Organic anion-transporting polypeptides (OATP) 1B1 and 1B3 are widely acknowledged as important and rate-limiting to the hepatic uptake of many drugs in clinical use. Accordingly, to better understand the in vivo relevance of OATP1B transporters, targeted disruption of murine Slco1b2 gene was carried out. It is noteworthy that Slco1b2(Ϫ/Ϫ) mice were fertile, developed normally, and exhibited no overt phenotypic abnormalities. We confirmed the loss of Oatp1b2 expression in liver using real-time polymerase chain reaction, Western Blot analysis, and immunohistochemistry. Expression of Oatp1a4 and Oatp2b1 but not Oatp1a1 was greater in female Slco1b2(Ϫ/Ϫ) mice, but expression of other non-OATP transporters did not significantly differ between wild-type and Slco1b2(Ϫ/Ϫ) male mice. Total bilirubin level was elevated by 2-fold in the Slco1b2(Ϫ/Ϫ) mice despite the fact that liver enzymes ALT and AST were normal. Pharmacological characterization was carried out using two prototypical substrates of human OATP1B1 and -1B3, rifampin and pravastatin. After a single intravenous dose of rifampin (1 mg/kg), a 1.7-fold increase in plasma area under the concentration-time curve (AUC) was observed, whereas the liver-to-plasma ratio was reduced by 5-fold, and nearly 8-fold when assessed at steady-state conditions after 24 h of continuous subcutaneous infusion in Slco1b2(Ϫ/Ϫ) mice. Likewise, continuous subcutaneous infusion at low (8 g/h) or high (32 g/h) dose rates of pravastatin resulted in a 4-fold lower liver-plasma ratio in the in Slco1b2(Ϫ/Ϫ) mice. This is the first report of altered drug disposition profile in the Slco1b2 knockout mice and suggests the utility of this model for understanding the in vivo role of hepatic OATP transporters in drug disposition.
Aim:To compare insertion characteristics of 2 different supraglottic devices [I-gel and Proseal laryngeal mask airway (PLMA)] and to observe any associated complications.Study Design:This prospective, randomized study was conducted in 80 patients [Group I - I-gel insertion (n = 40) and Group P - LMA Proseal insertion (n =40)] of ASA grades I/II, of either sex in the age group 18-65 years. Both groups were compared with respect to ease of insertion, insertion attempts, fiberoptic assessment, airway sealing pressure, ease of gastric tube placement, and other complications.Materials and Methods:All patients were asked to fast overnight. Patients were given alprazolam 0.25 mg orally at 10 p.m. the night before surgery and again 2 hours prior to surgery with 1-2 sips of water. Glycopyrrolate 0.2 mg, metoclopramide 10 mg, and ranitidine 50 mg were administered intravenously to the patients 45 minutes prior to the surgery. Once adequate depth of anesthesia was achieved either of the 2 devices, selected using a random computerized table, was inserted by an experienced anesthesiologist. In group I, I-gel was inserted and in patients of group P, PLMA was inserted.Statistical Analysis:Student t-test and Mann-Whitney test were employed to compare the means; for categorical variables, Chi-square test was used.Result:Mean insertion time for the I-gel (11.12 ± 1.814 sec) was significantly lower than that of the PLMA (15.13 ± 2.91 sec) (P = 0.001). I-gel was easier to insert with a better anatomic fit. Mean airway sealing pressure in the PLMA group (29.55 ± 3.53 cm H2O) was significantly higher than in the I-gel group (26.73 ± 2.52 cm H2O; P = 0.001). Ease of gastric tube insertion was significantly higher in the I-gel group (P = 0.001). Incidence of blood staining of the device, sore throat and dysphagia were observed more in PLMA group. No other complications were observed in either of the groups.
The pathological diagnosis of borderline rejection (BL‐R) denotes possible T cell–mediated rejection (TCMR), but its clinical significance is uncertain. This single‐center, cross‐sectional cohort study compared the functional and histological outcomes of consecutive BL‐R diagnoses (n = 146) against normal controls (n = 826) and acute TCMR (n = 55) from 551 renal transplant recipients. BL‐R was associated with the following: contemporaneous renal dysfunction, acute tubular necrosis, and chronic tubular atrophy (P < .001); progressive tubular injury with fibrosis by longitudinal sequential histology (45.3% at 1 year); increased subsequent acute rejection (39.4%), allograft failure (P < .001), and patient mortality (P = .007). BL‐R detected by biopsy indicated for impaired function was followed by suboptimal functional recovery (46.3%), persistent inflammation (27.2%), and acute rejection episodes (50.0%) despite antirejection treatment in 83.3%. By 1 year after BL‐R, the incidence of new‐onset microvascular inflammation (9.3%), C4d staining (22.3%), transplant glomerulopathy (13.3%), and de novo donor‐specific antibodies (31.5%) exceeded normal controls (P < .05‐.001). BL‐R inflammation in protocol biopsy persisted in 28.0% and progressed to acute rejection in 32.6%; however, it resolved in 61.6% of the untreated cases. In summary, BL‐R is a heterogeneous diagnostic grouping, ranging from mild inconsequential inflammation to clinically significant TCMR, which is capable of immune‐mediated tubular injury resulting in inferior functional, immunological, and histological consequences.
The hindbrain and cranial paraxial mesoderm have been implicated in the induction and patterning of the inner ear, but the precise role of the two tissues in these processes is still not clear. We have addressed these questions using the vitamin-A-deficient (VAD) quail model, in which VAD embryos lack the posterior half of the hindbrain that normally lies next to the inner ear. Using a battery of molecular markers, we show that the anlagen of the inner ear, the otic placode, is induced in VAD embryos in the absence of the posterior hindbrain. By performing grafting and ablation experiments in chick embryos, we also show that cranial paraxial mesoderm which normally lies beneath the presumptive otic placode is necessary for otic placode induction and that paraxial mesoderm from other locations cannot induce the otic placode. Two members of the fibroblast growth factor family, FGF3 and FGF19, continue to be expressed in this mesodermal population in VAD embryos, and these may be responsible for otic placode induction in the absence of the posterior hindbrain. Although the posterior hindbrain is not required for otic placode induction in VAD embryos, the subsequent patterning of the inner ear is severely disrupted. Several regional markers of the inner ear, such as Pax2, EphA4, SOHo1 and Wnt3a, are incorrectly expressed in VAD otocysts, and the sensory patches and vestibulo-acoustic ganglia are either greatly reduced or absent. Exogenous application of retinoic acid prior to 30 h of development is able rescue the VAD phenotype. By performing such rescue experiments before and after 30 h of development, we show that the inner ear defects of VAD embryos correlate with the absence of the posterior hindbrain. These results show that induction and patterning of the inner ear are governed by separate developmental processes that can be experimentally uncoupled from each other.
Neurodegenerative disorders have been considered as a growing health concern for decades. Increasing risk of neurodegenerative disorders creates a socioeconomic burden to both patients and care givers. Mitochondria are organelle that are involved in both neuroinflammation and neurodegeneration. There are few reports on the effect of mitochondrial metabolism on the progress of neurodegeneration and neuroinflammation. Therefore, the present review summarizes the potential contribution of mitochondrial metabolic pathways in the pathogenesis of neuroinflammation and neurodegeneration. Mitochondrial pyruvate metabolism plays a critical role in the pathogenesis of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. However, there its potential contribution in other neurodegenerative disorders is as yet unproven. The mitochondrial pyruvate carrier and pyruvate dehydrogenase can modulate mitochondrial pyruvate metabolism to attenuate neuroinflammation and neurodegeneration. Further, it has been observed that the mitochondrial citric acid cycle can regulate the pathogenesis of neuroinflammation and neurodegeneration. Additional research should be undertaken to target tricarboxylic acid cycle enzymes to minimize the progress of neuroinflammation and neurodegeneration. It has also been observed that the mitochondrial urea cycle can potentially contribute to the progression of neurodegenerative disorders. Therefore, targeting this pathway may control the mitochondrial dysfunction-induced neuroinflammation and neurodegeneration. Furthermore, the mitochondrial malate-aspartate shuttle could be another target to control mitochondrial dysfunction-induced neuroinflammation and neurodegeneration in neurodegenerative disorders.
Non-neoplastic epithelial pancreatic cysts are rare, benign lesions. In our institutional experience, these lesions are often indistinguishable from cystic neoplasms of the pancreas preoperatively. As such, many of these lesions are resected unknowingly. It is important for the clinician to be well informed of the nature of these lesions, in the hopes to avoid unnecessary resection whenever possible.
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