Der Einfluss von chronischem Stress während der Schwangerschaft auf die funktionelle Reifung des fetalen zentralen Nervensystems

Es gibt Hinweise, dass pränataler Stress zu schweren neuro-psychiatrischen Erkrankungen im späteren Leben wie z.B. Depressionen führt. Dies kann theoretisch Folge einer gestörten fetalen Hirnreifung sein. Durch experimentelle Untersuchungen ist bekannt, dass die pränatale Gabe von synthetischen Glukokortikoiden die Entwicklung des sich entwickelnden Gehirns stört - experimentelle Untersuchungen zur Auswirkung von pränatalem Stress auf die Hirnreifung fehlen aber. Diese Arbeit untersucht, ob pränataler Stress - vergleichbar mit der pränatalen Applikation von synthetischen Glukokortikoiden - die funktionelle Hirnreifung beeinflusst. Als Tiermodell dient das chronisch instrumentierte fetale Schaf, welches die intrauterine Ableitung des Elektrokortikogramms (ECoG) erlaubt, um so die fetalen Schlafstadien als Marker der fetalen Hirnreifung zu untersuchen. Es wurden die Schlafstadien von 14 trächtigen Schafen analysiert, welche vom 30. - 100. Gestationstag (0.2-0.66 Gestation) durch eine jeweils 180-minütige Isolation an zwei Tagen der Woche chronisch gestresst wurden. Die chronische Stressung führte zu einer reproduzierbaren maternalen Kortisolerhöhung. Der chronische Stress führte weiterhin zu einer fetalen Schlafstadienfragmentierung gleichen Ausmaßes und gleicher Qualität, wie sie auch durch die pränatale Gabe von synthetischen Glukokortikoiden am 105. Gestationstag (0.7 Gestation) ausgelöst wird. Diese war auch noch am letzten analysierten Gestationstag, 30 Tage nach der letzten Stressung, nachweisbar. Eine beschleunigte Reifung der Schlafstadien, wie sie durch die Gabe von synthetischen Glukokortikoiden am 105. Gestationstag ausgelöst wird, konnte nicht beobachtet werden. Mit dieser Arbeit ist es gelungen, die Empfindlichkeit des sich entwickelnden Gehirns für äußere Einflüsse nachzuweisen und so mögliche Konsequenzen für die Entstehung von Krankheiten im späteren Leben aufzuzeigen

Association between antenatal glucocorticoid exposure and the activity of the stress system, cognition, and behavior in 8‐ to 9‐year‐old children: A prospective observational study

Introduction Glucocorticoid (GC) ‐induced fetal programming of the activity of the hypothalamus–pituitary–adrenal axis (HPAA) and its associated cognitive and behavioral consequences in later life have been well characterized in several animal species. However, information on humans is scarce. In this study, we examined HPAA activity markers and associated outcomes at 8 to 9 years of age among children prenatally exposed to GC for suspected preterm birth. Our hypothesis was that antenatal exposure to the betamethasone (BM) is associated with exacerbation of HPAA activity in childhood. Material and methods Prospective observational study in 31 children whose mothers received single ( n = 19) or multiple ( n = 12) courses of BM for threatened preterm birth but born with normal weight appropriate for the gestational age (median 37+ 6 weeks of gestation) compared with 38 non‐exposed, age‐matched children. Primary end point was the activity of the HPAA in response to the Trier Social Stress Test. Secondary end points were changes in autonomic nervous system (ANS) activity, cognitive performance (IQ), attention‐deficit/hyperactivity disorder (ADHD) symptoms, and electrocortical activity (EEG). Results There was no statistically significant difference in HPAA activity markers between antenatal BM exposed and unexposed groups. ANS activity in BM‐exposed children shifted towards a higher parasympathetic tone reflected by a higher overall high‐frequency band power of heart rate variability. IQ scores were within normal limits for both groups; however, BM‐exposed children had lower IQ scores than the unexposed group. BM‐exposed group had marginally more ADHD core symptoms and increased electrocortical activity in the occipital brain region compared with controls. A monotonic dose–response relation between BM exposure and activity of the ANS and IQ was estimated in post‐hoc analyses. Conclusions Antenatal exposure to BM in the context of threatened preterm birth was not associated with changes in HPAA activity in childhood. However, BM exposure may be associated with changes in ANS activity. Antenatal GC prophylaxis is a valuable and often life‐saving therapy, but its prescription may warrant a well‐balanced risk–benefit assessment

Oral cladribine treatment and idiosyncratic drug-induced liver injury in multiple sclerosis

Background Oral cladribine (OC) is approved for the treatment of highly active relapsing multiple sclerosis. Postmarketing safety assessments have reported rare, but occasionally severe cases of liver injury in temporal association with OC, with pathophysiologic mechanisms still unknown. In the only detailed case report on this topic, idiosyncratic drug-induced liver injury (iDILI) during OC treatment was well characterised for the first time, but occurred in the context of prior high-dose steroid exposure. Although high-dose steroids are known to induce iDILI in patients with multiple sclerosis with a delay of up to 12 weeks, OC was assumed to be the culprit agent for observed liver injury and the role of steroid exposure was not further investigated.Case Herein, we describe a case of a 35-year-old women treated with high-dose oral prednisolone during the first treatment cycle OC and subsequently developed iDILI. A causality assessment of the role of prednisolone and OC was performed using the updated Roussel Uclaf Causality Assessment Method which also included a negative re-exposure test for OC during the second OC treatment cycle 1 year later.Conclusion Our observations suggest that prednisolone or interactions between prednisolone and OC are more likely to foster development of iDILI rather than OC treatment itself

A Systematic Review of Neuroprotective Strategies in the Management of Hypoglycemia

Severe hypogylcemia has been found to induce cerebral damage. While a number of illnesses can lead to hypoglycemic episodes, antidiabetic medications prescribed for glycemic control are a common cause. Considering the rising prevalence of diabetes mellitus in the population, we investigated neuroprotective strategies during hypoglycemia in the form of a systematic review in adherence to the PRISMA statement. A review protocol was registered in the PROSPERO database. A systematic literature search of PubMed, Web of Science, and CENTRAL was performed in September 2018. Based on a predefined inclusion protocol, results were screened and evaluated by two researchers. Both animal experiments and human studies were included, and their risk of bias was assessed with SYRCLE’s and the Cochrane risk of bias tools, respectively. Of a total of 16,230 results, 145 were assessed in full-text form: 27 articles adhered to the inclusion criteria and were qualitatively analyzed. The retrieved neuroprotective strategies could be categorized into three subsets: (1) Energy substitution, (2) hypoglycemia unawareness, and (3) other neuroprotective strategies. While on a study level, the individual results appeared promising, more research is required to investigate not only specific neuroprotective strategies against hypoglycemic cerebral damage, but also its underlying pathophysiological mechanisms

Study protocol: multimodal physiotherapy as an add-on treatment to botulinum neurotoxin type A therapy for patients with cervical dystonia: DysPT-multi—a prospective, multicentre, single-blind, randomized, controlled study

Background!#!Botulinum neurotoxin (BoNT) is currently the best therapeutic option in the treatment for cervical dystonia (CD). Additional treatments like physiotherapy (PT) may even improve the results of the BoNT injection with type A (BoNT-A), but there are no definite recommendations. In the last few years, some studies showed tendencies for PT as an adjuvant therapy to benefit. However, high-quality studies are required.!##!Methods!#!This study is a multicentre, randomized, single-blind, controlled trial to demonstrate the effectiveness of a multimodal PT program compared to a nonspecific cupping therapy, additionally to the BoNT-A therapy. Two hundred participants will be assigned into the multimodal PT plus BoNT intervention arm or the BoNT plus cupping arm using randomization. Primary endpoint is the total Score of Toronto Western Spasmodic Rating Scale (TWSTRS). Secondary endpoints are the mobility of the cervical spine (range of motion, ROM), the TWSTRS subscales, and the quality of life (measured by questionnaires: CDQ-24 and SF-36). Patients will be single-blind assessed every 3 months according to their BoNT injection treatment over a period of 9 months.!##!Discussion!#!The study aims to determine the effectiveness and therefore potential benefit of an additional multimodal physiotherapy for standardized treatment with BoNT-A in patients with CD, towards the BoNT-therapy alone. This largest randomized controlled trial in this field to date is intended to generate missing evidence for therapy guidelines.!##!Trial registration!#!The study was registered in the German Clinical Study Register before the start of the patient recruitment ( DRKS00020411 ; date: 21.01.2020)

Weather conditions associated with subarachnoid hemorrhage: a multicenter case-crossover study

Background!#!Most spontaneous subarachnoid hemorrhages (SAH) occur unexpectedly and independently of classical risk factors. In the light of increasing climate variability and change, we investigated weather and rapid weather changes as possible short-term risk factors for SAH.!##!Methods!#!Seven hundred ninety one patients admitted to three major hospitals in Germany for non-traumatic SAH with a determinable onset of SAH symptoms were included in this hospital-based, case-crossover study. The effects of atmospheric pressure, relative air humidity, and ambient temperature and their 24 h changes on the onset of SAH under temperate climate conditions were estimated.!##!Results!#!There was no association between the risk of SAH and 24 h weather changes, mean daily temperature or mean relative air humidity in the overall population. For every 11.5 hPa higher mean daily atmospheric pressure, the risk of SAH increased by 15% (OR 1.15, 95% confidence interval (CI) 1.01-1.30) in the entire study population with a lag time of three days.!##!Conclusion!#!Our results suggest no relevant association between 24 h-weather changes or absolute values of ambient temperature and relative humidity and the risk of SAH. The medical significance of the statistically weak increase in SAH risk three days after exposure to high atmospheric pressure is unclear. However, as the occurrence of stable high-pressure systems will increase with global warming and potentially affect SAH risk, we call for confirming studies in different geographical regions to verify our observations

Effects of Late Gestational Fetal Exposure to Dexamethasone Administration on the Postnatal Hypothalamus-Pituitary-Adrenal Axis Response to Hypoglycemia in Pigs

Background: Prenatal glucocorticoid administration alters the activity of the fetal hypothalamic-pituitary-adrenocortical axis (HPAA), and correspondingly the adenocorticotropic hormone (ACTH) and cortisol levels after birth. The dosages required for these effects are critically discussed. Activation of the HPAA is related to metabolic syndrome and diabetes mellitus. Hypoglycemia is the classic side effect of antidiabetic treatment. We hypothesized that a low dosage of dexamethasone in late pregnancy alters the HPAA response to hypoglycemia in pigs. Methods: 12 pregnant sows were randomly assigned to two groups which received either a low-dose intramuscular injection (99th and 100th day of gestation) of dexamethasone (0.06 μg/kg body weight) or vehicle. Three months after birth, 18 dexamethasone-treated anaesthetized offspring and 12 control offspring underwent a 75 min hypoglycemic clamp (blood glucose below 4 mmol/L) procedure. Heart rate (HR), blood pressure, ACTH and cortisol levels and body weight (at birth and after three months) were recorded. Results: Dexamethasone-treated animals exhibited significantly elevated ACTH (139.9 ± 12.7 pg/mL) and cortisol (483.1 ± 30.3 nmol/L) levels during hypoglycemia as compared to the control group (41.7 ± 6.5 pg/mL and 257.9 ± 26.7 nmol/L, respectively), as well as an elevated HR (205.5 ± 5.7 bpm) and blood pressure (systolic: 128.6 ± 1.5, diastolic: 85.7 ± 0.7 mmHg) response as compared to the control group (153.2 ± 4.5 bpm; systolic: 118.6 ± 1.6, diastolic: 79.5 ± 1.4 mmHg, respectively; p < 0.001). Conclusions: Low-dose prenatal administration of dexamethasone not only exerts effects on the HPAA (ACTH and cortisol concentration) and vital parameters (HR and diastolic blood pressure) under baseline conditions, but also on ACTH, HR and systolic blood pressure during hypoglycemia

Underlying mechanism of subcortical brain protection during hypoxia and reoxygenation in a sheep model - Influence of α1-adrenergic signalling.

While the cerebral autoregulation sufficiently protects subcortical brain regions during hypoxia or asphyxia, the cerebral cortex is not as adequately protected, which suggests that regulation of the cerebral blood flow (CBF) is area-specific. Hypoxia was induced by inhalation of 5% oxygen, for reoxygenation 100% oxygen was used. Cortical and subcortical CBF (by laser Doppler flowmetry), blood gases, mean arterial blood pressure (MABP), heart rate and renal blood flow were constantly monitored. Low dosed urapidil was used for α1A-adrenergic receptor blockade. Western blotting was used to determine adrenergic receptor signalling mediators in brain arterioles. During hypoxia cortical CBF decreased to 72 ± 11% (mean reduction 11 ± 3%, p < 0.001) of baseline, whereas subcortical CBF increased to 168±18% (mean increase 43 ± 5%, p < 0.001). Reoxygenation led to peak CBF of 194 ± 27% in the subcortex, and restored cortical CBF. α1A-Adrenergic blockade led to minor changes in cortical CBF, but massively reduced subcortical CBF during hypoxia and reoxygenation-almost aligning CBF in both brain regions. Correlation analyses revealed that α1A-adrenergic blockade renders all CBF-responses pressure-passive during hypoxia and reoxygenation, and confirmed the necessity of α1A-adrenergic signalling for coupling of CBF-responses to oxygen saturation. Expression levels and activation state of key signalling-mediators of α1-receptors (NOSs, CREB, ERK1/2) did not differ between cortex and subcortex. The dichotomy between subcortical and cortical CBF during hypoxia and reoxygenation critically depends on α1A-adrenergic receptors, but not on differential expression of signalling-mediators: signalling through the α1A-subtype is a prerequisite for cortical/subcortical redistribution of CBF

Primula kisoana Miquel

原著和名: カッコサウ キソコザクラ科名: サクラソウ科 = Primulaceae採集地: 群馬県 鳴神山 (上野 鳴神山)採集日: 1963/5/5採集者: 萩庭丈壽整理番号: JH024269国立科学博物館整理番号: TNS-VS-97426

Additional file 3: Figure S3. of Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia

Histological changes in the internal and external capsule. Reactive astrogliosis (A, E), microgliosis (B, F), axonal degeneration (C, G) and demyelination (D, H) in sham and BCAS animals in the internal capsule (upper row) and external capsule (lower row). (PDF 118 kb