Early Online (Volume - 4 | Issue - 4) at IgMin Research

Aims: Arterial baroreceptors are located in vessels which are subject to atherosclerotic changes. Using a rabbit model, we investigated effects of atherosclerosis on arterial baroreceptors, arterial baroreflex regulation and control of Mean Arterial Pressure (MAP).Methods and results: Seven-week-old male New Zealand White rabbits were placed on an atherogenic diet for 14 weeks (treatment). Treatment produced significant atherosclerosis along the aorta, but spared the carotid bifurcation. Treated animals had higher MAP: conscious–(treated:... 80.1 [77.3, 82.9] versus control: 70.9 [69.9, 71.9] mmHg; N = 7 and 9 respectively; p = < 0.001) (mean [90% confidence interval]), anaesthetized–(treated: 99.9 [97.2, 102.7] versus control: 95.6 [93.5, 97.7] mmHg, N = 24 for each group; p = 0.050). In anaesthetized animals Pulse Wave Velocity (PWV) along the aorta was higher in treated animals (5.64 [5.54, 5.74] versus 5.07 [4.98, 5.16] m/s in control, N = 24 for each group; p < 0.0001). MAP was ramped (from 40 to 140 mmHg) using inflatable cuffs around the descending aorta and posterior vena cava. Treatment did not affect the activity of individual A-fibre baroreceptors in the ADN. Multifibre records of activity in the left Aortic Depressor Nerve (ADN) and left Carotid Sinus Nerve (CSN), showed that treatment reduced C-fibre baroreceptor activity in the ADN; there was ~16.5% less integrated activity at MAP >100 mmHg in treated animals (4650 [4174, 4988] versus 5570 [5220, 5919] au in control; N = 22 and 20, respectively; p < 0.001). Treatment had no effect on multifibre recordings from the CSN.In conscious animals, baroreflex curves describing control of Renal Sympathetic Activity (RSNA) were obtained using i.v. phenylephrine and nitroprusside to modify MAP. Treatment shifted the mid-point of the curve to a higher MAP (72.4 [69.9, 74.8] versus 63.6 [61.3, 65.8] mmHg in control; N = 5 and 8, respectively; p = 0.02. In anaesthetized animals, baroreflex curves for RSNA were obtained using inflatable cuffs to control MAP. When input from the CSN was kept low and steady by common carotid artery occlusion, a high level of MAP was unable to fully inhibit RSNA (12.5 [8.4, 16.6] and 3.9 ([2.6, 5.2] n.u. at saturation in 5 treated and 7 control animals, respectively; p = 0.01).Conclusion: The loss of aortic C-fibre baroreceptor activity that occurs in this model of atherosclerosis may reset MAP to a higher value, since C-fibre input is likely a controller of MAP.Read more

Objective: Pancreatic cancer does not respond to immune checkpoint inhibitors, and therefore, it is considered a cancer that is not immunosensitive. However, even though pancreatic cancer may not produce the programmed cell death protein ligand 1 (PD-L1), it may produce immunomodulatory proteins, e.g., the progesterone-induced blocking factor (PIBF) produced by activating membrane progesterone receptors. If so, inhibition of pancreatic cancer regression and/or tumor regression may be found following treatment with a progesterone receptor modula...tor, e.g., mifepristone. Methods: Mifepristone 200 mg orally daily was given to a terminal 83-year-old patient suffering from stage IV pancreatic cancer with jaundice related to bile duct destruction, mid-epigastric pain, anorexia, and marked weakness. Results: Within 3 weeks, the jaundice was no longer present, and her pain, anorexia, fatigue, and cognition markedly improved. Unfortunately, she slipped in the shower and broke her nose and ribs. The hospital refused to allow her to take the Mifepristone because it was off-label. The cancer aggressively returned after being without mifepristone therapy for 2.5 weeks. Conclusion: This was the second case showing marked palliative benefits to well-tolerated mifepristone. It is also the second case shown that the cancer will resume active spread if the drug is stopped for more than a week.Read more

We establish a rigorous connection between pathwise (reparameterization) and score-function (Malliavin) gradient estimators by showing that both arise from the Malliavin integration-by-parts identity. Building on this equivalence, we introduce a unified and variance-aware hybrid estimator that adaptively combines pathwise and Malliavin gradients using their empirical covariance structure. The connection is established explicitly for Gaussian (and more generally exponential family) latent variable models, where integration-by-parts identities ad...mit closed-form representations. The resulting formulation provides a principled understanding of stochastic backpropagation and achieves minimum variance in theory among all unbiased linear combinations, with closed-form finite-sample convergence bounds. We demonstrate 9% variance reduction on VAEs (CIFAR-10) and up to 35% on strongly-coupled synthetic problems. Exploratory policy gradient experiments reveal that non-stationary optimization landscapes present challenges for the hybrid approach, highlighting important directions for future work. Overall, this work positions Malliavin calculus as a conceptually unifying and practically interpretable framework for stochastic gradient estimation, clarifying when hybrid approaches provide tangible benefits and when they face inherent limitations.Read more