Increasing atmospheric temperature implicates increasing risk for acute type A dissection in hypertensive patients

Background: Acute type A aortic dissection (AAAD) is a life-threatening condition with high mortality within 24 hours. We hypothesized if there is a correlation between seasonal weather changes and the occurrence of AAAD. The aim of the present study was to identify seasonal specific weather and patient characteristics predicting the occurrence of AAAD. Methods: This is a retrospective analysis of all consecutive patients of our department with AAAD between January 1st 2006 and December 31st 2016. The national meteorological department provided the data of temperature, humidity and air pressure during the study period. The occurrence of AAAD, preoperative neurological impairment and mortality were analyzed in correlation with the obtained daily weather data within the entire cohort and in patients with and without hypertension separately. Results: A total of 517 patients were included. Mean age was 63.4±13 years, 69.4% were male and 68.8% had documented hypertension. In-hospital mortality was 17.7%. In the whole cohort, the occurrence of AAAD was significantly increased in March, October, December (P=0.016). In hypertensive patients, the occurrence was increased 34% with rising temperature (0.1-9.6 °C, OR1.34, 95% CI: 1.06-1.69, P=0.015). There was no correlation between weather variables and preoperative neurological impairment or mortality. Conclusions: Our data suggests a relation between an increasing number of events of AAAD and certain months within our catchment area and a significantly increased occurrence with rising temperatures (independent from absolute temperature at time of the event) in hypertensive patients

An immunocompetent farmer with isolated cerebral alveolar echinococcosis: illustrative case

BACKGROUND: Alveolar echinococcosis is a rare condition, but living or working in a rural environment is a substantial risk factor. The liver is the organ primarily affected, with additional extrahepatic manifestations in approximately 25% of cases. Primary extrahepatic disease is rare, and isolated cerebral involvement is extremely unusual. OBSERVATIONS: The authors described an illustrative case of isolated cerebral alveolar echinococcosis in an immunocompetent farmer. Magnetic resonance imaging of the brain showed a predominantly cystic lesion with perifocal edema and a “bunch of grapes” appearance in the left frontal lobe. Histology revealed sharply demarcated fragments of a fibrous cyst wall accompanied by marked inflammation and necrosis. Higher magnification showed remnants of protoscolices with hooklets and calcified corpuscles. Immunohistochemistry and polymerase chain reaction (PCR) analysis confirmed the diagnosis of cerebral alveolar echinococcosis. Interestingly, serology and thoracic and abdominal computed tomography results were negative, indicative of an isolated primary extrahepatic manifestation. LESSONS: Isolated, primary central nervous system echinococcosis is extremely rare, with only isolated case reports. As in the authors’ case, it can occur in immunocompetent patients, especially persons with a rural vocational history. Negative serology results do not exclude cerebral echinococcosis, which requires histological confirmation. Immunohistochemical staining and PCR analysis are especially useful in cases without classic morphological findings

Metabolic markers of short and long-term exogenous DL-beta-hydroxybutyrate supplementation in episodic migraine patients: an exploratory analysis of a randomized-controlled-trial

Background: Emerging findings propose that the pathophysiology of migraine may be associated with dysfunctional metabolic mechanisms. Recent findings suggest that migraine attacks are a response to the cerebral energy deficit, and ingestion of ketone bodies stabilizes the generation of a migraine attack. Based on these findings, ketone body supplementation is postulated as a prophylactic treatment approach to restore cerebral metabolism deficiency. Metabolic markers are unexplored after exogenous ketone body supplementation in episodic migraineurs. Therefore, the present single-arm uncontrolled explorative analysis evaluated blood ketone body and glucose concentration after short and long-term 6 g exogenous DL-Mg-Ca-beta-hydroxybutyrate (DL-βHB) supplementation.Methods: The presented data are part of the MigraKet randomized-control cross-over clinical trial of 41 episodic migraineurs (Number NCT03132233). Patients were given a single dose of 6 g DL-βHB. Ketone body and glucose blood concentration were assessed before intake, 20, and 40 min after DL-βHB intake. Ketone body, glucose concentration and glycated hemoglobin values were evaluated after 12 weeks of 18 g DL-βHB ingestion (total dose), taken three times daily (6g/dose; 3x/day). Linear models explored the association between the ketone body and glucose levels.Results: Ketone body concentration increased within-group to a mean of 0.46 (0.30) mmol/L after 40 min post- DL-βHB supplementation [estimate = 0.24 mmol/L, CI = (0.20.0.27), p < 0.01]. This within-group increase of ketone body concentration did not change after repeated daily intake of DL-βHB supplementation over 12 weeks [estimate = 0.00 mmol/L, CI = (−0.03.0.04), p = 0.794]. DL-βHB intake significantly reduced blood glucose concentration within-group from a mean baseline of 4.91 (0.42) mmol/L to 4.75 (0.47) mmol/L 40 min post-DL-βHB supplementation [estimate = −0.16 mmol/L, CI = (−0.15, 0.03), p < 0.01]. Repeated DL-βHB supplementation for 12 weeks showed no change within-group in acute ketone bodies concentration [estimate = 0.00 mmol/L, CI = (−0.03.0.04), p = 0.794] and in the HbA1c value [estimate = 0.02, CI = (−0.07.0.11), p = 0.69].Conclusion: A single dose of 6 g DL-βHB significantly elevated blood ketone bodies and decreased blood glucose concentration within-group in episodic migraineurs. Long-term DL-βHB supplementation for 12 weeks showed no effect within-group on acute ketone body concentration and had not impact on HbA1c. The elevation of the ketone body concentration was moderate, indicating that nutritional ketosis was not reached. Therefore, a dose higher than 6 g of DL-βHB is required to reach the nutritional level of ketosis. ClinicalTrials.gov Identifier: NCT03132233

A conformational switch controlling the toxicity of the prion protein

Prion infections cause conformational changes of the cellular prion protein (PrPC) and lead to progressive neurological impairment. Here we show that toxic, prion-mimetic ligands induce an intramolecular R208-H140 hydrogen bond (‘H-latch’), altering the flexibility of the α2–α3 and β2–α2 loops of PrPC. Expression of a PrP2Cys mutant mimicking the H-latch was constitutively toxic, whereas a PrPR207A mutant unable to form the H-latch conferred resistance to prion infection. High-affinity ligands that prevented H-latch induction repressed prion-related neurodegeneration in organotypic cerebellar cultures. We then selected phage-displayed ligands binding wild-type PrPC, but not PrP2Cys. These binders depopulated H-latched conformers and conferred protection against prion toxicity. Finally, brain-specific expression of an antibody rationally designed to prevent H-latch formation prolonged the life of prion-infected mice despite unhampered prion propagation, confirming that the H-latch is an important reporter of prion neurotoxicity

Mate-guarding constrains feeding activity but not energetic status of wild male long-tailed macaques (Macaca fascicularis).

Mate-guarding is an important determinant of male reproductive success in a number of species. Little is known however about the constraints of this behaviour, e.g. the associated energetic costs. We investigated these costs in long-tailed macaques where alpha males mate guard females to a lesser extent than predicted by the priority of access model. The study was carried out during two mating periods on three wild groups living in the Gunung Leuser National Park, Indonesia. We combined behavioural observations on males' locomotion and feeding activity, GPS records of distance travelled and non-invasive measurements of urinary C-peptide (UCP), a physiological indicator of male energetic status. Mate-guarding led to a decrease in feeding time and fruit consumption suggesting a reduced intake of energy. At the same time, vertical locomotion was reduced, which potentially saved energy. These findings, together with the fact that we did not find an effect of mate-guarding on UCP levels, suggest that energy intake and expenditure was balanced during mate-guarding in our study males. Mate-guarding thus seems to not be energetically costly under all circumstances. Given that in strictly seasonal rhesus macaques, high-ranking males lose physical condition over the mating period, we hypothesise that the energetic costs of mate-guarding vary inter-specifically depending on the degree of seasonality and that males of non-strictly seasonal species might be better adapted to maintain balanced energetic condition year-round. Finally, our results illustrate the importance of combining behavioural assessments of both energy intake and expenditure with physiological measures when investigating energetic costs of behavioural strategies

The prion protein is not required for peripheral nerve de- and remyelination after crush injury

The cellular prion protein (PrP) is essential to the long-term maintenance of myelin sheaths in peripheral nerves. PrP activates the adhesion G-protein coupled receptor Adgrg6 on Schwann cells and initiates a pro-myelination cascade of molecular signals. Because Adgrg6 is crucial for peripheral myelin development and regeneration after nerve injury, we investigated the role of PrP in peripheral nerve repair. We performed experimental sciatic nerve crush injuries in co-isogenic wild-type and PrP-deficient mice, and examined peripheral nerve repair processes. Generation of repair Schwann cells, macrophage recruitment and remyelination were similar in PrP-deficient and wild-type mice. We conclude that PrP is dispensable for sciatic nerve de- and remyelination after crush injury. Adgrg6 may sustain its function in peripheral nerve repair independently of its activation by PrP

The Prion Protein and Its Receptor Adgrg6 in Peripheral Demyelinating Diseases

Treatment options for many peripheral nerve diseases are limited, and the regeneration in disease or after nerve injury is often incomplete. Currently, there are no interventions that successfully target the underlying axonal or Schwann cell dysfunctions. A better understanding of the key players and molecular mechanisms of myelination under normal and pathological conditions could help to devise novel therapies for peripheral neuropathies [13, 66, 91]. The adhesion G protein coupled receptor Adgrg6 in Schwann cells is important for development, maintenance and repair of myelin in the peripheral nervous system [72, 109, 115]. The prion protein (PrP) is an agonist of Adgrg6 and thereby contributes to myelin maintenance [90]. Mice devoid of PrP develop a chronic peripheral demyelinating neuropathy [17]. In my thesis, I used PrP knockout mice to study peripheral nervous system demyelination in three different projects. By RNA sequencing and protein analysis, I could show that the demyelinating neuropathy in PrP knockout mice is characterized by an early increase in repair Schwann cell and dedifferentiation markers, which has been previously shown in other unrelated human peripheral nerve diseases and respective animal models [59, 70, 80, 84, 86, 135]. This finding supports the role of PrP in maintaining a healthy interaction between axons and Schwann cells and a quiescent, differentiated state of Schwann cells. The early protein markers of the neuropathy in PrP knockout mice can be used as readouts or targets in future mechanistic or therapeutic studies, which I have cited in my treatment experiment. Given the fact that many approved drugs target G-protein coupled receptors, endogenous or exogenous ligands of Adgrg6 represent attractive targets to develop therapeutic strategies for peripheral nerve diseases. I proposed that PrP can be used to design a therapy targeting Adgrg6 to support myelin maintenance in peripheral nervous system diseases. I fused the Adgrg6-activating domain of PrP to mouse immunoglobulin Fc, which resulted in a stable macromolecule (FT2Fc) with a terminal serum half-life of 45 h. I showed that FT2Fc was a potent activator of Adgrg6 in vitro, but I could not detect a beneficial effect of chronic FT2Fc treatment in PrP knockout mice. While I will discuss several limitations of the treatment study, the most prominent explanation for the lack of a therapeutic effect is the hypothesis that FT2Fc was unable to reach Adgrg6 on Schwann cells. Finally, I hypothesized that PrP is the ligand required to activate Adgrg6 during nerve repair, and that PrP knockout mice develop similar defects in peripheral nerve regeneration as Adgrg6 knockout mice. My study of peripheral nerve repair processes in PrP knockout mice disproved this hypothesis. PrP knockout mice showed no difference in demyelination, repair Schwann cell generation, macrophage recruitment and remyelination after crush injury when compared to wild type mice. This finding suggests that Adgrg6 sustains its function in peripheral nerve repair independent of PrP, possibly being activated by other ligands such as collagen IV or laminin-211

Effects of different orthognathic surgery procedures on pharyngeal airway space: a single center study

Aim: The aim of this study is to reveal if different surgical procedures of the upper and lower jaw have an effect on the pharyngeal airway space (PAS). PAS is important considering the obstructive sleep apnea (OSA), since an enlargement or a reduction of the PAS can influence an existing OSA, or even be a risk factor to create an OSA. Subjects and methods: The sample consisted of pre- and postoperative lateral cephalograms of 18 males and 26 females (mean age 23.25 ± 5.84 years). The inclusion criterion was that all patients had undergone an orthodontic surgery, either a bilateral sagittal split osteotomy (BSSO) or a LeFort 1 osteotomy (LFO) or both. Only patient files, which were used for orthodontic specialization, were included in order to have all the necessary data available. Treating OSA was not an inclusion criterion. Statistics were performed with spearman correlation, Oneway ANOVA combined with a Scheffe post-hoc test and a paired t-test. Results: Diff ANB showed a positive statistically significant correlation to Diff Spp (CC 0.367, p 0.015), as well as a negative statistically significant correlation to Diff Pg (-0.341). A positive statistically significant correlation was found between Diff t and Diff p (0.412). According to one-way ANOVA there is no evidence that there are differences in Diff p (p= 0.552) and Diff t (p=0.666) with respect to the four groups A, B, C and D. The paired t-test revealed that there is a change in p measurements between preand postoperative time points: 1.4, 95% CI (0.2; 2.6), p=0.022. There is no evidence that there is a change in t measurements between the pre- and postoperative time points: 0.87, 95% CI (-0.2; 1.9), p=0.101 Conclusion: At group level it can be summarized, that an advancement of the lower jaw has on average a positive effect on the airways while the same cannot be said for surgical interventions of the upper jaw

Effect of an interdisciplinary inpatient program for patients with CRPS in reducing disease activity -a single center prospective cohort study.

OBJECTIVE The aim of this study was to evaluate the benefit of inpatient treatment in reducing disease activity in patients with CRPS who have exhausted outpatient options. Furthermore, the study sought to identify patient-related outcome variables that predict a reduction in disease activity. METHODS The primary outcome was disease severity (CRPS Severity Score, range 0-16 points)). Secondary outcomes included depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities, all of which were assessed using the Promis-29. Furthermore, pain catastrophizing, neuropathic pain, quality of life, pain self-efficacy, medication intake, and the patient's global impression of change were examined in accordance with current international agreed recommendations, assessed at discharge, three-month and six-month post-discharge. Mixed-effects models were conducted to identify baseline variables associated with CRPS severity. RESULTS Twenty-five patients completed the program (mean age 49.28 (SD 11.23) years, 92% females, mean symptom duration 8.5 (SD 6.5) months). Results showed a significant reduction between baseline and discharge of disease activity (CSS -2.36, p < 0.0001), pain (PROMIS-29 pain -0.88, p = 0.005) and emotional function (PROMIS-29 depression -5.05, p < 0.001; fatigue -4.63, p = 0.002). Moderate evidence for a reduction between baseline and discharge could be observed for pain interference (+2.27, p = 0.05), social participation (PROMIS-29 +1.93, p = 0.05), anxiety (PROMIS-29 -3.32, p = 0.02) and physical function (PROMIS-29 +1.3, p = 0.03). On discharge, 92% of patients (23 of 25) reported improvement in their overall condition. In the follow-up period, medication intake could be reduced after 3 (MQS -8.22, p = 0.002) and 6 months (MQS -8.69, p = 0.001), and there was further improvement in social participation after 3 months (PROMIS-29 +1.72, 0.03) and sleep after 6 months (PROMIS-29 +2.38, 0.008). In the mixed models, it was demonstrated that patients experiencing less pain at baseline also exhibited lower disease activity. CONCLUSION The results of this study confirm that inpatient interdisciplinary treatment of CRPS patients improves disease activity, pain, physical function, emotional function, and social participation. Most improvements were maintained for up six months after discharge. The majority of patients reported that their overall condition had improved during the study period