Background: Cardiac troponins I and T are highly sensitive and specific markers for acute myocardial infarction (AMI). However, a wide range of non-AMI conditions can also cause significant elevations in cardiac troponins. Given the deleterious impact of misdiagnosis of AMI, the ability to risk-stratify patients who present with an elevated troponin is paramount. We hypothesized that the maximum troponin level would be more predictive of mortality and the diagnosis of AMI than the initial troponin level or change in troponin level.Methods: Patient records from a 9-hospital system  in Texas were reviewed during a 24-month period in 2016-2017. Data collected for patients aged ≥40 years included International Classification of Diseases, Tenth Revision diagnoses, troponin I, demographic data , and death during hospitalization. We used logistic regression with the Firth penalized likelihood approach to determine the predictive ability of initial, maximum, and change in troponin level for mortality and the diagnosis of AMI.Results: Demographic characteristics of our cohort included a median age of 70 years, with 48.05% male and 51.95% female. The most common preexisting risk factor was hypertension in 78.81% of the cohort. Notable findings from the logistic regression include the predictive ability of maximum troponin on the odds of death by 0.7% for each unit of increase in troponin value. Also, the odds of AMI increased by 3.1% for each unit of increase in the maximum troponin value.Conclusion: Regardless of the level, a detectable amount of troponin in the serum results in a significantly elevated risk of mortality. Many patients with elevated troponin levels leave the hospital without a specific diagnosis, which can lead to poor outcomes because a detectable troponin does not represent a no-risk population. Our study demonstrates that maximum troponin level is a more sensitive and specific predictor of mortality than initial or change in troponin. Similarly, maximum troponin is the most predictive of AMI vs other causes of troponin elevation, likely because of the correlation between rising troponin levels and cardiomyocyte damage. Further studies are needed to correlate maximum troponin levels and clinical manifestations, which may be helpful in redefining AMI so that AMI can be distinguished more easily from non-AMI diagnoses. Institutional review board approval was obtained for this study under an expedited review as it involved no greater than minimal risk to subjects.The population in this analysis consisted of 77,408 unique patients  who presented to a 9-hospital system in Texas during 2016-2017. Patients younger than 40 years and patients without troponin tests were excluded, leaving a cohort of 30,173 patients who had at least 1 troponin test and were ≥40 years. The primary Baseline characteristics and risk factors included age, sex, smoking history, hypertension, hyperlipidemia, diabetes mellitus, coronary artery disease, chronic kidney disease including end-stage renal disease, chronic obstructive pulmonary disease, prior cerebrovascular accident, and prior AMI.9 A value of 0.0001 was used to assess statistical significance. All statistical analyses were performed in SAS statistical software, version 9.4 (SAS Institute Inc).Characteristics are described using descriptive statistics. Frequencies and percentages are used to describe categorical variables. Means and SDs (or medians and ranges where appropriate) are used to describe continuous variables. Chi-square test was used to test for associations in bivariate comparisons. Wilcoxon rank-sum test was used to test for differences in continuous variables among the 3 troponin categories. Logistic regression using the Firth penalized likelihood approach was used to test the predictive ability of variables of interest. Multinomial generalized logistic regression was used to test the predictive ability of variables of interest for categorical outcomes with more than 2 levels. Nonparametric comparisons using the method described by DeLong et al were performed to assess differences in receiver operating characteristic (ROC) curves.Baseline characteristics of this patient population are presented in Among the study population, the median initial troponin was 0.02 ng/dL (IQR 0.01-0.07 ng/dL), with a range of 0 to 360.92 ng/dL . The median maximum troponin was 0.03 ng/dL (IQR 0.01-0.10 ng/dL), with a range of 0 to 647.54 ng/dL, and the median change in troponin was 0.00 ng/dL (IQR 0.00-0.03 ng/gL) with a range of 0 to 647.54 ng/dL .Troponin as a significant predictor of death was analyzed showing that the odds of death increase by 0.9%  for each unit of increase of the initial troponin. Likewise, the odds of death increase by 0.7%  for each unit of increase in both the maximum and change in troponin . A ROC cA secondary analysis of initial troponin as a significant predictor of diagnosis of AMI vs other causes of troponin elevation showed that the odds of AMI increased by 7.4% for each unit of increase of the initial troponin value  . SimilarWhen comparing the initial, maximum, and change in troponin levels for prediction of AMI, all 3 levels are statistically significant predictors of AMI vs other cardiac causes (non-AMI), pulmonary, sepsis, or others  . When in3 The evolution of cardiac-specific troponins I and T from conventional to high-sensitivity troponins has presented a clinical conundrum as these troponins are often elevated above the 99th percentile in non-AMI conditions.10 The diagnostic utility of high-sensitivity cardiac troponins for AMI is dependent on the troponin level, which corresponds with the amount of cardiomyocyte injury.5 The ability to risk stratify is paramount in identifying patients with AMI vs other conditions. In several large prospective diagnostic studies, the absolute change consistently provided significantly higher diagnostic accuracy than the relative changes to distinguish AMI from non-AMI causes.1The ability to detect minute cardiomyocyte damage has resulted in a large burden to the health care system as a positive troponin value often results in an obligatory stay in the hospital to rule out an AMI, which is not a cost-effective solution but may be a necessary part of the workup process. In our study, we demonstrated that the maximum troponin level, compared to the initial level or the change in troponin level, resulted in the best detection of AMI and was most predictive of mortality. A change in troponin level during a 3- or 6-hour window, depending on conventional or sensitive assay, may not safely rule out AMI. Cardiac-specific troponins I and T are “organ-specific, but not disease-specific.”5 The development of highly sensitive cardiac troponin assays allows for faster risk stratification of individuals at high risk for AMI. However, a positive troponin value also leaves a large proportion of patients who will leave the hospital without a specific diagnosis, which can ultimately lead to significant morbidity and mortality.7 Our study indicates that the maximum troponin level is a more sensitive and specific predictor of mortality than the initial troponin level or change in troponin level. We hypothesize that maximum troponin is the best predictor of AMI because of the correlation of elevations in cardiac troponins to the amount of cardiac damage. Given the significant burden of troponin testing in the inpatient setting, using our model for every unit of increase in troponin signifies an increase in the odds of death by 0.7%. Therefore, individuals with significant elevations in cardiac troponins should have further diagnostic studies to identify a cause before discharge from the hospital. The optimal treatment for these patients is not known, and the mitigation of future risk of morbidity and mortality needs further study.11Regardless of the cause, an elevated cardiac troponin level is associated with a 4.5% 30-day risk of major adverse events defined as all-cause mortality and nonfatal outcomes.12 Elevations in cardiac troponins are seen in many non-AMI conditions such as sepsis, pulmonary embolism, heart failure, chronic kidney disease, stroke, hypertension or hypotension, and liver failure, making differentiating AMI from non-AMI conditions difficult for clinicians.5 Both AMI and non-AMI conditions can cause elevations in cardiac troponins that result in an increase in mortality regardless of the troponin level.10 Our study indicates that maximum troponin level is better able to distinguish between AMI and non-AMI conditions than initial troponin or change in troponin level, with 3.1% greater odds of diagnosing AMI for each unit of increase of maximum troponin. Clinically, this finding can help distinguish between different diagnostic studies and interventions needed for AMI and non-AMI conditions.Given the high sensitivity and specificity of cardiac troponins , they have clinical uses for both ruling in and ruling out AMI. However, cardiac troponins need to be ordered and interpreted in the right clinical context to achieve the intended purpose.Our study has several limitations. First, a retrospective analysis using electronic medical records introduces inherent biases; however, this bias was mitigated as we considered all cardiac troponins drawn in a 2-year period. Second, this study was conducted in a 9-hospital system in Texas, which may not be applicable to other populations across America.Our study demonstrates that maximum troponin level rather than initial or change in troponin is most predictive of mortality and AMI. The majority of elevated troponin levels do not represent AMI but rather a non-AMI condition. However, regardless of the troponin level, an increase in mortality was observed in the population. More studies need to be performed to determine the clinical significance of maximum troponin levels in clinical practice.


An external ventricular drain was inserted within 72 h after the onset of bleeding. CSF was drawn daily from day 1–10. CGRP levels were determined via competitive enzyme immunoassay and calculated as “area under the curve” (AUC). All patients underwent a hrQoL self-report assessment , ICD-10-Symptom-Rating questionnaire (ISR)) after the onset of sSAH (t1: day 11–35) and at the 6-month follow-up (t2). AUC CGRP  was excessively released into CSF after sSAH. AUC CGRP levels did not differ significantly when dichotomizing the aSAH (5.63 ± 1.77) and pSAH group (5.68 ± 2.08). aSAH patients revealed a higher symptom burden in the ISR supplementary item score (p = 0.021). Multiple logistic regression analyses corroborated increased mean levels of AUC CGRP in CSF at t1 as an independent prognostic factor for a significantly higher symptom burden in most ISR scores , anxiety , depression , the supplementary items ) and for a poorer performance in the SF-36 physical component summary score . In contrast, at t2, CSF AUC CGRP concentrations no longer correlated with hrQoL. To the best of our knowledge, this study is the first to correlate the levels of endogenous CSF CGRP with hrQoL outcome in good-grade sSAH patients. Excessive CGRP release into CSF may have a negative short-term impact on hrQoL and emotional health like anxiety and depression. While subacutely after sSAH, higher CSF levels of the vasodilator CGRP are supposed to be protective against vasospasm-associated cerebral ischemia, from a psychopathological point of view, our results suggest an involvement of CSF CGRP in the dysregulation of higher integrated behavior.The vasodilatory calcitonin gene-related peptide (CGRP) is excessively released after spontaneous subarachnoid hemorrhage (sSAH) and modulates psycho-behavioral function. In this pilot study, we prospectively analyzed the treatment-specific differences in the secretion of endogenous CGRP into cerebrospinal fluid (CSF) during the acute stage after good-grade sSAH and its impact on self-reported health-related quality of life (hrQoL). Twenty-six consecutive patients  with good-grade sSAH were enrolled (drop out 19% ( Spontaneous subarachnoid hemorrhage (sSAH) represents a complex and still devastating neurovascular disease, associated with substantial morbidity and mortality. Over the past 30 years, advances in neurovascular treatment strategies and specialized neurocritical care have led to decreasing case fatality rates , 2 with The underlying pathomechanisms are poorly understood and deemed to be multifactorially mediated , 21, 22.The 37-amino acid neuropeptide CGRP, firstly described in 1982 , is a hiBesides its eminent vasoactive role, peptidergic psychoactive implications of CGRP have been repeatedly described in humans and, translationally, in various animal models, with a crucial involvement in multifaceted neurobehavioral processes  such as To the best of our knowledge, no data are yet available on the relevance of CGRP in supratentorial CSF on hrQoL outcome after sSAH in humans. We hypothesize that the excessive release of endogenous CGRP in the subacute phase after sSAH might impact quality of life, even in good-grade patients.All procedures performed in studies involving human participants  were in accordance with the ethical standards of the institutional research committee  and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.The cohort has been reported previously , 24. TweAfter obtaining written informed consent, we selectively included native German speakers, aged 18 to 75 years, with non-traumatic sSAH. The patients either underwent microsurgical aneurysm occlusion (MS group) or endovascular aneurysm occlusion (EV group) for an intracranial aneurysm in the anterior or posterior circulation (aSAH). Patients with a non-aneurysmal pSAH received standardized treatment in the intensive care unit (ICU) (pSAH group). Each patient had been admitted to hospital within 48 h of ictus in prognostically favorable, good to moderate neurological condition, that means with a Hunt and Hess (HH) score  of 1 to The clinical database comprised all demographic, neurological, and radiological variables, comorbidities, non-/invasive procedures, complications, outcome grading  ). Pathophysiologically, the neurotransmitter CGRP is supposed to be released from the perivascular nerve terminals, either induced by the blood in the subarachnoid space  or, possIt might further be speculated that the increase of endogenous CSF CGRP might be a consequence of altered CGRP synthesis and metabolism in certain brain regions and in CSF, respectively, anatomical localization of the ruptured aneurysm, or aneurysm treatment-induced mechanical manipulation of the parent vessel. In serum, peak concentrations of CGRP have been measured after rupture of aneurysms of the middle cerebral artery (MCA) , 75 and—It has to be highlighted that—in many ways—pSAH has to be considered a different disease than aSAH. Short-term complications are rare, and long-term outcome is excellent with respect to disability and death , 8. aSAHInvestigations into the temporary dynamics of sSAH-induced CGRP secretion are scarce and limited to the short-term . As our The pathophysiology of impaired neurobehavioral processing following sSAH remains elusive because of its complex, multifactorial character . VariousBounded by our strict selection criteria and our institutional neurovascular volume, our pilot study is notably limited by the small sample size. It may be speculated that the five excluded patients were incapable to complete the hrQoL assessment due to severe neuropsychological impairment, resulting in an underestimation of the true impairment rate. Then, the inclusion of pSAH patients as a control group implicates a certain collective heterogeneity because pSAH and aSAH have a different pathogenesis, clinical course, different rates of CV and delayed ischemic neurological deficits, and also different neuropsychological and hrQoL outcomes. Though pSAH patients are deemed equally burdened by neuropsychological deficits and reduced hrQoL , the out1 nor at t2. However, we stress that in patients with a central nervous system disease, a confounding influence of fatigue ). Both of our utilized measurement tools, the SF-36 and the ISR, were completed within 10 to 20 min and no effects of fatigue were apparent during the testing, neither at t fatigue  and/or c fatigue  cannot c fatigue , 89. SinYet, our prospective, controlled study provides academically valuable data that offer new insight into the plausible interactions between CGRP in supratentorial CSF and psychopathology after good-grade sSAH as well as into the (to date still underreported) time course of hrQoL performance in the early stages of recovery. Standardized self-reported outcome measures are an important facet of a comprehensive hrQoL outcome assessment, the more since cognitive domain deficits are further complicated by reduced hrQoL, depression, anxiety, and sleep disturbances.Our study reveals the first insight into the potential capacity of endogenous CGRP as a predictive psychoactive biomarker in the ventricular CSF subacutely after the onset of sSAH and its potential contribution to neurobehavioral impairment and reduced hrQoL. In line with preclinical data and the psychiatric literature, the present data suggests that, after sSAH, increased CSF CGRP concentrations significantly adversely affect short-term psychological and physical health with respect to depression, anxiety, somatoform syndrome, compulsive-obsessive syndrome, the supplementary ISR items, general health perceptions, and the SF-36 physical component summary score. Of special note is the potential therapeutic dilemma as, on the one hand, it is highly conceivable that the psycho- and vasoactive neuropeptide CGRP is—at least in part—involved in the pathogenesis of reduced hrQoL after good-grade sSAH, whereas on the other hand, CGRP was certified a cerebroprotective role by counteracting sSAH-induced vasoconstriction and CV-related cerebral ischemia. Our interesting results justify further research on endogenous CGRP in CSF and plasma with a focus on the influencing factors of its release, the temporary dynamics, and the pathophysiological interactions with higher integrated neurobehavior.


Caspase-1 gene have been shown associated with cognitive function in elderly individuals and in predisposition to Alzheimer’s disease (AD), but its detailed mechanism before the typical AD onset was still unclear. Our current study evaluated the impact of Caspase-1 common variant rs554344 on the pathological processes of brain amyloidosis, tauopathy, and neurodegeneration.Genetic variations in the inflammatory Caspase-1 rs554344 allele carrier status with AD-related cerebrospinal fluid (CSF), PET, and MRI measures at baseline by using a multiple linear regression model. We also analyzed the longitudinal effects of this variant on the change rates of CSF biomarkers and imaging data using a mixed effect model.Data used in our study were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. We examined the relationship between Caspase-1 variant was significantly associated with FDG PET levels and CSF t-tau levels at baseline in total non-demented elderly group, and especially in mild cognitive impairment (MCI) subgroup. In addition, this variant was also detected associated with CSF p-tau levels in MCI subgroup. The mediation analysis showed that CSF p-tau partially mediated the association between Caspase-1 variant and CSF t-tau levels, accounting for 80% of the total effect.We found that Caspase-1 variant in influencing cognitive function might through changing tau related-neurodegeneration process.Our study indicated a potential role of The online version contains supplementary material available at 10.1186/s12883-022-02582-9. Caspase-1 gene were associated with cognitive function in elderly individuals with normal cognition [Immune system-mediated inflammation exerts an enormous function on neurodegenerative diseases, particularly in Alzheimer’s disease (AD) , 2. Receognition , and in ognition , but its42 or Aβ42/Aβ40 ratio; pathologic tau, including tau-PET, CSF phosphorylated tau (p-tau); Neurodegeneration, including fluorodeoxyglucose (FDG) PET, CSF total tau (t-tau) or brain structural MRI.As studies have shown, patients could experience a long period of time before developing into AD, accompanied by changes in cerebrospinal fluid (CSF) biomarkers and imaging data . RecentlCaspase-1 variant rs554344 on the pathological processes of brain amyloidosis, tauopathy, and neurodegeneration, using the baseline and follow-up data from AD-related CSF, PET, and MRI measures in a large non-demented population, including normal cognition (NC) and MCI subgroups, from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.Hence, our current study examined the impact of http://adni.loni.usc.edu). ADNI was launched in 2003 as a public-private partnership, led by Principal Investigator Michael W. Weiner, MD, VA Medical Center and University of California-San Francisco (www.loni.ucla.edu/ADNI), which provide clinical, imaging, genetic, and biochemical information for AD research. For more information, see www.adni-info.org [The data used in our analysis were obtained from the ADNI database (info.org .Caspase-1 rs554344 were available. It is noteworthy that rs554344 and rs580253 are in linkage disequilibrium (r2 = 1) and occur together in one haploblock [Here, we restricted our present analysis to MCI and NC subjects whose genotype data of ploblock . Further42, CSF t-tau, and CSF p-tau, was acquired from ADNI database. The collection and manipulation of CSF data have been mentioned in preceding study [CSF biomarker data, including CSF Aβng study . These dng study .http://adni.loni.usc.edu/datasamples/pet/. The PET data was obtained from UC Berkeley and the Jagust Lab on the website (http://adni.loni.usc.edu/data-samples/access-data/). The AV45-PET (amyloid-PET) standardized uptake value ratios (SUVRs) were formed by normalizing composite multi-region target regions of interest (ROIs) to the cerebellar crus gray matter as previously described [A detailed description of PET image acquisition and processing can be found at escribed . In addiescribed .Hippocampal volume (HV) and estimated intracranial volume (eICV) used in the ADNI subjects were acquired from UCSF data in ADNI dataset by a Siemens Trio 3.0 T or 1.5 T scanner. The method has been described in details . We seleCaspase-1 rs554344 allele carrier status with AD-related phenotypes at baseline by using multiple linear regression model. Since the minor allele homozygote (CC) frequency of rs554344 was less than 2%, we used a dominant genetic model to code Caspase-1 genotype as 0 and 1, which means whether or not they carry the C alleles. Then, basing on the methods proposed by Baron and Kenny [Caspase-1 rs554344 on CSF t-tau mediated through CSF p-tau, or on FDG PET mediated through CSF p-tau or t-tau. In this mediation analysis, the effect was defined in terms of the difference in regression coefficient by logistic regression models. Finally, over a mean follow-up of 3 years, range from 0.25 to 15 years, the association of Caspase-1 rs554344 with longitudinal CSF biomarkers and imaging data was analyzed by a mixed effects model in order to obtain the trend of the variable as time goes on. Follow-up information was available for 698 non-demented elderly individuals. In all of the above analyses, age, gender, education years and APOE ε4 status were taken as covariates for test. The APOE genotype was coded as 0, 1, and 2 to present owning 0, 1, and 2 ε4 alleles, respectively. The FDG PET levels fitted the normal distribution, and the data were all checked for normality. After log transformation, t-tau and p-tau levels also fitted the normal distribution. If p <  0.05, we considered the results are statistically significant.All statistical analyses were carried out through R 4.02 and PLINK 1.07. First, we examined the relationship between nd Kenny , we condCaspase-1 allele carriers (GG subjects and GC + CC subjects). As expected, the two subgroups had statistically significance in Mini-Mental State Examination (MMSE) scores and APOE ε4 allele frequency (p <  0.001). The MCI group had significantly smaller volumes in HVa (p <  0.001), and higher levels of CSF t-tau (p <  0.001), p-tau (p <  0.001) and AV45 PET (p <  0.001), while lower levels of CSF Aβ (p <  0.001) and FDG PET (p <  0.001) when compared to those of the NC group.The demographic information of the included subjects was shown in Table Caspase-1 rs554344 with AD-related phenotypes, including CSF biomarkers and image data at baseline  = − 0.068 (− 0.134 – − 0.002), p <  0.05) and FDG PET levels (β Coefficient and 95% CI = − 0.026 (− 0.46 – − 0.06), p <  0.05) at baseline in the total non-demented group, and further subgroup analysis shown the above positive findings were also in MCI subgroup (β Coefficient and 95% CI = − 0.100 (− 0.186 – − 0.015), p <  0.05 for CSF t-tau; β Coefficient and 95% CI = − 0.034 (− 0.060 – − 0.008), p <  0.05 for FDG PET levels). Besides, in MCI subgroup, Caspase-1 loci genotype showed statistical significance with CSF p-tau levels (β Coefficient and 95% CI = − 0.098 (− 0.195 – − 0.001), p <  0.05) , p <  0.001 for age; β Coefficient and 95% CI = − 0.049 (− 0.067 – − 0.032), p <  0.001 for APOE ε4 status) were closely correlated with CSF biomarkers, image data among covariates  the correlation between Caspase-1 variant and CSF p-tau levels; 2) the influence of Caspase-1 variant on CSF t-tau levels was mainly mediated by CSF p-tau. These findings indicated a potential role of Caspase-1 variant in influencing tau related-neurodegeneration process. Previous study has also supported that inflammasome activation could drive tau pathology process [In this study, for the first time, we investigate the association between Caspase-1 rs554344 and Aβ deposition biomarkers. This does not prevent Caspase-1 to becoming target for tau related-neurodegeneration diseases therapy, because the tau pathology plays an increasingly important role in AD pathogenesis [Caspase-1 rs554344 frequency between NC and MCI being similar, our current results support the role of Caspase-1 rs554344 in AD tauopathy. With the addition of the ADNI database, there will be a larger sample size to support our views in the future. Besides, a negative correlation between p-tau and cognitive functions was previously observed in patients with neurodegenerative tauopathy [According to the NIA-AA research framework in 2018, we know that FDG PET and CSF t-tau are biomarkers of Neurodegeneration, while CSF p-tau is indicator of aggregated Tau pathology . The comogenesis . Despiteauopathy . It has auopathy , 27, 28.Caspase-1 variant in influencing cognitive function through changing tau related-neurodegeneration process, suggesting this genetic locus plays a considerable role in tau related neurodegenerative diseases. The specific mechanism of how the genetic variations in Caspase-1 influence tau pathology still needs further study in cellular and animal models for the time to come.To sum up, our study indicated a potential role of Additional file 1: Table S1. The correlation between covariates and CSF biomarkers, image data at baseline in a multiple linear regression model. Table S2. The correlation between Caspase-1 rs554344 and longitudinal CSF biomarkers, image data in total non-demented elderly group. Figure S1. The results of mediation analyses. We found that Caspase-1 acting on FDG PET levels did not mediate through CSF t-tau or CSF p-tau.


Recent data from astronauts who have returned to Earth from a long-duration space flight have unequivocally distinguished spaceflight-associated neuro-ocular syndrome (SANS) from idiopathic intracranial hypertension (IIH) and pseudotumor cerebri (PTC). We review the semiology and pathogenesis of these three entities, noting that optic disc edema is what unites them, and this where the similarities between SANS and IIH/PTC end. We distinguish between PTC and IIH and between SANS and IIH/PTC and review the medical and surgical therapy of IIH/PTC. The key to understanding the phenomenon of optic disc edema is the geometry of the optic nerve sheath, which is a simulacrum of an inverted Venturi tube. This allows us to theoretically study the hydrodynamics of the optic nerve sheath by applying simple physical laws, including the Venturi effect, Poiseuille’s law, and Reynold’s number, and we speculate on nature’s design and the correlation of form and function in understanding how cerebrospinal fluid (CSF) circulates in the optic nerve sheath as it approaches the optic nerve head. Recent spectacular data on the histology of the blood nerve-barrier of the optic nerve disc and the glymphatic system of the optic nerve sheath will also help us understand the development of optic disc edema due to the microgravity-induced cephalad shift of CSF in SANS. We will explore the role of the sodium/potassium adenosine triphosphatase (ATPase) pump on choroid plexus epithelial cells and the aquaporin-4 water receptors located on astrocyte end-feet and their complex interactions with the tetracyclines, mineralocorticoids, and therapeutic agents with carbonic anhydrase activity. We also adumbrate the complex interactions between obesity, vitamin A, and 11-beta-hydroxysteroid dehydrogenase and how the aquaporin-4 receptor relates to these interactions. We distinguish between spaceflight-induced neuroocular syndrome (SANS), idiopathic intracranial hypertension (IIH), and pseudotumor cerebri (PTC). The common denominator of SANS, IIH, and PTC is altered cerebrospinal fluid (CSF) hydrodynamics, the absence of a space-occupying lesion of the brain, the absence of ventriculomegaly, non-inflammatory CSF, and optic disc edema. SANS is due to altered CSF hydrodynamics induced by microgravity in outer space and its effect on the optic nerve disc; CSF pressure may be normal or mildly increased. PTC is due to raised CSF pressure induced by venous hypertension as seen with venous sinus thrombosis, an exogenous agent, such as hypovitaminosis A, hypervitaminosis A or tetracycline/minocycline, or other endocrine and neuro-humoral factors and their effects on the optic disc. IIH is also due to raised CSF pressure and occurs predominantly in younger obese women with no obvious immediate, proximate, endogenous, or exogenous etiology. Whether IIH/PTC is due to altered venous blood flow or altered CSF hydrodynamics or both is still debatable, with altered CSF hydrodynamics being the most likely cause. We will consider the terms CSF pressure and intracranial pressure (ICP) to be synonymous and apply them interchangeably. By hydrodynamics, we mean the pressure gradient across the lamina cribrosa of the optic disc, CSF pressure both intracranially and within the optic nerve sheath, and the dynamics of CSF flow along the optic nerve sheath. The distinguishing clinical features between IIH/PTC and SANS are listed in Table Why SANS is mostly unilateral is not entirely clear, and the authors do not offer any explanation. It may have to do with local hydrodynamics and trabeculation/septation of the optic nerve sheath, as outlined in the Discussion section. Visual field testing in SANS revealed enlargement of the blind spot or scotomas. The nature of the scotomas was not identified in the report .Walter Dandy published a series of 22 patients that had symptoms of high CSF pressure , absence of tumor by ventriculography, and high CSF pressure with a lumbar puncture. All patients were decompressed by a subtemporal craniotomy with favorable long-term results. The absence of ventricular dilation suggested to him a lack of a CSF flow problem. He also made the astute observation that the chronicity of this condition precludes cerebral edema as a cause of this condition. The rapid relief with decompressive surgery was explained by invoking the Monroe-Kelley doctrine, that the drop in ICP reflects a drop in intracranial blood volume. He diagnosed these cases as " high intracranial pressure without a brain tumor," analogous to what we refer to now as pseudotumor cerebri .-13.12-13Papilledema reflects an increase in CSF pressure. Optic nerve swelling begins in the lower pole and progresses to the upper pole and then the nasal pole and reaches a climax in disc margin blurring and optic disc edema. There is concomitant venous distension and a loss of venous pulsation . InteresThe mainstay of therapy is weight loss and the use of carbonic anhydrase inhibitors. The latter reduce CSF production and induce diuresis -19. The Should medical therapy fail, surgical therapy falls into three categories: CSF diversion procedures, bariatric surgery, and venous stenting. A summary of the procedures and main principles and noteworthy points are listed below Table .SANS in a long-duration space flight leads to decreased near-vision; otherwise, astronauts are asymptomatic. Optic disc edema, eye-globe flattening, choroidal folds, and cotton-wool spots mimic what happens in terrestrial IIH. Globe flattening, which is the loss of curvature (convexity) of the posterior sclera, leads to the shortening of the globe and anterior displacement of the fovea, with a subsequent hyperopic shift of the refractive index. However, CSF pressure via lumbar puncture (LP) measurement is normal or mildly elevated post-flight. In microgravity, it is postulated that there is a cephalad shift in CSF leading to internal jugular vein distension and reduced CSF drainage into the venous system. This may lead to locally increased ICP and subsequent distension of the optic nerve sheath, stasis of axoplasmic flow, and disc edema. Surprisingly, despite the development of an empty sella, none of the astronauts developed any significant symptoms of increased ICP such as headaches, tinnitus, diplopia, or transient visual obscurations. The optic disc edema may last for six months post-mission . Why theInterestingly, head-down tilting and prolonged bed rest can mimic microgravity-induced internal jugular venous distension and thickening of the retinal nerve fiber layer of the optic nerve on ocular computerized tomography (OCT), with thickening of the retinal fiber layer with OCT being an early marker of optic disc edema . IncreasAnatomy of the optic nerve sheath and pressure differentialsThe optic nerve sheath is divided into three segments: the bulbar segment, the widest part, adjacent to the eye globe; and the intraorbital and intracanalicular segments. This tube is not necessarily a simple continuous tube with laminar flow Figure .Instead, between the pia and arachnoid layers, there is a fine trabeculated meshwork in the bulbar segment, loculation by septa and pillars in the intraorbital segment, and by trabeculae and pillars in the intracanalicular segment. This reticulated pattern is more like a complex web or a labyrinth where CSF reaches a dead-end at the eye-globe. CSF from the cisterns of the brain are pumped into this cavernous system almost like a hydraulic pump. Therefore, the optic disc is defended by the scleral lamina cribrosa, which is at the mercy of a pressure gradient between the intraocular pressure (IOP) and the ICP, where locally at the bulbar segment, the CSF pressure is referred to as the retrolaminar pressure (RLP). In glaucoma, IOP exceeds RLP and the optic disc is cupped into the retrobulbar space. When the RLP exceeds the IOP, the optic disc bulges into the eye-globe. Both scenarios alter the morphology of the lamina cribrosa, with compression leading to ischemia, retardation of axoplasmic flow, and neural degeneration of the retinal ganglion cells .Hydrodynamics of the optic nerve sheath: Venturi effect, Poiseuille's law, and Reynold's numberWhy is the optic nerve sheath wider at the bulbar end? To answer this question, we need to return to the basics of hydrodynamics. When describing the flow of a fluid, we use the parameters of pressure e Figure .Assuming the net flow of fluid volume across any section of the tube is a constant, we have the simple differential equation:This tells us that the velocity of flow To explain what happens to the pressure where ny point .In summary, as we approach the bulbar end of the optic nerve sheaths, theoretically, two physical events happen, the CSF pressure increases and the speed of flow decreases. This actually follows from the Law of Conservation of Energy, where the total energy of a system  is conserved.Again, we see that the pressure How does one explain the septation and trabeculation of the optic nerve sheath? Here, we need to understand the concepts of laminar flow and turbulent flow. We believe that the septation and trabeculation of the optic nerve sheath induce turbulent flow when the ICP rises to high enough levels. This blunts the pressure head and protects the optic nerve sheath and head. To understand this, we need to know what Reynold's number is. Reynolds's number When Reynold's number t Figure  35]..\begin{dThe septations and trabeculations create eddies and turbulent flow when the CSF pressure increases significantly, converting a laminar flow to a turbulent flow and reducing the pressure head at the optic nerve sheath Figure .These purely theoretical considerations are supported by experimental data. First, we know that CSF pressure determines the retrolaminar tissue pressure in the optic nerve sheath subarachnoid space based upon micropipette-pressure transducer recordings in an anesthetized dog . Second,The role of aquaporins and a possible pathway for tetracycline pathology in PTCCSF is produced by the choroid plexus (two-thirds of the volume) and the ependymal lining of the ventricles (one-third of the volume) with a gradual decline in the daily total volume with aging. Aquaporin-4 receptors on astrocyte end-feet facilitate the flow of water from the choroid plexus and ependymal epithelia into the CSF. There is also direct pumping of sodium into the CSF by the sodium/potassium adenosine triphosphates (ATPase) pump and the enzyme carbonic anhydrase that catalyzes the reaction between a carbon dioxide molecule and a water molecule to produce a proton and bicarbonate ions. The electrochemical gradient pushes protons and sodium ions along with water molecules into the CSF and drainage into the venous sinuses is across the arachnoid granulations and into the nasal lymphatics across the cribriform plate. The carbonic anhydrase activity inhibitors, acetazolamide, topiramate, and zonisamide have all been shown to inhibit aquaporin-4 activity. Nevertheless, the evidence for CSF overproduction in PTC/IIH is limited .After injury or inflammation, activated astrocytes release matrix metalloproteinase-9 (MMP-9), which disrupts the basal lamina between the astrocyte end-feet and the endothelial cells. This leads to a breakdown in the blood-brain barrier and vasogenic edema facilitated by the upregulation of aquaporin-4 receptors. Adult rats subjected to traumatic brain injury developed less blood-brain barrier disruption with less upregulation of MMP-9 and aquaporin-4 receptors after injection with minocycline, an MMP-9 inhibitor. This was a beneficial effect but nevertheless provides evidence whereby the tetracyclines can modulate aquaporin-4 receptors and potentially lead to excessive CSF production . WhetherObesity, inflammation, and 11-beta-hydroxysteroid dehydrogenase in IIHObesity and rapid weight gain in women are unequivocally very strongly associated with IIH, implying a major role for the neuroendocrine role of adiposity . Even a Obesity is associated with elevated levels of serum and adipose 11-beta-hydroxysteroid dehydrogenase levels (11-beta-HSD). 11-beta-HSD regulates cortisol action intracellularly and increases the activity of the sodium/potassium ATPase pump, increasing the production of CSF in the choroid plexus epithelium. A fall in serum and CSF 11-beta-HSD levels correlated with a drop in CSF pressure and weight loss in a group of 25 obese patients with IIH . There wObesity, polycystic ovarian syndrome (PCOS), vitamin A, and IIHAdipose tissue contains the enzyme aromatase, which converts the androgen androstenedione to estrogens. Adipose tissue contains the enzyme aromatase, which converts the androgen androstenedione to estrogens. Estrogens are known to influence aquaporin-4 receptors and retinoic acid synthesis (see below) .In IIH, the androgen profile is different from that in PCOS, despite the fact that PCOS is more prevalent in IIH than in the general population. In IIH, serum and CSF testosterone are increased and their precursors - dehydroepiandrosterone (DHEAS) and androstenedione - are decreased as compared to in PCOS and simple obesity. Testosterone is known to drive the choroidal plexus sodium/potassium ATPase, potentially increasing CSF output. The precursors DHEAS and androstenedione are the main circulating androgens in PCOS leading to hirsutism and android features, not seen in IIH .Adipose tissue also increases the production of active vitamin A, retinoic acid, from the pro-hormone retinal. Both hypervitaminosis A and hypovitaminosis A can lead to IIH/PTC. Hypovitaminosis A can lead to fibrosis of the arachnoid villi in calves and impaired CSF absorption .Microgravity-induced cephalad shift of fluid, local optic nerve sheath blood-nerve barrier defect, glymphatic flow, and SANSSANS is a disease of the optic nerve head. As we outlined earlier, lumbar punctures performed post-long duration flight in astronauts have shown normal or mildly elevated CSF pressures. The cephalad shift of fluid in a microgravity environment leads to internal jugular vein distension and a puffy face. All astronauts develop optic nerve fiber layer thickening of the optic nerve head when visualized with OCT while 15 % of astronauts develop papilledema. Prolonged head-down tilt table posture can replicate these findings in the laboratory . This prThe glymphatic system is a paravascular channel pathway delimited by astroglial endfeet that allows intravitreal and retinal fluid to flow posteriorly into the optic nerve sheath subarachnoid space. The trans-laminar cribrosa pressure, which is equal to the intraocular pressure minus the ICP is about 4 mmHg. In microgravity, with the cephalad shift of CSF, this pressure differential is reversed and fluid is pressure-forced into the pre-laminar optic disc with the formation of optic disc edema. This idea is not far-fetched, as, in certain instances of subarachnoid hemorrhage, blood finds its way into the vitreous of the eye (Terson syndrome) .As spaceflight becomes increasingly common, the National Aeronautics Space Administration (NASA) has made SANS a top priority. Up to 15% of astronauts will develop optic disc edema and mitigating strategies, such as veno-occlusive thigh compression devices, are being investigated to counteract the cephalad shift of body fluids during space travel. As space tourists and travelers become commonplace, knowledge of SANS will become a prerequisite for the practicing clinician. In this article, we have distinguished between the clinical features and pathophysiology of SANS and IIH/PTC. We delve deeper into the hydrodynamics of the optic nerve sheath and the unique histological features of the lamina cribrosa and the glymphatic system, where we emphasized the role of translaminar pressure in the pathogenesis of optic disc edema. The complex interactions between obesity, vitamin A, the steroidogenic enzyme 11-beta-hydroxysteroid dehydrogenase, the aquaporin-4 receptor of astrocytes, and the sodium/potassium ATPase pump on choroid plexus epithelial cells and the generation of optic disc edema were explored. Finally, we draw attention to the non-traditional and novel mechanisms of action of the pharmacological agents used to treat PTC/IIH. This article is one of the earliest articles to address SANS in a non-space science-related journal.


Posidonia oceanica (L.) Delile seagrass residues (leaves and fibers) as growing media component to improve the nutritional quality of two different brassica microgreens (Mizuna and Rapini). We hypothesized that addition of posidonia residues in the substrate would result in higher concentration of certain mineral nutrients in the edible parts of plants. Substrates were obtained by mixing leaves and fibers, each material at the rate of 25, 50 and 75% (v/v), with a peat based commercial substrate, that was also used at 100% rate as a control treatment. Two experiments were carried out . Plant growth measurements and chemical analysis on edible parts  were performed in order to evaluate the effects of the different substrates on growth and nutritional composition of brassica microgreens. In order to evaluate the consumer safety, daily intake, percentage of recommended daily allowance for I (RDA-I) and hazard quotient (HQ) for I intake through consumption of 50 and 100 g portions of Rapini microgreens were calculated. Posidonia in the growing media mixtures increased I and B content in edible parts of microgreens. The calculated HQ underlines the safety of these products. Results confirm the possibility to improve nutritional profile of brassica microgreens by using this natural material as a growing media component, resulting in a sustainable approach.The aim of this study was to test  The agrifood sector tends to adopt and promote sustainable patterns of production and consumption, in order to cope with the increasing needs of the growing world population and the necessity to increase sustainability. The primary objective of agriculture is to ensure adequate quantities of food, to satisfy nutritional exigencies and to fight nutritional deficiencies, with the effort to minimize negative impacts of production processes on the environment. In this framework, plant foods are considered as a fundamental source of important nutrients, such as vitamins, minerals and bioactive compounds. However, nutritional deficiencies still affect an important part of the world population.In the last years, several studies were published dealing with different approaches to enhance the nutritional status of target groups of population, thus providing a public health benefit. A promising approach is biofortification. It consists in increasing the content or the bioavailability of nutrients, e.g., vitamins (mainly folate and vitamin A), minerals  and bioactive compounds (polyphenols and carotenoids) in plant foods, in order to ameliorate their nutritional profile in terms of their contribution to satisfy the Recommended Daily Allowance (RDA) for nutrients . This apAn interesting agronomic technique approach for biofortification consists in the use of soilless cultivation (which includes pure hydroponic or growing media-based systems), allowing for the possibility to act on the nutrient solution composition in order to manipulate at a certain extent the plant nutrients uptake .Posidonia oceanica (L.) Del.). Detached parts of plants  accumulate in huge amount along the coasts, representing a problem in many coastal sites, with environmental, economic, social and hygienic implications . The commercial production of microgreens is usually performed under controlled environment, inside greenhouse, indoor, or tunnel with different levels of technologies. The main critical aspect in the production of microgreens is the selection of the growing media. This plays an important role in determining the visual and nutritional quality of products .Posidonia oceanica (L.) Del. in mixture with peat for microgreens production. Specifically, we focused on investigating the effects of increasing rates of posidonia residues in the substrate on plant tissues mineral content. We hypothesized that the addition of raw Posidonia residues in the substrate might represent a natural and renewable source of mineral nutrients able to increase vegetable nutritional quality. Two experiments were performed. In a preliminary test in growth chamber we evaluated the suitability of peat-Posidonia mixtures as growing media at laboratory scale. Then, in a second experiment, we tested the use of such growing media to produce microgreens of two species (Rapini and Mizuna) in real greenhouse cultivation conditions.According to the above considerations, the objective of this study was to test a growing substrate based on Posidonia oceanica (L.) Delile (PO) residues, both leaves (L) and fibers (F), were collected on a beach in Mola di Bari , a coastal town in Apulia region . After the collection, F and L were washed with rain water (previously collected) in order to remove sand and salt, and successively air dried for 1 week inside a greenhouse at the Experimental farm La Noria of CNR-ISPA (Mola di Bari). The air dried materials were milled (1 mm) and used to prepare the growing substrates under comparison for the production of microgreens, in mixture with a peat-based (50% white peat – 50% black peat) commercial substrate , as described in details in section “Experiment 1: Indoor Production of Mizuna Microgreens in Growth Chamber Conditions.” Electrical conductivity (EC) and pH of peat and PO residues (L and F) were analyzed on water-soluble extract (1:5 v/v) according to Samples of rd to 22th 2018, in a growth chamber  at the Institute of Sciences of Food Production, National Research Council, Italy (ISPA-CNR) in Bari. Mizuna (Brassica rapa L.) plants were grown in plastic trays  filled with seven different mixtures (percentages expressed on a DW basis): (i) CTR ; (ii) L25% (75% peat and 25% PO L); (iii) L50% (50% peat and 50% PO L); (iv) L75% (25% peat and 75% PO L); (v) F25% (75% peat and 25% PO F); (vi) F50% (50% peat and 50% PO F) and (vii) F75% (25% peat and 75% PO F). EC and pH of each mixture were measured on water-soluble extract . Total Porosity (TP), water holding capacity (WC), air capacity (AC) and bulk density (BD) of the mixtures were determined by using a method described by 2. The Mizuna plants were grown at a constant temperature of 20°C and a relative humidity of 80%. During the first three days, lights were kept off to allow seeds germination in the dark. On day 4, the seedlings were exposed to white light . Photoperiod conditions were 12 h dark and 12 h light. The trays were irrigated manually every day using 100 ml of tap water until the germination was completed. After germination, trays were irrigated with a half strength Hoagland nutrient solution (NS). The NS was prepared by mixing macro and micronutrients with distilled water, resulting in a final concentration of (mg/L) 112 N, 117.5 K, 80 Ca, 31 P, 16 S, 12 Mg, 0.135 B, 0.56 Fe, 0.055 Mn, 0.0655 Zn, 0.016 Cu, and 0.025 Mo. A NO3-N:NH4-N ratio of 84:16 was applied. The NS pH was adjusted to 5.5 – 6.0 using 1 M H2SO4.The trial was carried out from July 3A completely randomized design with four replications and seven treatments was adopted for the study, for a total of twenty-eight experimental units each one represented by a single microgreens growing tray.th to October 3rd 2018, in a plastic greenhouse at the experimental farm “La Noria” of the Institute of Sciences of Food Production (ISPA-CNR) in Mola di Bari (BA), southern Italy . Plants of Mizuna and Rapini (Brassica rapa L.) were grown in plastic trays  filled with seven different substrate mixtures as reported in Experiment 1 (section “Experiment 1: Indoor Production of Mizuna Microgreens in Growth Chamber Conditions”). The seeds were uniformly distributed on the substrate surface with density of six seeds per cm2. During the first three days, the trays were covered in order to allow seeds germination in the dark. On day 4, the seedlings were exposed to natural light. Mean air temperature, relative humidity, and photosynthetically active radiation (PAR) inside the greenhouse during the experiments were: 24°C, 58%, and 211 μmol/m2/sec.The trial was carried out from September 17The trays were irrigated manually every day using 100 ml of tap water until the germination was complete. After germination, trays were irrigated with a half strength Hoagland NS as reported in the first experiment. A completely randomized design with four replications and seven treatments was adopted for the study, for a total of twenty-eight experimental units each one represented by a single microgreens growing tray.–2] was evaluated. After weighing, harvested microgreens were maintained in a forced draft oven at 65°C until constant weight for the measurement of DW.At the harvest, 22 days after sowing in the first experiment and 16 days in the second experiment, yield [expressed as kg of fresh weight (FW) m2O (Milli-Q Millipore 18 M Ω/cm) at 60°C and stirred for 30 min. After extraction, the samples were allowed to cool down to room temperature. The product extract was well mixed and centrifuged at 10,000 × g at room temperature and successively filtered by using 0.45 μm filters . The absorbance of samples was determined at 454 nm, using a UV-1800 spectrophotometer . The quantification of I in samples was determined by interpolation with a calibration standard curve .The quantification of inorganic iodine (I) in different samples of peat, PO residues and brassica microgreens was performed by using the protocol described by 3, PO4 and SO4 ions were determined by ion exchange chromatography technique  with a conductivity detector performed as reported by 2CO3 (3.5 mM) and NaHCO3 (1 mM), for 30 min at room temperature. Then, the extracts were diluted and filtered by using 0.45 μm (RC) followed with a Dionex OnGuard IIP (Thermo Scientific) in order to remove organic compounds such as humic acids, phenolic fraction, anthocyanins, tannic acids, lignins and azo dyes from sample matrices. The solutions obtained were analyzed by ion chromatography (IC-Dionex DX120) with a conductivity detector, by using an IonPac AG14 precolumn and an IonPac AS14 separation column (Thermo Scientific) at 35°C, flow 1 mL/min.The Cl, NOtot) content was measured only in peat and PO residue (L and F) sample, by using the protocol of Kjeldahl modified by tot in the samples was determined by interpolation with a calibration standard curve .The total nitrogen . The digestion procedure was carried out in two steps: 15 min to reach 200°C and 10 min maintained at 200°C . Each solution was diluted to volume with ultrapure H2O (Milli-Q Millipore 18 M Ω/cm) and filtered using a 0.45 μm filter. Samples were analyzed with Inductively Coupled Plasma - Optical Emission Spectrometry  to measure Ca, K, Mg, and Na in radial mode and Al, B, Cr, Mn, Zn, and Fe in axial mode  were evaluated by using two different certified reference materials (CRM): NIST_1573a —tomato leaves and SPIN-1_spinach. The certified and experimental value of CRM are provided in n = 10), LOD (sd × 10) and LOQ (sd × 10).For Al, B, Ca, Fe, K, Mg, Na, Mn, Cr, and Zn determinations, 0.3 g samples of peat, PO (L and F) residues and brassica microgreens were digested in a closed-vessel microwave digestion system  with 10 ml of HNOial mode . In addi2O:CH3COOH, 79:20:1% v/v/v). The vials were then placed in a sonicator bath at ambient temperature for 30 min, followed by 1 h in a magnetic stirrer. The mixture was centrifuged at 10,000 × g at 4°C for 10 min and the supernatant was transferred into a volumetric tube. The residue was resuspended in 10 mL of MeOH:H2O:CH3COOH (79:20:1% v/v/v), gently mixed manually, and sonicated for an additional 30 min, followed by stirring (1 h) and centrifugation . The TP content was determined using gallic acid (R2 = 0.9991) as a calibration standard by using a Perkin–Elmer Lambda 25 spectrophotometer .Only for the second experiments the content of total polyphenols was carried out according to the Folin–Ciocalteu method by using the extraction methods reported by 3H6O:H2O, v/v) and stirred for 24 h at room temperature. After extraction, the samples were diluted and filtered by using 0.45 μm  and the absorbance of the extracts were measured at 662, 645, and 470 nm, using a UV-1800 spectrophotometer .Chlorophylls and total carotenoid content were determined spectrophotometrically, using the extraction procedure reported by The I recommended daily allowance (RDA-I) for children over 12 years and adults is 150 μg . Daily iP = 0.05. The statistical software STATISTICA 10.0  was used for the analysis.Effects of different treatments were tested using analysis of variance followed by means separation with Fisher’s protected least-significant difference at tot concentration, followed by peat, while PO L showed the lowest value  are reported in st value . The PO st value . Peat an75% treatment  compared to the control (100% peat). TP was not affected by the addition of PO residues in the mixtures, with a mean value of 92% (data not shown). A slight effect was observed on WC when PO residues, in particular L, were added in the mixtures, although only at the highest rates the effect was significant (P = 0.016). The observed values ranged from 68% in the control to 78% in PO L75 .Increasing PO rate in the growing media mixture resulted in higher pH and EC values, especially when leaves residues were used in the mixture . In factn PO L75 . Conversn PO L75 . BD was Posidonia oceanica (L.) Delile leaves (PO L) yield was similar to CTR up to a PO residues rate of 50% (in the case of L) and 25% (in the case of F) in the mixture, while generally lower yield values were observed at higher rates , even if the K content in the PO residues was, on average, lower than peat  observed in F75% treatment  followed by F75% (54.61 μg/100 g FW), L50% (48.0.3 μg/100 g FW) and F50% (38.41 μg/100 g FW). In the other treatments, values were below 25.5 μg/100 g FW. High increase of B content was also found in Mizuna microgreens produced by adding PO residues in the growing media  followed by F25% (126.66 μg/100 g of FW), L50% and L75% , L25% (43.38 μg/100 g of FW) and CTR (21.57 μg/100 g of FW). DI, percentage of RDA-I and HQ for the intake of I with 50 and 100 g portions of Mizuna microgreens are reported in 75% Mizuna microgreens, the RDA-I for adults (150 μg I/day) would not be covered. However, the percentage of RDA-I covered by the consumption of Mizuna microgreens cultivated by using PO residues in growing media was substantially higher than CTR. In addition, the consume of 100 g of serving size of Mizuna microgreens at major content of I was characterized by a HQ value lower than 1, which represents a safe dose , with a 23% increase compared to peat. The highest DM content was observed in Mizuna plants grown in L75% mixture (18% higher than other treatments), while the PO residues did not affect DW content in Rapini  Mg content compared to peat when PO residues, both L and F, were used at 75% rate, with higher values in Rapini. A similar trend was observed for NO3, with a 23% higher content, on average, in L75% and F75% compared to peat, although in this case Mizuna showed higher values. As expected, Cl and Na contents were dramatically affected by the presence of PO residues in the growing media, reaching almost double values, in general, at highest PO rates compared to CTR. Rapini showed, on average, higher plant tissue content for both Cl (12%) and Na (13%) compared to Mizuna , while in Rapini the highest rate of PO in the growing media reduced the PO4 content of 27% compared to the CTR; Yield and DM were influenced by PO residues in the growing media, although to a different extent for Mizuna and Rapini . Mizuna ubstrate . In the n Rapini . The mino Mizuna . The pre75%, with a 936% and 866% increase compared to CTR observed in Mizuna and Rapini, respectively. As a general trend, plants grown in PO F accumulated less I than in PO F. As regard B content, the highest concentration was reached in Rapini plants grown with PO F at 50% e 75% rates . On the contrary, in Mizuna PO F (50–75% application rate) and PO L (at any rate) reduced the Mn concentration in the leaves . The highest values of Al were founded in Mizuna and Rapini CTR, Mizuna L25%, L50% and L75% , while the use of PO F residues at any rate, and of PO L at 75% rate, resulted in a reduction of Al content in edible parts of Mizuna microgreens respect to the CTR, with the lowest values observed in PO F treatments . However, the percentage of RDA-I covered by the consumption of brassica microgreens (both species) cultivated by using PO residues in growing media was higher than CTR. In addition, the consume of 100 g serving size of Mizuna or Rapini microgreens at the highest content of I was characterized by a HQ value lower than 1, which represents a safe dose , in Rapini no differences were observed compared to CTR (72 mg/100 g of FW).The main bioactive compounds  measured in microgreens are reported in 50% treatment . No differences were observed between genotypes .The chlorophyll-A, B and total showed only slight alterations as an effect of treatments. Only CHL-B and CHL-tot showed a relevant increase in Rapini subjected to Freatment . Mizuna reatment . On averIn the current study we aimed to evaluate the possibility to improve the nutritional quality of products by using not composted PO residues as growing media component, this representing a novelty.tot in the PO F with respect to PO L is likely due to the partially decomposed state of F. The Ntot content measured in peat has to be related mainly with the mineral fertilizers added by the manufacturer, that also influenced NO3 and K content, respectively 3.0 and 1.7 times higher in peat than in PO residues, and SO4 content as well. Thus, the natural endowment of PO residues in terms of plant nutrients may contribute to reduce the use of mineral fertilizers in substrate-based cropping processes  and the period of collection . TherefoIn general, the high content of certain elements outlines the feasibility of PO residues use as a renewable source of plant nutrients, with particular reference to micro-nutrients endowment and with the related beneficial effects on the nutritional quality of vegetable products.Higher EC in PO L raw material and PO L based substrates is likely determined by the higher salt accumulation in intact leaves compared to fibers, with particular reference to vacuolar ion sequestering and cytosolic osmolyte accumulation . MininniR2 = −0.807, P < 0.000017)  . HoweverIn indoor production, the environmental conditions, such as stable mean air temperature, relative humidity, and photosynthetically active radiation (PAR), combined with a higher availability of K in growing media containing PO, has determinated an increase of K tissue concentration in PO L treatment compared to CTR and fibers. The quality of light used in growth chamber may have affected to a certain extent the uptake of macro e micronutrient as reported by different Authors .Ocimum basilicum, L.) grown in media based on different percentage of PO compost. In Mizuna and Rapini microgreens this reduction can be related to an increase of Mg content, confirming the antagonism between Ca and Mg. However, it should be noted that in Rapini microgreens only a slight tendency to Mg increase was observed.On the contrary, in all microgreens produced in this study the Ca plant tissue concentration was reduced by PO in growing media, compared to peat that showed the highest values. 3 content in vegetables is an important nutritional and consumer health parameter for quality of fresh leafy vegetable products because this anion is listed as an anti-nutritional factor in vegetables  No 1258/2011 for other leafy vegetables, such as lettuce (3–5 g/kg of FW) and rocket (6–7 g/kg of FW), and to the values reported by Brassica oleracea, L. var. italica, capitata and nipponistica).The NOgetables . In factgetables  the curr3 content in edible parts of plant, thus resulting in improved nutritional quality of Mizuna microgreens.In the indoor production an increasing rate of PO (both L and F) in the growing mixture allowed to reduce the NO3 could be related with the higher I content in growing media and in Mizuna microgreens tissues. 3 in edible parts of lettuce (Lactuca sativa L.) after increasing levels of I  in NS, probably related with high phyto-availability of this element. In fact, since the plants absorb this element through ionic channels and transporters of chloride  Delile (PO) leaves (L) and fibers (F) in the growing media. CTR (control 100% peat),Total polyphenols, chlorophyll and carotenoids contents in 3 in brassica microgreens produced under greenhouse conditions at high rates of PO residues (L and F) in growing media could be related with a different interaction between treatments and environmental conditions. There are different factors involved in NO3 metabolism, such as temperature and light intensity  microgreens  would imply a low intake of this element  was quite high respect to data reported by United States Department of Agriculture  for comm element  if compa element . As rega element .Ocimum basilicum L.) grown in PO based compost  in order to improve the nutritional profile of edible plants. In another case (The low I found in CTR (100% peat) was quite expected, since on one hand it is documented that seeds generally have extremely low I contents , and on her case  an increRegarding consumer safety, the Daily intake, the percentage of recommended daily allowance for I (RDA-I) and the hazard quotient (HQ) for intake of I through consumption of 50 and 100 g portions of brassica microgreens, showed low values with respect to other studies . It shouHowever, according to our findings, the consume of a 100 g serving size  of our brassica microgreens poses no risk to consumer health, contrary to the results reported by It is worth mentioning that the aim of a biofortification study should not be to obtain products suitable to satisfy the RDA, but possibly to help in filling the dietary gaps (related to I in this case) in specific target groups of population. Excessive concentration of this element in vegetables would pose a risk of excessive iodine intake for humans (the tolerable upper intake level is 1100 μg I/day).We documented the possibility to improve nutritional profile of brassica microgreens without using iodine chemical fertilizers. On the contrary, we proposed a sustainable approach consisting in the use of a material often managed as a waste.Pearson correlation, R2 = 0.978, p < 0.05 in Mizuna microgreens produced in indoor; R2 = 0.934, p < 0.222 in Mizuna produced in greenhouse; R2 = 0.874, p < 0.008 in Rapini). In general, the application of B in NS increases the tissue content of this element in different parts of vegetables as reported by –3. In our previous study (Portulaca oleracea L.). However, the high increase of B in edible parts of brassica microgreens, in both experiments, did not induce symptoms of plant toxicity, probably related to the typical short growing cycle for microgreens. Similarly, High increase of B contents was also found in both microgreens species produced by adding PO residues in the growing media , 4, whilus study  the applAlthough generally not considered essential for human health, there are many scientific evidences that B intake within the usual dietary range may influence the metabolism and utilization of Ca and vitamin D in humans, and may have positive effects on bone health . Sheng eIron is an essential element for human health: a deficitary intake can induce different chronic and acute effects. 43% of children and 29% of women in reproductive age around the World show different phenomena of anemia, and about 50% of these cases could be the result of iron deficiency . In our An impairment to Fe absorption in plants is represented by high pH conditions in the root environment, as the case of the substrates containing PO . HoweverOcimum basilicum L.), when plants were grown in PO based compost.On the contrary, Manganese is also an essential element for human health, being a coenzyme in various biochemical processes, and the overall Mn contents in this study were similar to the results found in 30 commercially grown microgreens in Brassicaceae family .Brassica vegetables are known to be rich sources of bioactive compounds, such as glucosinolates, polyphenols, ascorbic acid, carotenoids, and tocopherols, which have human-health effects reportedly involved in preventing cardiovascular diseases and some types of cancers . In geneAccording to the objective of the study, we demonstrated the possibility to increase the content of some beneficial elements  in two different brassica microgreens (Mizuna and Rapini) by using an innovative “ecofriendly” biofortification approach based on the use of PO residues (leaves and fibers) in the growing substrate. This resulted in a source of mineral elements suitable for this scope. In general, the addition of PO in the growing media did not induce phenomena of toxicity neither substantial alteration of plant growth and yield. The microgreens produced with this ecofriendly method showed a high increase of I in edible parts. The HQ calculated underline the safety of these products. Our results support the possibility to produce microgreens with high nutritional profile by recovering an organic material generally treated as a waste, without needs of specific material processing other than crushing and washing. Growing media based on PO residues could allow to reduce the use of peat. Further research is needed to better investigate the physiological mechanisms regulating plant tissue concentrations of beneficial compounds and minerals resulting from the use of the proposed growing media. The effectiveness of the proposed biofortification approach will be tested for the production of other high-health-profile vegetables in soilless conditions, such as baby leafy or fruit vegetables.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.MD’I and AP made the substantial contributions to the conception or design of the work, performed the analysis of posidonia and microgreens, drafted the work, and did the final approval of the version to be published. FM revised the article critically, drafted the work, and did the final approval of the version to be published. NM revised the article critically and did the final approval of the version to be published. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Some persons conceived with donor gametes react negatively when they found their birth via donor conception. They request access to information about and seek to communicate with the donor. However, some countries mandate donor anonymity. Other countries allow donor-conceived persons to access donor information, but they can only use this access if their parents have disclosed donor conception to them. We investigated a thorny issue of donor conception: whether donor conception should be shifted from an anonymous basis to a non-anonymous basis.We review the issues and concerns regarding donor conception. We then consider the impact of direct-to-consumer genetic testing on donor conception, as well as the influence of donor conception on offspring’s identity and the potential of different types of donors. To discuss the future policy of donor conception, the policies on the anonymity of gamete donors were investigated using publicly-available documents in 15 countries.The aim of mandating donor anonymity is to protect the privacy of the donor and intended parents. However, the diffusion of direct-to-consumer genetic testing may make it impossible to maintain anonymity. Birth via donor conception shapes the offspring’s identity, and the donor may further influence the development of offspring’s identity through communications. It remains important to disclose donor conception to donor-conceived offspring and to provide them with donor information. However, that information might be insufficient for some donor-conceived persons. Here are benefits to having open-identity donors and known donors. Such donors can make an agreement with the parents regarding future communication with the offspring, although both sides should respect privacy. Subsequent counseling for all parties involved can result in better tripartite communication agreements.In sum, ethical and practical issues that complicate donor anonymity are driving a shift to non-anonymous donor conception, in which all parties come to a communication agreement. To pave the way for such a donor conception system, transitional measures can be put into place. For countries that already adopted non-anonymous donor conception, ensuring the communication agreements is important to protect the rights of parents, donor, and offspring.The online version contains supplementary material available at 10.1186/s12910-022-00756-1. Reproductive techniques such as artificial insemination (AI), in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), cannot help infertile couples conceive unless the two partners themselves have fertile eggs and sperm (gametes) respectively. However, such aspiring parents can build a family if they are willing to forgo having a full genetic relationship with their children and if a third-party donates viable gametes to them. However, conception using donor gametes (donor conception: DC) raises complicated ethical issues –5. One tThere are two general types of policies regarding donor anonymity: maintaining donor anonymity and allowing access to information about the donor , 5–7. FoEarlier surveys regarding donor-conceived adolescents and adults in the UK, USA, Canada and Australia revealed that donor-conceived persons who learned in adolescence that the circumstances of their birth had been hidden from them express a variety of feelings, and some reported feeling shocked, deceived, and distressed , 12. MorIn the last years, there is a growing pressure to opt for non-anonymous systems. In 2019, at the United Nations Convention on the Rights of the Child, donor-conceived people requested international and national frameworks and laws that ensure their right to access information about their origins and to preserve relations with their genetic and social families . SimilarThe present paper examines whether DC should be shifted from an anonymous basis to a non-anonymous basis, while considering the identity of donor-conceived persons, as well as the impact of direct-to-consumer genetic testing. First, it holds that existing DC systems have difficulty in harmonizing respect for donor anonymity, as well as parental reproductive autonomy, with the offspring’s right to access donor information. Second, it considers the impact of direct-to-consumer genetic testing on parties involved in DC. Third, it examines the influence of DC on the identity of donor-conceived persons and on the development of that identity. We conclude that countries should shift to non-anonymous DC and point out the potential for using open-identity donors and known donors, including relatives, who can come to an agreement with the parents regarding communication with the DC offspring. Finally, this study explores possible ways of shifting to such a non-anonymous DC system via transitional measures.https://pubmed.ncbi.nlm.nih.gov/) and Google Scholar (https://scholar.google.com/) with keywords: donor conception, donor-conceived, gamete donation, egg donation, oocyte donation, sperm donation, gamete donor, egg donor, oocyte donor, sperm donor, recipient parent, recipient couple, donor-conceived child, donor-conceived offspring, donor-conceived adolescent, donor-conceived adult, and donor-conceived family. The findings and implications of survey reports on gamete donors, parents who conceived with donor gametes, and offspring born via DC are shown in Additional file We reviewed the health, ethical, legal, and social issues and concerns regarding DC based on the survey reports, as well as literatures and administrative documents, that were searched and selected using PubMed  to female donors . In addiGamete donation has raised two ethical concerns about the commodification and exploitation of invaluable human reproductive cells , 21. TheRegarding social conflicts due to inconsistencies between legitimate parenthood and biological parenthood, civil law stipulates the parental authority for parties involved in DC . TypicalAs partly mentioned in the Introduction section above, the policy on donor anonymity varies among countries Table . CountriThe risks inherent in gamete donation and DC are substantially reduced by testing, screening, registering, and managing donors. Moreover, the ethical concerns over gamete donation can also be alleviated by prior counseling as well as by establishing payment rules. However, it is nearly impossible to balance respect for the donor’s anonymity and parental reproductive autonomy with the offspring’s right to access to donor information.People conceived through DC will not know that they were conceived with donor gametes unless their parents or others disclose the fact to them , 12. ManNow, inexpensive, direct-to-consumer genetic testing for health and genealogical purposes is becoming widespread throughout the world. Many people will be likely to use such widely-available genetic testing purely out of curiosity or because they feel that they do not resemble their parents in appearance –18. SomeEven in countries that guarantee donor-conceived individuals’ access to donor information, direct-to-consumer genetic testing may also impact the three parties involved in DC to some extent. Donor-conceived persons, once they reach a certain age  donor have a communication agreement, the people concerned can respond to such requests from the child while undergoing counseling. Nonetheless, it may currently be impossible for the relevant countries to shift to DC involving open-identity donors or known donors due to administrative costs and the need to hire a necessary number of counselors. In that case, allowing anonymous donors, as well as open-identity and known donors, is one transitional measure that can be taken. It could be argued that the transitional measures suggested for countries mandating donor anonymity and for countries allowing offspring to access donor information are inconsistent and insufficient to ensure the welfare of donor-conceived offspring, and that fully shifting to a non-anonymous DC system is the only viable solution. However, previous studies have shown that not all donor-conceived offspring have serious concerns about their birth via DC , 34. In The involvement of open-identity or known donors is the premise on which DC with a communication agreement is based. Indeed, Belgium, Denmark, Germany and Switzerland allow known donors and/or open-identity donors at present Table  6]. Not. Not6]. A shift to non-anonymous DC with a communication agreement between the parents, an open-identity or known donor, and the donor-conceived offspring is highly desirable. However, this policy change may have to proceed by transitionally allowing both anonymous DC and non-anonymous DC, or by allowing both open-identity and/or known donors and donors who remain anonymous to the parents.Countries that have already adopted the policy of non-anonymous DC should also acknowledge the possibility that donor-conceived people who were born prior to the removal of donor anonymity or who may not know about the details of their conception may use direct-to-consumer genetic testing. Such uses of genetic testing bypass the aforementioned coordination of communications between DC offspring, donors, and parents to protect or guarantee their rights. From now on, such countries should ensure that their non-anonymous DC system entails a communication agreement among the parents, donor, and offspring.Considering the practical difficulty of maintaining donor anonymity and the substantial influence of DC on the offspring’s identity, the present paper contends that DC should be shifted to a non-anonymous basis, in which the parents, the gamete donor, and the donor-conceived offspring should agree on how communication among them should proceed. This policy change to guarantee or protect the rights of donor-conceived offspring, parents, and donors is premised on allowing open-identity donors and/or known donors who can agree with the aspiring parents on how they will communicate with the donor-conceived offspring. Although persons conceived via DC might feel unsatisfied with or distressed about the agreement made prior to their birth, subsequently providing appropriate counseling and honoring the offspring’s concerns and requests may lead to a better tripartite communication agreement. Although there will be challenges in enacting such a DC system, transitionally allowing both anonymous DC and non-anonymous DC, or allowing both open-identity and/or known donors and donors who remain anonymous to the parents, can be put into place to pave the way for DC with a communication agreement. With the advent of direct-to-consumer genetic testing, countries adopting non-anonymous DC should also ensure the use of communication agreements among the parents, donor, and offspring in each DC.Additional file 1. Findings and Implications of Survey Reports of Gamete Donors, Parents Who Used Donor Gametes, and Offspring Born via Donor Conception. The table provides the authors, their country(ies), survey subjects, and findings and implications regarding the searched and selected surveys of donors, parents, and donor-conceived offspring.


Treponema pallidum. The clinical presentation is variable and nonspecific. Neuroimaging findings are complex and that the diagnosis is based on clinical presentation, cerebrospinal fluid (CSF) parameters, and serologic and CSF evidence of syphilis. To date, there is no case report describing Treponema pallidum detected by metagenomic next-generation sequencing (mNGS) in CSF.Neurosyphilis refers to infection of the central nervous system by Treponema pallidum for the first time.In this report, we describe a case of neurosyphilis in a HIV-negative, 29-year-old man, who was admitted to our hospital with an epileptic seizure and progressive cognitive impairment. Brain magnetic resonance imaging (MRI) revealed fluid-attenuated inversion recovery (FLAIR) high signal intensities in bilateral medial and anterior temporal lobes, insula, right pulvinar of the thalami, precuneus, frontal and temporo-occipital lobes. Laboratory examination showed positive results by means of nontreponemal or specific treponemal test in serum and CSF. mNGS of the CSF was also performed to identify This case underscores the importance of considering neurosyphilis as a potential cause of mesiotemporal abnormality. In addition, the rapid improvement and wide usability of mNGS technology will bring new breakthroughs in the clinical diagnosis of neurosyphilis. Treponema pallidum. The incidence of syphilis has increased in the past 20 years in China [Treponema pallidum was detected by metagenomic next-generation sequencing (mNGS) in the current report for the first time.Syphilis is known as the “Great Imitator” caused by the organism in China . It is ain China , 4. Recein China –8. Tradi2O, which revealed pleocytosis (58 cells/µL), low glucose (2.18 mmol/L), and raised protein (1.39 g/L), his CSF TRUST also showed positive titres of 1:2. Furthermore, CSF sample was collected for mNGS to rule out co-infection. Interestingly, after 48 h, the results revealed 2288 sequence reads uniquely corresponding to the Treponema pallidum genome with 11.6483% coverage  score was 22 out of 30. The remainder of his neurologic examination was normal. An electroencephalogram showed diffuse generalized slow spike-wave discharges. The blood work-up indicated a positive tolulized red unheated serum test (TRUST) with a titer of 1:32 and a positive fluorescent treponemal antibody-absorbed (FTA-ABS) test. Serum biochemistry, HIV and hepatitis serology, thyroid stimulating hormone, and glycated hemoglobin levels were unremarkable. Brain MRI showed high signal intensities on FLAIR images involving of bilateral medial and anterior temporal structures, insula, right pulvinar of the thalami, precuneus, frontal and temporo-occipital lobes, with focal meningeal enhancement  and protein level (> 40 mg/dL) . SerologThere is increasing evidence that mNGS can play a role in neuroinfectious diseases, such as unexplained encephalitis and meningitis , 17, altIn conclusion, misdiagnosis rate of neurosyphilis is still high due to atypical neuroimaging and clinical manifestations. Therefore, recognizing MR manifestations plays an important role in the diagnosis of neurosyphilis. We further emphasize the importance of early diagnosis and treatment in patients with mesiotemporal abnormality, because cognitive impairment resulting from neurosyphilis is considered to be “reversible dementia”. Despite its lack of sensitivity for use alone as a diagnostic test, mNGS should be preferred to offer a supplementary method for the diagnosis and differential diagnosis of neurosyphilis, and a larger number of cases will be needed to confirm this method.