Marksjohannsen1789

arch and what we can anticipate in the future concerning new indications, improved/novel target selection and stimulation paradigms, closed-loop technology, and a better understanding of the mechanisms of action of DBS.

This overview of past and present DBS-related studies provides insight into the status of DBS research and what we can anticipate in the future concerning new indications, improved/novel target selection and stimulation paradigms, closed-loop technology, and a better understanding of the mechanisms of action of DBS.

The aim of the present study was to evaluate fetal umbilical artery (UA) and middle cerebral artery (MCA) blood flow in patients with gestational diabetes (GD), in order to determine whether minimal anomalies of glucose metabolism may influence fetal placental function.

UA and MCA flows were prospectively measured by transabdominal ultrasound in singleton pregnancies between 34 and 37 weeks of gestation.

The study included 35 women with GD and 217 nondiabetic patients. Middle cerebral pulsatility index (PI) was significantly higher in the GD group (mean MCA-PI = 1.82 ± 0.27 vs. 1.71 ± 0.26; p < 0.02). Likewise, MCA peak systolic velocity (MCA-PSV) was higher in the GD group compared to the non-GD group, though the difference was not significant (mean of MCA-PSV = 47.14 ± 8.45 vs. 47.09 ± 11.21; p = 0.98). UA-PI resulted higher in the non-GD group without significant differences (mean of UA-PI = 0.88 ± 0.14 vs. 0.86 ± 0.15; p = 0.32).

Our study shows that even in cases of minimal metabolic derangements, GD is characterized by a significant variation in fetal Doppler velocimetry, particularly in the brain.

Our study shows that even in cases of minimal metabolic derangements, GD is characterized by a significant variation in fetal Doppler velocimetry, particularly in the brain.

Chronic cerebral hypoperfusion (CCH) is a clinical syndrome, which is characterized by significantly decreased cerebral blood flow (CBF). CCH is a common consequence of cerebrovascular and cardiovascular diseases and the elderly. CCH results in a series of pathological damages, increasing cell death, autophagy dysfunction, amyloid β (Aβ) peptide accumulation, blood-brain barrier (BBB) disruption, and endothelial damage, which are found in CCH models. In addition, CCH is a prominent risk factor of cognitive impairment, such as vascular dementia, and CCH contributes to the occurrence and development of Alzheimer's disease. Therefore, the treatment of patients with CCH is of great value. It has been confirmed that remote ischemic conditioning (RIC) is a safe, promising treatment for acute and chronic cerebrovascular diseases. RIC significantly increases CBF in both CCH models and patients, inhibits neuronal apoptosis, reduces Aβ deposition, protects BBB integrity and endothelial function, alleviates neuroinflammation, improves cognitive impairment, and exerts neuroprotection.

With the development of animal models, the pathophysiological mechanisms of CCH and RIC are increasingly revealed.

We discuss the mechanisms related to hypoperfusion in the brain and explore the potential treatment of RIC for CCH to promote its transformation and application in humans.

We discuss the mechanisms related to hypoperfusion in the brain and explore the potential treatment of RIC for CCH to promote its transformation and application in humans.

Noninvasive biomarkers that reflect tubular health and allow early recognition of accelerated graft fibrosis development are warranted. Serum uromodulin (sUmod) and urinary epidermal growth factor (uEGF) originate from kidney tubules and may reflect functional nephron mass. The aim of this study was to investigate the associations between sUmod and uEGF with measured glomerular filtration rate (mGFR) and kidney allograft interstitial fibrosis percentage (IF%) score.

sUmod and uEGF measurements, mGFR by iohexol-clearance and kidney allograft biopsies were obtained from kidney transplant recipients (KTRs) included in the Omega-3 fatty acids in Renal Transplantation (ORENTRA) trial at 8 weeks (baseline) and at 1 year after transplantation (end of study). Associations were analyzed with univariable and multivariable linear regression.

Ninety patients at baseline and 48 patients at end of study had complete study variable assessments. uEGF normalized to urinary creatinine (uEGF/Cr) was associated with mGFR both at baseline (standardized β-coefficient [Std. β-coeff] = 0.457 [p = <0.001]) and at end of study (Std. β-coeff = 0.637 [p = <0.001]). sUmod was only associated with mGFR at end of study (Std. β-coeff = 0.443 [p = 0.002]). uEGF/Cr, sUmod, and mGFR were associated with graft IF% score both at baseline (Std. β-coeff = -0.349 [p = 0.001], -0.274 [p = 0.009] and -0.289 [p = 0.006], respectively) and at end of study (Std. β-coeff = -0.365 [p = 0.011], -0.347 [p = 0.016] and -0.405 [p = 0.004], respectively). The results remained largely unchanged in multivariable analysis.

uEGF/Cr and sUmod were associated with mGFR and graft IF% score. Our results indicate a possible role of uEGF/Cr and sUmod in the follow-up of KTRs.

uEGF/Cr and sUmod were associated with mGFR and graft IF% score. Our results indicate a possible role of uEGF/Cr and sUmod in the follow-up of KTRs.

Moyamoya disease is characterized by progressive stenotic changes in the terminal segment of the internal carotid artery and the development of abnormal vascular networks called moyamoya vessels. The objective of this review was to provide a holistic view of the epidemiology, etiology, clinical findings, treatment, and pathogenesis of moyamoya disease. A literature search was performed in PubMed using the term "moyamoya disease," for articles published until 2021.

Artificial intelligence (AI) clustering was used to classify the articles into 5 clusters (1) pathophysiology (23.5%); (2) clinical background (37.3%); (3) imaging (13.2%); (4) treatment (17.3%); and (5) genetics (8.7%). Many articles in the "clinical background" cluster were published from the 1970s. However, in the "treatment" and "genetics" clusters, the articles were published from the 2010s through 2021. In 2011, it was confirmed that a gene called Ringin protein 213 (RNF213) is a susceptibility gene for moyamoya disease. Since then, tremendous progress in genomic, transcriptomic, and epigenetic profiling (e.g., methylation profiling) has resulted in new concepts for classifying moyamoya disease. Our literature survey revealed that the pathogenesis involves aberrations of multiple signaling pathways through genetic mutations and altered gene expression.

We analyzed the content vectors in abstracts using AI, and reviewed the pathophysiology, clinical background, radiological features, treatments, and genetic peculiarity of moyamoya disease.

We analyzed the content vectors in abstracts using AI, and reviewed the pathophysiology, clinical background, radiological features, treatments, and genetic peculiarity of moyamoya disease.Mycobacterium tuberculosis (M. tuberculosis) causes an enormous burden of disease worldwide. As a central aspect of its pathogenesis, M. tuberculosis grows in macrophages, and host and microbe influence each other's metabolism. To define the metabolic impact of M. tuberculosis infection, we performed global metabolic profiling of M. tuberculosis-infected macrophages. M. tuberculosis induced metabolic hallmarks of inflammatory macrophages and a prominent signature of cholesterol metabolism. We found that infected macrophages accumulate cholestenone, a mycobacterial-derived, oxidized derivative of cholesterol. We demonstrated that the accumulation of cholestenone in infected macrophages depended on the M. tuberculosis enzyme 3β-hydroxysteroid dehydrogenase (3β-Hsd) and correlated with pathogen burden. Because cholestenone is not a substantial human metabolite, we hypothesized it might be diagnostic of M. tuberculosis infection in clinical samples. Indeed, in 2 geographically distinct cohorts, sputum cholestenone levels distinguished subjects with tuberculosis (TB) from TB-negative controls who presented with TB-like symptoms. We also found country-specific detection of cholestenone in plasma samples from M. tuberculosis-infected subjects. While cholestenone was previously thought to be an intermediate required for cholesterol degradation by M. tuberculosis, we found that M. tuberculosis can utilize cholesterol for growth without making cholestenone. Thus, the accumulation of cholestenone in clinical samples suggests it has an alternative role in pathogenesis and could be a clinically useful biomarker of TB infection.PD-1 signaling on T cells is the major pathway that limits T cell immunity, but the efficacy of anti-PD-1 therapy has been limited to a small proportion of patients with advanced cancers. We fortuitously observed that anti-PD-1 therapy depends on IL-2 signaling, which raises the possibility that a lack of IL-2 limits anti-PD-1-induced effector T cell expansion. To selectively deliver IL-2 to PD-1+CD8+ tumor-infiltrating lymphocytes (TILs), we engineered a low-affinity IL-2 paired with anti-PD-1 (PD-1-laIL-2), which reduced affinity to peripheral Treg cells but enhanced avidity to PD-1+CD8+ TILs. find more PD-1-laIL-2 exerted better tumor control and lower toxicity than single or mixed treatments. Mechanistically, PD-1-laIL-2 could effectively expand dysfunctional and tumor-specific CD8+ T cells. Furthermore, we discovered that presumably dysfunctional PD-1+TIM3+ TILs are the dominant tumor-specific T cells responding to PD-1-laIL-2. Collectively, these results highlight that PD-1-laIL-2 can target and reactivate tumor-specific TILs for tumor regression as a unique strategy with stronger efficacy and lower toxicity.As the curtain draws on the 5-year term of the JCI editorial board at Johns Hopkins, I am filled with gratitude and would like to extend a warm ayekoo (Ghanaian salutation meaning "well done") to our editors, staff, reviewers, and scientists for supporting the Journal. I am delighted to welcome the next JCI Editor in Chief, Elizabeth McNally - the first woman to lead the JCI since it was founded almost a century ago - and her team from Northwestern University.IL-2 is a pleiotropic cytokine. In this issue of the JCI, Ren et al. report on the development of a low-affinity IL-2 paired with anti-PD-1 (PD-1-laIL-2) that reactivates intratumoral CD8+ T cells, but not CD4+ Treg cells. PD-1-laIL-2 treatment synergized with anti-PD-L1 therapy to overcome tumor resistance to immune checkpoint blockade (ICB) in tumor-bearing mice. Rejection of rechallenged tumors following PD-1-laIL-2 therapy demonstrated the establishment of a potent T cell memory response. Furthermore, PD-1-laIL-2 therapy manifested no obvious toxicity. These findings suggest the potential of PD-1-laIL-2 therapy in treating patients with cancer.Sortilin is a glycoprotein mainly known for its role as a trafficking molecule directing proteins to specific secretory or endocytic compartments of the cell. Its actual contribution to essential hypertension has remained hitherto elusive. Combining top-notch in vivo, ex vivo, and in vitro approaches to clinical investigations, Di Pietro et al. explored the signaling pathway evoked by sortilin in endothelial cells and report on such exploration in this issue of the JCI. The researchers identified circulating sortilin as a biomarker associated with high blood pressure. Mechanistically, they demonstrate that sortilin altered sphingolipid/ceramide homeostasis, initiating a signaling cascade that, from sphingosine-1-phosphate (S1P), leads to the augmented production of reactive oxygen species. Herein, we discuss the main implications of these findings, and we anticipate some of the potential avenues of investigation prompted by this discovery, which could eventually lead to treatments for cardiometabolic disorders.