Fgf9 signaling regulates inner ear morphogenesis through epithelial–mesenchymal interactions

AbstractThe mammalian inner ear comprises the cochleovestibular labyrinth, derived from the ectodermal otic placode, and the encasing bony labyrinth of the temporal bone. Epithelial–mesenchymal interactions are thought to control inner ear development, but the modes and the molecules involved are largely unresolved. We show here that, during the precartilage and cartilage stages, Fgf9 is expressed in specific nonsensory domains of the otic epithelium and its receptors, Fgfr1(IIIc) and Fgfr2(IIIc), widely in the surrounding mesenchyme. To address the role of Fgf9 signaling, we analyzed the inner ears of mice homozygous for Fgf9 null alleles. Fgf9 inactivation leads to a hypoplastic vestibular component of the otic capsule and to the absence of the epithelial semicircular ducts. Reduced proliferation of the prechondrogenic mesenchyme was found to underlie capsular hypoplasticity. Semicircular duct development is blocked at the initial stages, since fusion plates do not form. Our results show that the mesenchyme directs fusion plate formation and they give direct evidence for the existence of reciprocal epithelial–mesenchymal interactions in the developing inner ear. In addition to the vestibule, in the cochlea, Fgf9 mutation caused defects in the interactions between the Reissner's membrane and the mesenchymal cells, leading to a malformed scala vestibuli. Together, these data show that Fgf9 signaling is required for inner ear morphogenesis

Executive function subdomains are associated with post-stroke functional outcome and permanent institutionalization

Background and purposeImpairment of executive functions (EFs) is a common cognitive symptom post-stroke and affects independence in daily activities. Previous studies have often relied on brief cognitive tests not fully considering the wide spectrum of EF subdomains. A detailed assessment of EFs was used to examine which of the subdomains and tests have the strongest predictive value on post-stroke functional outcome and institutionalization in long-term follow-up. MethodsA subsample of 62 patients from the Helsinki Stroke Aging Memory Study was evaluated with a battery of seven neuropsychological EF tests 3 months post-stroke and compared to 39 healthy control subjects. Functional impairment was evaluated with the modified Rankin Scale (mRS) and Instrumental Activities of Daily Living (IADL) scale at 3 months, and with the mRS at 15 months post-stroke. Institutionalization was reviewed from the national registers of permanent hospital admissions in up to 21-year follow-up. ResultsThe stroke group performed more poorly than the control group in multiple EF tests. Tests of inhibition, set shifting, initiation, strategy formation and processing speed were associated with the mRS and IADL scale in stroke patients. EF subdomain scores of inhibition, set shifting and processing speed were associated with functional outcome. In addition, inhibition was associated with the risk for earlier institutionalization. ConclusionsExecutive function was strongly associated with post-stroke functional impairment. In follow-up, poor inhibition was related to earlier permanent institutionalization. The results suggest the prognostic value of EF subdomains after stroke.Peer reviewe

Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

IMPORTANCE: Evidence from preclinical models indicates that xenon gas can prevent the development of cerebral damage after acute global hypoxic-ischemic brain injury but, thus far, these putative neuroprotective properties have not been reported in human studies. OBJECTIVE: To determine the effect of inhaled xenon on ischemic white matter damage assessed with magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: A randomized single-blind phase 2 clinical drug trial conducted between August 2009 and March 2015 at 2 multipurpose intensive care units in Finland. One hundred ten comatose patients (aged 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized. INTERVENTIONS: Patients were randomly assigned to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours (n = 55 in the xenon group) or hypothermia treatment alone (n = 55 in the control group). MAIN OUTCOMES AND MEASURES: The primary end point was cerebral white matter damage as evaluated by fractional anisotropy from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest. Secondary end points included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months. RESULTS: Among the 110 randomized patients (mean age, 61.5 years; 80 men [72.7%]), all completed the study. There were MRI data from 97 patients (88.2%) a median of 53 hours (interquartile range [IQR], 47-64 hours) after cardiac arrest. The mean global fractional anisotropy values were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group. The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005-0.027], P = .006). At 6 months, 75 patients (68.2%) were alive. Secondary end points at 6 months did not reveal statistically significant differences between the groups. In ordinal analysis of the modified Rankin Scale, the median (IQR) value was 1 (1-6) in the xenon group and 1 (0-6) in the control group (median difference, 0 [95% CI, 0-0]; P = .68). The 6-month mortality rate was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01]; P = .053). CONCLUSIONS AND RELEVANCE: Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00879892

White matter hyperintensities and working memory: an explorative study

Contains fulltext : 73317.pdf (publisher's version ) (Closed access)White matter hyperintensities (WMH) are commonly observed in elderly people and may have the most profound effect on executive functions, including working memory. Surprisingly, the Digit Span backward, a frequently employed working memory task, reveals no association with WMH. In the present study, it was investigated whether more detailed analyses of WMH variables and study sample selection are important when establishing a possible relationship between the Digit Span backward and WMH. To accomplish this, the Digit Span backward and additional working memory tests, WMH subscores, and cardiovascular risk factors were examined. The results revealed that performance on the Digit Span backward test is unrelated to WMH, whereas a relationship between other working memory tests and WMH was confirmed. Furthermore, a division between several white matter regions seems important; hyperintensities in the frontal deep white matter regions were the strongest predictor of working memory performance.16 p

Intracapsular tonsillectomy in the treatment of recurrent and chronic tonsillitis in adults : a protocol of a prospective, single-blinded, randomised study with a 5-year follow-up (the FINITE trial)

Introduction The standard surgical treatment for recurrent or chronic tonsillitis is extracapsular tonsillectomy. Recent studies show that intracapsular tonsillectomy has the potential to reduce the postoperative morbidity of patients undergoing tonsil surgery. The Finnish Intracapsular Tonsillectomy (FINITE) trial aims to provide level I evidence to support the hypothesis that the recovery time from tonsil surgery can be reduced with intracapsular tonsillectomy. Additionally, from this trial, major benefits in quality of life, reduction of postoperative complications, treatment costs and throat symptoms might be gained. Methods and analysis The FINITE trial is a prospective, randomised, controlled, patient-blinded, three-arm clinical trial. It is designed to compare three different surgical methods being extracapsular monopolar tonsillectomy versus intracapsular microdebrider tonsillectomy versus intracapsular coblation tonsillectomy in the treatment of adult patients (16-65 years) suffering from recurrent or chronic tonsillitis. The study started in September 2019, and patients will be enrolled until a maximum of 200 patients are randomised. Currently, we are in the middle of the study with 125 patients enrolled as of 28 February 2022 and data collection is scheduled to be completed totally by December 2027. The primary endpoint of the study will be the recovery time from surgery. Secondary endpoints will be the postoperative pain scores and the use of analgesics during the first 3 weeks of recovery, postoperative haemorrhage, quality of life, tonsillar remnants, need for revision surgery, throat symptoms, treatment costs and sick leave. A follow-up by a questionnaire at 1-21 days and at 1, 6, 24 and 60 months will be conducted with a follow-up visit at the 6-month time point. Ethics and dissemination Ethical approval was obtained from the Medical Ethics Committee of the Hospital District of Southwest Finland (reference number 29/1801/2019). Results will be made publicly available in peer-reviewed scientific journals.Peer reviewe

Degree of explanation

Partial explanations are everywhere. That is, explanations citing causes that explain some but not all of an effect are ubiquitous across science, and these in turn rely on the notion of degree of explanation. I argue that current accounts are seriously deficient. In particular, they do not incorporate adequately the way in which a cause’s explanatory importance varies with choice of explanandum. Using influential recent contrastive theories, I develop quantitative definitions that remedy this lacuna, and relate it to existing measures of degree of causation. Among other things, this reveals the precise role here of chance, as well as bearing on the relation between causal explanation and causation itself

External representations and scientific understanding

This paper provides an inferentialist account of model-based understanding by combining a counterfactual account of explanation and an inferentialist account of representation with a view of modeling as extended cognition. This account makes it understandable how the manipulation of surrogate systems like models can provide genuinely new empirical understanding about the world. Similarly, the account pro- vides an answer to the question how models, that always incorporate assumptions that are literally untrue of the model target, can still provide factive explanations. Finally, the paper shows how the contrastive counterfactual theory of explanation can provide tools for assessing the explanatory power of models.Peer reviewe

The Search for Invariance: Repeated Positive Testing Serves the Goals of Causal Learning

Positive testing is characteristic of exploratory behavior, yet it seems to be at odds with the aim of information seeking. After all, repeated demonstrations of one’s current hypothesis often produce the same evidence and fail to distinguish it from potential alternatives. Research on the development of scientific reasoning and adult rule learning have both documented and attempted to explain this behavior. The current chapter reviews this prior work and introduces a novel theoretical account—the Search for Invariance (SI) hypothesis—which suggests that producing multiple positive examples serves the goals of causal learning. This hypothesis draws on the interventionist framework of causal reasoning, which suggests that causal learners are concerned with the invariance of candidate hypotheses. In a probabilistic and interdependent causal world, our primary goal is to determine whether, and in what contexts, our causal hypotheses provide accurate foundations for inference and intervention—not to disconfirm their alternatives. By recognizing the central role of invariance in causal learning, the phenomenon of positive testing may be reinterpreted as a rational information-seeking strategy

Intracapsular tonsillectomy in the treatment of recurrent and chronic tonsillitis in adults: a protocol of a prospective, single-blinded, randomised study with a 5-year follow-up (the FINITE trial)

INTRODUCTIONThe standard surgical treatment for recurrent or chronic tonsillitis is extracapsular tonsillectomy. Recent studies show that intracapsular tonsillectomy has the potential to reduce the postoperative morbidity of patients undergoing tonsil surgery. The Finnish Intracapsular Tonsillectomy (FINITE) trial aims to provide level I evidence to support the hypothesis that the recovery time from tonsil surgery can be reduced with intracapsular tonsillectomy. Additionally, from this trial, major benefits in quality of life, reduction of postoperative complications, treatment costs and throat symptoms might be gained.METHODS AND ANALYSISThe FINITE trial is a prospective, randomised, controlled, patient-blinded, three-arm clinical trial. It is designed to compare three different surgical methods being extracapsular monopolar tonsillectomy versus intracapsular microdebrider tonsillectomy versus intracapsular coblation tonsillectomy in the treatment of adult patients (16-65 years) suffering from recurrent or chronic tonsillitis. The study started in September 2019, and patients will be enrolled until a maximum of 200 patients are randomised. Currently, we are in the middle of the study with 125 patients enrolled as of 28 February 2022 and data collection is scheduled to be completed totally by December 2027. The primary endpoint of the study will be the recovery time from surgery. Secondary endpoints will be the postoperative pain scores and the use of analgesics during the first 3 weeks of recovery, postoperative haemorrhage, quality of life, tonsillar remnants, need for revision surgery, throat symptoms, treatment costs and sick leave. A follow-up by a questionnaire at 1-21 days and at 1, 6, 24 and 60 months will be conducted with a follow-up visit at the 6-month time point.ETHICS AND DISSEMINATIONEthical approval was obtained from the Medical Ethics Committee of the Hospital District of Southwest Finland (reference number 29/1801/2019). Results will be made publicly available in peer-reviewed scientific journals.</p