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.     

Older people with hip fracture: depression in the postoperative first year

Title. Older people with hip fracture: depression in the postoperative first year. Aim. This paper is a report of a study conducted to describe changes in risk of depressive symptoms and their predictors for older people with hip fracture during the first year following hospital discharge. Background. The prevalence of depression in older people with hip fracture has been reported as 9–47%. However, the longitudinal changes in prevalence rate following hip fracture have not been well‐studied, particularly in Asian countries. Methods. The study was conducted in Taiwan in 2001–2003. A sample of 147 older people with hip fracture was assessed for depressive symptoms before discharge, and at 1, 3, 6 and 12 months after discharge using the Chinese version of the Geriatric Depression Scale. Longitudinal data were analysed by the generalized estimating equation approach. Findings. The majority of participants were at risk for depressive symptoms before discharge (n = 147, 57·8%) and 35·6% (n = 118) 12 months after discharge. These numbers decreased statistically significantly from before discharge to the 1st month after discharge (57·8% vs. 42·6%, P = 0·008), and from the 1st to the 6th month (42·6% vs. 31·3%, P = 0·03), and then remained stable until the 12th month after discharge. Lower emotional‐social support predicted persistent depressive symptoms after discharge (P < 0·01). Conclusion. Timely psychological interventions are suggested within the first 6 months after discharge, especially the first 3 months. Healthcare professionals need to pay attention to older patients with hip fracture who are female, with poorer prefracture functioning and particularly those with lower emotional‐social support.     

Peroxisome proliferator-activated receptor delta agonists attenuated the C-reactive protein-induced pro-inflammation in cardiomyocytes and H9c2 cardiomyoblasts

C-reactive protein (CRP) has emerged as a new marker for cardiovascular diseases. Activation of peroxisome proliferator-activated receptor δ (PPARδ) plays beneficial roles in cardiac disorders. However, the relationship between CRP and PPARδ in cardiac cells remains unclear. This study focused on the underlying molecular mechanisms of CRP and PPARδagonists. Cardiomyocytes and cardiomyoblast cell line (H9c2) were used in different groups: Untreated; 15 μg/ml CRP with or without 1 μM PPARδ agonists (L-165041). CRP increased PPARδ and interleukin-6 expression in cardiomyocytes and H9c2 cardiomyoblasts. NF-κB inducing kinase (NIK) and NF-κB pathway also activated by CRP stimulation. These changes could be inhibited by L-165041 through p38MAPK and c-JNK pathways. However, transfection with siRNA of CD32 CRP receptor did not decrease CRP signaling or reverse the effects of L-165041 in CRP-treated cardiomyocytes and H9c2. Pretreatment with L-165041 attenuated apoptosis induced by hypoxia with or without CRP in H9c2 cardiomyoblasts. CRP up-regulated PPARδ expression in cardiomyocytes and H9c2. L-165041 attenuated CRP-induced pro-inflammatory signaling through p38MAPK and c-JNK in H9c2 cardiomyoblasts. However, PPARδ activation attenuated CRP-induced NF-κB pathway may be independent of CD32. These results may provide new evidence of PPARδ beneficial effects for inflammatory cardiomyopathy.     

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.     

Pharmacokinetics of didanosine in patients with acquired immunodeficiency syndrome or acquired immunodeficiency syndrome-related complex

The pharmacokinetics of didanosine (2',3'-dideoxyinosine) after intravenous and oral administration were evaluated in an open, escalating-dose phase I study in patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex. Didanosine was administered twice a day for 2 weeks as an intravenous infusion of 60 minutes duration at doses ranging from 0.4 to 16.5 mg/kg, followed by 4 weeks of oral treatment at twice the intravenous dose. Serial blood and urine samples were obtained on the first and final day of intravenous administration and after the first oral dose, as well as at steady state. Didanosine demonstrated linear pharmacokinetic behavior over the dose ranges of 0.4 to 16.5 mg/kg intravenously and 0.8 to 10.2 mg/kg orally. There was no indication of significant changes in pharmacokinetic parameters with repeated administration. The apparent elimination half-life after oral administration was approximately 1.4 hour. Renal clearance values exceeded the glomerular filtration rate, indicating that active tubular secretion of didanosine occurs. Bioavailability of didanosine when administered as a solution with an antacid was approximately 43% for doses from 0.8 to 10.2 mg/kg in patients with AIDS and advanced AIDS-related complex. Bioavailability of didanosine from the citrate-phosphate-buffered solution, the formulation currently used in phase II and expanded access studies, was comparable to the formulation used in the phase I trials.     

Prenatal depiction of angioarchitecture of an aneurysm of the vein of Galen with three-dimensional color power angiography.

A fetus with a large supratentorial cyst and cardiomegaly was encountered at 33 weeks of gestation. The cyst appeared as an aneurysmal, fluid-filled structure extending posteriorly with a finger-like appendage. Using color flow mapping, we disclosed rapid in-and-out blood flow with marked turbulence within the cyst. For evaluation of its blood supply and venous drainage of the vascular malformation, a three-dimensional reconstruction of the power Doppler image was conducted. The results revealed that the vascular malformation was supplied by a small contralateral aneurysm from the branches of Willis' circle, draining posteriorly into an abnormal falcine sinus and then into the superior sagittal sinus. No other fetal abnormality such as hydrocephalus or hydrops was discovered. The prenatal diagnosis of an aneurysm of the vein of Galen was made on the basis of the gray-scale, color Doppler findings, and also the angioarchitecture obtained by three-dimensional power Doppler imaging. The woman was admitted at 37 weeks of gestation due to labor onset and delivered the baby via the vaginal route without complication. Postnatal angiography and magnetic resonance imaging confirmed the diagnosis of an aneurysm of the vein of Galen, and the angioarchitecture depicted it before birth. We suggest that three-dimensional power Doppler ultrasonography may assist in the diagnosis of an aneurysm of the vein of Galen, and precisely delineate the complicated corresponding vasculature. This may guide postnatal management and predict the prognosis more accurately.     

A minimal stress model for the assessment of electroacupuncture analgesia in rats under halothane.

The use of anesthetics in acupuncture analgesia is controversial. We evaluate a steady-state light anesthesia model to test whether minimal stress manipulation and reliable measurement of analgesia could be simultaneously achieved during electroacupuncture (EA) in animals. A series of experiments were performed. Firstly, EA compliance and tail-flick latencies (TFL) were compared in rats under 0.1%, 0.3%, 0.5%, 0.7%, or 1.1% halothane for 120min. Under 0.5% halothane, TFL were then measured in groups receiving EA at intensity of 3, 10 or 20 volt (V), 1 or 2mg/kg morphine, 20V EA plus naloxone, or control. Subsequently, the effect of EA on formalin-induced hyperalgesia was tested and c-fos expression in the spinal dorsal horn was analyzed. Rats exhibited profound irritable behaviors and highly variable TFL under 0.1% or 0.3% halothane, as well as a time-dependent increase of TFL under 0.7% or 1.1% halothane. TFL remained constant at 0.5% halothane, and needle insertion and electrical stimulation were well tolerated. Under 0.5% halothane, EA increased TFL and suppressed formalin-induced hyperalgesia in an intensity-dependent and naloxone-reversible manner. EA of 20V prolonged TFL by 74%, suppressed formalin-induced hyperalgesia by 32.6% and decreased c-fos expression by 29.7% at the superficial and deep dorsal horn with statistically significant difference. In conclusion, 0.5% halothane provides a steady-state anesthetic level which enables the humane application of EA stimulus with the least interference on analgesic assessment. This condition serves as a minimal stress EA model in animals devoid of stress-induced analgesia while maintaining physiological and biochemical response in the experiment.     

Selective COX2 inhibition improves whole body and muscular insulin resistance in fructose‐fed rats

Background The effects of cyclooxygenase‐1 (COX1) and cyclooxygenase‐2 (COX2) inhibition on insulin resistance in subjects with the metabolic syndrome remain elusive. Aims of this study were to examine the effects of COX1 and COX2 inhibitors on whole body and muscular insulin resistance in fructose‐fed rats, an animal model of the metabolic syndrome. Materials and methods The rats on regular or 60% fructose‐enriched diets for 6 weeks were further divided into rats combined with or without piroxicam (a selective COX1 inhibitor) or celecoxib (a selective COX2 inhibitor) treatment for an additional 2 weeks. Euglycaemic hyperinsulinaemic clamp (EHC) with a tracer dilution method was performed at the end of the study. Results The present result showed that fructose‐induced increases in systolic blood pressure and fasting plasma insulin levels were significantly suppressed in rats treated with celecoxib but not piroxicam. In the EHC period, celecoxib significantly reversed fructose‐induced decreases in whole body glucose uptake, mainly by glucose storage. Hepatic glucose production and whole body glycolysis were not significantly changed among groups. Celecoxib but not piroxicam significantly reversed fructose‐induced decreases in glycogen synthase activities in red and white quadriceps muscles and insulin‐stimulated membrane GLUT4 recruitment in soleus muscles. Celecoxib and piroxicam both significantly diminished fructose‐induced increases in plasma thromboxane B2 and 6‐keto prostaglandin (PG) F1α; but only celecoxib treatment significantly attenuated a fructose‐induced increase in 8‐isoprostane levels. Plasma PGE metabolites were not different among groups. Conclusions This study demonstrates that a therapeutic dose of celecoxib, but not piroxicam, could significantly attenuate fructose‐induced whole body and muscular insulin resistance in rats.     

Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration.

The pharmacokinetics and tissue penetration, as judged by skin blister fluid, of cefprozil and cefaclor were examined in 12 healthy male volunteers. Doses of 250 and 500 mg of each drug were given to fasting subjects in a crossover fashion. Serially obtained plasma, skin blister fluid, and urine samples were analyzed for cefprozil or cefaclor by validated high-pressure liquid chromatographic methods. After oral administration of 250 and 500 mg of cefprozil, mean concentrations in plasma rose to peak levels (Cmax) of 6.1 and 11.2 micrograms/ml, respectively, and those of cefaclor were 10.6 and 17.3 micrograms/ml, respectively. The elimination half-life of cefprozil (1.3 h) was significantly longer than that of cefaclor (0.6 h), and as a result, the area under the curve for cefprozil was about two times greater than that for cefaclor. Both cephalosporins were primarily excreted unchanged in urine. The mean skin blister Cmax values were 3.0 and 5.8 micrograms/ml for cefprozil and 3.6 and 6.5 micrograms/ml for cefaclor after the 250- and 500-mg oral doses, respectively. The mean Cmax values in skin blister fluid for both cephalosporins were comparable and were significantly lower than the corresponding Cmax values in plasma. However, the levels of cefprozil and cefaclor in skin blister fluid declined more slowly than they did in plasma. The skin blister fluid half-life estimates for cefprozil were significantly longer than they were for cefaclor. Parallel to the observation in plasma, the mean skin blister fluid areas under the curve for cefprozil were significantly higher than they were for cefaclor. The plasma and skin blister fluid pharmacokinetic analyses suggest that the exposure of humans to cefprozil is significantly greater than that to cefaclor at the same dose.     

Pharmacokinetics of the novel cephalosporin cefepime (BMY-28142) in rats and monkeys.

The disposition of the novel cephalosporin cefepime (BMY-28142) was characterized for intravenous administration of single doses to rats and cynomolgus monkeys, the species used most extensively for safety evaluation of the compound. Serial blood samples were collected from individual animals, and plasma was analyzed for intact cefepime by a high-pressure liquid chromatography-UV method. Assay results were evaluated by compartmental and noncompartmental methods to characterize pharmacokinetics for each species and dosage regimen. For intravenous (i.v.) bolus administration of 28 to 386 mg/kg (body weight) to rats, total body clearance (CL; 11.0 ml/min per kg) was essentially invariant with the dose; however, the terminal half-life (t1/2) and the steady-state distribution volume (Vss) increased with increasing dose level. After administration of 87 to 1,502 mg/kg by i.v. infusion, CL (12.5 ml/min per kg) was again similar for all dose groups. Mean t1/2 values (1.3 to 4.6 h) appeared unusually long for a cephalosporin in rats, and inordinately variable. No consistent differences among dose group mean Vss values were found. The maximal concentration of drug in plasma at the end of infusion was not a linear function of dose. For the cynomolgus monkey, kinetic parameters for 5-min i.v. infusions were linearly related to dose over the range of 10 to 600 mg/kg. Mean parameter values were t1/2 = 1.7 h, CL = 1.6 ml/min per kg, and Vss = 0.21 liters/kg. The pharmacokinetic results indicate substantive differences between the two species with respect to their response to toxicologic doses of cefepime.