CD44, a non-kinase transmembrane glycoprotein, is overexpressed in several cell types including cancer stem cells and frequently shows alternative spliced variants that are thought to play a role in ...cancer development and progression. Hyaluronan, the main ligand for CD44, binds to and activates CD44 resulting in activation of cell signaling pathways that induces cell proliferation, increases cell survival, modulates cytoskeletal changes, and enhances cellular motility. The different functional roles of CD44 standard (CD44s) and specific CD44 variant (CD44v) isoforms are not fully understood. CD44v contain additional peptide motifs that can interact with and sequester growth factors and cytokines at the cell surface thereby functioning as coreceptors to facilitate cell signaling. Moreover, CD44v were expressed in metastasized tumors, whereas switching between CD44v and CD44s may play a role in regulating epithelial to mesenchymal transition (EMT) and in the adaptive plasticity of cancer cells. Here, we review current data on the structural and functional properties of CD44, the known roles for CD44 in tumorigencity, the regulation of CD44 expression, and the potential for targeting CD44 for cancer therapy.
Hippocampal neurons encode physical variables
such as space
or auditory frequency
in cognitive maps
. In addition, functional magnetic resonance imaging studies in humans have shown that the ...hippocampus can also encode more abstract, learned variables
. However, their integration into existing neural representations of physical variables
is unknown. Here, using two-photon calcium imaging, we show that individual neurons in the dorsal hippocampus jointly encode accumulated evidence with spatial position in mice performing a decision-making task in virtual reality
. Nonlinear dimensionality reduction
showed that population activity was well-described by approximately four to six latent variables, which suggests that neural activity is constrained to a low-dimensional manifold. Within this low-dimensional space, both physical and abstract variables were jointly mapped in an orderly manner, creating a geometric representation that we show is similar across mice. The existence of conjoined cognitive maps suggests that the hippocampus performs a general computation-the creation of task-specific low-dimensional manifolds that contain a geometric representation of learned knowledge.
Aldosterone synthase controls the synthesis of aldosterone and has been a pharmacologic target for the treatment of hypertension for several decades. Selective inhibition of aldosterone synthase is ...essential but difficult to achieve because cortisol synthesis is catalyzed by another enzyme that shares 93% sequence similarity with aldosterone synthase. In preclinical and phase 1 studies, baxdrostat had 100:1 selectivity for enzyme inhibition, and baxdrostat at several dose levels reduced plasma aldosterone levels but not cortisol levels.
In this multicenter, placebo-controlled trial, we randomly assigned patients who had treatment-resistant hypertension, with blood pressure of 130/80 mm Hg or higher, and who were receiving stable doses of at least three antihypertensive agents, including a diuretic, to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily for 12 weeks or placebo. The primary end point was the change in systolic blood pressure from baseline to week 12 in each baxdrostat group as compared with the placebo group.
A total of 248 patients completed the trial. Dose-dependent changes in systolic blood pressure of -20.3 mm Hg, -17.5 mm Hg, -12.1 mm Hg, and -9.4 mm Hg were observed in the 2-mg, 1-mg, 0.5-mg, and placebo groups, respectively. The difference in the change in systolic blood pressure between the 2-mg group and the placebo group was -11.0 mm Hg (95% confidence interval CI, -16.4 to -5.5; P<0.001), and the difference in this change between the 1-mg group and the placebo group was -8.1 mm Hg (95% CI, -13.5 to -2.8; P = 0.003). No deaths occurred during the trial, no serious adverse events were attributed by the investigators to baxdrostat, and there were no instances of adrenocortical insufficiency. Baxdrostat-related increases in the potassium level to 6.0 mmol per liter or greater occurred in 2 patients, but these increases did not recur after withdrawal and reinitiation of the drug.
Patients with treatment-resistant hypertension who received baxdrostat had dose-related reductions in blood pressure. (Funded by CinCor Pharma; BrigHTN ClinicalTrials.gov number, NCT04519658.).
...one wonders whether a patient with initial lower-grade (good) Hunt-Hess SAH who suffers a seizure might benefit from earlier or continuous EEG monitoring and ASM treatment? During the tonic phase ...of a clinical seizure, Valsalva increases intrathoracic pressure and systolic blood pressure, which can lead to aneurysm rerupture and cause hypercapnia from inadequate ventilation and relative hypermetabolic physical activity. Treiman, DM; Walton, NY; Kendrick, C. A progressive sequence of electroencephalographic changes during generalized convulsive status epilepticus. Neurological Emergencies Treatment Trials; Pediatric Emergency Care Applied Research Network investigators.
Management of Intracranial Pressure Freeman, W David
Continuum (Minneapolis, Minn.),
2015-October, Letnik:
21, Številka:
5 Neurocritical Care
Journal Article
Intracranial pressure (ICP) can be elevated in traumatic brain injury, large artery acute ischemic stroke, intracranial hemorrhage, intracranial neoplasms, and diffuse cerebral disorders such as ...meningitis, encephalitis, and acute hepatic failure. Raised ICP is also known as intracranial hypertension and is defined as a sustained ICP of greater than 20 mm Hg.
ICP must be measured through an invasive brain catheter, typically an external ventricular catheter that can drain CSF and measure ICP, or through an intraparenchymal ICP probe. Proper recognition of the clinical signs of elevated ICP is essential for timely diagnosis and treatment to prevent cerebral hypoperfusion and possible brain death. Clinical signs of elevated ICP include headache, papilledema, nausea, and vomiting in the early phases, followed by stupor and coma, pupillary changes, hemiparesis or quadriparesis, posturing and respiratory abnormalities, and eventually cardiopulmonary arrest.
Management of elevated ICP is, in part, dependent on the underlying cause. Medical options for treating elevated ICP include head of bed elevation, IV mannitol, hypertonic saline, transient hyperventilation, barbiturates, and, if ICP remains refractory, sedation, endotracheal intubation, mechanical ventilation, and neuromuscular paralysis. Surgical options include CSF drainage if hydrocephalus is present and decompression of a surgical lesion, such as an intracranial hematoma/large infarct or tumor, if the patient's condition is deemed salvageable. Future research should continue investigating medical and surgical options for the treatment of raised ICP, such as hypothermia, drugs that reduce cerebral edema, and operations aimed at reducing intracranial mass effect.
An increased risk of depressive symptoms has been associated with the transition to menopause, but the risk of depressive symptoms in the early postmenopausal years has not been well characterized.
...To identify within-woman changes in depressive symptoms during a 14-year period around menopause, determine associations of a history of depression with the pattern of depressive symptoms, and evaluate the rate of change in reproductive hormones as predictors of depressive symptoms following menopause.
A randomly identified, population-based sample in Philadelphia County, Pennsylvania, of 203 late-reproductive-age women who were premenopausal at baseline and reached natural menopause.
Center for Epidemiologic Studies Depression Scale.
The prevalence of high scores on the Center for Epidemiologic Studies Depression Scale decreased from 10 years before to 8 years after the final menstrual period (FMP), with a decrease of approximately 15% of baseline per year (odds ratio, 0.85; 95% CI, 0.81-0.89; P < .001). Relative to the FMP, the risk of depressive symptoms was higher in the years before and lower in the years after the FMP. Among women with a history of depression, the likelihood of depressive symptoms was more than 13 times greater overall and 8 times greater after menopause compared with women with no depression history. Among women who first experienced depressive symptoms approaching menopause, the risk of depressive symptoms declined after the FMP, with a significantly lower risk the second year after menopause. The risk of depressive symptoms after menopause decreased by 35% for each unit (SD) increase before the FMP in the log rate of change of follicle-stimulating hormone (odds ratio, 0.65; 95% CI, 0.46-0.91; P = .01).
The FMP was pivotal in the overall pattern of decreasing depressive symptoms in midlife women, with higher risk before and lower risk after the FMP. A history of depression strongly increased the risk both before and after menopause. Women who had no history of depression before the menopause transition had a low risk of depressive symptoms 2 or more years after the FMP.
Type 2 diabetes is a chronic age-associated degenerative metabolic disease that reflects relative insulin deficiency and resistance. Extracellular vesicles (EVs) (exosomes, microvesicles, and ...apoptotic bodies) are small (30-400 nm) lipid-bound vesicles capable of shuttling functional proteins, nucleic acids, and lipids as part of intercellular communication systems. Recent studies in mouse models and in cell culture suggest that EVs may modulate insulin signaling. Here, we designed cross-sectional and longitudinal cohorts of euglycemic participants and participants with prediabetes or diabetes. Individuals with diabetes had significantly higher levels of EVs in their circulation than euglycemic control participants. Using a cell-specific EV assay, we identified that levels of erythrocyte-derived EVs are higher with diabetes. We found that insulin resistance increases EV secretion. Furthermore, the levels of insulin signaling proteins were altered in EVs from individuals with high levels of insulin resistance and β-cell dysfunction. Moreover, EVs from individuals with diabetes were preferentially internalized by circulating leukocytes. Cytokine levels in the media and in EVs were higher from monocytes incubated with diabetic EVs. Microarray of these leukocytes revealed altered gene expression pathways related to cell survival, oxidative stress, and immune function. Collectively, these results suggest that insulin resistance increases the secretion of EVs, which are preferentially internalized by leukocytes, and alters leukocyte function.
Context:
Anti-Mullerian hormone (AMH) has emerged as a marker of ovarian reserve and a possible surrogate measure of reproductive aging.
Objective:
The aim of the study was to evaluate the predictive ...value of AMH levels in determining the median time to menopause for late reproductive age women and the predictive ability of AMH compared to FSH and inhibin b.
Design and Setting:
A 14-yr follow-up in the Penn Ovarian Aging Study, 1996–2010, was conducted for a randomly identified population-based cohort.
Subjects:
A total of 401 late reproductive age women participated in the study.
Main Outcome Measure:
Observed time to menopause was measured.
Results:
All participants were premenopausal, with a mean (sd) age of 41.47 (3.52) yr and a median AMH level of 0.68 ng/ml at baseline. AMH strongly predicted time to menopause; age further improved predictions. Among women with a baseline AMH level below 0.20 ng/ml, the median time to menopause was 5.99 yr 95% confidence interval (CI), 4.20–6.33 in the 45- to 48-yr age group and 9.94 yr (95% CI, 3.31–12.73) in the 35- to 39-yr age group. With higher baseline AMH levels above 1.50 ng/ml, the median time to menopause was 6.23 yr in the oldest age group and more than 13.01 yr in the youngest age group. Smoking significantly reduced the time to menopause (hazard ratio, 1.61; 95% CI, 1.19–2.19; P = 0.002). AMH was a stronger predictor of time to menopause than FSH or inhibin b.
Conclusions:
AMH is a strong predictor of median time to menopause in late reproductive age women. Age and smoking are significant and independent contributors to the predictions of AMH.
Orientation selectivity is a key property of primary visual cortex that contributes, downstream, to object recognition. The origin of orientation selectivity, however, has been debated for decades. ...It is known that on- and off-centre subcortical pathways converge onto single neurons in primary visual cortex, and that the spatial offset between these pathways gives rise to orientation selectivity. On- and off-centre pathways are intermingled, however, so it is unclear how their inputs to cortex come to be spatially segregated. We here describe a model in which the segregation occurs through Hebbian strengthening and weakening of geniculocortical synapses during the development of the visual system. Our findings include the following. 1. Neighbouring on- and off-inputs to cortex largely cancelled each other at the start of development. At each receptive field location, the Hebbian process increased the strength of one input sign at the expense of the other sign, producing a spatial segregation of on- and off-inputs. 2. The resulting orientation selectivity was precise in that the bandwidths of the orientation tuning functions fell within empirical estimates. 3. The model produced maps of preferred orientation-complete with iso-orientation domains and pinwheels-similar to those found in real cortex. 4. These maps did not originate in cortical processes, but from clustering of off-centre subcortical pathways and the relative location of neighbouring on-centre clusters. We conclude that a model with intermingled on- and off-pathways shaped by Hebbian synaptic plasticity can explain both the origin and development of orientation selectivity.
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