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Daily Injections (daily + injection)
Kinds of Daily Injections Selected AbstractsInhibitory effects of a new bisphosphonate, minodronate, on proliferation and invasion of a variety of malignant bone tumor cellsJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2006Tadahiko Kubo Abstract Little is known about the biological effects of bisphosphonates on primary malignant bone tumors. The purpose of this study was to investigate the antitumor effects of newly developed minodronate (MIN) on a variety of human malignant bone tumors. We examined the effects of MIN and clinically relevant incadronate (INC) on the proliferation, apoptosis, and cell cycle of two osteosarcoma (Saos-2, MG-63), two chondrosarcoma (SW1353, OUMS27), and two Ewing's sarcoma (RD-ES, SK-ES-1) cell lines. Furthermore, we investigated the anti-invasion effects of MIN on sarcoma cells and the effects of MIN on tumor growth in nude mice. MIN inhibited the viability of all six cell lines in a dose-dependent manner with IC50 values of 2.7 to 5.0 µM, which were significantly lower than those of INC. Importantly, both bisphosphonates affected the viability of normal bone marrow stromal cells much less than sarcoma cells. Both bisphosphonates induced cell cycle perturbation in all sarcoma cells tested and apoptosis in Saos-2 and SW1353 cells, although they failed to induce apoptosis in RD-ES and SK-ES-1 cells. MIN significantly suppressed invasion, even at a low concentration of 1 µM (p,<,0.01). Daily injection of 5 µg of MIN inhibited the growth of SK-ES-1 xenograft sarcoma in nude mice without loss of body weight. These findings suggest that MIN may have a beneficial adjuvant role in the treatment of patients with malignant bone tumors. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 24:1138,1144, 2006 [source] Mid- and high-ratio premix insulin analogues: potential treatment options for patients with type 2 diabetes in need of greater postprandial blood glucose controlDIABETES OBESITY & METABOLISM, Issue 2 2010J. S. Christiansen Some patients with type 2 diabetes continue to have high postprandial blood glucose levels on twice-daily regimens of ,low-ratio' premix insulin formulations (up to 30% rapid-acting, with 70% protracted insulin). These patients require intensified insulin therapy, which can be provided by a twice- or thrice-daily regimen of mid-ratio (50% rapid-acting and 50% protaminated intermediate-acting insulin , human or analogue) or high-ratio (70% rapid-acting and 30% protaminated insulin , analogue only) premix insulin. Alternatively, a third daily injection of low-ratio premix insulin can be added to the regimen, with the option of incorporating one or more injections of mid- or high-ratio premix as required, and as an alternative to basal,bolus therapy. How these mid- and high-ratio formulations differ from the low-ratio premix insulins is reviewed here, with the aim of identifying the role of these formulations in diabetes management. Glucose clamp studies have shown that premix analogues give serum insulin levels proportional to their percentage of rapid-acting uncomplexed insulin: the higher the proportion, the greater the maximum level reached. Other pharmacokinetic parameters were not always significantly different between the mid- and high-ratio formulations. In clinical trials, postprandial plasma glucose and glycated haemoglobin A1c (HbA1c) levels were significantly reduced with thrice-daily mid- /high-ratio premix analogue when compared with twice-daily low-ratio biphasic human insulin (BHI) 30/70 or once-daily insulin glargine. Moreover, glycaemic control with mid-/high-ratio premix analogue was found to be similar to that with a basal,bolus therapy. Mid- and high-ratio premix regimens are generally well tolerated. The frequency of minor hypoglycaemia was reportedly higher with mid- /high-ratio premix analogues than with BHI 30, but nocturnal hypoglycaemia was less frequent. Although there is little evidence that clinical outcomes with mid-ratio premix analogues are different from those with high-ratio, they are useful additions to the low-ratio formulations for the management of diabetes, and addressing postprandial hyperglycaemia in particular. [source] Recent advances in treatment of youth with Type 1 diabetes: better care through technologyDIABETIC MEDICINE, Issue 11 2001W. V. Tamborlane Abstract While treatment of Type 1 diabetes mellitus (T1DM) in children and adolescents is especially difficult, recent technological advances have provided new therapeutic options to clinicians and patients. The urgency to achieve strict diabetes control and the introduction of new and improved insulin pumps have been accompanied by a marked increase in use of continuous subcutaneous insulin infusion (CSII) therapy in youth with diabetes. Results of clinical outcome studies indicate that CSII provides a safe and effective alternative to multiple daily injection (MDI) therapy, even when employed in a regular clinic setting in a large number of children. The safety and efficacy of CSII is further enhanced by the introduction of lispro and aspart insulin. The sharper peaks and shorter duration of action of these very rapid-acting insulin analogues provides a means to achieve better control of post-prandial hyperglycaemia with less late post-prandial and nocturnal hypoglycaemia. Glargine insulin, a soluble and essentially peakless long-acting insulin analogue, may provide a better basal insulin for MDI regimens, but there are limited published data with this agent in children with T1DM. A number of systems for pulmonary delivery of insulin are in development and preliminary results of Phase III studies have been promising. Like CSII, inhaled insulin allows the child to take bolus insulin doses before each meal without having to take a premeal injection. A major obstacle to effective treatment is that self-monitoring of three to four blood glucose levels a day often misses the marked glycaemic excursions that characterize T1DM in young patients. On the other hand, new continuous glucose sensing systems provide a wealth of data that can be used to optimize basal and bolus therapy, regardless of how insulin is administered. Even more important, we may finally be at the threshold of development of a practically applicable artificial pancreas. Diabet. Med. 18, 864,870 (2001) [source] Changes in Canadian heroin supply coinciding with the Australian heroin shortageADDICTION, Issue 5 2006Evan Wood ABSTRACT Aims Previous studies have largely attributed the Australian heroin shortage to increases in local law enforcement efforts. Because western Canada receives heroin from similar source nations, but has not measurably increased enforcement practices or funding levels, we sought to examine trends in Canadian heroin-related indices before and after the Australian heroin shortage, which began in approximately January 2001. Methods During periods before and after January 2001, we examined the number of fatal overdoses and ambulance responses to heroin-related overdoses that required the use of naloxone in British Columbia, Canada. As an overall marker of Canadian supply reduction, we also examined the quantity of heroin seized during this period. Lastly, we examined trends in daily heroin use among injection drug users enrolled in the Vancouver Injection Drug Users Study (VIDUS). Results There was a 35% reduction in overdose deaths, from an annual average of 297 deaths during the years 1998,2000 in comparison to an average of 192 deaths during 2001,03. Similarly, use of naloxone declined 45% in the period coinciding with the Australian heroin shortage. Interestingly, the weight of Canadian heroin seized declined 64% coinciding with the Australian heroin shortage, from an average of 184 kg during 1998,2000 to 67 kg on average during 2001,03. Among 1587 VIDUS participants, the period coinciding with the Australian heroin shortage was associated independently with reduced daily injection of heroin [adjusted odds ratio: 0.55 (95% CI: 0.50,0.61); P < 0.001]. Conclusions Massive decreases in three independent markers of heroin use have been observed in western Canada coinciding with the Australian heroin shortage, despite no increases in funding to Canadian enforcement efforts. Markedly reduced Canadian seizure activity also coincided with the Australian heroin shortage. These findings suggest that external global heroin supply forces deserve greater investigation and credence as a potential explanation for the Australian heroin shortage. [source] Blockade of caspase-1 increases neurogenesis in the aged hippocampusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2007Carmelina Gemma Abstract Adult hippocampal neurogenesis dramatically decreases with increasing age, and it has been proposed that this decline contributes to age-related memory deficits. Central inflammation contributes significantly to the decrease in neurogenesis associated with ageing. Interleukin-1, is a proinflammatory cytokine initially synthesized as an inactive precursor that is cleaved by caspase-1 to generate the biologically active mature form. Whether IL-1, affects neurogenesis in the aged hippocampus is unknown. Here we analysed cells positive for 5-bromo-2-deoxyuridine (BrdU; 50 mg/kg) in animals in which cleavage of IL-1, was inhibited by the caspase-1 inhibitor Ac-YVAD-CMK (10 pmol). Aged (22 months) and young (4 months) rats received Ac-YVAD-CMK for 28 days intracerebroventricularly through a brain infusion cannula connected to an osmotic minipump. Starting on day 14, animals received a daily injection of BrdU for five consecutive days. Unbiased stereology analyses performed 10 days after the last injection of BrdU revealed that the total number of newborn cells generated over a 5-day period was higher in young rats than in aged rats. In addition, there was a 53% increase in the number of BrdU-labelled cells of the aged Ac-YVAD-CMK-treated rats compared to aged controls. Immunofluorescence studies were performed to identify the cellular phenotype of BrdU-labelled cells. The increase in BrdU-positive cells was not due to a change in the proportion of cells expressing neuronal or glial phenotypes in the subgranular zone. These findings demonstrate that the intracerebroventricular administration of Ac-YVAD-CMK reversed the decrease in hippocampal neurogenesis associated with ageing. [source] An adaptive clinical Type 1 diabetes control protocol to optimize conventional self-monitoring blood glucose and multiple daily-injection therapyINTERNATIONAL JOURNAL OF ADAPTIVE CONTROL AND SIGNAL PROCESSING, Issue 5 2009Xing-Wei Wong Abstract The objective of this study was to develop a safe, robust and effective protocol for the clinical control of Type 1 diabetes using conventional self-monitoring blood glucose (SMBG) measurements, and multiple daily injection (MDI) with insulin analogues. A virtual patient method is used to develop an in silico simulation tool for Type 1 diabetes using data from a Type 1 diabetes patient cohort (n=40) . The tool is used to test two prandial insulin protocols, an adaptive protocol (AC) and a conventional intensive insulin therapy (IIT) protocol (CC) against results from a representative control cohort as a function of SMBG frequency. With the prandial protocols, optimal and suboptimal basal insulin replacement using a clinically validated, forced-titration regimen is also evaluated. A Monte Carlo (MC) analysis using variability and error distributions derived from the clinical and physiological literature is used to test efficacy and robustness. MC analysis is performed for over 1 400 000 simulated patient hours. All results are compared with control data from which the virtual patients were derived. In conditions of suboptimal basal insulin replacement, the AC protocol significantly decreases HbA1c for SMBG frequencies ,6/day compared with controls and the CC protocol. With optimal basal insulin, mild and severe hypoglycaemia is reduced by 86,100% over controls for all SMBG frequencies. Control with the CC protocol and suboptimal basal insulin replacement saturates at an SMBG frequency of 6/day. The forced-titration regimen requires a minimum SMBG frequency of 6/day to prevent increased hypoglycaemia. Overaggressive basal dose titration with the CC protocol at lower SMBG frequencies is likely caused by uncorrected postprandial hyperglycaemia from the previous night. From the MC analysis, a defined peak in control is achieved at an SMBG frequency of 8/day. However, 90% of the cohort meets American Diabetes Association recommended HbA1c with just 2 measurements a day. A further 7.5% requires 4 measurements a day and only 2.5% (1 patient) required 6 measurements a day. In safety, the AC protocol is the most robust to applied MC error. Over all SMBG frequencies, the median for severe hypoglycaemia increases from 0 to 0.12% and for mild hypoglycaemia by 0,5.19% compared with the unrealistic no error simulation. While statistically significant, these figures are still very low and the distributions are well below those of the controls group. An adaptive control protocol for Type 1 diabetes is tested in silico under conditions of realistic variability and error. The adaptive (AC) protocol is effective and safe compared with conventional IIT (CC) and controls. As the fear of hypoglycaemia is a large psychological barrier to appropriate glycaemic control, adaptive model-based protocols may represent the next evolution of IIT to deliver increased glycaemic control with increased safety over conventional methods, while still utilizing the most commonly used forms of intervention (SMBG and MDI). The use of MC methods to evaluate them provides a relevant robustness test that is not considered in the no error analyses of most other studies. Copyright © 2008 John Wiley & Sons, Ltd. [source] Differential effect of hyperthyroidism on rat epididymal glycosidasesINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 4 2001R. R. M. Maran The impact of hyperthyroidism on epididymal glycosidases was studied in albino rats. Hyperthyroidism was induced in Wistar rats aged 30 days by daily injection of T4 (25 ,g/100 g body weight/day intramuscularly) for 30 or 60 days; control rats were injected with vehicle (alkaline saline, pH 7.8). One set of hyperthyroid rats was reverted to euthyroid status by withdrawing T4 treatment after 30 days of hyperthyroidism. To asses the direct effect of thyroid hormone on epididymal hexosaminidases, caput, corpus and cauda tissues were stimulated with 25, 50 or 100 ng/mL T3 for 24 h, after an initial culture of 24 h. The activity of ,-glucosidase decreased in caput, corpus and cauda epididymis of hyperthyroid rats. ,-Galactosidase activity increased in the caput epididymis irrespective of the duration of hyperthyroidism. While a similar decrease occurred in the corpus and cauda epididymis in the 30 day hyperthyroid group, an opposite trend was observed in 60 day hyperthyroid rats. Caput ,- N -acetylglucosaminidase activities increased at both time points, whereas activity decreased in the corpus and cauda in 30 day, but increased in 60 day hyperthyroid rats. Hyperthyroidism consistently increased caput and corpus ,- N -acetylgalactosaminidase activity irrespective of the duration. Cauda epididymal ,- N -acetylgalactosaminidase activity was decreased in 30 day and increased in 60 day hyperthyroid rats. Hyperthyroidism induced changes in caput ,-galactosidase, ,- N -acetylgalactosaminidases, corpus ,-N-acetylglucosaminidase and cauda ,- N -acetylgalactosaminidase which were irreversible while the remaining actvities were brought back to normal when T4 treatment was withdrawn. In vitro studies showed that T3 stimulates epididymal hexosaminidases (,- N -acetylglucosaminidase and ,- N -acetylgalactosaminidase) irrespective of the dose. These data suggest that thyroid hormones have a specific and direct influence on glycosidases in specific regions of the epididymis. [source] Enhancing Effect of Tob Deficiency on Bone Formation Is Specific to Bone Morphogenetic Protein-Induced Osteogenesis,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2002Michihiko Usui Abstract Tob is a recently reported novel bone morphogenetic protein (BMP) inhibitor, which originally was identified by West-Western procedure using ErbB2 as a probe and contains a nuclear localization signal. To further characterize the effects of Tob deficiency on BMP-induced new bone (NB) formation, we examined microcomputed tomography (,CT) on the cross-section of the bone induced by daily injection with BMP onto the calvariae of newborn mice. The calvariae of the saline-injected Tob-deficient (TD) mice were similar to those of the saline-injected or untreated wild-type (WT) mice. BMP injection locally produced NB on the calvaria in WT mice as known previously. In contrast to WT mice, BMP injection onto the calvariae of TD mice produced a calcified area in the cross-section of NB, which was more than that produced by BMP in the WT calvariae. In addition, the horizontal width and the vertical height of the NB induced by BMP in TD mice were several-fold more than those in WT mice. The effect of Tob deficiency on bone-forming activity was selective to the response to the injection with BMP because the levels of injury-induced NB formation examined by ,CT 10 days after bone marrow ablation in the femora were similar between the TD and WT mice. These data indicate that Tob acts as a novel specific antagonist against bone formation induced by BMP treatment in bone. [source] Protective effect of melatonin against hippocampal injury of rats with intermittent hypoxiaJOURNAL OF PINEAL RESEARCH, Issue 2 2008Ming-Wai Hung Abstract:, Obstructive sleep apnea (OSA) patients suffer from intermittent hypoxia (IH) and neuropsychologic impairments. Oxidative stress is involved in the pathogenesis of OSA, so the application of an antioxidant may be useful. We evaluated the hypothesis that melatonin would reduce IH-induced hippocampal injury via an increased expression of antioxidant enzymes. Adult Sprague,Dawley rats that had received a daily injection of melatonin or vehicle were exposed to IH for 8 hr/day for 7 or 14 days. The serum and hippocampus were harvested for the measurement of malondialdehyde (MDA). Apoptotic cell death was studied histologically in hippocampal sections. The mRNA expression of inflammatory mediators including tumor necrosis factor-alpha, inducible nitric oxide synthase, cyclooxygenase-2 and antioxidant enzymes including glutathione peroxidase, catalase and copper/zinc superoxide dismutase were examined in the hippocampus by RT-PCR. The results show significant increases in levels of serum and hippocampal MDA, apoptotic cell death and mRNA levels of inflammatory mediators in hypoxic rats when compared with the normoxic controls. Also, mRNA levels of the antioxidant enzymes were decreased in hypoxic animals. In the melatonin-treated hypoxic rats, serum MDA levels were comparable with those in normoxic control rats. Also, melatonin treatment significantly reduced hippocampal MDA levels and totally prevented apoptosis. Moreover, there were a decreased expression of the inflammatory mediators and an elevated expression of antioxidant enzymes in the melatonin injected rats when compared with vehicle-treated animals. These results indicate that melatonin mitigates oxidative stress and the pathogenesis of IH-induced hippocampal injury via its antioxidant and anti-inflammatory properties which includes stimulation of transcriptional regulation of antioxidant enzymes. [source] Stimulatory and entraining effect of melatonin on tuberoinfundibular dopaminergic neuron activity and inhibition on prolactin secretionJOURNAL OF PINEAL RESEARCH, Issue 4 2000Yeh-Shiu Chu The aims of the present study were to determine if melatonin exerts an effect on prolactin (PRL) secretion via the tuberoinfundibular dopaminergic (TIDA) neurons and if endogenous or exogenous melatonin has an entraining effect on the rhythmic changes of TIDA neuronal activity and PRL secretion. Melatonin given in the morning (10:00 h), dose- (0.01,1 mg/kg, ip) and time- (at 15 and 60 min, but not at 30 min) dependently stimulated TIDA neuronal activity in ovariectomized (OVX), estrogen-treated rats as determined by 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the median eminence (ME). Serum PRL was concurrently inhibited by the injection. Melatonin administered in the afternoon (15:00 h) was even more effective in stimulating the lowered TIDA neuronal activity and inhibiting the increased PRL level than that given in the morning (10:00 h). S-20098, a melatonin agonist was also effective in stimulating the TIDA neurons. In contrast, S-20928, a putative melatonin antagonist, while it had no effect by itself, blocked the effect of S-20098. Although S-20928 failed to prevent melatonin's effect on ME DOPAC levels, six interspaced injections of S-20928, from 18:00 to 01:30 h, significantly blocked the increase of ME DOPAC levels at 03:00 h, indicating that the endogenous melatonin may play a role. We further used rats that received daily injection of melatonin (1 mg/kg, ip) at 18:00 h for 10 days and found that the injection augmented basal TIDA neuronal activity at 11:00 h and blunted the afternoon PRL surge. In all, melatonin can have an inhibitory effect on PRL secretion by stimulating the TIDA neurons, and it may help to entrain the circadian rhythms of both TIDA neuronal activity and PRL secretion. [source] Nerve growth factor and gastric hyperalgesia in the ratNEUROGASTROENTEROLOGY & MOTILITY, Issue 4 2003K. Lamb Abstract We recently demonstrated an association between the development of hyperalgesia and an increase in nerve growth factor (NGF) during gastric inflammation. We hypothesized that block of NGF signalling will blunt injury-induced hyperalgesia. Male Sprague,Dawley rats (300,400 g) were anaesthetized, the stomach was exposed and placed in a circular clamp. Acetic acid (60%) or saline (control) was injected into this area and aspirated 45 s later, resulting in kissing ulcers. A balloon was surgically placed into the stomach and electromyographic responses to gastric distension (GD) were recorded from the acromiotrapezius muscle. Animals received a daily injection of neutralizing NGF antibody or control serum for 5 days. NGF in the stomach wall was measured with an ELISA. The severity of gastric injury was assessed macroscopically and by determination of myeloperoxidase (MPO) activity. Gastric injury enhanced the visceromotor response to GD and increased NGF content. Anti-NGF significantly blunted the development of hyperalgesia and led to a decrease in gastric wall thickness and MPO activity. Increases in NGF contribute to the development of hyperalgesia after gastric injury. This may be partly mediated by direct effects on afferent nerves and indirectly by modulatory effects on the inflammatory response. [source] Hemolymph ecdysteroids during the last three molt cycles of the blue crab, Callinectes sapidus: quantitative and qualitative analyses and regulationARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY (ELECTRONIC), Issue 1 2010J. Sook Chung Abstract The profiles of circulating ecdysteroids during the three molt cycles prior to adulthood were monitored from the juvenile blue crab, Callinectes sapidus. Ecdysteroid patterns are remarkably similar in terms of peak concentrations ranging between 210,330,ng/ml hemolymph. Analysis of hemolymph at late premolt stage revealed six different types of ecdysteroids with ponasterone A (PoA) and 20-OH ecdysone (20-OH E) as the major forms. This ecdysteroid profile was consistent in all three molt cycles. Bilateral eyestalk ablation (EA) is a procedure that removes inhibitory neurohormones including crustacean hyperglycemic hormone (CHH) and molt-inhibiting hormone (MIH) and often results in precocious molting in crustaceans. However, the inhibitory roles of these neuropeptides in vivo have not yet been tested in C. sapidus. We determined the regulatory roles of CHH and MIH in the circulating ecdysteroid from ablated animals through daily injection. A daily administration of purified native CHH and MIH at physiological concentration maintained intermolt levels of ecdysteroids in the EA animals. This suggests that Y organs (YO) require a brief exposure to CHH and MIH in order to maintain the low level of ecdysteroids. Compared to intact animals, the EA crabs did not exhibit the level of peak ecdysteroids, and the major ecdysteroid turned out to be 20-OH E, not PoA. These results further underscore the important actions of MIH and CHH in ecdysteroidogenesis, as they not only inhibit, but also control the composition of output of the YO activity. © 2009 Wiley Periodicals, Inc. [source] Lithium Restores Neurogenesis in the Subventricular Zone of the Ts65Dn Mouse, a Model for Down SyndromeBRAIN PATHOLOGY, Issue 1 2010Patrizia Bianchi Abstract Down syndrome (DS), a high-incidence genetic pathology, involves brain hypoplasia and mental retardation. Emerging evidence suggests that reduced neurogenesis may be a major determinant of brain underdevelopment in DS. To establish whether it is possible to improve neurogenesis in DS, Ts65Dn mice,the most widely used model for DS,and euploid mice were treated with control or lithium chow for 1 month. During the last 3 days animals received one daily injection of 5-bromo-2-deoxyuridine (BrdU),a marker of proliferating cells,and were sacrificed 24 h after the last injection. Neurogenesis was examined in the subventricular zone (SVZ), a region that retains a neurogenic potential across life. We found that Ts65Dn mice had less (,40%) BrdU+ cells than euploid mice, indicating severe proliferation impairment. Treatment with lithium increased the number of Brdu+ cells in both euploid and Ts65Dn mice. In the latter the number of Brdu+ cells became similar to that of untreated euploid mice. Our study shows that lithium is able to restore cell proliferation in the SVZ of the Ts65Dn mouse and point at treatments with mood stabilizers as a potential tool to improve neurogenesis in patients with DS. [source] (Pro3)GIP[mPEG]: novel, long-acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity-diabetes (diabesity) therapyBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2008P L McClean Background and purpose: Antagonism of the gastric inhibitory polypeptide (GIP) receptor with daily injection of proline-3 gastric inhibitory polypeptide ((Pro3)GIP) can reverse or prevent many of the metabolic abnormalities associated with diet-induced obesity-diabetes (diabesity). This study has examined the ability of a novel and longer-acting form of (Pro3)GIP, (Pro3)GIP mini-polyethylene glycol ((Pro3)GIP[mPEG]), to counter diet-induced diabesity in mice, using a daily and intermittent dosing regime. Experimental approach: We studied the actions of (Pro3)GIP[mPEG] at the GIP receptor in vitro and in vivo in both dietary and genetic diabesity. Key results: (Pro3)GIP[mPEG] was completely resistant to degradation by dipeptidyl peptidase IV. (Pro3)GIP[mPEG] inhibited GIP-induced cAMP and insulin production in vitro. A greater and prolonged antagonism of GIP-induced glucose-lowering action was followed (Pro3)GIP[mPEG] administration, compared with (Pro3)GIP. In contrast with (Pro3)GIP, mice injected once every 3 days for 48 days with (Pro3)GIP[mPEG] displayed reduced body weight gain and hyperinsulinemia with improved glucose tolerance and insulin secretory responses, compared with high-fat-fed controls. Daily i.p. injection of (Pro3)GIP, (Pro3)GIP[mPEG] or (Pro3)GIP b.i.d. for 21 days also decreased body weight, circulating plasma insulin levels and improved glucose tolerance, compared with high-fat controls. Plasma triglycerides were decreased by (Pro3)GIP[mPEG] and (Pro3)GIP b.i.d. treatment groups. The observed changes were accompanied by enhancement of insulin sensitivity in all treatment regimes. (Pro3)GIP[mPEG] was also effective over 16 days treatment of genetically obese-diabetic ob/ob mice. Conclusions and implications: These data demonstrate the utility of GIP receptor antagonism for the treatment of diabesity and the potential offered by (Pro3)GIP[mPEG] as a long-acting stable GIP receptor antagonist. British Journal of Pharmacology (2008) 155, 690,701; doi:10.1038/bjp.2008.317; published online 11 August 2008 [source] Alteration of Ca2+ -ATPase activity in the homogenate, plasma membrane and microsomes of the salivary glands of streptozotocin-induced diabetic ratsCELL BIOCHEMISTRY AND FUNCTION, Issue 3 2009José Nicolau Abstract Diabetes has been implicated in the dryness of the mouth, loss of taste sensation, sialosis, and other disorders of the oral cavity, by impairment of the salivary glands. The aim of the present study was to examine the plasma membrane, microsomal, and homogenate Ca2+ -ATPase activity in the rat submandibular and parotid salivary glands of streptozotocin-induced diabetes. We have also examined the influence of the acidosis state on this parameter. Diabetes was induced by an intraperitoneal injection of streptozotocin and acidosis was induced by daily injection of NH4Cl. At 15 and 30 days after diabetes induction, the animals were euthanized and the submandibular and parotid salivary glands were removed and analyzed. Ca2+ -ATPase (total, independent, and dependent) was determined in the homogenate, microsomal, and plasma membranes of the salivary glands of diabetic and control rats. Calcium concentration was also determined in the glands and showed to be higher in the diabetic animals. Ca2+ -ATPase activity was found to be reduced in all cell fractions studied in the diabetic animals compared with control. Similar results were obtained for the submandibular salivary glands of acidotic animals; however in the parotid salivary glands it was found an increase in the enzyme activity. Copyright © 2009 John Wiley & Sons, Ltd. [source] The role of lox and LOXL2 in inflammation and fibrosis in a laser induced mouse modelACTA OPHTHALMOLOGICA, Issue 2009S VAN DE VEIRE Purpose Lysyl oxidase (LOX) and lysyl oxidase-like protein 2 (LOXL2) are involved in the cross-linking of collagen and elastin in the extracellular space. The aim of this study was to investigate the expression LOX and LOXL2 in the eye (choroidea and retina) after laser-induced chroidal neovascularization (CNV). We also want to check the anti-angiogenic, anti-inflammatory and anti-fibrotic efficacy of anti-LOX and anti-LOXL2 antibody in a mouse model of age related macular degeneration (ARMD). Methods CNV will be induced in 8 to 10 weeks old C75Bl/6 mice, by placing 3 laser spots at 9, 12 and 3 o'clock position (50µm, 0.05 s and 400mW). Two daily injection with LOX(L) antibodies or control solution (PBS-Tween 20%) will be given intraperitoneally from day 0 after lasering until day 34. Immediately after death, both eyes will be enucleated. One eye will be used to check RNA-expression of LOX and LOXL. The other eye will be used to perform different immunohistochemical stainings (HE, Sirius Red, Trichrome, CD31, CD45 and LOX(L)). Results Preliminary results showed a significant increase of LOX and LOXL2 in the choroid and retina after lasering compared to control. Conclusion ARMD remains the most common cause of irreversible vision loss in people aged 50 years and older, due to (sub-)retinal neovascularisation and scarring. It is already known that LOX and LOXL are playing a role in the cross linking of collagen and elastin, leading to an increase of fibrosis, and there is growing evidence that these molecules also play a role in neovascularisation. Therefore, a therapeutic potential of anti-LOX and/or anti-LOXL therapy can open new perspectives to treat CNV. [source] Elevated corticosterone levels in stomach milk, serum, and brain of male and female offspring after maternal corticosterone treatment in the ratDEVELOPMENTAL NEUROBIOLOGY, Issue 10 2010Susanne Brummelte Abstract Early influences such as maternal stress affect the developmental outcome of the offspring. We created an animal model of postpartum depression/stress based on giving high levels of corticosterone (CORT) to the rat dam, which resulted in behavioral and neural changes in the offspring. This study investigated whether highly elevated levels of maternal CORT during pregnancy or the postpartum result in higher levels of CORT in the stomach milk, serum, and brain of offspring. Dams received daily injections of CORT (40 mg/kg) or oil (control) either during pregnancy (gestational days 10,20) or the postpartum (Days 2,21). Pups that were exposed to high gestational maternal CORT had higher CORT levels in serum, but not in stomach milk or brain, on postnatal day (PND) 1. However, on PND7, pups that were exposed to high postpartum maternal CORT had higher CORT levels in stomach milk and brain, but not in serum. Conversely on PND18, pups that were exposed to high postpartum maternal CORT had higher CORT levels in serum, but not in brain (prefrontal cortex, hypothalamus, or hippocampus). Moreover, 24 h after weaning, there were no significant differences in serum CORT levels between the groups. Thus, CORT given to the dam during pregnancy or the postpartum results in elevated levels of CORT in the offspring, but in an age- and tissue-dependent manner. Developmental exposure to high CORT could reprogram the HPA axis and contribute to the behavioral and neural changes seen in adult offspring. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 70: 714,725, 2010 [source] Premixed insulin treatment for type 2 diabetes: analogue or human?DIABETES OBESITY & METABOLISM, Issue 5 2007Alan J. Garber The progressive nature of type 2 diabetes makes insulin initiation a necessary therapeutic step for many patients. Premixed insulin formulations containing both basal and prandial insulin (so called biphasic insulin) are often prescribed because they are superior to long- or intermediate-acting insulin in obtaining good metabolic control. In addition, they are considered as an attractive alternative to classical basal-bolus therapy as fewer daily injections are required. Premixed insulin formulations include conventional (e.g. biphasic human insulin 70/30, or 30/70 in European countries, BHI 30) and newer premixed human analogues (e.g. biphasic insulin aspart 70/30, or 30/70 in Europe, BIAsp 30; insulin lispro mix 75/25,Mix 75/25, or Mix 25/75 in Europe). Like conventional premixed human insulin, premixed insulin analogues contain a fixed proportion of soluble, rapid-acting insulin analogue, with protaminated analogue comprising the remainder. Unlike conventional premixes, analogue premixes have more physiological pharmacokinetic and therapeutically more desirable pharmacodynamic profiles than premixed human insulin. Consequently, postprandial glycaemic control is better with premixed insulin analogues than with premixed human insulin. In nontreat-to-target registration trials, the lowering of haemoglobin A1c with premixed insulin analogues was not inferior to that seen with premixed human insulin. Minor hypoglycaemia was similar for premixed analogue and premixed human insulins, while major hypoglycaemia appears to be rare with either formulation. The occurrence of adverse events, other than hypoglycaemia, was also similar between various premix insulins. The premixed insulin analogues, BIAsp 30 and Mix 75/25, like the fast-acting analogues from which they are derived, also allow flexible injection timing, relative to meal timing, thus improving adherence, compliance and quality of life compared with premixed human insulin. Overall, the evidence suggests that premixed insulin analogues are cost effective and have useful advantages over premixed human insulin for the treatment of type 2 diabetes. [source] Insulin therapy and quality of life.DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue S1 2009A review Abstract Three central goals in the treatment of diabetes mellitus are (1) the avoidance of hyperglycaemia to prevent the development or progression of diabetes complications over time, (2) the avoidance of hypoglycaemia and (3) the maintenance or achievement of good quality of life. Insulin is the most powerful agent that can be used to control blood glucose levels. This article reviews the studies that have investigated the effects of different types of insulin and insulin delivery techniques on quality of life of patients with type 1 or type 2 diabetes. First, the concept of ,quality of life' (QoL) is defined and different ways of measuring QoL are explained. Secondly, the effects of different aspects of insulin therapy on QoL are reviewed: (1) the phenomenon of ,psychological insulin resistance'; (2) the effects of different types of insulin: regular insulin versus short-acting insulin analogues, long-acting insulin analogues or biphasic mixtures; (3) multiple daily injections versus pump therapy. Having multiple complications of diabetes is clearly associated with decreased QoL. Results from large studies such as the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS) suggest that intensive treatment itself does not impair QoL. Recent findings further suggest that pump therapy, compared to multiple daily injections, has beneficial effects on QoL. The fact that multiple tools are used to assess QoL makes it difficult to draw conclusions regarding the effects of different types of insulin on QoL. More work on the standardization of the assessment of QoL in diabetes is urgently needed. Copyright © 2009 John Wiley & Sons, Ltd. [source] Continuous subcutaneous insulin infusion (CSII) 30 years later: still the best option for insulin therapyDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 2 2009Daniela Bruttomesso Abstract Thirty years after its introduction, the use of continuous subcutaneous insulin infusion (CSII) keeps increasing, especially among children and adolescents. The technique, when used properly, is safe and effective. Compared with traditional NPH-based multiple daily injections (MDI), CSII provides a small but clinically important reduction of HbA1c levels, diminishes blood glucose variability, decreases severe hypoglycaemic episodes and offers a better way to cope with the dawn phenomenon. Insulin analogues have improved the treatment of diabetes, eroding part of the place previously occupied by CSII, but CSII still remains the first option for patients experiencing severe hypoglycaemic episodes, high HbA1c values or marked glucose variability while being treated with optimized MDI. Furthermore CSII is better than MDI considering the effects on quality of life and the possibility to adjust insulin administration according to physical activity or food intake. CSII may be limited by cost. Present estimates suggest that CSII may be cost-effective just for patients experiencing a marked improvement in HbA1c or a decrease in severe hypoglycaemic episodes, but the effects on quality of life are difficult to measure. CSII does not merely imply wearing an external device; it requires a multidisciplinary team, intensive patient education and continuous follow up. Copyright © 2009 John Wiley & Sons, Ltd. [source] Diabetes management in the new millennium using insulin pump therapyDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue S1 2002Bruce W. Bode Abstract Current goals of therapy of type 1 and 2 diabetes are to achieve near normal glycemia, minimize the risk of severe hypoglycemia, limit excessive weight gain, improve quality of life and delay or prevent late vascular complications. As discussed in this review, insulin pump or continuous subcutaneous insulin infusion (CSII) therapy provides a treatment option that can dramatically aid in achieving all of these goals. In comparison to multiple daily injections (MDI), CSII uses only rapid-acting insulin, provides greater flexibility in timing of meals and snacks, has programmable basal rates to optimize overnight glycemic control, can reduce the risk of exercise-induced hypoglycemia, and enhances patients' ability to control their own diabetes. Most important, in adults and adolescents with type 1 diabetes, CSII has been shown to lower HbA1c levels, reduce the frequency of severe hypoglycemia and limit excessive weight gain versus MDI without increasing the risk of diabetic ketoacidosis. Similarly positive results are being seen with CSII in adults with type 2 diabetes. The effectiveness of CSII and improvements in pump technology have fueled a dramatic increase in the use of this therapy. Practical guidelines are presented for selection of patients, initiation of treatment, patient education, follow-up assessments and troubleshooting. The recent introduction of methods for continuous glucose monitoring provides a new means to optimize the basal and bolus capabilities of CSII and offers the hope of the development of a feedback-controlled artificial pancreas. Copyright © 2002 John Wiley & Sons, Ltd. [source] Comparison of continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) in paediatric Type 1 diabetes: a multicentre matched-pair cohort analysis over 3 yearsDIABETIC MEDICINE, Issue 1 2008B. I. Jakisch Abstract Aims To conduct a multicentre, matched-pair cohort analysis comparing glycaemic control and adverse events of continuous subcutaneous insulin infusion (CSII) with multiple daily injections (MDI) in paediatric patients. Methods Using standardized computer-based prospective documentation, HbA1c, insulin dose, body mass index,standard deviation score (BMI,SDS), rate of hypoglycaemia, rate of diabetic ketoacidosis (DKA) and intensity of care were analysed in 434 matched pairs during a follow-up period of 3 years after initiation of MDI or CSII. Results HbA1c was significantly lower in the CSII group during the first year of new regimen (CSII 7.5 ± 0.05 vs. MDI 7.7 ± 0.06; P < 0.05), but rose to the same level as in the MDI group during year 3. Insulin requirement remained significantly lower in the CSII group. The BMI,SDS increased in both study groups, with no significant difference. The rate of severe hypoglycaemia decreased significantly after the change of regimen (CSII 17.87 ± 2.85 vs. MDI 25.14 ± 3.79; P < 0.05) and during year 3 of the regimen, particularly when compared with baseline (,21% vs. ,16%). The rate of DKA was lower at baseline in the CSII group and remained significantly lower over all 3 years. Intensity of care was the same in both subsets. Conclusions Employing a large cohort, this matched-pair analysis has demonstrated over a 3-year study period that CSII is a safe form of intensive insulin therapy with similar glycaemic effects, but with significantly reduced rates of hypoglycaemia and DKA and a lower insulin requirement when compared with MDI. [source] Reliably assessing the cost-effectiveness of continuous subcutaneous insulin infusion vs. multiple daily injections in the UK: what are the issues?DIABETIC MEDICINE, Issue 10 2007C. J. Currie No abstract is available for this article. [source] Insulin pump therapy vs. multiple daily injections in obese Type 2 diabetic patientsDIABETIC MEDICINE, Issue 8 2005J. Wainstein Abstract Aims To compare the efficacy of insulin pump treatment with multiple daily injections in the treatment of poorly controlled obese Type 2 diabetic patients already receiving two or more daily injections of insulin plus metformin. Methods Forty obese Type 2 diabetic subjects (using insulin) were randomized to treatment with continuous subcutaneous infusion pump (CSII) (Minimed®) or multiple daily insulin injections (MDI). At the end of the first 18-week treatment period, patients underwent a 12-week washout period during which they were treated with MDI plus metformin. They were then crossed-over to the other treatment for an 18-week follow-up period. Patients performed 4-point daily self blood-glucose monitoring (SBGM) on a regular basis and 7-point monitoring prior to visits 2, 8, 10 and 16. A subset of patients underwent continuous glucose monitoring using the Minimed® continuous glucose monitoring system (CGMS) at visits 2, 8, 10 and 16. A standard meal test was performed in which serum glucose was tested at fasting and once each hour for 6 h following a test meal. Glucose levels were plotted against time and the area under the curve (AUC) was calculated. HbA1c, weight, daily insulin dose and hypoglycaemic episodes were recorded. Results In obese Type 2 diabetic patients already treated with insulin, treatment with CSII significantly reduced HbA1c levels compared with treatment with MDI. An additional CSII treatment benefit was demonstrated by reduced meal-test glucose AUC. Initial reduction of daily insulin requirement observed in CSII-treated subjects during the first treatment period was attributable to a period effect and did not persist over time. Conclusions In the intent-to-treat analysis, CSII appeared to be superior to MDI in reducing HbA1c and glucose AUC values without significant change in weight or insulin dose in obese, uncontrolled, insulin-treated Type 2 diabetic subjects. [source] The cost-effectiveness of continuous subcutaneous insulin infusion compared with multiple daily injections for the management of diabetesDIABETIC MEDICINE, Issue 7 2003P. Scuffham Abstract Aims To estimate the cost effectiveness of continuous subcutaneous insulin infusion (CSII) compared with multiple daily injections (MDI) for patients using insulin pumps. Methods We constructed a Markov model to estimate the costs and outcomes for patients with insulin-dependent diabetes (IDDM) treated with CSII using an insulin pump compared with MDI. Key parameters were obtained from the published scientific literature. The primary outcome was quality-adjusted life years (QALYs). Monte Carlo simulations were undertaken for 10 000 hypothetical patients over 8 years of monthly cycles (the expected life of a pump). Results Over an 8-year period an average patient could expect to gain 0.48 [standard deviation (sd) 0.20] QALYs using CSII compared with MDI. The additional cost over 8 years for this gain was £5462 (sd£897). The incremental cost per QALY was £11 461 (sd£3656). CSII was most cost-effective in patients who had more than two severe hypoglycaemic events per year and who required admission to hospital at least once every year. Cases where CSII might be not economically viable are cases where diabetes is well controlled with few severe hypoglycaemic events. Results were most sensitive to the number of hypoglycaemic events per patient and the utility weights used to estimate QALYs. Conclusion CSII is a worthwhile investment when targeted to those who might benefit most. Diabet. Med. 20, 586,593 (2003) [source] Efficacy of doublecortin as a marker to analyse the absolute number anddendritic growth of newly generated neurons in the adult dentate gyrusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2004Muddanna S. Rao Abstract Doublecortin (DCX), a microtubule-associated phosphoprotein, has been recently utilized as a marker of newly born neurons in the adult dentate gyrus (DG). Nonetheless, it is unknown whether DCX exclusively labels newly formed neurons, as certain granule cells with the phenotype of differentiated neurons express DCX. We addressed the authenticity of DCX as a marker of new neurons in the adult DG by quantifying cells that are positive for 5,-bromodeoxyuridine (BrdU), DCX and both BrdU and DCX in hippocampal tissues of adult rats treated with daily injections of BrdU for 12 consecutive days. We provide new evidence that neurons visualized with DCX immunostaining in the adult rat DG are new neurons that are predominantly born during the 12 days before euthanasia. This is confirmed by the robust expression of BrdU in 90% of DCX-positive neurons in the DG of animals injected with BrdU for 12 days. Furthermore, DCX expression is specific to newly generated healthy neurons, as virtually all DCX-positive cells express early neuronal antigens but lack antigens specific to glia, undifferentiated cells or apoptotic cells. As DCX expression is also robust in the dendrites, DCX immunocytochemistry of thicker sections facilitates quantification of the dendritic growth in newly born neurons. Thus, both absolute number and dendritic growth of new neurons that are generated in the adult DG over a 12-day period can be quantified reliably with DCX immunostaining. This could be particularly useful for analysing changes in dentate neurogenesis in human hippocampal tissues as a function of ageing or neurodegenerative diseases. [source] Adult-onset deficiency in growth hormone and insulin-like growth factor-I alters oligodendrocyte turnover in the corpus callosumGLIA, Issue 10 2009Kun Hua Abstract Growth hormone (GH) and insulin-like growth factor-I (IGF-I) provide trophic support during development and also appear to influence cell structure, function and replacement in the adult brain. Recent studies demonstrated effects of the GH/IGF-I axis on adult neurogenesis, but it is unclear whether the GH/IGF-I axis influences glial turnover in the normal adult brain. In the current study, we used a selective model of adult-onset GH and IGF-I deficiency to evaluate the role of GH and IGF-I in regulating glial proliferation and survival in the adult corpus callosum. GH/IGF-I-deficient dwarf rats of the Lewis strain were made GH/IGF-I replete via twice daily injections of GH starting at postnatal day 28 (P28), approximately the age at which GH pulse amplitude increases in developing rodents. GH/IGF-I deficiency was initiated in adulthood by removing animals from GH treatment. Quantitative analyses revealed that adult-onset GH/IGF-I deficiency decreased cell proliferation in the white matter and decreased the survival of newborn oligodendrocytes. These findings are consistent with the hypothesis that aging-related changes in the GH/IGF-I axis produce deficits in ongoing turnover of oligodendrocytes, which may contribute to aging-related cognitive changes and deficits in remyelination after injury. © 2008 Wiley-Liss, Inc. [source] Dehydroepiandrosterone regulates astroglia reaction to denervation of olfactory glomeruliGLIA, Issue 3 2004Zsófia Hoyk Abstract Effects of dehydroepiandrosterone (DHEA) on glial reactions of the peripherally denervated olfactory bulb were studied in adult male rats. Denervation was achieved by destroying the olfactory mucosa with ZnSO4 (0.17 M) irrigation of the nasal cavities. In one series of experiments, chronic DHEA treatment was applied (daily injections for 7 days, i.p., 10 mg/kg b.w. and 25 mg/kg b.w.); in the other series of experiments, animals received a single injection of DHEA (i.p., 10 mg/kg b.w., 25 mg/kg b.w. and 50 mg/kg b.w.) 2 h following ZnSO4 treatment. To determine whether DHEA conversion to estradiol was involved in the mechanism of DHEA action on glia, a third series of experiments was carried out in which the aromatase inhibitor fadrozole (4.16 mg/ml) was administered using subcutaneously implanted osmotic minipumps. Rats were killed on day 7 after chemical denervation, and the reaction of glial cells was monitored within the olfactory bulb, using GFAP and vimentin immunohistochemistry. Qualitative changes in GFAP expression were analyzed by Western blot. Chronic DHEA treatment with both doses (10 mg/kg b.w. and 25 mg/kg b.w.) and acute DHEA treatment with the highest dose applied (50 mg/kg b.w.), inhibited the increase in GFAP expression induced by the denervation of the olfactory bulb. Furthermore, GFAP and vimentin immunostaining in the glomerular layer of the olfactory bulb were diminished in the denervated and DHEA treated groups. However, when DHEA treatment was combined with fadrozole administration, such a decrease in GFAP expression could not be detected in the chemically denervated olfactory bulb. These findings indicate that DHEA, depending on the dose applied and the mode of administration, attenuates glial reaction to denervation and may regulate glial plasticity in the olfactory glomeruli. These effects are likely to be mediated at least in part by the conversion of DHEA to estradiol. © 2004 Wiley-Liss, Inc. [source] Parathyroid hormone (PTH),induced bone gain is blunted in SOST overexpressing and deficient miceJOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2010Ina Kramer Abstract Intermittent parathyroid hormone (PTH) treatment is a potent bone anabolic principle that suppresses expression of the bone formation inhibitor Sost. We addressed the relevance of Sost suppression for PTH-induced bone anabolism in vivo using mice with altered Sost gene dosage. Six-month-old Sost overexpressing and 2-month-old Sost deficient male mice and their wild-type littermates were subjected to daily injections of 100,µg/kg PTH(1,34) or vehicle for a 2-month period. A follow-up study was performed in Sost deficient mice using 40 and 80,µg/kg PTH(1,34). Animals were sacrificed 4 hours after the final PTH administration and Sost expression in long bone diaphyses was determined by qPCR. Bone changes were analyzed in vivo in the distal femur metaphysis by pQCT and ex vivo in the tibia and lumbar spine by DXA. Detailed ex vivo analyses of the femur were performed by pQCT, µCT, and histomorphometry. Overexpression of Sost resulted in osteopenia and Sost deletion in high bone mass. As shown before, PTH suppressed Sost in wild-type mice. PTH treatment induced substantial increases in bone mineral density, content, and cortical thickness and in aging wild-type mice also led to cancellous bone gain owing to amplified bone formation rates. PTH-induced bone gain was blunted at all doses and skeletal sites in Sost overexpressing and deficient mice owing to attenuated bone formation rates, whereas bone resorption was not different from that in PTH-treated wild-type controls. These data suggest that suppression of the bone formation inhibitor Sost by intermittent PTH treatment contributes to PTH bone anabolism. © 2010 American Society for Bone and Mineral Research [source] Insulin-Like Growth Factor I Is Required for the Anabolic Actions of Parathyroid Hormone on Mouse Bone,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2002Daniel D. Bikle M.D., Ph.D. Abstract Parathyroid hormone (PTH) is a potent anabolic agent for bone, but the mechanism(s) by which it works remains imperfectly understood. Previous studies have indicated that PTH stimulates insulin-like growth factor (IGF) I production, but it remains uncertain whether IGF-I mediates some or all of the skeletal actions of PTH. To address this question, we examined the skeletal response to PTH in IGF-I-deficient (knockout [k/o]) mice. These mice and their normal littermates (NLMs) were given daily injections of PTH (80 ,g/kg) or vehicle for 2 weeks after which their tibias were examined for fat-free weight (FFW), bone mineral content, bone structure, and bone formation rate (BFR), and their femurs were assessed for mRNA levels of osteoblast differentiation markers. In wild-type mice, PTH increased FFW, periosteal BFR, and cortical thickness (C.Th) of the proximal tibia while reducing trabecular bone volume (BV); these responses were not seen in the k/o mice. The k/o mice had normal mRNA levels of the PTH receptor and increased mRNA levels of the IGF-I receptor but markedly reduced basal mRNA levels of the osteoblast markers. Surprisingly, these mRNAs in the k/o bones increased several-fold more in response to PTH than the mRNAs in the bones from their wild-type littermates. These results indicate that IGF-I is required for the anabolic actions of PTH on bone formation, but the defect lies distal to the initial response of the osteoblast to PTH. [source] | ||||||||||||||||