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- Lack of effect of a P2Y6 receptor antagonist on neuropathic pain behavior in mice. [JOURNAL ARTICLE]
- Pharmacol Biochem Behav 2014 Jul 17.
Accumulating evidence indicates that various subtypes of purinergic receptors (P2X and P2Y receptor families) play an essential role in the development and the maintenance of neuropathic pain. However, there is only limited data available about the role of P2Y6 receptors in pain processing. Here we detected P2Y6 receptor immunoreactivity in primary afferent neurons of mice and observed an upregulation in response to peripheral nerve injury. However, systemic and intrathecal administration of the P2Y6 receptor antagonist MRS2578 failed to affect the injury-induced neuropathic pain behavior. Our results suggest that P2Y6 receptors, in contrast to other purinergic receptor subtypes, are not critically involved in nerve injury-induced neuropathic pain processing in mice.
- PHEX 3'-UTR c.*231A > G Near The Polyadenylation Signal Is A Relatively Common, Mild, American Mutation That Masquerades As Sporadic Or X-Linked Recessive Hypophosphatemia. [JOURNAL ARTICLE]
- J Bone Miner Res 2014 Jul 7.
Heritable forms of hypophosphatemic rickets (HR) include X-linked dominant (XLH), autosomal recessive, and autosomal dominant HR (from deactivating mutations in PHEX, or DMP1 or ENPP1, or activating mutations in FGF23, respectively). Over 30 years, we have cared for 284 children with HR. For those 72 deemed sporadic XLH, we preliminarily reported mutation analysis for 30 subjects. Eleven had PHEX mutations. However, the remaining 19 lacked readily identifiable defects in PHEX, DMP1, or FGF23. In 2008, a novel single-base change near the polyadenylation (pA) signal in the 3'-UTR of PHEX was identified in XLH by other investigators. This c.*231A > G mutation is 3-bp upstream of the putative pA signal (AATAAA) in PHEX. Accordingly, we investigated whether this 3'-UTR defect accounted for HR in any of these 19 sporadic XLH patients. PCR amplification and sequencing of their 3'-UTR region showed the c.*231A > G mutation in 4 unrelated boys. Then, among an additional 22 of our 72 "sporadic" XLH patients, one boy and one girl were found to have the 3'-UTR defect, totaling 6 patients. Among these 52 sporadic XLH patients with PHEX analysis, 36 were girls and 16 were boys; i.e., an ∼ 2:1 gender ratio consistent with XLH. However, finding the 5 boys and only one girl with this 3'-UTR mutation presented an unexplained gender bias (p = 0.02). Haplotyping for the 5 boys, all reportedly unrelated, showed a common core haplotype suggesting a founder. Five of their 6 mothers had been studied clinically and biochemically (3 radiologically). Remarkably, the seemingly unaffected mothers of 4 of these boys carried the 3'-UTR mutation. These healthy women had normal height, straight limbs, lacked the radiographic presentation of XLH, and showed normal or slight decreases in fasting serum Pi levels and/or TmP/GFR. Hence, PHEX c.*231A > G can masquerade as sporadic or X-linked recessive HR. © 2014 American Society for Bone and Mineral Research.
- Invasive pneumococcal disease following adult allogeneic hematopoietic stem cell transplantation. [JOURNAL ARTICLE]
- Transpl Infect Dis 2014 Jul 21.
Allogeneic hematopoietic stem cell transplantation (alloHSCT) recipients are at high risk of invasive pneumococcal disease (IPD). We investigated the incidence and risk factors of IPD in alloHSCT recipients from 4 regional transplant centers over an 11-year period. This study aimed to inform future improvements in post-transplant care.We conducted a retrospective nested 1:2 case-control study in patients aged ≥18 years who underwent alloHSCT between 2001 and 2011 in 4 major allogeneic transplant centers. Controls were matched with IPD cases on the basis of conditioning intensity and donor relationship (related or unrelated). Demographics and clinical characteristics of cases and controls were summarized. Univariate analysis of risk factors in matched case-control sets, and multivariate conditional logistic regression to control for confounding, were performed.In 23 alloHSCT recipients, 26 IPD episodes were identified. The cumulative incidence over 11 years was 2.3% (95% confidence interval [CI] 1.45-3.15) and the incidence density 956 per 100,000 transplant years of follow-up (95% CI 580-1321). Multivariate risk factor analysis and backwards elimination showed a significant positive association between mycophenolate mofetil (MMF), hyposplenism/asplenia, and IPD, whereas trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was associated with lower odds of IPD cases. Of alloHSCT recipients with IPD, 38.5% required intensive care, and, of deaths documented in cases over the period of review, 30% were attributable to IPD. Serotypes causing IPD matched currently available vaccines in 15/22 (68.1%) episodes.The incidence of IPD in alloHSCT recipients is an important cause of morbidity and mortality, with rates of disease being many fold higher than the general population. Patients with evidence of hyposplenism/asplenia define a high-risk group in the alloHSCT population for IPD, and the independent association with IPD and MMF in the adjusted model from this study requires further evaluation. The occurrence of post-transplant IPD may be reduced by measures such as vaccination with both 13-valent and 23-valent pneumococcal vaccines. TMP/SMX prophylaxis for the prevention of PJP may offer incidental protection against IPD in alloHSCT recipients.
- [Effect of tetramethylpyrazine and rat CTGF miRNA plasmids on connective tissue growth factor, transforming growth factor-beta in high glucose stimulated hepatic stellate cells]. [English Abstract, Journal Article]
- Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 2014 Apr; 31(2):394-9.
The aim of this research is to evaluate the effect of tetramethylpyrazine (TMP) and connective tissue growth factor (CTGF) miRNA plasmids on the expressive levels of CTGF, transforming growth factor-beta (TGFbeta) and type I collagen of rat hepatic stellate cells (HSC) which are stimulated by high glucose. The rat HSCs which were successfully transfected rat CTGF miRNA plasmids and the rat HSCs which were successfully transfected negative plasmids were cultured in vitro. After stimulus of the TMP and the high glucose, the protein levels and gene expressive levels of CTGF, TGF-beta and type I collagen were tested. The results indicated that high glucose increased the expression of CTGF mRNA, CTGF protein, TGF-beta mRNA,TGF-beta protein and type I collagen (P < 0.05). The expressive levels of CTGF mRNA, CTGF protein, TGF-beta mRNA, TGF-beta and type I collagen in TMP group were lower than those in high glucose group and showed statistically significant differences (P < 0.05). Compared with high glucose group, the expressive levels of CTGF mRNA, CTGF protein, TGF-beta mRNA, TGF-beta and type I collagen in rat CTGF miRNA plasmid interference group were significantly lower (P < 0.05). However, no statistically significant difference was found in CTGF mRNA and CTGF protein levels between TMP group and CTGF miRNA group (P > 0.05), while type I collagen levels showed statistically significant differences (P < 0.05). It is concluded that high glucose could promote the expressions of CTGF, TGF-beta and type I collagen, and TMP and rat CTGF miRNA plasmids could reduce the expressions of CTGF, TGF-beta, type I collagen.
- Radiosynthesis and Bioevaluation of [(68)Ga]-Labeled 5,10,15,20-Tetra(4-methylpyridyl)-porphyrin for Possible Application as a PET Radiotracer for Tumor Imaging. [JOURNAL ARTICLE]
- Mol Imaging Biol 2014 Jul 19.
Porphyrins have inherent ability to localize preferentially in tumor lesions. Cationic porphyrins are readily water soluble and reported to exhibit strong DNA-binding capabilities. Therefore, attempt has been made to prepare a water soluble [(68)Ga]-labeled cationic porphyrin, viz., 5,10,15,20-tetra(4-methylpyridyl)porphyrin (TMP), and evaluate its potential as a positron emission tomography (PET) radiotracer for tumor imaging.The cationic porphyrin TMP was synthesized following a two-step procedure and subsequently radiolabeled with Ga-68, eluted from a commercial (68)Ge/(68)Ga generator. Purification of the [(68)Ga]-labeled porphyrin derivative was carried out using Sep-Pak(®) cartridges. The tumor-targeting potential of the [(68)Ga]-labeled-5,10,15,20-tetra(4-methylpyridyl)porphyrin was evaluated by biodistribution studies in Swiss mice bearing fibrosarcoma tumor.Under optimized reaction conditions, [(68)Ga]-labeled TMP was obtained with ~90 % radiochemical purity which was subsequently improved to >99 % after purification through Sep-Pak(®) cartridges. Biodistribution studies revealed high tumor uptake of the radiotracer within 30-min post-injection (6.47 ± 0.87 % of injected activity) and retention until the final 2 h post-administration (4.48 ± 1.11 % of injected activity) time point. The initial uptake observed in non-target organs cleared away with time resulting in gradually improving tumor/blood and tumor/muscle ratios.Preliminary bioevaluation studies indicated the potential of the radiolabeled porphyrin derivative for tumor imaging, and further detailed studies are warranted to evaluate the true potential of the developed radiotracer.
- Prevalence of and Risk Factors for Methicillin-Resistant Staphylococcus aureus Colonization in HIV Infection: A Meta-Analysis of Studies. [JOURNAL ARTICLE]
- Clin Infect Dis 2014 Jul 16.
HIV-infected individuals that are colonized with methicillin-resistant Staphylococcus aureus (MRSA) have increased risk for MRSA infection. We conducted a meta-analysis of published studies to estimate the prevalence of MRSA colonization in this population. We performed a systematic literature review and meta-analysis. The PubMed and EMBASE databases were searched and studies reporting prevalence of MRSA colonization among HIV infected individuals were included. Among 7,940 citations, 32 studies reporting data on 6,558 HIV-infected individuals were considered eligible for our meta-analysis. We found that 6.9% (95% CI; 4.8%-9.3%) of individuals with HIV infection are MRSA carriers with the corresponding figure across North American studies being 8.8% (95% CI; 6.0%-12.2%). History of hospitalization during the previous 12 months was associated with a 3.1 times higher risk of MRSA colonization (RR 3.11; 95% CI 1.62-5.98), while previous or current incarceration was associated with a higher risk for carriage (RR 1.77; 95% CI 1.26-2.48). Current antiretroviral therapy or use of trimethoprim-sulfamethoxazole (TMP-SMX) did not impact the risk of MRSA carriage [(RR 1.02; 95% CI 0.64-1.63), (RR 1.45; 95% CI 0.69-3.03) respectively]. Extra-nasal screening increased the detection of MRSA colonization by at least 31.6% (95% CI 15.8%-50.0%). The added yield from groin screening was 19.3% (95% CI 11.5%-28.5%), from perirectal screening 18.5% (95% CI 7.4%-33.2%) and from throat cultures is 17.5% (95% CI 12.0%-24%). Individuals with HIV infection constitute a highly vulnerable population for MRSA colonization and prior exposure to hospital or incarceration are significant factors. Nasal screening alone will underestimate the rate of colonization by at least 1/3.
- Tetramethylpyrazine alleviated cytokine synthesis and dopamine deficit and improved motor dysfunction in the mice model of Parkinson's disease. [JOURNAL ARTICLE]
- Neurol Sci 2014 Jul 17.
It was previously reported that cytokines and neurotoxins released from activated inflammatory cells induced the loss of projecting dopaminergic neurons in the substantia nigra, which triggered the pathogenesis of PD. The present study investigated the effect of treatment with tetramethylpyrazine (TMP) on the central cytokine synthesis, striatal dopamine content and glutamatergic transmission, and behavioral performance in the rotarod task in mice injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Treatment with TMP significantly improved the behavioral performance in the rotarod task in mice injected with MPTP. It also decreased the upregulation of cytokines (tumor necrosis factor-α and interleukin-1β) in the substantia nigra and striatum in these modeled mice. Furthermore, treatment with TMP significantly improved the dopamine deficits and attenuated the upregulation of striatal basal glutamatergic strength in the striatum of mice injected with MPTP. These results indicated that TMP might serve as a novel approach for the treatment of patients with PD.
- Effect of Paricalcitol on Circulating Parathyroid Hormone in X-linked Hypophosphatemia: A Randomized, Double-blind, Placebo-controlled Study. [JOURNAL ARTICLE]
- J Clin Endocrinol Metab 2014 Jul 16.:jc20142017.
Context: Hyperparathyroidism occurs frequently in X-Linked Hypophosphatemia (XLH) and may exacerbate phosphaturia, potentially affecting skeletal abnormalities. Objective: To suppress elevated PTH levels in XLH patients. Design: Prospective, randomized, placebo-controlled, double-blind, 1-year trial of paricalcitol, with outcomes measured at entry and 1 year later. Setting: Patients were recruited from the investigators' clinics or referred from throughout the US. Data were collected in an in-patient hospital research unit. Patients: Subjects with a clinical diagnosis of XLH and hyperparathyroidism were offered participation, and eligible if ≥9 years old, non-pregnant, and serum calcium <10.7 mg/dl, 25-OHD ≥20 ng/ml, and creatinine ≤1.5 mg/dl. Intervention: Paricalcitol or placebo for one year. Main outcome measures: Determined prior to trial onset: change in PTH-area-under-the-curve (PTHauc). Secondary outcomes: renal phosphate threshold (TmP/GFR), serum phosphorus, serum alkaline phosphatase activity (ALP) and (99m)Tc-methylenediphosphonate bone scans. Results: PTHauc decreased 17% with paricalcitol, differing (P=0.007) from the 20% increase with placebo. TmP/GFR increased 17% with paricalcitol, and decreased 21% with placebo (P=0.05). Serum phosphorus increased 12% with paricalcitol, but did not differ from placebo. Paricalcitol decreased ALP in adults by 21% (no change with placebo, P=0.04). Bone scans improved in 6/17 paricalcitol subjects, while no placebo-treated subject improved. Hypercalciuria developed in 6 paricalcitol subjects and persisted from baseline in 1 placebo subject. Conclusions: Suppression of PTH may be a useful strategy for skeletal improvement in XLH patients with hyperparathyroidism, and paricalcitol appears to be an effective adjunct to standard therapy in this setting. Although paricalcitol was well-tolerated, urinary calcium, and serum calcium and creatinine should be monitored closely with its use.
- PWE-171 Assessing The Utility Of Key Mri Parameters In Characterising The Mode Of Action Of A Proven Effective Laxative, Ispaghula. [Journal Article]
- Gut 2014 Jun.:A200.
Half of the patients who suffer from chronic constipation are dissatisfied with their treatments, which has initiated a recent surge in novel treatments. Assessing the efficacy of these treatments requires techniques that are patient acceptable and non-invasive and allow characterisation of the underlying mode of action. This study assessed the utility of key parameters likely to give insight into laxatives' mode of action including: colonic volumes, transit, ascending colon water content (ACWC) and small bowel water content (SBWC) by means of a randomised double-blind, placebo-controlled, crossover study (RCT) of a known effective laxative, ispaghula.16 healthy volunteers (24 ± 4 years old, BMI 23 ± 4 kg m(-2)) participated in this three-way RCT. They took either 21 g/day of ispaghula, 10.5 g/day of ispaghula or a placebo daily on days 1-6. On day 5 they swallowed 5 transit marker pills (TMP) filled with a dilute MR contrast agent and on day 6 were scanned serially for 7 h. The TMPs were assigned a weighted average position score (WAPS) based on their location in the bowel. Protocol compliance was assessed and 9 subjects were included in the per protocol analysis.(mean AUC±SEM, n = 9) Relative to the placebo, 21 g/day but not 10.5 g/day of ispaghula increased the ACWC (Figure 1) significantly (11 ± 4 L.min vs. 1.0 ± 0.5 L.min, p < 0.001), while SBWC (Figure 2) was increased significantly by both doses (68 ± 15 L.min vs placebo 25 ± 6 L.min, p= < 0.01), and (49 ± 11 L.min, p= < 0.05) respectively. Both doses significantly increased the total colon volume, and there was a significant increase in colon volume at fasted baseline measurement. Ascending colon T1 was also increased by the 21 g/day dose (p < 0.01), but 24 h WAPS for transit were not significantly changed by treatment. gutjnl;63/Suppl_1/A200-a/F1F1F1 Abstract PWE-171 Figure 1 Time course of freely mobile water in the ascending colon (ACWC) throughout the MRI study day gutjnl;63/Suppl_1/A200-a/F2F2F2 Abstract PWE-171 Figure 2 Time course of the freely mobile water in the small bowel (SBWC) throughout the MRI study dayThe volume of water in both the ascending colon and the small bowel are significantly increased by ispaghula and could be useful biomarkers of a laxative effect. Ispaghula also increased colonic volumes and ascending colon T1 without altering transit times, suggesting it or its metabolites does not stimulate motility. These MRI methods could be readily used in assessing the mode of action of a range of novel agents in constipated patients will provide unique information on the mechanisms of action.None Declared.
Human experimental pain models are widely used to study drug effects under controlled conditions. However, efforts to improve both animal and human experimental model selection, on the basis of increased understanding of the underlying pathophysiological pain mechanisms, have been disappointing with poor translation of results to clinical analgesia. We have developed an alternative approach to the selection of suitable pain models which can correctly predict drug efficacy in particular clinical settings. This is based on the analysis of successful or unsuccessful empirical prediction of clinical analgesia using experimental pain models. We analyzed statistically the distribution of published mutual agreements or disagreements between drug efficacy in experimental and clinical pain settings. Significance limits were derived by random permutations of agreements. We found that a limited subset of pain models predicts a large number of clinically relevant pain settings, including efficacy against neuropathic pain for which novel analgesics are particularly needed. Thus, based on empirical evidence of agreement between drugs for their efficacy in experimental and clinical pain settings, it is possible to identify pain models that reliably predict clinical analgesic drug efficacy in cost-effective experimental settings.