Early reversal cardiac with esmolol in hypertensive rats: The role of subcellular organelle phenotype

BackgroundOur group has previously shown that short-term treatment (48 h) with esmolol reduces left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHRs). However, we do not know the mechanism that explain this effect. The aim of this study was to assess the role that the subcellular organelle phenotype plays in early cardiac reverse after short-term treatment with esmolol.Methods14-Month-old male SHRs were randomly assigned to receive esmolol (300 μg/kg/min) (SHR-E) or vehicle (SHR). Age-matched male Wistar-Kyoto rats (WKY) served as controls. After 48 h of treatment, an ultrastructural analysis of heart tissue (left ventricle) was performed. We studied cardiomyocyte ultrastructural remodeling of subcellular organelles by electronic microcopy in all groups.ResultsSHR group showed significant morphometric and stereological changes in mitochondria and subcellular organelles (cytoplasm and nucleus, myofibril structure, mitochondria structure, Z-Disk, intercalated disk, T-system and cystern), and also changes in the extracellular matrix (collagen) with respect to WKY group. Esmolol significantly improved the morphology and stereology mitochondrial, reduced the organelle phenotype abnormalities but no produced changes in the extracellular matrix with respect to SHR group. Interesantly, parameters of mitochondria (regularity factor, ellipsoidal form factor and density of volume), and all parameters of subcellular organelles returned to the normality in SHR-E.ConclusionOur results show that left ventricular hypertrophy reversal after short-term treatment with esmolol is associated with reversal of subcellular organelle phenotype.     

Type 1 reaction in leprosy: a model for a better understanding of tissue immunity under an immunopathological condition

Type 1 reaction (T1R) or reversal reaction is the leading cause of physical disabilities and deformities in leprosy. Leprosy patients, even after being considered cured and released from treatment, may suffer from reactional episodes for long periods of time. Early diagnosis is a great challenge for effectively treating and managing T1R. There is an urgent need to identify the most significant biomarkers to prevent recurrent T1R and to differentiate late T1R from relapse. T1R continues to be treated with corticosteroids and complications due to iatrogenic treatment remain frequent. This review aims to provide a framework from which to approach the great challenges that still persist in T1R management and debate key issues in order to reduce the distance between basic research and the clinic.     

Functional analysis of congenital stationary night blindness type-2 CACNA1F mutations F742C, G1007R, and R1049W

Congenital stationary night blindess-2 (incomplete congenital stationary night blindness (iCSNB) or CSNB-2) is a nonprogressive, X-linked retinal disease which can lead to clinical symptoms such as myopia, hyperopia, nystagmus, strabismus, decreased visual acuity, and impaired scotopic vision. These clinical manifestations are linked to mutations found in the CACNA1F gene which encodes for the Ca(v)1.4 voltage-gated calcium channel. To better understand the physiological effects of these mutations, three missense mutants, F742C, G1007R and R1049W, previously shown to be mutated in patients with CSNB-2, were transiently expressed in human embryonic kidney (HEK) tsA-201 cells and characterized using whole-cell patch clamp. The G1007R mutation is located in transmembrane segment 5 (S5) of domain III and R1049W is located in the extracellular linker between S5 and the P-loop of domain III. Both mutants produced full length proteins that targeted to the membrane but did not support ionic currents. In 20 mM Ba(2+), F742C (S6 domain II) produced a approximately 21 mV hyperpolarizing shift in half activation potential (V(a[1/2])) and a approximately 23 mV hyperpolarizing shift in half inactivation potential (V(h[1/2])). Additionally, F742C displayed slower inactivation kinetics and a smaller whole cell conductance (G(max)). In physiological 2 mM Ca(2+), F742C produced a approximately 19 mV hyperpolarizing shift in V(a[1/2]). These findings suggest that the pathology of CSNB-2 in patients with these missense mutations in the Ca(v)1.4 calcium channel is the result in either a gain of function (F742C) or a loss of function (G1007R, R1049W).     

Nicotine improves probabilistic reward learning in wildtype but not alpha7 nAChR null mutants,yet alpha7 nAChR agonists do not improve probabilistic learning

Cognitive impairments, e.g., reward learning, are present in various psychiatric disorders and warrant treatment. Improving reward-related learning could synergistically enhance psychosocial treatments and cognition generally. A critical first step is to understand the mechanisms underlying reward learning. The dopamine system has been implicated in such learning, but less known is how indirect activation of this system may affect reward learning. We determined the role of alpha7 nicotinic acetylcholine receptors (nAChR) on a probabilistic reversal learning task (PRLT) in mice that includes reward and punishment. Male alpha7 knockout (KO), heterozygous (HT), and wildtype (WT) littermate mice (n?=?84) were treated with vehicle, 0.03, or 0.3?mg/kg nicotine. Two cohorts of C57BL/6NJ male mice were treated with various alpha7 nAChR ligands, including the full agonists PNU282877 and AR-R-17779, the positive allosteric modulator CCMI, the partial agonist SSR180711, and the antagonist methyllycaconitine. All mice were then tested in the PRLT. Nicotine (0.3?mg/kg) significantly improved initial reward learning in alpha7 WT and HT mice but did not improve learning in KO mice, suggesting an involvement of the alpha7 nAChR in the pro-learning effects of nicotine. Neither alpha7 nAChR treatments (PNU282987, AR-R-17779, CCMI, SSR180711, nor methyllycaconitine) affected mouse PRLT performance however. Nicotine improved reward learning via a mechanism that may include alpha7 nAChRs. This improvement unlikely relied solely on alpha7 nAChRs however, since no alpha7 nAChR ligand improved reward learning in normal mice. Future assessments of the effects of other nAChR subtypes on reward learning are needed.     

VAMP加逆转剂治疗难治性急性淋巴细胞白血病的体内、外研究

目的：观察VAMP方案加维拉帕米或环孢菌素A逆转治疗难治性ALL的疗效。方法：选择原发和继发耐药的ALL患者13例，采用VAMP方案加维拉帕米或环孢菌素A逆转体内、外研究。结果：13例ALL中7例达CR,3例达PR,3例无效。体外VAMP方案加VRP或CsA可有效逆转耐药。结论：采用VAMP方案加维拉帕米或环孢菌素A逆转治疗难治性ALL,可取得较好的疗效,为争取移植治疗创造了条件。     

Surgical delay in acute admissions on warfarin: are we doing enough?

Warfarin anti-coagulation can cause significant delay in acute surgical admissions. We reviewed fracture neck of femur patients operated over a period of 4 years in our unit. There was an average delay to surgery of 4.36 days in patients on warfarin as against an average delay of 1.78 days in patients not on warfarin (p < 0.001). The review was followed up with a questionnaire-based survey of consultant haematologists, and a general agreement towards a protocol-based use of vitamin K(1) was noted. The reasons for limited use of vitamin K(1) include the lack of studies and guidelines specifically addressing the pre-operative emergency admissions. We highlight a practical problem shared across different specialities and identify the areas for future studies.     

Nature cures nature: Hypericum perforatum attenuates physical withdrawal signs in opium dependent rats

Context: Hypericum perforatum Linn. (Hypericaceae) (St. John’s wort) attenuates opium withdrawal signs.

Aim: To explore the therapeutic potential of Hypericum perforatum in the management of opium-induced withdrawal syndrome.

Materials and methods: The effect of the Hypericum perforatum hydro-ethanol extract was investigated for potential to reverse naloxone (0.25?mg/kg)-induced opium withdrawal physical signs. Rats received opium extract (80–650?mg/kg) twice daily for 8 days along with Hypericum perforatum (20?mg/kg, orally) twice daily in chronic treatment and the same single dose 1?h before induction of withdrawal syndrome in the acute treated group.

Results: Hypericum perforatum reduced stereotype jumps and wet dog shake number in the chronic treatment compared to the saline control group (F(2, 24)?=?3.968, p?F(2, 24)?=?3.689, p?F(2, 24)?=?4.850, p?F(2, 24)?=?4.88, p?F(2, 240?=?5.364, p?F(2, 24)?=?4.907, p?Discussion and conclusion: This study reveals that the extract of Hypericum perforatum attenuates some physical signs of opium withdrawal syndrome possibly through direct or indirect interaction with opioid receptors. Further study is needed to clarify its mechanism.