Absence of ongoing activity in fibres arising from proximal nerve ends regenerating into mesothelial chambers

Morphological studies have indicated that proximal nerve ends of transected rat sciatic nerves regenerating into preformed mesothelial chambers show a different organization as compared to neuromas developed in contact with a muscle fascia. We have studied the physiological properties of nerve fibres arising from these types of preparations with reference to ongoing activity, response to mechanical stimulation and noradrenaline sensitivity. The study included also fibres arising from ligated and encapsulated neuromas. Fibres with ongoing activity arising from the neuroma could be found from neuromas in contact with a muscle fascia and also from ligated and encapsulated neuromas. This ongoing activity was enhanced by mechanical stimulation and i.v. infusion of noradrenaline. In contrast, fibres arising from proximal nerve ends in mesothelial chambers did not show ongoing activity. These silent fibres responded dynamically to light mechanical stimulation. Noradrenaline did not induce ongoing activity in these fibres.     

Second trimester maternal serum hCG level in an Asian population: normal reference values by ultrasound dating

OBJECTIVE: To establish normative data of maternal serum chorionic gonadotropin (hCG) during the second trimester in an Asian population. METHODS: We measured the maternal serum hCG levels in 17,955 normal singleton pregnancies between 15 and 21 weeks of gestation. The gestation age was estimated by measurement of fetal biparietal distance (BPD) in all cases. Median values of hCG at various gestational weeks were calculated and the values of hCG were converted to multiple of median (MoM). The incidences of low MoM value and high MoM value were also calculated. RESULTS: The mean and median values of hCG were 57,153 mIU/ml and 50,120 mIU/ml, respectively, at 15 weeks of gestation and then decreased to 30,898 mIU/ml and 26,226 mIU/ml, respectively, at 21 weeks. We found 8.6% and 9.4% of normal singleton pregnancies have hCG MoM values >2.0 MoM and <0.5 MoM, respectively. CONCLUSIONS: Our report provides a normal reference data of second trimester maternal hCG levels by ultrasound dating in an Asian population.     

Assessment of cytochrome P450‐mediated drug–drug interaction potential of orteronel and exposure changes in patients with renal impairment using physiologically based pharmacokinetic modeling and simulation

Orteronel is a nonsteroidal, selective inhibitor of 17,20‐lyase that was recently in phase 3 clinical development as a treatment for castration‐resistant prostate cancer. In humans, the primary clearance route for orteronel is renal excretion. Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9 and 2C19, with IC₅₀ values of 17.8, 27.7, 30.8 and 38.8 µm , respectively, whereas orteronel does not inhibit CYP2B6, 2D6 or 3A4/5 (IC₅₀ > 100 µm ). Orteronel also does not exhibit time‐dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5. The results of a static model indicated an [I]/K_i ratio >0.1 for CYP1A2, 2C8, 2C9 and 2C19. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to assess the potential for drug–drug interactions (DDIs) between orteronel and theophylline, repaglinide, (S)‐warfarin and omeprazole, which are sensitive substrates of CYP1A2, 2C8, 2C9 and 2C19, respectively. Simulation of the area under the plasma concentration–time curve (AUC) of these four CYP substrates in the presence and absence of orteronel revealed geometric mean AUC ratios <1.25. Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a ‘non‐inhibitor’ and further clinical DDI evaluation is not required. In PBPK models of moderate and severe renal impairment, the AUC of orteronel was predicted to increase by 52% and 83%, respectively. These results are in agreement with those of a clinical trial in which AUC increases of 38% and 87% were observed in patients with moderate and severe renal impairment, respectively. Copyright © 2014 John Wiley & Sons, Ltd.     

Chronic treatment with tempol does not significantly ameliorate renal tissue hypoxia or disease progression in a rodent model of polycystic kidney disease

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Prolonged treatment of genetically obese mice with conjugated linoleic acid improves glucose tolerance and lowers plasma insulin concentration: possible involvement of PPAR activation

Background

Studies in rodents and some studies in humans have shown that conjugated linoleic acid (CLA), especially its trans -10, cis -12 isomer, reduces body fat content. However, some but not all studies in mice and humans (though none in rats) have found that CLA promotes insulin resistance. The molecular mechanisms responsible for these effects are unclear, and there are conflicting reports on the effects of CLA on peroxisomal proliferator-activated receptor-γ (PPARγ) activation and expression. We have conducted three experiments with CLA in obese mice over three weeks, and one over eleven weeks. We have also investigated the effects of CLA isomers in PPARγ and PPARα reporter gene assays.

Results

Inclusion of CLA or CLA enriched with its trans -10, cis -12 isomer in the diet of female genetically obese (lep ^ob /lep ^ob ) mice for up to eleven weeks reduced body weight gain and white fat pad weight. After two weeks, in contrast to beneficial effects obtained with the PPARγ agonist rosiglitazone, CLA or CLA enriched with its trans -10, cis -12 isomer raised fasting blood glucose and plasma insulin concentrations, and exacerbated glucose tolerance. After 10 weeks, however, CLA had beneficial effects on glucose and insulin concentrations. At this time, CLA had no effect on the plasma TNFα concentration, but it markedly reduced the plasma adiponectin concentration. CLA and CLA enriched with either isomer raised the plasma triglyceride concentration during the first three weeks, but not subsequently. CLA enriched with its trans -10, cis -12 isomer, but not with its cis -9, trans -11 isomer, stimulated PPARγ-mediated reporter gene activity; both isomers stimulated PPARα-mediated reporter gene activity.

Conclusions

CLA initially decreased but subsequently increased insulin sensitivity in lep ^ob /lep ^ob mice. Activation of both PPARγ and PPARα may contribute to the improvement in insulin sensitivity. In the short term, however, another mechanism, activated primarily by trans -10, cis -12-CLA, which probably leads to reduced adipocyte number and consequently reduced plasma adiponectin concentration, may decrease insulin sensitivity.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: PHYSIOLOGICAL ACTIONS OF ANGIOTENSIN II MEDIATED BY AT1 AND AT2 RECEPTORS IN THE BRAIN

• 1 Autoradiographic binding studies have shown that the AT₁ receptor is the predominant angiotensin II (AngII) receptor subtype in the central nervous system (CNS). Major sites of AT₁ receptors are the lamina terminalis, hypothalamic paraventricular nucleus, the lateral parabrachial nucleus, rostral and caudal ventrolateral medulla, nucleus of the solitary tract and the intermediolateral cell column of the thoraco-lumbar spinal cord.
• 2 While there are differences between species, AT₂ receptors are found mainly in the cerebellum, inferior olive and locus coeruleus of the rat.
• 3 Circulating AngII acts on AT₁ receptors in the subfornical organ and organum vasculosum of the lamina terminalis (OVLT) to stimulate neurons that may have a role in initiating water drinking.
• 4 Centrally administered AngII may act on AT₁ receptors in the median preoptic nucleus and elsewhere to induce drinking, sodium appetite, a sympathetic vasoconstrictor response and vasopressin secretion.
• 5 Recent evidence shows that centrally administered AT₁ antagonists inhibit dipsogenic, natriuretic, pressor and vasopressin secretory responses to intracerebroventricular infusion of hypertonic saline. This suggests that an angiotensinergic neural pathway has a role in osmoregulatory responses.
• 6 Central angiotensinergic pathways which include neural inputs to the rostral ventrolateral medulla may use AT₁ receptors and play a role in the function of sympathetic pathways maintaining arterial pressure.

     

Implicit exchanges in family caregiving for frail elders in Taiwan

In this study, the authors use in-depth interviews with inductive analysis to develop a conceptual framework for exploring social exchanges and their implicit calculations for caregivers in Taiwan. They interviewed 12 caregivers, based on theory-based sampling and maximum variation. They found some components of implicit exchanges of the caregivers, and drew a framework to describe it. At the beginning of care, motivations were mostly from obligation accompanied by reciprocity or repaying motives. In the process of caregiving, some unique, implicit cultural implicit exchanges were found, such as karma, a demonstrative behavior to investment, equitable share of responsibility, and the pressure or rewards from public opinion. These implicit exchanges might be intermediary factors in helping caregivers cope with their burden or even in influencing their continuation of care. The findings are implicated to help family caregivers continue their care and not damage their quality of care.     

The RARgamma selective agonist CD437 inhibits gastric cell growth through the mechanism of apoptosis.

Retinoids are differentiation-inducing agents that exhibit multiple functions. Their activities are mediated through interaction with nuclear retinoic acid receptors (RAR) and retinoid X receptors (RXR). We have investigated the activities of synthetic retinoids on the growth of five gastric cancer cell lines. The effects of agonists selective for RARalpha, RARbeta and RARgamma (AM580, CD2019 and CD437, respectively) on cell growth were determined, in comparison to all-trans retinoic acid, by measuring total cellular DNA. AM580 and CD2019 had little or no effect on the growth of all five cell lines. In contrast, the RARgamma agonist CD437 inhibited cell growth up to 90-99% in both retinoic acid sensitive and resistant gastric cancer cells at a concentration of 1 microM. The growth suppression caused by CD437 was accompanied by the induction of apoptosis as judged by morphological criteria and DNA ladder formation. However, the extent of CD437-induced growth suppression was not correlated with RARgamma mRNA levels, which indicates that CD437 induces apoptosis in gastric cancer cells via an RARgamma independent pathway.