tumor size was an excellent predictor of RAI-R disease (AUC = 0.90). TLG/MTV > upper quartile and early thyroglobulin progression were significantly associated with shorter median OS (29.0 months vs. 56.9 months, < 0.05; 57.8 months vs. not reached < 0.005, respectively).

Discussion: PDTC patients, especially those with additional risk factors, should be assessed for RAI-R disease at initial diagnosis and in the course of disease, allowing for early implementation of multimodal treatment. Primary tumor size >40 mm, ETE, and age >55 are significant risk factors for RAI-R disease. High MTV/TLG is a significant risk factor for premature death and can help identify patients requiring intervention.
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http://dx.doi.org/10.3390/cancers13071728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038667PMC
April 2021

The performance of the heart rate variability-derived Newborn Infant Parasympathetic Evaluation Index as a measure of early postoperative pain and discomfort in infants-A prospective observational study.

Paediatr Anaesth 2021 07 6;31(7):787-793. Epub 2021 May 6.

Department of Anesthesia, Erasmus University Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.

Background: The heart rate variability-derived Newborn Infant Parasympathetic Evaluation (NIPE™) Index is a continuous noninvasive tool for the assessment of pain and discomfort in infants. Little is known about its performance in the early postoperative setting, where assessment of pain/discomfort is usually based on discontinuous observational scoring systems or personal experience of medical staff.

Aims: To investigate the performance of the NIPE as a measure of early postoperative pain and/or discomfort in infants.

Methods: The potential of the NIPE to detect pain/discomfort, as assessed by two clinical scoring systems (FLACC and COMFORT-B scale), was investigated in postoperative infants (0-2 years).

Results: Receiver operating curve (ROC) analyses investigating the power of the NIPE to distinguish between comfort and pain/discomfort, revealed areas under the curve (AUC) of 0.77 for the FLACC, 0.81 for the COMFORT-B score, and 0.77 for a combination of FLACC & COMFORT-B. Logistic regression analysis provided initial evidence that the NIPE is an independent predictor of a FLACC score ≥4 and/or a COMFORT-B score ≥17, though R values were below .2. NIPE values associated with a FLACC ≥4 (48 [45-56]), a COMFORT-B score ≥17 (47 [42-53]), and a FLACC ≥4 & COMFORT-B ≥17 (47 [42-57]) were lower than NIPE values associated with a FLACC <4 (60 [53-68], 95% CI of difference -14 to -8, p < .0001), a COMFORT-B score <17 (61 [54-68], 95% CI of difference -16 to -10, p < .0001), and a FLACC <4 & COMFORT-B score <17 (60 [53-68], 95% CI of difference -15 to -8, p < .0001). We found no evidence of a predictive value of the NIPE regarding the occurrence of pain.

Conclusions: The NIPE detected pain and discomfort in infants after general anesthesia with reasonable areas under the ROC curve (±0.8), whereas it was not predictive of clinically detectable pain or discomfort.
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http://dx.doi.org/10.1111/pan.14188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251861PMC
July 2021

Exceptionality of Distant Metastasis in Node-Negative Hereditary and Sporadic Medullary Thyroid Cancer: Lessons Learned.

J Clin Endocrinol Metab 2021 07;106(8):e2968-e2979

Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06097 Halle (Saale), Germany.

Context: Risk factors of lymph node and distant metastases have rarely been analyzed in hereditary and sporadic medullary thyroid cancer (MTC) using large genetic-clinical data sets.

Objective: This comprehensive investigation aimed to explore risk factors of lymph node and distant metastases and interdependencies between age at thyroidectomy, primary tumor size, lymph node metastasis, and distant metastasis in patients with hereditary and sporadic MTC.

Methods: We performed comparative analyses of risk factors of metastasis, stratified by hereditary MTC (4 mutational risk categories) and sporadic MTC.

Results: There were 1115 patients with hereditary MTC (307 patients) or sporadic MTC (808 patients). Age at thyroidectomy increased proportionately from 12.2, 22.7, 34.3, and 49.8 years for patients with decreasing mutational risk, compared with 52.1 years for patients with sporadic MTC. Metastatic primary tumors overall were 10.7 to 19.4 mm larger in node-positive patients and 15.9 to 19.3 mm larger in distant metastatic patients at thyroidectomy than nonmetastatic tumors. Distant metastases were noted in 13% to 50% of node-positive vs 0% of node-negative hereditary MTC, and in 23.5% of node-positive vs 1.7% of node-negative sporadic MTC. In multivariable logistic regression analysis for sporadic MTC, lymph node metastasis contributed to distant metastasis (odds ratio 12.4) more than primary tumor size (odds ratios of 7.8, 5.5, and 2.4 for tumors measuring >60, 41-60, and 21-40 mm, respectively).

Conclusion: When thyroidectomy is performed before lymph node metastases have developed, distant metastases are exceptional, both in patients with hereditary MTC (irrespective of mutational risk level) and patients with sporadic MTC.
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http://dx.doi.org/10.1210/clinem/dgab214DOI Listing
July 2021

Do arachnoid cysts grow? A retrospective volumetric study.

J Neurol 2021 Oct 27;268(10):3777-3780. Epub 2021 Mar 27.

Department of Research and Development, German Air Force Center of Aerospace Medicine, 82242, Fürstenfeldbruck, Germany.

Objective: Arachnoid cysts (ACs) are frequent incidental findings and may be associated with neuropsychiatric symptoms. Usually growth of the ACs with pressure on adjacent brain tissue is regarded as cause of the symptoms. This study was undertaken to identify if and which ACs grow with time.

Methods: We used a large database of cranial MRIs for a retrospective analysis.

Results: During a period of 10 years, we collected 166 ACs of 50 persons, mean observational period was 2.5 years. Among these, only larger cysts at the temporal pole, i.e., Galassi II ACs, grew with a rate of 0.3 ml a year (β = 0.32, SE 0.07, p = 0.003); all other ACs remained constant in size or became smaller. All cysts were clinically silent.

Conclusions: Most ACs remain constant in size or become smaller.

Classification Of Evidence: This study provides Class III evidence that the majority of arachnoid cysts does not grow.
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http://dx.doi.org/10.1007/s00415-021-10440-wDOI Listing
October 2021

Incidental Finding Prevalences in 3-Tesla Brain and Spine MRI of Military Pilot Applicants.

Aerosp Med Hum Perform 2021 Mar;92(3):146-152

Incidental findings in brain and spine MRI are common. In aerospace medicine, pilot selection may be affected by improved sensitivity of modern MRI devices. We investigated the occurrence of medically unfit rates caused by incidental findings in military pilot applicants using a 3-Tesla scanner as compared to the outcomes of a lower field strength 1-Tesla device based on similar screening protocols. A total of 3315 military pilot applicants were assessed by a standardized German Air Force Imaging Screening Protocol and retrospectively subdivided into two cohorts, one of which was assessed by 1-Tesla MRI (2012-2015; 1782), while in the second cohort (2016-2019; 1808), a 3-Tesla MRI was used. Cohorts were statistically analyzed relating to three entities of incidental findings: 1) intervertebral disc displacements, 2) intracerebral vessel malformations, and 3) other abnormal findings in the brain. Pooled prevalences of incidental findings in medically unfit applicants significantly increased by use of 3-Tesla MRI as compared to lower resolution 1-Tesla MRI. Regarding the spine, prevalences more than doubled (1.46 vs. 4.99%; < 0.05) for intervertebral disc displacements. Similarly, prevalences of cerebral vessel malformations as well as other abnormal CNS incidental findings considerably increased by use of 3-Tesla MRI (0.28 vs. 1.67%; < 0.05, and 5.12 vs. 9.80%; < 0.05). Effect sizes and correlations were substantial in all conditions analyzed (Cohens d > 0.8; Pearsons r > 0.75). Our data suggest a strong dependency of incidental cerebrospinal findings on image resolution and sensitivity of MRI devices used for screening, which is enhanced by refined imaging protocols and followed by increased medical unfit rates in prospective aviators. Adjusted strategies in the assessment of such lesions are needed to redefine their natural history and physiological impact, and to optimize screening protocols for future pilot selection.
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http://dx.doi.org/10.3357/AMHP.5749.2021DOI Listing
March 2021

The effects of 12 weeks of functional strength training on muscle strength, volume and activity upon exposure to elevated G forces in high-performance aircraft personnel.

Mil Med Res 2021 02 23;8(1):15. Epub 2021 Feb 23.

Integrative & Experimental Exercise Science & Training, Institute of Sport Science, University of Wuerzburg, 97082, Wuerzburg, Germany.

Background: Technological advancements in modern military and acrobatic jet planes have resulted in extraordinary psychophysiological loads being exerted upon flying personnel, including inducing neck and back pain. The purpose of this study was to examine the effects of 12 weeks of functional strength training on 1) the volume and strength of the neck and shoulder muscles and 2) muscular activity upon exposure to helmets of different masses and elevated G forces in a long-arm centrifuge in high-performance aircraft personnel.

Methods: Eighteen participants underwent 12 weeks of functional strength training (n = 12) or the control protocol (n = 6) without additional strength training. Pre- and post-intervention tests included evaluations of isometric strength of the head extensor muscles, flexion, and lateral flexion and rotation, as well as magnetic resonance imaging (MRI) to measure the volume of the m. sternocleidomastoideus, m. trapezius, and deep neck muscles. Furthermore, during a long-arm centrifuge (+ 1.4 and + 3 G) protocol, the muscular activity levels of the m. sternocleidomastoideus, m. trapezius and m. erector spinae muscles were assessed without a flight helmet, with a helmet, and with a helmet and night vision goggles. Each participant's perception of muscular strain was noted immediately after the long-arm centrifuge protocol.

Results: The maximal isometric strength in all exercises and muscle volumes increased in the training group but not the control group (P < 0.05). Relative muscle activity (%MVC) with a helmet decreased after the intervention in the training but not the control group (P = 0.01). Relative muscle activity while wearing a helmet and night vision goggles was higher after intervention in the control group than in the training group (P < 0.01). The perceived muscular strain of the neck muscles induced by the long-arm centrifuge did not differ between the groups.

Conclusion: Twelve weeks of functional strength training improves the maximal isometric strength and volume of neck and shoulder muscles and leads to lower relative muscle activation upon exposure to elevated G forces in a long-arm centrifuge.
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http://dx.doi.org/10.1186/s40779-021-00305-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901111PMC
February 2021

Concentration-Dependent Type 1 Interferon-Induced Regulation of MX1 and FABP3 in Bovine Endometrial Explants.

Animals (Basel) 2021 Jan 21;11(2). Epub 2021 Jan 21.

Clinic for Ruminants with Ambulatory and Herd Health Services, Centre for Clinical Veterinary Medicine Ludwig Maximilians University Munich, 85764 Oberschleissheim, Germany.

The inadequate maternal recognition of embryonic interferon τ (IFNτ) might explain subfertility in cattle. This study aimed at modeling the inducibility of type 1 interferon receptor subunits 1/2 (IFNAR1/2), mimicking competition between IFNτ and infection-associated interferon α (IFNα), and simulating type 1 interferon pathways in vitro. Endometrial explants (n = 728 from n = 26 healthy uteri) were collected at the abattoir, challenged with IFNτ and/or IFNα in different concentrations, and incubated for 24 h. Gene expression analysis confirmed the inducibility of IFNAR1/2 within this model, it being most prominent in IFNAR2 with 10 ng/mL IFNα ( = 0.001). The upregulation of interferon-induced GTP-binding protein (MX1, classical pathway) was higher in explants treated with 300 ng/mL compared to 10 ng/mL IFNτ ( < 0.0001), whereas the non‑classical candidate fatty acid binding protein 3 (FABP3) exhibited significant downregulation comparing 300 ng/mL to 10 ng/mL IFNτ. The comparison of explants challenged with IFNτ + IFNα indicated the competition of IFNτ and IFNα downstream of the regulatory factors. In conclusion, using this well-defined explant model, interactions between infection-associated signals and IFNτ were indicated. This model can be applied to verify these findings and to mimic and explore the embryo-maternal contact zone in more detail.
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http://dx.doi.org/10.3390/ani11020262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912598PMC
January 2021

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

Proc Natl Acad Sci U S A 2021 01;118(1)

Department of Neurology, Neuroimmunological Section, University of Rostock, 18051 Rostock, Germany.

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies ( = 946, = 990). Additionally, effect-modification by medication and photosensitivity-associated variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β-treated patients. In carriers of :rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.
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http://dx.doi.org/10.1073/pnas.2018457118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817192PMC
January 2021

Interval estimation of the overall treatment effect in random-effects meta-analyses: Recommendations from a simulation study comparing frequentist, Bayesian, and bootstrap methods.

Res Synth Methods 2021 May 22;12(3):291-315. Epub 2020 Dec 22.

Department of Statistics, TU Dortmund University, Dortmund, Germany.

There exists a variety of interval estimators for the overall treatment effect in a random-effects meta-analysis. A recent literature review summarizing existing methods suggested that in most situations, the Hartung-Knapp/Sidik-Jonkman (HKSJ) method was preferable. However, a quantitative comparison of those methods in a common simulation study is still lacking. Thus, we conduct such a simulation study for continuous and binary outcomes, focusing on the medical field for application. Based on the literature review and some new theoretical considerations, a practicable number of interval estimators is selected for this comparison: the classical normal-approximation interval using the DerSimonian-Laird heterogeneity estimator, the HKSJ interval using either the Paule-Mandel or the Sidik-Jonkman heterogeneity estimator, the Skovgaard higher-order profile likelihood interval, a parametric bootstrap interval, and a Bayesian interval using different priors. We evaluate the performance measures (coverage and interval length) at specific points in the parameter space, that is, not averaging over a prior distribution. In this sense, our study is conducted from a frequentist point of view. We confirm the main finding of the literature review, the general recommendation of the HKSJ method (here with the Sidik-Jonkman heterogeneity estimator). For meta-analyses including only two studies, the high length of the HKSJ interval limits its practical usage. In this case, the Bayesian interval using a weakly informative prior for the heterogeneity may help. Our recommendations are illustrated using a real-world meta-analysis dealing with the efficacy of an intramyocardial bone marrow stem cell transplantation during coronary artery bypass grafting.
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http://dx.doi.org/10.1002/jrsm.1471DOI Listing
May 2021

[Thyroid cancer in change].

Chirurg 2020 Dec;91(12):991-993

Sektion Endokrine Chirurgie, Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Hufelandstr. 55, 45147, Essen, Deutschland.

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http://dx.doi.org/10.1007/s00104-020-01290-9DOI Listing
December 2020

Prophylactic neck surgery for second-generation multiple endocrine neoplasia type 2B.

Eur J Surg Oncol 2021 04 13;47(4):924-927. Epub 2020 Nov 13.

Medical Faculty, Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, D-06097, Halle (Saale), Germany; Department of General, Visceral and Transplantation Surgery, Section of Endocrine Surgery, University of Duisburg-Essen, D-45122, Essen, Germany.

There is no evidence-based guidance on the extent of prophylactic neck surgery for second-generation multiple endocrine neoplasia type 2B (MEN 2B), a newly emerging entity in the molecular era. In this investigation of MEN 2B children who inherited the M918T RET germline mutation from a phenotypically affected MEN 2B parent, 6 MEN 2B children (4 girls and 2 boys) from 5 MEN 2B parents (4 mothers and 1 father) were identified. None of the 6 second-generation MEN 2B children who had preoperative calcitonin serum levels between 2 and 105 pg/mL and underwent prophylactic total thyroidectomy before the age of 4 years after receiving a positive RET gene test harbored node metastases. There was no recurrent laryngeal nerve palsy or postoperative hypoparathyroidism. Within the limitations of this study, total thyroidectomy alone is adequate therapy for second-generation MEN 2B children aged 1-4 years old with preoperative calcitonin serum levels ≤100 pg/mL.
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http://dx.doi.org/10.1016/j.ejso.2020.11.006DOI Listing
April 2021

Gene Expression in Spontaneous Experimental Autoimmune Encephalomyelitis Is Linked to Human Multiple Sclerosis Risk Genes.

Front Immunol 2020 18;11:2165. Epub 2020 Sep 18.

Max Planck Institute of Psychiatry, Munich, Germany.

Recent genome-wide association studies have identified over 230 genetic risk loci for multiple sclerosis. Current experimental autoimmune encephalomyelitis (EAE) models requiring active induction of disease may not be optimally suited for the characterization of the function of these genes. We have thus used gene expression profiling to study whether spontaneous opticospinal EAE (OSE) or MOG-induced EAE mirrors the genetic contribution to the pathogenesis of multiple sclerosis more faithfully. To this end, we compared gene expression in OSE and MOG EAE models and analyzed the relationship of both models to human multiple sclerosis risk genes and T helper cell biology. We observed stronger gene expression changes and an involvement of more pathways of the adaptive immune system in OSE than MOG EAE. Furthermore, we demonstrated a more extensive enrichment of human MS risk genes among transcripts differentially expressed in OSE than was the case for MOG EAE. Transcripts differentially expressed only in diseased OSE mice but not in MOG EAE were significantly enriched for T helper cell-specific transcripts. These transcripts are part of immune-regulatory pathways. The activation of the adaptive immune system and the enrichment of both human multiple sclerosis risk genes and T helper cell-specific transcripts were also observed in OSE mice showing only mild disease signs. These expression changes may, therefore, be indicative of processes at disease onset. In summary, more human multiple sclerosis risk genes were differentially expressed in OSE than was observed for MOG EAE, especially in T1 cells. When studying the functional role of multiple sclerosis risk genes and pathways during disease onset and their interactions with the environment, spontaneous OSE may thus show advantages over MOG-induced EAE.
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http://dx.doi.org/10.3389/fimmu.2020.02165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531036PMC
May 2021

A de novo frameshift mutation in ZEB2 causes polledness, abnormal skull shape, small body stature and subfertility in Fleckvieh cattle.

Sci Rep 2020 10 12;10(1):17032. Epub 2020 Oct 12.

Population Genomics Group, Department of Veterinary Sciences, Ludwig-Maximilians-University Munich, 80539, Munich, Germany.

Polledness in cattle is an autosomal dominant trait. Previous studies have revealed allelic heterogeneity at the polled locus and four different variants were identified, all in intergenic regions. In this study, we report a case of polled bull (FV-Polled1) born to horned parents, indicating a de novo origin of this polled condition. Using 50K genotyping and whole genome sequencing data, we identified on chromosome 2 an 11-bp deletion (AC_000159.1:g.52364063_52364073del; Del11) in the second exon of ZEB2 gene as the causal mutation for this de novo polled condition. We predicted that the deletion would shorten the protein product of ZEB2 by almost 91%. Moreover, we showed that all animals carrying Del11 mutation displayed symptoms similar to Mowat-Wilson syndrome (MWS) in humans, which is also associated with genetic variations in ZEB2. The symptoms in cattle include delayed maturity, small body stature and abnormal shape of skull. This is the first report of a de novo dominant mutation affecting only ZEB2 and associated with a genetic absence of horns. Therefore our results demonstrate undoubtedly that ZEB2 plays an important role in the process of horn ontogenesis as well as in the regulation of overall development and growth of animals.
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http://dx.doi.org/10.1038/s41598-020-73807-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550345PMC
October 2020
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