Cable Bacteria Skeletons as Catalytically Active Electrodes.

Cable bacteria are multicellular, filamentous bacteria that use internal conductive fibers to transfer electrons over centimeter distances from donors within anoxic sediment layers to oxygen at the surface. We extracted the fibers and used them as free-standing bio-based electrodes to investigate their electrocatalytic behavior. The fibers catalyzed the reversible interconversion of oxygen and water, and an electric current was running through the fibers even when the potential difference was generated solely by a gradient of oxygen concentration. Oxygen reduction as well as oxygen evolution were confirmed by optical measurements. Within living cable bacteria, oxygen reduction by direct electrocatalysis on the fibers and not by membrane-bound proteins readily explains exceptionally high cell-specific oxygen consumption rates observed in the oxic zone, while electrocatalytic water oxidation may provide oxygen to cells in the anoxic zone.

Cerebrovascular Reactivity in Patients With Small Vessel Disease: A Cross-Sectional Study.

BACKGROUND: Cerebrovascular reactivity (CVR) is inversely related to white matter hyperintensity severity, a marker of cerebral small vessel disease (SVD). Less is known about the relationship between CVR and other SVD imaging features or cognition. We aimed to investigate these cross-sectional relationships. METHODS: Between 2018 and 2021 in Edinburgh, we recruited patients presenting with lacunar or cortical ischemic stroke, whom we characterized for SVD features. We measured CVR in subcortical gray matter, normal-appearing white matter, and white matter hyperintensity using 3T magnetic resonance imaging. We assessed cognition using Montreal Cognitive Assessment. Statistical analyses included linear regression models with CVR as outcome, adjusted for age, sex, and vascular risk factors. We reported regression coefficients with 95% CIs. RESULTS: Of 208 patients, 182 had processable CVR data sets (median age, 68.2 years; 68% men). Although the strength of association depended on tissue type, lower CVR in normal-appearing tissues and white matter hyperintensity was associated with larger white matter hyperintensity volume (BNAWM=-0.0073 [95% CI, -0.0133 to -0.0014] %/mm Hg per 10-fold increase in percentage intracranial volume), more lacunes (BNAWM=-0.00129 [95% CI, -0.00215 to -0.00043] %/mm Hg per lacune), more microbleeds (BNAWM=-0.00083 [95% CI, -0.00130 to -0.00036] %/mm Hg per microbleed), higher deep atrophy score (BNAWM=-0.00218 [95% CI, -0.00417 to -0.00020] %/mm Hg per score point increase), higher perivascular space score (BNAWM=-0.0034 [95% CI, -0.0066 to -0.0002] %/mm Hg per score point increase in basal ganglia), and higher SVD score (BNAWM=-0.0048 [95% CI, -0.0075 to -0.0021] %/mm Hg per score point increase). Lower CVR in normal-appearing tissues was related to lower Montreal Cognitive Assessment without reaching convention statistical significance (BNAWM=0.00065 [95% CI, -0.00007 to 0.00137] %/mm Hg per score point increase). CONCLUSIONS: Lower CVR in patients with SVD was related to more severe SVD burden and worse cognition in this cross-sectional analysis. Longitudinal analysis will help determine whether lower CVR predicts worsening SVD severity or vice versa. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: ISRCTN12113543.

Longitudinal Metabolite Changes in Progressive Multiple Sclerosis: A Study of 3 Potential Neuroprotective Treatments.

BACKGROUND: 1 H-magnetic resonance spectroscopy (1 H-MRS) may provide a direct index for the testing of medicines for neuroprotection and drug mechanisms in multiple sclerosis (MS) through measures of total N-acetyl-aspartate (tNAA), total creatine (tCr), myo-inositol (mIns), total-choline (tCho), and glutamate + glutamine (Glx). Neurometabolites may be associated with clinical disability with evidence that baseline neuroaxonal integrity is associated with upper limb function and processing speed in secondary progressive MS (SPMS). PURPOSE: To assess the effect on neurometabolites from three candidate drugs after 96-weeks as seen by 1 H-MRS and their association with clinical disability in SPMS. STUDY-TYPE: Longitudinal. POPULATION: 108 participants with SPMS randomized to receive neuroprotective drugs amiloride [mean age 55.4 (SD 7.4), 61% female], fluoxetine [55.6 (6.6), 71%], riluzole [54.6 (6.3), 68%], or placebo [54.8 (7.9), 67%]. FIELD STRENGTH/SEQUENCE: 3-Tesla. Chemical-shift-imaging 2D-point-resolved-spectroscopy (PRESS), 3DT1. ASSESSMENT: Brain metabolites in normal appearing white matter (NAWM) and gray matter (GM), brain volume, lesion load, nine-hole peg test (9HPT), and paced auditory serial addition test were measured at baseline and at 96-weeks. STATISTICAL TESTS: Paired t-test was used to analyze metabolite changes in the placebo arm over 96-weeks. Metabolite differences between treatment arms and placebo; and associations between baseline metabolites and upper limb function/information processing speed at 96-weeks assessed using multiple linear regression models. P-value<0.05 was considered statistically significant. RESULTS: In the placebo arm, tCho increased in GM (mean difference = -0.32 IU) but decreased in NAWM (mean difference = 0.13 IU). Compared to placebo, in the fluoxetine arm, mIns/tCr was lower (ß = -0.21); in the riluzole arm, GM Glx (ß = -0.25) and Glx/tCr (ß = -0.29) were reduced. Baseline tNAA(ß = 0.22) and tNAA/tCr (ß = 0.23) in NAWM were associated with 9HPT scores at 96-weeks. DATA CONCLUSION: 1 H-MRS demonstrated altered membrane turnover over 96-weeks in the placebo group. It also distinguished changes in neuro-metabolites related to gliosis and glutaminergic transmission, due to fluoxetine and riluzole, respectively. Data show tNAA is a potential marker for upper limb function. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 4.

Indoor Airborne Microbiome and Endotoxin: Meteorological Events and Occupant Characteristics Are Important Determinants.

Airborne bacteria and endotoxin may affect asthma and allergies. However, there is limited understanding of the environmental determinants that influence them. This study investigated the airborne microbiomes in the homes of 1038 participants from five cities in Northern Europe: Aarhus, Bergen, Reykjavik, Tartu, and Uppsala. Airborne dust particles were sampled with electrostatic dust fall collectors (EDCs) from the participants' bedrooms. The dust washed from the EDCs' clothes was used to extract DNA and endotoxin. The DNA extracts were used for quantitative polymerase chain (qPCR) measurement and 16S rRNA gene sequencing, while endotoxin was measured using the kinetic chromogenic limulus amoebocyte lysate (LAL) assay. The results showed that households in Tartu and Aarhus had a higher bacterial load and diversity than those in Bergen and Reykjavik, possibly due to elevated concentrations of outdoor bacterial taxa associated with low precipitation and high wind speeds. Bergen-Tartu had the highest difference (ANOSIM R = 0.203) in ß diversity. Multivariate regression models showed that α diversity indices and bacterial and endotoxin loads were positively associated with the occupants' age, number of occupants, cleaning frequency, presence of dogs, and age of the house. Further studies are needed to understand how meteorological factors influence the indoor bacterial community in light of climate change.

A daily temperature rhythm in the human brain predicts survival after brain injury.

Patients undergo interventions to achieve a 'normal' brain temperature; a parameter that remains undefined for humans. The profound sensitivity of neuronal function to temperature implies the brain should be isothermal, but observations from patients and non-human primates suggest significant spatiotemporal variation. We aimed to determine the clinical relevance of brain temperature in patients by establishing how much it varies in healthy adults. We retrospectively screened data for all patients recruited to the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) High Resolution Intensive Care Unit Sub-Study. Only patients with direct brain temperature measurements and without targeted temperature management were included. To interpret patient analyses, we prospectively recruited 40 healthy adults (20 males, 20 females, 20-40 years) for brain thermometry using magnetic resonance spectroscopy. Participants were scanned in the morning, afternoon, and late evening of a single day. In patients (n = 114), brain temperature ranged from 32.6 to 42.3°C and mean brain temperature (38.5 ± 0.8°C) exceeded body temperature (37.5 ± 0.5°C, P < 0.0001). Of 100 patients eligible for brain temperature rhythm analysis, 25 displayed a daily rhythm, and the brain temperature range decreased in older patients (P = 0.018). In healthy participants, brain temperature ranged from 36.1 to 40.9°C; mean brain temperature (38.5 ± 0.4°C) exceeded oral temperature (36.0 ± 0.5°C) and was 0.36°C higher in luteal females relative to follicular females and males (P = 0.0006 and P < 0.0001, respectively). Temperature increased with age, most notably in deep brain regions (0.6°C over 20 years, P = 0.0002), and varied spatially by 2.41 ± 0.46°C with highest temperatures in the thalamus. Brain temperature varied by time of day, especially in deep regions (0.86°C, P = 0.0001), and was lowest at night. From the healthy data we built HEATWAVE-a 4D map of human brain temperature. Testing the clinical relevance of HEATWAVE in patients, we found that lack of a daily brain temperature rhythm increased the odds of death in intensive care 21-fold (P = 0.016), whilst absolute temperature maxima or minima did not predict outcome. A warmer mean brain temperature was associated with survival (P = 0.035), however, and ageing by 10 years increased the odds of death 11-fold (P = 0.0002). Human brain temperature is higher and varies more than previously assumed-by age, sex, menstrual cycle, brain region, and time of day. This has major implications for temperature monitoring and management, with daily brain temperature rhythmicity emerging as one of the strongest single predictors of survival after brain injury. We conclude that daily rhythmic brain temperature variation-not absolute brain temperature-is one way in which human brain physiology may be distinguished from pathophysiology.

A National Survey of United States-Based Endocrinologists Who Prescribe Gender-Affirming Hormone Therapy.

OBJECTIVE: The World Professional Association for Transgender Health Standards of Care Version 7 recommended that before initiating gender-affirming hormone therapy (GAHT), patients should seek a psychosocial evaluation from a mental health professional documenting a diagnosis of persistent gender dysphoria. The Endocrine Society published guidelines in 2017 recommending against an obligatory psychosocial evaluation, which was affirmed in the recently published World Professional Association for Transgender Health Standards of Care Version 8 from 2022. Little is known about how endocrinologists ensure appropriate psychosocial assessment for their patients. This study assessed the protocols and characteristics of U.S.-based adult endocrinology clinics that prescribe GAHT. METHODS: An anonymous electronic survey sent to members of a professional organization and the "Endocrinologists" Facebook group was responded by 91 practicing board-certified adult endocrinologists who prescribe GAHT. RESULTS: Thirty-one states were represented by the respondents. Overall, 83.1% of GAHT-prescribing endocrinologists reported accepting Medicaid. They reported working in university practices (28.4%), community practices (22.7%), private practices (27.3%), and other practice settings (21.6%). Overall, 42.9% of the respondents reported that their practice required documentation of a psychosocial evaluation from a mental health professional before initiating GAHT. CONCLUSION: Endocrinologists who prescribe GAHT are divided about requiring a baseline psychosocial evaluation before prescribing GAHT. Further work is needed to understand the impact of psychosocial assessment on patient care and facilitate the uptake of new guidelines into clinical practice.

A mutation inactivating the distal SF1 binding site on the human anti-Müllerian hormone promoter causes persistent Müllerian duct syndrome.

The persistent Müllerian duct syndrome (PMDS) is a 46,XY disorder of sexual development characterized by the persistence of Müllerian duct derivatives, uterus and tubes, in otherwise normally masculinized males. The condition, transmitted as a recessive autosomal trait, is usually due to mutations in either the anti-Müllerian hormone (AMH) gene or its main receptor. Many variants of these genes have been described, all targeting the coding sequences. We report the first case of PMDS due to a regulatory mutation. The AMH promoter contains two binding sites for steroidogenic factor 1 (SF1), one at -102 and the other at -228. Our patient carries a single base deletion at -225, significantly decreasing its capacity for binding SF1, as measured by the electrophoresis mobility shift assay. Furthermore, by linking the AMH promoter to the luciferase gene, we show that the transactivation capacity of the promoter is significantly decreased by the mutation, in contrast to the disruption of the -102 binding site. To explain the difference in impact we hypothesize that SF1 could partially overcome the lack of binding to the -102 binding site by interacting with a GATA4 molecule linked to a nearby response element. We show that disruption of both the -102 SF1 and the -84 GATA response elements significantly decreases the transactivation capacity of the promoter. In conclusion, we suggest that the distance between mutated SF1 sites and potentially rescuing GATA binding motifs might play a role in the development of PMDS.

Effect of salinity on cable bacteria species composition and diversity.

Cable bacteria (CB) are Desulfobulbaceae that couple sulphide oxidation to oxygen reduction over centimetre distances by mediating electric currents. Recently, it was suggested that the CB clade is composed of two genera, Ca. Electronema and Ca. Electrothrix, with distinct freshwater and marine habitats respectively. However, only a few studies have reported CB from freshwater sediment, making this distinction uncertain. Here, we report novel data to show that salinity is a controlling factor for the diversity and the species composition within CB populations. CB sampled from a freshwater site (salinity 0.3) grouped into Ca. Electronema and could not grow under brackish conditions (salinity 21), whereas CB from a brackish site (salinity 21) grouped into Ca. Electrothrix and decreased by 93% in activity under freshwater conditions. On a regional scale (Baltic Sea), salinity significantly influenced species richness and composition. However, other environmental factors, such as temperature and quantity and quality of organic matter were also important to explain the observed variation. A global survey of 16S rRNA gene amplicon sequencing revealed that the two genera did not co-occur likely because of competitive exclusion and identified a possible third genus.

Sources of systematic error in DCE-MRI estimation of low-level blood-brain barrier leakage.

PURPOSE: Dynamic contrast-enhanced (DCE) -MRI with Patlak model analysis is increasingly used to quantify low-level blood-brain barrier (BBB) leakage in studies of pathophysiology. We aimed to investigate systematic errors due to physiological, experimental, and modeling factors influencing quantification of the permeability-surface area product PS and blood plasma volume vp , and to propose modifications to reduce the errors so that subtle differences in BBB permeability can be accurately measured. METHODS: Simulations were performed to predict the effects of potential sources of systematic error on conventional PS and vp quantification: restricted BBB water exchange, reduced cerebral blood flow, arterial input function (AIF) delay and B1+ error. The impact of targeted modifications to the acquisition and processing were evaluated, including: assumption of fast versus no BBB water exchange, bolus versus slow injection of contrast agent, exclusion of early data from model fitting and B1+ correction. The optimal protocol was applied in a cohort of recent mild ischaemic stroke patients. RESULTS: Simulation results demonstrated substantial systematic errors due to the factors investigated (absolute PS error ≤ 4.48 × 10-4 min-1 ). However, these were reduced (≤0.56 × 10-4 min-1 ) by applying modifications to the acquisition and processing pipeline. Processing modifications also had substantial effects on in-vivo normal-appearing white matter PS estimation (absolute change ≤ 0.45 × 10-4 min-1 ). CONCLUSION: Measuring subtle BBB leakage with DCE-MRI presents unique challenges and is affected by several confounds that should be considered when acquiring or interpreting such data. The evaluated modifications should improve accuracy in studies of neurodegenerative diseases involving subtle BBB breakdown.

Cable bacteria at oxygen-releasing roots of aquatic plants: a widespread and diverse plant-microbe association.

Cable bacteria are sulfide-oxidising, filamentous bacteria that reduce toxic sulfide levels, suppress methane emissions and drive nutrient and carbon cycling in sediments. Recently, cable bacteria have been found associated with roots of aquatic plants and rice (Oryza sativa). However, the extent to which cable bacteria are associated with aquatic plants in nature remains unexplored. Using newly generated and public 16S rRNA gene sequence datasets combined with fluorescence in situ hybridisation, we investigated the distribution of cable bacteria around the roots of aquatic plants, encompassing seagrass (including seagrass seedlings), rice, freshwater and saltmarsh plants. Diverse cable bacteria were found associated with roots of 16 out of 28 plant species and at 36 out of 55 investigated sites, across four continents. Plant-associated cable bacteria were confirmed across a variety of ecosystems, including marine coastal environments, estuaries, freshwater streams, isolated pristine lakes and intensive agricultural systems. This pattern indicates that this plant-microbe relationship is globally widespread and neither obligate nor species specific. The occurrence of cable bacteria in plant rhizospheres may be of general importance to vegetation vitality, primary productivity, coastal restoration practices and greenhouse gas balance of rice fields and wetlands.

Phyllobacterium calauticae sp. nov. isolated from a microaerophilic veil transversed by cable bacteria in freshwater sediment.

Microaerophilic veils of swimming microorganisms form at oxic-anoxic interfaces, mostly described in sediments where sulfide from below meets oxygen diffusing in from the water phase. However, microaerophilic veils form even when these gradients do not overlap, for example when cable bacteria activity leads to a suboxic zone. This suggests that veil microorganisms can use electron donors other than sulfide. Here we describe the extraction of microorganisms from a microaerophilic veil that formed in cable-bacteria-enriched freshwater sediment using a glass capillary, and the subsequent isolation of a motile, microaerophilic, organoheterotrophic bacterium, strain R2-JLT, unable to oxidize sulfide. Based on phenotypic, phylogenetic, and genomic comparison, we propose strain R2-JLT as a novel Phyllobacterium species, P. calauticae sp. nov.. The type strain is R2-JLT (= LMG 32286T = DSM 112555T). This novel isolate confirms that a wider variety of electron donors, including organic compounds, can fuel the activity of microorganisms in microaerophilic veils.

An antimicrobial Staphylococcus sciuri with broad temperature and salt spectrum isolated from the surface of the African social spider, Stegodyphus dumicola.

Some social arthropods engage in mutualistic symbiosis with antimicrobial compound-producing microorganisms that provide protection against pathogens. Social spiders live in communal nests and contain specific endosymbionts with unknown function. Bacteria are also found on the spiders' surface, including prevalent staphylococci, which may have protective potential. Here we present the genomic and phenotypic characterization of strain i1, isolated from the surface of the social spider Stegodyphus dumicola. Phylogenomic analysis identified i1 as novel strain of Staphylococcus sciuri within subgroup 2 of three newly defined genomic subgroups. Further phenotypic investigations showed that S. sciuri i1 is an extremophile that can grow at a broad range of temperatures (4 °C-45 °C), high salt concentrations (up to 27%), and has antimicrobial activity against closely related species. We identified a lactococcin 972-like bacteriocin gene cluster, likely responsible for the antimicrobial activity, and found it conserved in two of the three subgroups of S. sciuri. These features indicate that S. sciuri i1, though not a specific symbiont, is well-adapted to survive on the surface of social spiders and may gain a competitive advantage by inhibiting closely related species.

Relationship Between Venules and Perivascular Spaces in Sporadic Small Vessel Diseases.

Background and Purpose- Perivascular spaces (PVS) around venules may help drain interstitial fluid from the brain. We examined relationships between suspected venules and PVS visible on brain magnetic resonance imaging. Methods- We developed a visual venular quantification method to examine the spatial relationship between venules and PVS. We recruited patients with lacunar stroke or minor nondisabling ischemic stroke and performed brain magnetic resonance imaging and retinal imaging. We quantified venules on gradient echo or susceptibility-weighted imaging and PVS on T2-weighted magnetic resonance imaging in the centrum semiovale and then determined overlap between venules and PVS. We assessed associations between venular count and patient demographic characteristics, vascular risk factors, small vessel disease features, retinal vessels, and venous sinus pulsatility. Results- Among 67 patients (69% men, 69.0±9.8 years), only 4.6% (range, 0%-18%) of venules overlapped with PVS. Total venular count increased with total centrum semiovale PVS count in 55 patients after accounting for venule-PVS overlap (ß=0.468 [95% CI, 0.187-0.750]) and transverse sinus pulsatility (ß=0.547 [95% CI, 0.309-0.786]) and adjusting for age, sex, and systolic blood pressure. Conclusions- Despite increases in both visible PVS and suspected venules, we found minimal spatial overlap between them in patients with sporadic small vessel disease, suggesting that most magnetic resonance imaging-visible centrum semiovale PVS are periarteriolar rather than perivenular.

Sub-seafloor biogeochemical processes and microbial life in the Baltic Sea.

The post-glacial Baltic Sea has experienced extreme changes that are archived today in the deep sediments. IODP Expedition 347 retrieved cores down to 100 m depth and studied the climate history and the deep biosphere. We here review the biogeochemical and microbiological highlights and integrate these with other studies from the Baltic seabed. Cell numbers, endospore abundance and organic matter mineralization rates are extremely high. A 100-fold drop in cell numbers with depth results from a small difference between growth and mortality in the ageing sediment. Evidence for growth derives from a D:L amino acid racemization model, while evidence for mortality derives from the abundance and potential activity of lytic viruses. The deep communities assemble at the bottom of the bioturbated zone from the founding surface community by selection of organisms suited for life under deep sediment conditions. The mean catabolic per-cell rate of microorganisms drops steeply with depth to a life in slow-motion, typical for the deep biosphere. The subsurface life under extreme energy limitation is facilitated by exploitation of recalcitrant substrates, by biochemical protection of nucleic acids and proteins and by repair mechanisms for random mismatches in DNA or damaged amino acids in proteins.

Model-based super-resolution reconstruction of T2 maps.

PURPOSE: High-resolution isotropic T2 mapping of the human brain with multi-echo spin-echo (MESE) acquisitions is challenging. When using a 2D sequence, the resolution is limited by the slice thickness. If used as a 3D acquisition, specific absorption rate limits are easily exceeded due to the high power deposition of nonselective refocusing pulses. A method to reconstruct 1-mm3 isotropic T2 maps is proposed based on multiple 2D MESE acquisitions. Data were undersampled (10-fold) to compensate for the prolonged scan time stemming from the super-resolution acquisition. THEORY AND METHODS: The proposed method integrates a classical super-resolution with an iterative model-based approach to reconstruct quantitative maps from a set of undersampled low-resolution data. The method was tested on numerical and multipurpose phantoms, and in vivo data. T2 values were assessed with a region-of-interest analysis using a single-slice spin-echo and a fully sampled MESE acquisition in a phantom, and a MESE acquisition in healthy volunteers. RESULTS: Numerical simulations showed that the best trade-off between acceleration and number of low-resolution datasets is 10-fold acceleration with 4 acquisitions (acquisition time = 18 min). The proposed approach showed improved resolution over low-resolution images for both phantom and brain. Region-of-interest analysis of the phantom compartments revealed that at shorter T2 , the proposed method was comparable with the fully sampled MESE. For the volunteer data, the T2 values found in the brain structures were consistent across subjects (8.5-13.1 ms standard deviation). CONCLUSION: The proposed method addresses the inherent limitations associated with high-resolution T2 mapping and enables the reconstruction of 1 mm3 isotropic relaxation maps with a 10 times faster acquisition.

Bacterial Respiration Used as a Proxy to Evaluate the Bacterial Load in Cooling Towers.

Evaporative cooling towers to dissipate excess process heat are essential installations in a variety of industries. The constantly moist environment enables substantial microbial growth, causing both operative challenges (e.g., biocorrosion) as well as health risks due to the potential aerosolization of pathogens. Currently, bacterial levels are monitored using rather slow and infrequent sampling and cultivation approaches. In this study, we describe the use of metabolic activity, namely oxygen respiration, as an alternative measure of bacterial load within cooling tower waters. This method is based on optical oxygen sensors that enable an accurate measurement of oxygen consumption within a closed volume. We show that oxygen consumption correlates with currently used cultivation-based methods (R2 = 0.9648). The limit of detection (LOD) for respiration-based bacterial quantification was found to be equal to 1.16 × 104 colony forming units (CFU)/mL. Contrary to the cultivation method, this approach enables faster assessment of the bacterial load with a measurement time of just 30 min compared to 48 h needed for cultivation-based measurements. Furthermore, this approach has the potential to be integrated and automated. Therefore, this method could contribute to more robust and reliable monitoring of bacterial contamination within cooling towers and subsequently increase operational stability and reduce health risks.

Management of congenital adrenal hyperplasia: beyond conventional glucocorticoid therapy.

PURPOSE OF REVIEW: The most common enzyme defect associated with congenital adrenal hyperplasia (CAH) is 21-hydroxylase deficiency (21OHD). Glucocorticoid therapy aiming to suppress adrenocorticotrophic hormone (ACTH)-mediated hyperandrogenemia and to replace glucocorticoid deficiency, if indicated, remains the first line of management in CAH with or without mineralocorticoid replacement therapy and salt supplementation. We review interventions that may address unmet needs in the management of CAH. Although the objective of this review is to highlight some potential benefits of supplemental therapies, the authors do not recommend for or against the use of the reviewed therapies. In the review, the terms 'male' and 'female' refer to 'genetic male (46,XY)' and 'genetic female (46,XX)' respectively. RECENT FINDINGS: Supplemental therapies, some of which appear to be promising, attempt to address CAH-associated morbidity but long-term efficacy and safety data are still lacking. SUMMARY: We highlight main ideas behind the use of interventions that target an improvement in physiological glucocorticoid replacement, adult height outcome, and management of female genital virilization in CAH.

MRI Relaxometry for Quantitative Analysis of USPIO Uptake in Cerebral Small Vessel Disease.

A protocol for evaluating ultrasmall superparamagnetic particles of iron oxide (USPIO) uptake and elimination in cerebral small vessel disease patients was developed and piloted. B1-insensitive R1 measurement was evaluated in vitro. Twelve participants with history of minor stroke were scanned at 3-T MRI including structural imaging, and R1 and R2* mapping. Participants were scanned (i) before and (ii) after USPIO (ferumoxytol) infusion, and again at (iii) 24⁻30 h and (iv) one month. Absolute and blood-normalised changes in R1 and R2* were measured in white matter (WM), deep grey matter (GM), white matter hyperintensity (WMH) and stroke lesion regions. R1 measurements were accurate across a wide range of values. R1 (p < 0.05) and R2* (p < 0.01) mapping detected increases in relaxation rate in all tissues immediately post-USPIO and at 24⁻30 h. R2* returned to baseline at one month. Blood-normalised R1 and R2* changes post-infusion and at 24⁻30 h were similar, and were greater in GM versus WM (p < 0.001). Narrower distributions were seen with R2* than for R1 mapping. R1 and R2* changes were correlated at 24⁻30 h (p < 0.01). MRI relaxometry permits quantitative evaluation of USPIO uptake; R2* appears to be more sensitive to USPIO than R1. Our data are explained by intravascular uptake alone, yielding estimates of cerebral blood volume, and did not support parenchymal uptake. Ferumoxytol appears to be eliminated at 1 month. The approach should be valuable in future studies to quantify both blood-pool USPIO and parenchymal uptake associated with inflammatory cells or blood-brain barrier leak.

Intracranial pulsatility in patients with cerebral small vessel disease: a systematic review.

Growing evidence suggests that increased intracranial pulsatility is associated with cerebral small vessel disease (SVD). We systematically reviewed papers that assessed intracranial pulsatility in subjects with SVD. We included 27 cross-sectional studies (n=3356): 20 used Doppler ultrasound and 7 used phase-contrast MRI. Most studies measured pulsatility in the internal carotid or middle cerebral arteries (ICA, MCA), whereas few assessed veins or cerebrospinal fluid (CSF). Methods to reduce bias and risk factor adjustment were poorly reported. Substantial variation between studies in assessment of SVD and of pulsatility indices precluded a formal meta-analysis. Eight studies compared pulsatility by SVD severity (n=26-159, median = 74.5): arterial pulsatility index was generally higher in more severe SVD (e.g. MCA: standardized mean difference = 3.24, 95% confidence interval [2.40, 4.07]), although most did not match for age. Seventeen studies (n=9-700; median = 110) performed regression or correlation analysis, of which most showed that increased pulsatility was associated with SVD after adjustment for age. In conclusion, most studies support a cross-sectional association between higher pulsatility in large intracranial arteries and SVD. Future studies should minimize bias, adjust for potential confounders, include pulsatility in veins and CSF, and examine longitudinal relationship between pulsatility and SVD. Agreement on reliable measures of intracranial pulsatility would be helpful.

AMP-activated Protein Kinase Deficiency Blocks the Hypoxic Ventilatory Response and Thus Precipitates Hypoventilation and Apnea.

RATIONALE: Modulation of breathing by hypoxia accommodates variations in oxygen demand and supply during, for example, sleep and ascent to altitude, but the precise molecular mechanisms of this phenomenon remain controversial. Among the genes influenced by natural selection in high-altitude populations is one for the adenosine monophosphate-activated protein kinase (AMPK) α1-catalytic subunit, which governs cell-autonomous adaptations during metabolic stress. OBJECTIVES: We investigated whether AMPK-α1 and/or AMPK-α2 are required for the hypoxic ventilatory response and the mechanism of ventilatory dysfunctions arising from AMPK deficiency. METHODS: We used plethysmography, electrophysiology, functional magnetic resonance imaging, and immediate early gene (c-fos) expression to assess the hypoxic ventilatory response of mice with conditional deletion of the AMPK-α1 and/or AMPK-α2 genes in catecholaminergic cells, which compose the hypoxia-responsive respiratory network from carotid body to brainstem. MEASUREMENTS AND MAIN RESULTS: AMPK-α1 and AMPK-α2 deletion virtually abolished the hypoxic ventilatory response, and ventilatory depression during hypoxia was exacerbated under anesthesia. Rather than hyperventilating, mice lacking AMPK-α1 and AMPK-α2 exhibited hypoventilation and apnea during hypoxia, with the primary precipitant being loss of AMPK-α1 expression. However, the carotid bodies of AMPK-knockout mice remained exquisitely sensitive to hypoxia, contrary to the view that the hypoxic ventilatory response is determined solely by increased carotid body afferent input to the brainstem. Regardless, functional magnetic resonance imaging and c-fos expression revealed reduced activation by hypoxia of well-defined dorsal and ventral brainstem nuclei. CONCLUSIONS: AMPK is required to coordinate the activation by hypoxia of brainstem respiratory networks, and deficiencies in AMPK expression precipitate hypoventilation and apnea, even when carotid body afferent input is normal.