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891.
Dietary protein restriction in the rat compromises the maternal cardiovascular adaptations to pregnancy and leads to raised blood pressure and endothelial dysfunction in the offspring. In this study we have hypothesized that dietary folate supplementation of the low-protein diet will improve maternal vascular function and also restore offspring cardiovascular function. Pregnant Wistar rats were fed either a control (18% casein) or protein-restricted (9% casein) diet +/-5 mg/kg folate supplement. Function of isolated maternal uterine artery and small mesenteric arteries from adult male offspring was assessed, systolic blood pressure recorded, and offspring thoracic aorta levels of endothelial nitric oxide (NO) synthase mRNA measured. In the uterine artery of late pregnancy dams, vasodilatation to vascular endothelial growth factor was attenuated in the protein-restricted group but restored with folate supplementation, as was isoprenaline-induced vasodilatation (P<0.05). In male offspring, protein restriction during pregnancy led to raised systolic blood pressure (P<0.01), impaired acetylcholine-induced vasodilatation (P<0.01), and reduced levels of endothelial NO synthase mRNA (P<0.05). Maternal folate supplementation during pregnancy prevented this elevated systolic blood pressure associated with a protein restriction diet. With folate supplementation, endothelium-dependent vasodilatation and endothelial NO synthase mRNA levels were not significantly different from either the control or protein-restricted groups. Maternal folate supplementation of the control diet had no effect on blood pressure or vasodilatation. This study supports the hypothesis that folate status in pregnancy can influence fetal development and, thus, the risks of cardiovascular disease in the next generation. The concept of developmental origins of adult disease focuses predominately on fetal life but must also include a role for maternal cardiovascular function.  相似文献   
892.
BACKGROUND AND PURPOSE: Transurethral Needle Ablation of the prostate TUNA has been accepted as an office-based treatment for benign prostatic hyperplasia (BPH) for many years. Clinical outcomes have been reported, but the amount and location of the necrosis produced have yet to be characterized. The necrosis caused by TUNA was evaluated by gadolinium-enhanced magnetic resonance imaging (MRI) of the pelvis. PATIENTS AND METHODS: Twelve patients with BPH/lower urinary-tract symptoms underwent standard TUNA, and MRI scans with gadolinium enhancement were performed before and 1 week after treatment. The images were studied using Analyze software to quantify the amount of necrosis compared with the prostatic volume. Transverse, coronal, and sagittal images were obtained to identify the location of the necrosis. RESULTS: New gadolinium defects were seen in all patients after TUNA. The lesions coalesced into continuous areas of necrosis and correlated with the site of needle placement. The mean volume of necrosis was 6.84 cc and equated to 8.6% of the prostate volume. No lesions were found near the apex, urethra, or rectum; and none extended beyond the prostate capsule. CONCLUSIONS: Gadolinium-enhanced MRI demonstrates new vascular defects representing necrosis caused by TUNA of the prostate. This therapy for BPH produces necrotic lesions that can be placed strategically by the surgeon. The standard protocol produces lesions that coalesce to create larger lesions. This MRI study has characterized, for the first time, the heating pattern and intraprostatic necrosis of a complete TUNA procedure.  相似文献   
893.
Factors associated with suicidal ideation and attempts were examined among a national probability sample of adolescents. Sample prevalences of suicidal ideation and attempts were 24.3% and 3.3%, respectively, yielding weighted population prevalence estimates of 23.3% and 3.1%. Suicidal ideation was positively associated with female gender, age, family alcohol and drug problems, violence exposure, lifetime depression, and posttraumatic stress disorder (PTSD). Suicide attempts were associated with female gender, age, sexual and physical assault, lifetime substance abuse or dependence, PTSD, and depression. Implications for intervention and prevention are discussed.  相似文献   
894.
895.
896.
Aim/hypothesis  Low-grade inflammation may contribute to obesity-related insulin resistance and has been associated with increased risk of type 2 diabetes mellitus. The present study evaluated whether treatment with salsalate, a traditional anti-inflammatory medication, would improve insulin action in obese non-diabetic individuals. Methods  The study was a randomised, double-blind, placebo-controlled, parallel trial conducted at the inpatient clinical research unit of the NIDKK (Phoenix, AZ, USA). Participants were 54 adults (18 to 45 years of age) with BMI ≥ 30 kg/m2. The intervention was salsalate (3 g/day, n = 28) or identical placebo (n = 26) for 7 days. The allocation was kept concealed by giving the investigator only a number corresponding to a vial of placebo or salsalate sequentially randomised in blocks by sex. Main outcomes were changes in insulin action assessed as rate of glucose disposal (R d) by euglycaemic–hyperinsulinaemic clamp (insulin infusion rate 40 mU m−2 min−1) and glucose tolerance by 75 g OGTT. Results  The study was completed by 47 participants, of which 40 were analysed (salsalate n = 22, placebo n = 18). Salsalate treatment resulted in decreased fasting plasma glucose concentration (mean [SD]; 4.83 [0.28] vs 5.11 [0.33] mmol/l, p = 0.001) and glucose AUC during the OGTT (p = 0.01), and in increased R d (20 [8] vs 18 [6] μmol [kg estimated metabolic body size]−1 min−1, p = 0.002), while there was no significant change in these variables with placebo (p > 0.3 for all). The effect of salsalate on R d disappeared (p = 0.9) after normalising to increased insulin concentrations (701 [285] vs 535 [201] pmol/l, p < 0.0001) measured during the clamp. No side effects of salsalate were observed during the study. Conclusions/interpretation  The glucose-lowering potential of salicylates appears to be due to effects on insulin concentration rather than improved insulin action. Salicylate-based compounds may be useful for the treatment and prevention of type 2 diabetes. Trial registration: ClinicalTrials.gov NCT 00339833. Funding: Intramural research programme of the NIDDK/NIH/DHHS. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users. J. Koska and E. Ortega contributed equally to this work.  相似文献   
897.
The blood–brain barrier (BBB) limits the distribution of systemically administered therapeutics to the central nervous system (CNS), posing a significant challenge to drug development efforts to treat neurological and psychiatric diseases and disorders. Intranasal delivery is a noninvasive and convenient method that rapidly targets therapeutics to the CNS, bypassing the BBB and minimizing systemic exposure. This review focuses on the current understanding of the mechanisms underlying intranasal delivery to the CNS, with a discussion of pathways from the nasal cavity to the CNS involving the olfactory and trigeminal nerves, the vasculature, the cerebrospinal fluid, and the lymphatic system. In addition to the properties of the therapeutic, deposition of the drug formulation within the nasal passages and composition of the formulation can influence the pathway a therapeutic follows into the CNS after intranasal administration. Experimental factors, such as head position, volume, and method of administration, and formulation parameters, such as pH, osmolarity, or inclusion of permeation enhancers or mucoadhesives, can influence formulation deposition within the nasal passages and pathways followed into the CNS. Significant research will be required to develop and improve current intranasal treatments and careful consideration should be given to the factors discussed in this review. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1654–1673, 2010  相似文献   
898.
The aim of the study was to determine the concentrations of serum antibodies against Haemophilus influenzae type b in preschool children in relation to the distribution of idiotypic antibodies 1 and 2 (Id-1 and Id-2) and the exposure to breastfeeding in infancy. Sera were obtained from 74 control children recruited in an earlier case-control study before the introduction of general Hib vaccination. Duration of breastfeeding was monitored, and prevalence of noninvasive infections was registered. Concentrations of IgG1 and IgG2 anti-Hib, as well as of total Id-1 and Id-2, were determined in ELISA. The expression of Id-1 antibodies increased with age in contrast to the Id-2 antibodies that were found only in children up to 24 months of age. Expression of Id-1 antibodies was positively correlated with higher anti-Hib levels of both the IgG1 and IgG2 isotype. Children expressing Id-2 antibodies showed higher IgG2 anti-Hib concentrations than those who did not have Id-2 (P = 0.001). The concentrations of neither Id-1 nor Id-2 antibodies were related to the duration of breastfeeding. Duration of breastfeeding was related to increased anti-Hib IgG2 in healthy children above 18 months of age. These study shows that the expression of idiotype-1 and idiotype-2 antibodies was associated with higher IgG2 anti-Hib concentration and that breastfeeding could enhance the anti-Hib IgG2 production in children.  相似文献   
899.
The doxycycline-inducible, gene regulatory system allows tight control of transgene expression for the study of organ development and disease pathogenesis. Multiple recent reports have employed this model to investigate various lung diseases including emphysema. For our study, we used this transgenic system to test whether prolonged, lung-specific, overexpression of the serine protease urokinase plasminogen activator (uPA) would result in alveolar wall destruction. Double transgenic mice were generated that possessed: (1) the rat Clara cell secretory protein promoter controlling the reverse tetracycline transactivator gene (CCSP:rtTA) and (2) the tetracycline operator controlling the murine uPA cDNA (tet[O]:muPA). Mice were treated with doxycycline beginning at age 6 wk to initiate uPA overexpression. Single transgenic and wild-type animals served as controls. A second group of double transgenic and control animals were maintained off of doxycycline. At ages 10, 18, and 30 wk, the mice underwent measurements of alveolar size, lung compliance, and total lung capacity. We found that, although the uPA overexpressing mice demonstrated an emphysema phenotype, similar abnormalities occurred in the CCSP-rtTA control animals. These CCSP-rtTA-related alterations occurred even without doxycycline exposure. Evaluation of a second transgenic line possessing the human surfactant protein C promoter controlling rtTA expression also exhibited lung abnormalities consistent with emphysema. These findings indicate that pulmonary epithelial expression of rtTA alone causes an emphysema phenotype in mice. Therefore, when using this system to study emphysema pathogenesis, the inclusion of proper controls is essential for accurate data interpretation.  相似文献   
900.
The International Registry of Werner syndrome (www.wernersyndrome.org) has been providing molecular diagnosis of the Werner syndrome (WS) for the past decade. The present communication summarizes, from among 99 WS subjects, the spectrum of 50 distinct mutations discovered by our group and by others since the WRN gene (also called RECQL2 or REQ3) was first cloned in 1996; 25 of these have not previously been published. All WRN mutations reported thus far have resulted in the elimination of the nuclear localization signal at the C-terminus of the protein, precluding functional interactions in the nucleus; thus, all could be classified as null mutations. We now report two new mutations in the N-terminus that result in instability of the WRN protein. Clinical data confirm that the most penetrant phenotype is bilateral ocular cataracts. Other cardinal signs were seen in more than 95% of the cases. The median age of death, previously reported to be in the range of 46-48 years, is 54 years. Lymphoblastoid cell lines (LCLs) have been cryopreserved from the majority of our index cases, including material from nuclear pedigrees. These, as well as inducible and complemented hTERT (catalytic subunit of human telomerase) immortalized skin fibroblast cell lines are available to qualified investigators.  相似文献   
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