Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange ...between injected 1-13Cpyruvate and the endogenous tumor lactate pool. Treatment-naïve breast cancer patients were recruited: four triple-negative grade 3 cancers; two invasive ductal carcinomas that were estrogen and progesterone receptor-positive (ER/PR+) and HER2/neu-negative (HER2−), one grade 2 and one grade 3; and one grade 2 ER/PR+ HER2− invasive lobular carcinoma (ILC). Dynamic 13C MRSI was performed following injection of hyperpolarized 1-13Cpyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13C label exchange between pyruvate and lactate, hypoxia-inducible factor-1 (HIF1α), and the monocarboxylate transporters MCT1 and MCT4 were quantified using immunohistochemistry and RNA sequencing. We have demonstrated the feasibility and safety of hyperpolarized 13C MRI in early breast cancer. Both intertumoral and intratumoral heterogeneity of the hyperpolarized pyruvate and lactate signals were observed. The lactate-to-pyruvate signal ratio (LAC/PYR) ranged from 0.021 to 0.473 across the tumor subtypes (mean ± SD: 0.145 ± 0.164), and a lactate signal was observed in all of the grade 3 tumors. The LAC/PYR was significantly correlated with tumor volume (R = 0.903, P = 0.005) and MCT 1 (R = 0.85, P = 0.032) and HIF1α expression (R = 0.83, P = 0.043). Imaging of hyperpolarized 1-13Cpyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia.
Decreased but Diverse Activity of Cortical and Thalamic Neurons in Consciousness-Impairing Rodent Absence Seizures
McCafferty C, Gruenbaum BF, Tung R, Li JJ, Zheng X, Salvino P, Vincent P, Kratochvil ...Z, Ryu JH, Khalaf A, Swift K, Akbari R, Islam W, Antwi P, Johnson EA, Vitkovskiy P, Sampognaro J, Freedman IG, Kundishora A, Depaulis A, David F, Crunelli V, Sanganahalli BG, Herman P, Hyder F, Blumenfeld H. Nat Commun. 2023;14(1):117. doi:10.1038/s41467-022-35535-4
Absence seizures are brief episodes of impaired consciousness, behavioral arrest, and unresponsiveness, with yet-unknown neuronal mechanisms. Here we report that an awake female rat model recapitulates the behavioral, electroencephalographic, and cortical functional magnetic resonance imaging characteristics of human absence seizures. Neuronally, seizures feature overall decreased but rhythmic firing of neurons in cortex and thalamus. Individual cortical and thalamic neurons express one of four distinct patterns of seizure-associated activity, one of which causes a transient initial peak in overall firing at seizure onset, and another which drives sustained decreases in overall firing. 40-60 s before seizure onset there begins a decline in low frequency electroencephalographic activity, neuronal firing, and behavior, but an increase in higher frequency electroencephalography and rhythmicity of neuronal firing. Our findings demonstrate that prolonged brain state changes precede consciousness-impairing seizures, and that during seizures distinct functional groups of cortical and thalamic neurons produce an overall transient firing increase followed by a sustained firing decrease, and increased rhythmicity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Hyperpolarised magnetic resonance imaging (HP
13
C-MRI) is an emerging clinical technique to detect 1-
13
Clactate production in prostate cancer (PCa) following intravenous injection of ...hyperpolarised 1-
13
Cpyruvate. Here we differentiate clinically significant PCa from indolent disease in a low/intermediate-risk population by correlating 1-
13
Clactate labelling on MRI with the percentage of Gleason pattern 4 (%GP4) disease. Using immunohistochemistry and spatial transcriptomics, we show that HP
13
C-MRI predominantly measures metabolism in the epithelial compartment of the tumour, rather than the stroma. MRI-derived tumour 1-
13
Clactate labelling correlated with epithelial mRNA expression of the enzyme lactate dehydrogenase (LDHA and LDHB combined), and the ratio of lactate transporter expression between the epithelial and stromal compartments (epithelium-to-stroma MCT4). We observe similar changes in MCT4, LDHA, and LDHB between tumours with primary Gleason patterns 3 and 4 in an independent TCGA cohort. Therefore, HP
13
C-MRI can metabolically phenotype clinically significant disease based on underlying metabolic differences in the epithelial and stromal tumour compartments.
Hyperpolarized 13C Magnetic Resonance Imaging (13C-MRI) provides a highly sensitive tool to probe tissue metabolism in vivo and has recently been translated into clinical studies. We report the ...cerebral metabolism of intravenously injected hyperpolarized 1–13Cpyruvate in the brain of healthy human volunteers for the first time. Dynamic acquisition of 13C images demonstrated 13C-labeling of both lactate and bicarbonate, catalyzed by cytosolic lactate dehydrogenase and mitochondrial pyruvate dehydrogenase respectively. This demonstrates that both enzymes can be probed in vivo in the presence of an intact blood-brain barrier: the measured apparent exchange rate constant (kPL) for exchange of the hyperpolarized 13C label between 1–13Cpyruvate and the endogenous lactate pool was 0.012 ± 0.006 s−1 and the apparent rate constant (kPB) for the irreversible flux of 1–13Cpyruvate to 13Cbicarbonate was 0.002 ± 0.002 s−1. Imaging also revealed that 1–13Cpyruvate, 1–13Clactate and 13Cbicarbonate were significantly higher in gray matter compared to white matter. Imaging normal brain metabolism with hyperpolarized 1–13Cpyruvate and subsequent quantification, have important implications for interpreting pathological cerebral metabolism in future studies.
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Gain-of-Function and Loss-of-Function GABRB3 Variants Lead to Distinct Clinical Phenotypes in Patients With Developmental and Epileptic Encephalopathies
Absalom NL, Liao VW, Johannesen KM, Gardella ...E, Jacobs J, Lesca G, Gokce-Samar Z, Arzimanoglou A, Zeidler S, Striano P, Meyer P, Benkel-Herrenbrueck I, Mero I-L, Rummel J, Chebib M, Møller RS, Ahring PK. Nat Commun. 2022;13(1):1822. doi:10.1038/s41467-022-29280-x
Many patients with developmental and epileptic encephalopathies present with variants in genes coding for GABAA receptors. These variants are presumed to cause loss-of-function receptors leading to reduced neuronal GABAergic activity. Yet, patients with GABAA receptor variants have diverse clinical phenotypes and many are refractory to treatment despite the availability of drugs that enhance GABAergic activity. Here we show that 44 pathogenic GABRB3 missense variants segregate into gain-of-function and loss-of-function groups and respective patients display distinct clinical phenotypes. The gain-of-function cohort (n = 27 patients) presented with a younger age of seizure onset, higher risk of severe intellectual disability, focal seizures at onset, hypotonia, and lower likelihood of seizure freedom in response to treatment. Febrile seizures at onset are exclusive to the loss-of-function cohort (n = 47 patients). Overall, patients with GABRB3 variants that increase GABAergic activity have more severe developmental and epileptic encephalopathies. This paradoxical finding challenges our current understanding of the GABAergic system in epilepsy and how patients should be treated.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Aberrant Neuronal Connectivity in the Cortex Drives Generation of Seizures in Rat Absence Epilepsy
Studer F, Jarre G, Pouyatos B, et al. Brain 2022;145(6):1978-1991. doi:10.1093/brain/awab438.
...Absence epilepsy belongs to genetic epilepsies and is characterized by recurrent generalized seizures that are concomitant with alterations of consciousness and associated with cognitive comorbidities. Little is known about the mechanisms leading to occurrence of epileptic seizures (i.e., epileptogenesis) and, in particular, it remains an open question whether neuronal hypersynchronization, a key feature in seizure initiation, could result from aberrant structural connectivity within neuronal networks endowing them with epileptic properties. In the present study, we addressed this question using a genetic model of absence epilepsy in the rat where seizures initiate in the whisker primary somatosensory cortex. We hypothesized that alterations in structural connectivity of neuronal networks within wS1 contribute to pathological neuronal synchronization responsible for seizures. First, we used rabies virus-mediated retrograde synaptic tracing and evidenced that cortical neurons located in both upper- and deep-layers of whisker primary somatosensory cortex displayed aberrant and significantly increased connectivity the genetic model of absence epilepsy, as highlighted by a higher number of presynaptic partners. Next, we showed at the functional level that disrupting these aberrant whisker primary somatosensory cortex neuronal networks with synchrotron X-ray-mediated cortical microtransections drastically decreased both whisker primary somatosensory cortex neuron synchronization and seizure power, as revealed by in vivo local field potential recordings with multichannel probes. Taken together, our data provide for the first time strong evidence that increased structural connectivity patterns of cortical neurons represent critical pathological substrates for increased neuronal synchronization and generation of absence seizures.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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•Different generalized tonic clonic seizure (GTCS) subtypes occur in various genetic generalized epilepsy syndromes and in individual patients.•At onset, GTCS subtypes activate ...similar brain regions but differ in long-range connectivity.•GTCS evolution to tonic-start epoch associates with reduced long-range connectivity, particularly at δ/θ frequencies.
To determine EEG spatiospectral activation and connectivity in the generalized tonic-clonic seizure (GTCS) semiological subtypes.
39 patients with genetic generalized epilepsy (GGE) who had GTCS (n = 58) during video-EEG monitoring were identified in the Vanderbilt Epilepsy database. GTCSs were classified as absence tonic-clonic, myoclonic tonic-clonic, or tonic-clonic. Patient characteristics and semiological features were compared. Spectral power and node degree, a network measure of connectivity, were calculated at two seizure epochs, electrographic and tonic-start.
Different GTCS subtypes occurred within individual patients. At electrographic-onset, all subtypes activated midline frontal cortex at delta/theta and beta frequencies but differed in network connectivity. In all subtypes, GTCS evolution from electrographic to tonic-start associated with preserved beta frequency spectral power, but reduced connectivity and delta/theta power.
Our findings suggest that at GTCS onset, the subtypes activate similar cortical regions and their different initial semiologies relate to their distinct onset long-range connectivity. Upon transition to the tonic-start epoch, the ictal activity is predominantly conveyed by β frequency activity and connectivity.
Future neurostimulation therapies for medically intractable GTCSs may target the same brain regions for all GTCS subtypes and may be most effective prior to the tonic-start epoch.
Ethiopia is a developing sub-Saharan African country with increasing prevalence of non-communicable diseases (NCDs), including oral conditions. Oral health and dental care have been given little ...consideration, and there is limited information relating to population oral health and use of dental services in the country. The aim of this study was to examine the burden and associated factors of dental caries experience and investigate access to dental care amongst adults within Ethiopia.
This community-based oral health survey is a baseline study for the ASSET - Health System Strengthening in sub-Saharan Africa project undertaken in the Butajira area, south-central Ethiopia. A stratified random sample of households and individuals participated in the study. The survey instruments were mainly based on the WHO Oral Health Survey Methods manual (5
ed.). Face-to-face interviews and clinical dental examinations were conducted. The data were analysed for descriptive statistics; and Poisson regression models were built to assess the association of dental caries and predictor variables in adults (≥18 years).
Most of the study population (n = 626) were female (63.9%), married (71.4%) and Muslim (76.0%). Just over half (53.2%) lived in rural areas and many (44.4%) had no formal education. A majority (74.0%) reported never utilising dental care services, and the main reason was never experiencing any dental problem (71.3%). Sixty percent (n = 377) of the adults had experienced dental caries, 88.0% (n = 332) of whom had untreated carious teeth. Pain or discomfort was reported by 16.5, and 7.2% had one or more PUFA component. Most (59.9%) adults with dental caries experience reported tooth pain or discomfort during the last year. In the fully adjusted Poisson regression model, increasing age, dental care utilisation and Khat chewing had positive significant associations with dental caries experience, whilst education status was negatively associated (p < 0.05).
This study demonstrated a high burden of dental caries and considerable consequences resulting from untreated disease in this population of adults. There was evidence of social inequity, limited utilisation of dental care and oral health awareness. This highlights the need for oral health system strengthening focusing on health promotion and expanding overall access to care.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract While epidemiological data suggest a female prevalence in human childhood- and adolescence-onset typical absence epilepsy syndromes, the sex difference is less clear in adult-onset ...syndromes. In addition, although there are more females than males diagnosed with typical absence epilepsy syndromes, there is a paucity of studies on sex differences in seizure frequency and semiology in patients diagnosed with any absence epilepsy syndrome. Moreover, it is unknown if there are sex differences in the prevalence or expression of atypical absence epilepsy syndromes. Surprisingly, most studies of animal models of absence epilepsy either did not investigate sex differences, or failed to find sex-dependent effects. However, various rodent models for atypical syndromes such as the AY9944 model (prepubertal females show a higher incidence than prepubertal males), BN model (also with a higher prevalence in males) and the Gabra1 deletion mouse in the C57BL/6J strain offer unique possibilities for the investigation of the mechanisms involved in sex differences. Although the mechanistic bases for the sex differences in humans or these three models are not yet known, studies of the effects of sex hormones on seizures have offered some possibilities. The sex hormones progesterone, estradiol and testosterone exert diametrically opposite effects in genetic absence epilepsy and pharmacologically-evoked convulsive types of epilepsy models. In addition, acute pharmacological effects of progesterone on absence seizures during proestrus are opposite to those seen during pregnancy. 17β-Estradiol has anti-absence seizure effects, but it is only active in atypical absence models. It is speculated that the pro-absence action of progesterone, and perhaps also the delayed pro-absence action of testosterone, are mediated through the neurosteroid allopregnanolone and its structural and functional homolog, androstanediol. These two steroids increase extrasynaptic thalamic tonic GABAergic inhibition by selectively targeting neurosteroid-selective subunits of GABAA receptors (GABAA Rs). Neurosteroids also modulate the expression of GABAA R containing the γ2, α4, and δ subunits. It is hypothesized that differences in subunit expression during pregnancy and ovarian cycle contribute to the opposite effects of progesterone in these two hormonal states.
Denosumab treatment for 3 years significantly reduced the incidence of new vertebral and hip fractures in women at higher risk for experiencing these fractures.
Context:
The FREEDOM (Fracture ...REduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial showed denosumab significantly reduced the risk of fractures in postmenopausal women with osteoporosis.
Objective:
We evaluated the effect of denosumab on the incidence of new vertebral and hip fractures in subgroups of women at higher risk for these fractures.
Design:
FREEDOM was a 3-yr, randomized, double-blind, placebo-controlled, phase 3 trial.
Participants and Setting:
Postmenopausal women (N = 7808) with osteoporosis were enrolled at 213 study sites worldwide.
Interventions:
Subjects received sc denosumab (60 mg) or placebo every 6 months and daily supplements of calcium (≥1000 mg) and vitamin D (≥400 IU).
Main Outcome Measures:
This post hoc analysis evaluated fracture incidence in women with known risk factors for fractures including multiple and/or moderate or severe prevalent vertebral fractures, aged 75 yr or older, and/or femoral neck bone mineral density T-score of −2.5 or less.
Results:
Compared with placebo, denosumab significantly reduced the risk of new vertebral fractures in women with multiple and/or severe prevalent vertebral fractures (16.6% placebo vs. 7.5% denosumab; P < 0.001). Similarly, denosumab significantly reduced the risk of hip fractures in subjects aged 75 yr or older (2.3% placebo vs. 0.9% denosumab; P < 0.01) or with a baseline femoral neck bone mineral density T-score of −2.5 or less (2.8% placebo vs. 1.4% denosumab; P = 0.02). These risk reductions in higher-risk individuals were consistent with those seen in patients at lower risk of fracture.
Conclusions:
Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at higher risk for fracture. These results highlight the consistent antifracture efficacy of denosumab in patients with varying degrees of fracture risk.
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