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1.
Molecules ; 29(17)2024 Sep 04.
Article in English | MEDLINE | ID: mdl-39275047

ABSTRACT

This work presents ab initio calculations for the Kα spectrum of manganese (Z = 25, [Ar]3d54s2), a highly complex system due to the five open orbitals in the 3d shell. The spectrum is composed of the canonical diagram line [1s]→[2p] and shake-off satellite lines [1snl]→[2pnl] (nl∈{2s,2p,3s,3p,3d,4s}), where square brackets denote a hole state. The multiconfiguration Dirac-Hartree-Fock method with the active set approach provides the initial and final atomic wavefunctions. Results are presented as energy eigenvalue spectra for the diagram and satellite transitions. The calculated wavefunctions include over one hundred million configuration state functions and over 280,000 independent transition energies for the seven sets of spectra considered. Shake-off probabilities and Auger transition rates determine satellite intensities. The number of configuration state functions ensures highly-converged wavefunctions. Several measures of convergence demonstrate convergence in the calculated parameters. We obtain convergence of the transition energies in all eight transitions to within 0.06 eV and shake-off probabilities to within 4.5%.

2.
Radiographics ; 44(9): e240006, 2024 09.
Article in English | MEDLINE | ID: mdl-39146204

ABSTRACT

Hepatic sinusoids are highly specialized microcirculatory conduits within the hepatic lobules that facilitate liver functions. The sinusoids can be affected by various disorders, including sinusoidal dilatation, sinusoidal obstruction syndrome (SOS), sinusoidal cellular infiltration, perisinusoidal infiltration, and endothelial neoplasms, such as hemangioendothelioma and angiosarcoma. While these disorders, particularly SOS and neoplasms, can be life threatening, their clinical manifestation is often nonspecific. Patients may present with right upper quadrant pain, jaundice, hepatomegaly, ascites, splenomegaly, and unexplained weight gain, although the exact manifestation depends on the cause, severity, and duration of the disease. Ultimately, invasive tests may be necessary to establish the diagnosis. A comprehensive understanding of imaging manifestations of various sinusoidal disorders contributes to early diagnosis and can help radiologists detect subclinical disease. Additionally, specific imaging features may assist in identifying the cause of the disorder, leading to a more focused and quicker workup. For example, a mosaic pattern of enhancement of the liver parenchyma is suggestive of sinusoidal dilatation; peripheral and patchy reticular hypointensity of the liver parenchyma on hepatobiliary MR images is characteristic of SOS; and associated diffuse multiple hyperintensities on diffusion-weighted images may be specific for malignant sinusoidal cellular infiltration. The authors provide an overview of the pathogenesis, clinical features, and imaging appearances of various hepatic sinusoidal disorders, with a special emphasis on SOS. ©RSNA, 2024 Supplemental material is available for this article.


Subject(s)
Hepatic Veno-Occlusive Disease , Humans , Hepatic Veno-Occlusive Disease/diagnostic imaging , Liver Neoplasms/diagnostic imaging , Diagnosis, Differential
3.
JCEM Case Rep ; 2(7): luae110, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38989269

ABSTRACT

Adrenal cysts are a rare benign adrenal pathology. Although the majority of adrenal cysts are asymptomatic, large cysts may present with debilitating symptoms of mass effect. Surgical adrenalectomy or cyst fenestration has been the primary mode of management for such symptomatic cysts, but these interventions can be associated with excessive morbidity, particularly when considered in the context of benign disease. Here, we present a case of a 34-year-old female with a longstanding, growing, benign left adrenal cyst associated with nonspecific abdominal symptoms. After multidisciplinary discussion, the patient was managed with primary ultrasound/fluoroscopic guided percutaneous sclerotherapy of her adrenal cyst. This technique achieved complete cyst resolution that was durable on 7-month follow-up and was associated with significant improvement of the patient's symptoms. This case illustrates the potential for primary percutaneous sclerotherapy for primary management of benign adrenal cysts.

4.
J Vasc Interv Radiol ; 2024 Jul 22.
Article in English | MEDLINE | ID: mdl-39047934

ABSTRACT

PURPOSE: To evaluate the feasibility of intraoperative neurophysiological monitoring (IONM) during magnetic resonance (MR) imaging-guided ablations and identify strategies to reduce IONM electrode radiofrequency (RF) heating during MR imaging. MATERIALS AND METHODS: Ex vivo experiments with a porcine tissue phantom simulating a typical high RF heating risk IONM setup during an MR imaging-guided ablation procedure on the shoulder were performed using a 1.5-T scanner. Mutual interference between MR imaging and IONM was evaluated. To assess RF heating risks, 4 pairs of IONM electrodes were inserted into the phantom at regions corresponding to the shoulders, midarm, and wrist. MR imaging of the "shoulder" was performed at 3 different specific absorption rates (SARs) with electrode wires positioned in various geometric configurations. Different combinations of electrode connections to the IONM system were investigated. Temperatures of each electrode were recorded using fiber-optic sensors. RESULTS: Simultaneous IONM readout and MR imaging resulted in distortion of the IONM signal, but interleaving MR imaging and IONM without moving electrodes was feasible. During MR imaging, temperature elevations greater than 60°C at the electrode insertion sites were observed. Temperature reductions were achieved by routing electrode wires along the scanner central axis, reducing the wire length within the scanner bore, or lowering the SAR of the imaging sequence. Altering the electrode connection with the IONM system did not result in consistent changes in RF heating. CONCLUSIONS: With electrodes in the scanner bore, interleaving IONM and MR imaging is desired to avoid signal interference, and several strategies identified herein can reduce risk of electrode RF heating during MR imaging-guided ablation.

6.
J Vasc Interv Radiol ; 2024 Jun 22.
Article in English | MEDLINE | ID: mdl-38914160

ABSTRACT

PURPOSE: To evaluate the safety and effectiveness of magnetic resonance (MR) imaging-guided cryoablation of prostate cancer metastatic lymph nodes (LNs). MATERIALS AND METHODS: Fifty-two patients with prostate cancer who underwent MR imaging-guided LN ablation from September 2013 to June 2022 were retrospectively reviewed. Of these, 6 patients were excluded because adequate ablation margins (3-5 mm) could not be achieved secondary to adjacent structures. The remaining 46 patients (mean age, 70 years [SD ± 7]) underwent 55 MR imaging-guided cryoablation procedures of metastatic LNs (25 in the pelvic sidewall, 20 within the pelvic region, and 10 in the abdomen) with procedural intent of complete ablation. Locoregional tumor control (ie, technical success in the target LN) was evaluated on initial follow-up positron emission tomography (PET) scans at a mean of 4 months (SD ± 2). Preablation and postablation prostate-specific antigen (PSA) levels were recorded. Imaging follow-up continued until a median of 27.5 months (range: 3-108 months). RESULTS: Ninety-five percent (52/55) of treated LNs demonstrated no considerable activity on PET scans at initial follow-up at 4 months (SD ± 2). PSA decreased to an undetectable level of <0.1 ng/mL after cryoablation in 14 of 46 (30.4%) patients with corresponding lack of activity in 13 of 46 (28.2%) patients on continued PET imaging follow-up. Only 6 of 55 (10.9%) patients had transient adverse events, which all resolved with no long-term sequalae. CONCLUSIONS: MR imaging-guided percutaneous cryoablation of metastatic LNs is a safe and technically effective technique for treating metastatic prostate cancer in LNs.

7.
CVIR Endovasc ; 7(1): 45, 2024 May 11.
Article in English | MEDLINE | ID: mdl-38733497

ABSTRACT

BACKGROUND: Internal hemorrhoids (IH) is a common medical condition that can result in morbidity secondary to bleeding and discomfort. Treatment for IH has traditionally consisted of dietary and conservative medical management, focal treatments including banding and sclerotherapy or hemorrhoidectomy. Recently, rectal artery embolization (RAE) has been studied as a potential treatment for bleeding predominant IH. We performed a common design and data element analysis of studies that report on RAE. MATERIALS AND METHODS: We conducted a qualitative systematic literature review for rectal artery embolization (RAE) for symptomatic hemorrhoidal disease. The screening process involved five online databases (PubMed, Embase, Google Scholar, DOAJ, and Scopus). Additionally, ClinicalTrials.gov was examined for active, unpublished completed studies. The initial search yielded 2000 studies, with 15 studies meeting the inclusion criteria after screening and assessment. The included studies comprised one RCT, one case series, one pilot study and 12 cohort studies. RESULTS: The population analysis revealed a male predominance across all studies, with varying cohort sizes. The baseline Goligher hemorrhoid grade was utilized in 80% of studies. The majority (73.3%) employed a transfemoral approach, and coils were the primary embolic material in 60% of studies, 26.6% were combination of coils and particles, and 6.6% were particles only. Patient selection criteria highlighted RAE's applicability for high surgical risk patients and those with anemia, chronic hematochezia, or treatment-refractory cases. Exclusion criteria emphasized factors such as previous surgeries, colorectal cancer, rectal prolapse, acute hemorrhoidal complications, and contrast allergy. Study designs varied, with cohort studies being the most common (12/15; 80%). Procedural details included the use of metallic coils and detachable micro-coils, with a high technical success rate reported in most studies ranging from 72 to 100%. The follow-up ranged from 1 to 18 months. The majority of studies reported no major immediate or post-procedural complications. CONCLUSION: While all studies focused on RAE as a treatment for IH, there was a great degree of heterogeneity among included studies, particularly regarding inclusion criteria, exclusion criteria, outcomes measures and timeframe. Future literature should attempt to standardize these design elements to help facilitate secondary analyses and increase understanding of RAE as a treatment option.

8.
Nat Commun ; 15(1): 4444, 2024 May 24.
Article in English | MEDLINE | ID: mdl-38789421

ABSTRACT

Mitochondrial respiration is essential for the survival and function of T cells used in adoptive cellular therapies. However, strategies that specifically enhance mitochondrial respiration to promote T cell function remain limited. Here, we investigate methylation-controlled J protein (MCJ), an endogenous negative regulator of mitochondrial complex I expressed in CD8 cells, as a target for improving the efficacy of adoptive T cell therapies. We demonstrate that MCJ inhibits mitochondrial respiration in murine CD8+ CAR-T cells and that deletion of MCJ increases their in vitro and in vivo efficacy against murine B cell leukaemia. Similarly, MCJ deletion in ovalbumin (OVA)-specific CD8+ T cells also increases their efficacy against established OVA-expressing melanoma tumors in vivo. Furthermore, we show for the first time that MCJ is expressed in human CD8 cells and that the level of MCJ expression correlates with the functional activity of CD8+ CAR-T cells. Silencing MCJ expression in human CD8 CAR-T cells increases their mitochondrial metabolism and enhances their anti-tumor activity. Thus, targeting MCJ may represent a potential therapeutic strategy to increase mitochondrial metabolism and improve the efficacy of adoptive T cell therapies.


Subject(s)
CD8-Positive T-Lymphocytes , Immunotherapy, Adoptive , Mitochondria , Animals , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Mitochondria/metabolism , Humans , Immunotherapy, Adoptive/methods , Mice , Mice, Inbred C57BL , Mitochondrial Proteins/metabolism , Mitochondrial Proteins/genetics , Cell Respiration , Cell Line, Tumor , Female , Ovalbumin/immunology , Melanoma, Experimental/immunology , Melanoma, Experimental/therapy
9.
Mol Psychiatry ; 2024 May 31.
Article in English | MEDLINE | ID: mdl-38816586

ABSTRACT

The serotonin deficit hypothesis explanation for major depressive disorder (MDD) has persisted among clinicians and the general public alike despite insufficient supporting evidence. To combat rising mental health crises and eroding public trust in science and medicine, researchers and clinicians must be able to communicate to patients and the public an updated framework of MDD: one that is (1) accessible to a general audience, (2) accurately integrates current evidence about the efficacy of conventional serotonergic antidepressants with broader and deeper understandings of pathophysiology and treatment, and (3) capable of accommodating new evidence. In this article, we summarize a framework for the pathophysiology and treatment of MDD that is informed by clinical and preclinical research in psychiatry and neuroscience. First, we discuss how MDD can be understood as inflexibility in cognitive and emotional brain circuits that involves a persistent negativity bias. Second, we discuss how effective treatments for MDD enhance mechanisms of neuroplasticity-including via serotonergic interventions-to restore synaptic, network, and behavioral function in ways that facilitate adaptive cognitive and emotional processing. These treatments include typical monoaminergic antidepressants, novel antidepressants like ketamine and psychedelics, and psychotherapy and neuromodulation techniques. At the end of the article, we discuss this framework from the perspective of effective science communication and provide useful language and metaphors for researchers, clinicians, and other professionals discussing MDD with a general or patient audience.

10.
Materials (Basel) ; 17(3)2024 Jan 23.
Article in English | MEDLINE | ID: mdl-38591418

ABSTRACT

Cylindrical Inconel 718 specimens were fabricated via a blown-powder, laser-directed energy deposition (DED-L) additive manufacturing (AM) process equipped with a dual thermal monitoring system to learn key process-structure relationships. Thermographic inspection of the heat affected zone (HAZ) and melt pool was performed with different layer-to-layer time intervals of ~0 s, 5 s, and 10 s, using an infrared camera and dual-wavelength pyrometer, respectively. Maximum melt pool temperatures were found to increase with layer number within a substrate affected zone (SAZ), and then asymptotically decrease. As the layer-to-layer time interval increased the HAZ temperature responses became more repetitive, indicating a desirable approach for achieving a more homogeneous microstructure along the height of a part. Microstructural variations in grain size and the coexistence of specific precipitate phases and Laves phases persisted among the investigated samples despite the employed standard heat treatment. This indicates that the effectiveness of any post DED-L heat treatment depends significantly on the initial, as-printed microstructure. Overall, this study demonstrates the importance of part size, part number per build, and time intervals on DED-L process parameter selection and post-process heat treatments for achieving better quality control.

11.
Curr Oncol Rep ; 26(6): 601-613, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38647995

ABSTRACT

PURPOSE OF REVIEW: To provide an update on the current state of percutaneous thermal ablation in the treatment of sarcoma. RECENT FINDINGS: Data continue to accrue in support of ablation for local control and palliation of specific sarcoma subtypes such as extra-abdominal desmoid fibromatosis and for broader indications such as the treatment of oligometastatic disease. The synergistic possibilities of various combination therapies such as cryoablation and immunotherapy represent intriguing areas of active investigation. Histotripsy is an emerging non-invasive, non-thermal ablative modality that may further expand the therapeutic arsenal for sarcoma treatment. Percutaneous thermal ablation is a valuable tool in the multidisciplinary management of sarcoma, offering a minimally invasive adjunct to surgery and radiation therapy. Although there remains a paucity of high-level evidence specific to sarcomas, ablation techniques are demonstrably safe and effective for achieving local tumor control and providing pain relief in select patients and are of particular benefit in those with metastatic disease or requiring palliative care.


Subject(s)
Sarcoma , Humans , Sarcoma/surgery , Sarcoma/therapy , Sarcoma/pathology , Ablation Techniques/methods , Cryosurgery/methods
12.
Radiographics ; 44(2): e230075, 2024 02.
Article in English | MEDLINE | ID: mdl-38271257

ABSTRACT

Lymphatic flow and anatomy can be challenging to study, owing to variable lymphatic anatomy in patients with diverse primary or secondary lymphatic pathologic conditions and the fact that lymphatic imaging is rarely performed in healthy individuals. The primary components of the lymphatic system outside the head and neck are the peripheral, retroperitoneal, mesenteric, hepatic, and pulmonary lymphatic systems and the thoracic duct. Multiple techniques have been developed for imaging components of the lymphatic system over the past century, with trade-offs in spatial, temporal, and contrast resolution; invasiveness; exposure to ionizing radiation; and the ability to obtain information on dynamic lymphatic flow. More recently, dynamic contrast-enhanced (DCE) MR lymphangiography (MRL) has emerged as a valuable tool for imaging both lymphatic flow and anatomy in a variety of congenital and acquired primary or secondary lymphatic disorders. The authors provide a brief overview of lymphatic physiology, anatomy, and imaging techniques. Next, an overview of DCE MRL and the development of an MRL practice and workflow in a hybrid interventional MRI suite incorporating cart-based in-room US is provided, with an emphasis on multidisciplinary collaboration. The spectrum of congenital and acquired lymphatic disorders encountered early in an MRL practice is provided, with emphasis on the diversity of imaging findings and how DCE MRL can aid in diagnosis and treatment of these patients. Methods such as DCE MRL for assessing the hepatic and mesenteric lymphatic systems and emerging technologies that may further expand DCE MRL use such as three-dimensional printing are introduced. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.


Subject(s)
Lymphatic Diseases , Lymphography , Humans , Lymphography/methods , Contrast Media , Magnetic Resonance Imaging/methods , Lymphatic Diseases/diagnostic imaging , Lymphatic Diseases/pathology , Lymphatic System/pathology
13.
Acad Radiol ; 31(3): 977-993, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37722951

ABSTRACT

RATIONALE AND OBJECTIVES: Genicular artery embolization (GAE) is an emerging, potentially effective treatment option in patients with knee osteoarthritis (OA). This study aimed to describe the current state of common design data elements (CDDEs) and core outcome measures (COMs) in recent trials of GAE for knee OA. MATERIALS AND METHODS: A comprehensive search of seven online databases were searched within the Nested Knowledge AutoLit living review platform, followed by categorization of primary and secondary outcomes. Studies were tagged with the relevant outcomes of interest in each article. Results were synthesized and examined for the CDDEs. RESULTS: Pain is the most frequent reported outcome, present in 23 of the 24 studies (95.8%). However, there is considerable variability in the description of in the study designs, procedural techniques, embolic materials, time points, and MRI parameters. Greater consistency is observed in eligibility criteria, and adverse events reporting. Although findings thus far have been favorable, current data is still constrained by the heterogeneity of the study design, embolization area nomenclature, limited follow-up, and in many cases, the absence of control group. CONCLUSION: To enhance the potential for future meta-analyses and robust, evidence-based evaluations of GAE as a treatment for knee OA, further research is required to address the identified shortcomings. By establishing more standardized protocols, the efficacy and safety of GAE can be more accurately assessed and understood.


Subject(s)
Osteoarthritis, Knee , Humans , Osteoarthritis, Knee/therapy , Osteoarthritis, Knee/drug therapy , Outcome Assessment, Health Care , Treatment Outcome , Magnetic Resonance Imaging , Arteries
14.
Neuropsychopharmacology ; 49(2): 443-454, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37833589

ABSTRACT

Trauma and chronic stress exposure are the strongest predictors of lifetime neuropsychiatric disease presentation. These disorders often have significant sex biases, with females having higher incidences of affective disorders such as major depression, anxiety, and PTSD. Understanding the mechanisms by which stress exposure heightens disease vulnerability is essential for developing novel interventions. Current rodent stress models consist of a battery of sensory, homeostatic, and psychological stressors that are ultimately integrated by corticotropin-releasing factor (CRF) neurons to trigger corticosteroid release. These stress paradigms, however, often differ between research groups in the type, timing, and duration of stressors utilized. These inconsistencies, along with the variability of individual animals' perception and response to each stressor, present challenges for reproducibility and translational relevance. Here, we hypothesized that a more direct approach using chemogenetic activation of CRF neurons would recapitulate the effects of traditional stress paradigms and provide a high-throughput method for examining stress-relevant phenotypes. Using a transgenic approach to express the Gq-coupled Designer Receptor Exclusively Activated by Designer Drugs (DREADD) receptor hM3Dq in CRF-neurons, we found that the DREADD ligand clozapine-N-oxide (CNO) produced an acute and robust activation of the hypothalamic-pituitary-adrenal (HPA) axis, as predicted. Interestingly, chronic treatment with this method of direct CRF activation uncovered a novel sex-specific dissociation of glucocorticoid levels with stress-related outcomes. Despite hM3Dq-expressing females producing greater corticosterone levels in response to CNO than males, hM3Dq-expressing males showed significant typical physiological stress sensitivity with reductions in body and thymus weights. hM3Dq-expressing females while resistant to the physiological effects of chronic CRF activation, showed significant increases in baseline and fear-conditioned freezing behaviors. These data establish a novel mouse model for interrogating stress-relevant phenotypes and highlight sex-specific stress circuitry distinct for physiological and limbic control that may underlie disease risk.


Subject(s)
Corticotropin-Releasing Hormone , Neurons , Mice , Male , Animals , Female , Corticotropin-Releasing Hormone/pharmacology , Reproducibility of Results , Anxiety , Fear
15.
J Neurophysiol ; 131(1): 64-74, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-38050689

ABSTRACT

(2R,6R)-Hydroxynorketamine (HNK) is a ketamine metabolite that shows rapid antidepressant-like effects in preclinical studies and lacks the adverse N-methyl-d-aspartate receptor (NMDAR) inhibition-related properties of ketamine. Investigating how (2R,6R)-HNK exerts its antidepressant actions may be informative in the design of novel pharmacotherapies with improved safety and efficacy. We sought to identify the molecular substrates through which (2R,6R)-HNK induces functional changes at excitatory synapses, a prevailing hypothesis for how rapid antidepressant effects are initiated. We recorded excitatory postsynaptic potentials in hippocampal slices from male Wistar Kyoto rats, which have impaired hippocampal plasticity and are resistant to traditional antidepressants. (2R,6R)-HNK (10 µM) led to a rapid potentiation of electrically evoked excitatory postsynaptic potentials at Schaffer collateral CA1 stratum radiatum synapses. This potentiation was associated with a decrease in paired pulse facilitation, suggesting an increase in the probability of glutamate release. The (2R,6R)-HNK-induced potentiation was blocked by inhibiting either cyclic adenosine monophosphate (cAMP) or its downstream target, cAMP-dependent protein kinase (PKA). As cAMP is a potent regulator of brain-derived neurotrophic factor (BDNF) release, we assessed whether (2R,6R)-HNK exerts this acute potentiation through a rapid increase in cAMP-dependent BDNF-TrkB signaling. We found that the cAMP-PKA-dependent potentiation was not dependent on TrkB activation by BDNF, which functionally delimits the acute synaptic effects of (2R,6R)-HNK from its sustained BDNF-dependent actions in vivo. These results suggest that, by potentiating glutamate release via cAMP-PKA signaling, (2R,6R)-HNK initiates acute adaptations in fast excitatory synaptic transmission that promote structural plasticity leading to maintained antidepressant action.NEW & NOTEWORTHY Ketamine is a rapid-acting antidepressant and its preclinical effects are mimicked by its (2R,6R)-(HNK) metabolite. We found that (2R,6R)-HNK initiates acute adaptations in fast excitatory synaptic transmission by potentiating glutamate release via cAMP-PKA signaling at hippocampal Schaffer collateral synapses. This cAMP-PKA-dependent potentiation was not dependent on TrkB activation by BDNF, which functionally delimits the rapid synaptic effects of (2R,6R)-HNK from its sustained BDNF-dependent actions that are thought to maintain antidepressant action in vivo.


Subject(s)
Ketamine , Rats , Animals , Male , Ketamine/pharmacology , Brain-Derived Neurotrophic Factor/metabolism , Antidepressive Agents/metabolism , Antidepressive Agents/pharmacology , Hippocampus/metabolism , Glutamic Acid/metabolism
16.
Neuropsychopharmacology ; 49(1): 83-95, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37709943

ABSTRACT

The predominant inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA), acts at ionotropic GABAA receptors to counterbalance excitation and regulate neuronal firing. GABAA receptors are heteropentameric channels comprised from subunits derived from 19 different genes. GABAA receptors have one of the richest and well-developed pharmacologies of any therapeutic drug target, including agonists, antagonists, and positive and negative allosteric modulators (PAMs, NAMs). Currently used PAMs include benzodiazepine sedatives and anxiolytics, barbiturates, endogenous and synthetic neurosteroids, and general anesthetics. In this article, I will review evidence that these drugs act at several distinct binding sites and how they can be used to alter the balance between excitation and inhibition. I will also summarize existing literature regarding (1) evidence that changes in GABAergic inhibition play a causative role in major depression, anxiety, postpartum depression, premenstrual dysphoric disorder, and schizophrenia and (2) whether and how GABAergic drugs exert beneficial effects in these conditions, focusing on human studies where possible. Where these classical therapeutics have failed to exert benefits, I will describe recent advances in clinical and preclinical drug development. I will also highlight opportunities to advance a generation of GABAergic therapeutics, such as development of subunit-selective PAMs and NAMs, that are engendering hope for novel tools to treat these devastating conditions.


Subject(s)
Anti-Anxiety Agents , Receptors, GABA-A , Humans , Receptors, GABA-A/metabolism , gamma-Aminobutyric Acid/metabolism , Binding Sites , Brain/metabolism
17.
Environ Monit Assess ; 195(10): 1187, 2023 Sep 12.
Article in English | MEDLINE | ID: mdl-37698727

ABSTRACT

Ambient PM2.5 (particles less than 2.5 µm in diameter) is monitored in many countries including Australia. Occasionally PM2.5 instruments may report negative measurements, although in realty the ambient air can never contain negative amounts of particles. Some negative readings are caused by instrument faults or procedural errors, thus can be simply invalidated from air quality reporting. There are occasions, however, when negative readings occur due to other factors including technological or procedural limitations. Treatment of such negative data requires consideration of factors such as measurement uncertainty, instrument noise and risk for significant bias in air quality reporting. There is very limited documentation on handling negative PM2.5 data in the literature. This paper demonstrates how a threshold is determined for controlling negative hourly PM2.5 readings in the New South Wales (NSW) air quality data system. The investigation involved a review of thresholds used in different data systems and an assessment of instrument measurement uncertainties, zero air test data and impacts on key reporting statistics when applying different thresholds to historical datasets. The results show that a threshold of -10.0 µg/m3 appears optimal for controlling negative PM2.5 data in public reporting. This choice is consistent with the measurement uncertainty estimates and the zero air test data statistics calculated for the NSW Air Quality Monitoring Network, and is expected not to have significant impacts on key compliance reporting statistics such as data availability and annual average pollution levels. The analysis can be useful for air quality monitoring in other Australian jurisdictions or wider context.


Subject(s)
Air Pollution , Environmental Monitoring , Australia , Environmental Pollution , Particulate Matter
18.
eNeuro ; 10(9)2023 Sep.
Article in English | MEDLINE | ID: mdl-37699705

ABSTRACT

The sucrose preference test (SPT) is a widely used preclinical assay for studying stress-sensitive reward behaviors and antidepressant treatments in rodents, with some face, construct, and predictive validity. However, while stress-induced loss of sucrose preference is presumed to reflect an anhedonic-like state, little detail is known about what behavioral components may influence performance in the SPT in stress-naive or stressed rodents. We analyzed the licking microstructure of mice during the SPT to evaluate how preference is expressed and lost following chronic stress. In stress-naive mice, preference is expressed as both longer and more numerous drinking bouts at the sucrose bottle, compared with the water bottle. We also found evidence that memory of the sucrose bottle location supports preference. Through manipulations of the caloric content of the sweetener or caloric need of the mouse, we found that energy demands and satiety signals do not affect either preference or the underlying drinking behavior. Both acute and chronic stress impaired sucrose location memory and reduced the number of drinking bouts at the sucrose bottle, the latter of which explained the loss of sucrose preference in stress susceptible mice compared with stress resilient mice. Female mice generally exhibited similar drinking behavior to male mice but may be less susceptible to chronic stress and display better memory performance than male mice, both before and after chronic stress. Our data suggest that chronic stress inhibits a sucrose preference by reducing reward seeking behavior without affecting palatability.


Subject(s)
Sucrose , Sweetening Agents , Mice , Male , Female , Animals , Behavior, Animal , Drinking Behavior
19.
AJOG Glob Rep ; 3(4): 100257, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37701754

ABSTRACT

INTRODUCTION: Vaginal stenosis is a common complication following construction of a neovagina with vascularized myocutaneous flaps. This is primarily because of inconsistent or inappropriate vaginal dilator use. Image-guided recanalization, especially for obstructed genitourinary tracts, is an emerging idea in interventional radiology. Although multiple surgical techniques have been reported to treat vaginal agenesis or obstruction, the idea of image-guided recanalization of vaginal stenosis is a relatively new management strategy for vaginal stenosis. CASE: We present a challenging case of a patient who initially presented with the complaint of increasing pelvic pressure after the creation of a neovagina via vaginoplasty. She had a distal neovagina created after extensive surgical resection for a large infiltrating pelvic rectal adenocarcinoma. A computed tomography scan revealed a fluid-filled neovaginal abscess. Examination under anesthesia revealed complete stenosis of the neovagina with no identifiable tract for dilation. INTERVENTION: A computed tomography scan and fluoroscopy-guided sharp recanalization of the stenosed neovagina was performed, followed by serial fluoroscopic balloon angioplasty to dilate the stenosed neovagina. Finally, the patient underwent a gynecologic surgery for the excision of remaining granulation tissue to produce a more permanent patent neovagina, followed by regular and proper use of vaginal dilators to ensure patency. CONCLUSION: This case report demonstrates that image-guided techniques can be used to aid in vaginal recanalization in the postoperative setting.

20.
Nat Med ; 29(7): 1821-1831, 2023 07.
Article in English | MEDLINE | ID: mdl-37414898

ABSTRACT

Chronic pain is a complex condition influenced by a combination of biological, psychological and social factors. Using data from the UK Biobank (n = 493,211), we showed that pain spreads from proximal to distal sites and developed a biopsychosocial model that predicted the number of coexisting pain sites. This data-driven model was used to identify a risk score that classified various chronic pain conditions (area under the curve (AUC) 0.70-0.88) and pain-related medical conditions (AUC 0.67-0.86). In longitudinal analyses, the risk score predicted the development of widespread chronic pain, the spreading of chronic pain across body sites and high-impact pain about 9 years later (AUC 0.68-0.78). Key risk factors included sleeplessness, feeling 'fed-up', tiredness, stressful life events and a body mass index >30. A simplified version of this score, named the risk of pain spreading, obtained similar predictive performance based on six simple questions with binarized answers. The risk of pain spreading was then validated in the Northern Finland Birth Cohort (n = 5,525) and the PREVENT-AD cohort (n = 178), obtaining comparable predictive performance. Our findings show that chronic pain conditions can be predicted from a common set of biopsychosocial factors, which can aid in tailoring research protocols, optimizing patient randomization in clinical trials and improving pain management.


Subject(s)
Chronic Pain , Humans , Chronic Pain/epidemiology , Prognosis , Chronic Disease , Risk Factors , Pain Management/methods
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