All-cause and cardiovascular mortality in diabetic subjects increases significantly with reduced estimated glomerular filtration rate (eGFR): 10 years' data from the South Tees Diabetes Mortality study.

AIMS: To investigate the association between estimated glomerular filtration rate (eGFR) and total and cardiovascular mortality in a population-based cohort of diabetic subjects. METHODS: A longitudinal study using a population-based district diabetes register comprising 3288 subjects in South Tees, UK. The eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) study equation. Patients were stratified by baseline eGFR into five stages as per the National Kidney Foundation guidelines: Stage 1, eGFR > 90; Stage 2, eGFR 60-89; Stage 3, eGFR 30-59; Stage 4, eGFR 15-29; and Stage 5, eGFR < 15 ml/min per 1.73 m(2). Main outcome was all-cause and cardiovascular mortality between 1 January 1994 and 31 July 2004. RESULTS: At baseline, mean age (58.4 years) differed between groups. Persons with lower eGFR were older (P < 0.001). Thirty-six percent (n = 1193, males 56%) had died by 10 years (cardiovascular cause in 60%). Median follow-up was 10.5 years amounting to 28 342 person years. Stages 4 and 5 (eGFR 相似文献   

Regulation of COX-2 mediates acid-induced bone calcium efflux in vitro.

Chronic metabolic acidosis induces net Ca efflux from bone; this osteoclastic bone resorption is mediated by increased osteoblastic prostaglandin synthesis. Cyclooxygenase, the rate-limiting enzyme in prostaglandin synthesis, is present in both constitutive (COX-1) and inducible (COX-2) forms. We report here that acidosis increases both osteoblastic RNA and protein levels for COX-2 and that genetic deficiency or pharmacologic inhibition of COX-2 significantly reduces acid-induced Ca efflux from bone. INTRODUCTION: Incubation of neonatal mouse calvariae in medium simulating physiologic metabolic acidosis induces an increase in osteoblastic prostaglandin E2 (PGE2) release and net calcium (Ca) efflux from bone. Increased PGE2 is necessary for acid-induced bone resorption, because inhibition of cyclooxygenase activity with indomethacin significantly decreases not only PGE2 production but also Ca release. Cyclooxygenase is present in both constitutive (COX-1) and inducible (COX-2) forms. Because COX-2 activity has been implicated in several forms of pathological bone resorption, we tested the hypothesis that COX-2 is critical for acid-induced, cell-mediated bone Ca efflux. MATERIALS AND METHODS: To determine the effect of metabolic acidosis on COX-2 RNA and protein, primary cells isolated from neonatal CD-1 mouse calvariae were cultured in neutral (Ntl) or physiologically acidic medium (Met). RNA levels for COX-2 and COX-1 were measured by quantitative real-time PCR. Levels of COX-2 and COX-1 protein were measured by immunoblot analysis. To determine the effect of acidosis on bone Ca efflux in genetically deficient COX-2 mice, mice heterozygous for the COX-2 knockout (strain B6;129S7-Ptgs2(tm1Jed)/J) were used as breeders, and neonatal calvariae were cultured in Ntl or Met. To determine the effects of the specific COX-2 inhibitor, NS398, on acid-induced bone resorption, CD-1 calvariae were incubated in Ntl or Met with or without NS398 (1 microM). Medium PGE2 was assayed by ELISA. RESULTS: Incubation of mouse calvarial cells in Met significantly increased COX-2 RNA and protein levels without a change in COX-1. Increased COX-2 protein levels in response to Met were also observed in cultured calvariae. Acid-induced, cell-mediated Ca efflux from B6;129S7-Ptgs2(tm1Jed)/J calvariae was dependent on genotype. From 0 to 24 h, when physicochemical Ca efflux predominates, Met significantly increased net Ca efflux in all genotypes. After 24 h, when cell-mediated Ca efflux predominates, Met induced greater Ca efflux from (+/+) than from (+/-), and there was no increase from (-/-). In calvariae from CD-1 mice, NS398 significantly inhibited both the acid-induced increase in PGE2 and Ca release. CONCLUSIONS: The specific acid-induced increase in COX-2 RNA and protein levels and the dependency of the increased Ca efflux on COX-2 activity, as determined by both genetic deficiency and pharmacologic inhibition, show that COX-2 is critical for acid-induced, cell-mediated bone resorption.     

Onset, progression, and plateau of skeletal lesions in fibrous dysplasia and the relationship to functional outcome.

Most lesions in FD and their attendant functional disability occur within the first decade; 90% of lesions are present by 15 years, and the median age when assistive devices are needed is 7 years. These findings have implications for prognosis and determining the timing and type of therapy. INTRODUCTION: Fibrous dysplasia of bone (FD) is an uncommon skeletal disorder in which normal bone is replaced by abnormal fibro-osseous tissue. Variable amounts of skeletal involvement and disability occur. The age at which lesions are established, the pace at which the disease progresses, if (or when) the disease plateaus, and how these parameters relate to the onset of disability are unknown. To answer these questions, we performed a retrospective analysis of a group of subjects with FD. MATERIALS AND METHODS: One hundred nine subjects with a spectrum of FD were studied for up to 32 years. Disease progression was assessed in serial (99)Tc-MDP bone scans by determining the location and extent of FD lesions using a validated bone scan scoring tool. Physical function and the need for ambulatory aids were assessed. RESULTS: Ninety percent of the total body disease skeletal burden was established by age 15. Disease was established in a region-specific pattern; in the craniofacial region, 90% of the lesions were present by 3.4 yr, in the extremities, 90% were present by 13.7 yr, and in the axial skeleton, 90% were present by 15.5 yr. Twenty-five of 103 subjects eventually needed ambulatory aids. The median age at which assistance was needed was 7 yr (range, 1-43 yr). The median bone scan score for subjects needing assistance was 64.3 (range, 18.6-75) compared with 23.1 (range, 0.5-63.5) in the unassisted subjects (p < 0.0001). Among subjects needing assistance with ambulation, 92% showed this need by 17 yr. CONCLUSIONS: The majority of skeletal lesions and the associated functional disability occur within the first decade of life. The implication is that the window of time for preventative therapies is narrow. Likewise, therapeutic interventions must be tailored to where the patient is in the natural history of the disease (i.e., progressive disease [young] versus established disease [older subjects]). These findings have implications for prognosis, the timing and type of therapy, and the development of trials of new therapies and their interpretation.     

TGF-beta promotes the establishment of renal cell carcinoma bone metastasis.

Bone metastases develop in approximately 30% of patients with RCC, and the mechanisms responsible for this phenomenon are unknown. We found that TGF-beta1 stimulation of RCC bone metastasis cells promotes tumor growth and bone destruction possibly by stimulating paracrine interactions between tumor cells and the bone. INTRODUCTION: Bone metastasis is a frequent complication and causes marked morbidity in patients with renal cell carcinoma (RCC). Surprisingly, the specific mechanisms of RCC interaction with bone have been scarcely studied despite the inability to prevent or effectively treat bone metastasis. Bone is a reservoir for various growth factors including the pleiotropic cytokine TGF-beta1. TGF-beta1 has been shown to have tumor-supportive effects on advanced cancers and evidence suggests its involvement in promoting the development of breast cancer bone metastasis. Here, we studied the potential role of TGF-beta1 in the growth of RCC bone metastasis (RBM). MATERIALS AND METHODS: To inhibit TGF-beta1 signaling, RBM cells stably expressing a dominant-negative (DN) TGF-betaRII cDNA were generated. The in vivo effect of TGF-beta1 on RBM tumor growth and osteolysis was determined by histological and radiographic analysis, respectively, of athymic nude mice after intratibial injection of parental, empty vector, or DN RBM cells. The in vitro effect of TGF-beta1 on RBM cell growth was determined after TGF-beta1 treatment by MTT assay. RESULTS: TGF-beta1 and the TGF-beta receptors I and II (TGF-betaRI/II) were consistently expressed in both RBM tissues and cell lines. Inhibition of TGF-beta1 signaling in RBM cells significantly reduced tumor establishment and osteolysis observed in vivo after injection into the murine tibia, although no effect on tumor establishment was observed after injection of RBM cells subcutaneously or into the renal subcapsule. Treatment of five RBM cell lines with TGF-beta1 in vitro either had no effect (2/5) or resulted in a significant inhibition (3/5) of cell growth, suggesting that TGF-beta1 may promote RBM tumor growth indirectly in vivo. CONCLUSIONS: TGF-beta1 stimulation of RBM cells plays a role in promoting tumor growth and subsequent osteolysis in vivo, likely through the initiation of tumor-promoting paracrine interactions between tumor cells and the bone microenvironment. These data suggest that inhibition of TGF-beta1 signaling may be useful in the treatment of RBM.     

Outcomes of Project Wall Talk: an HIV/AIDS peer education program implemented within the Texas State Prison system.

We report select outcomes from an evaluation of Project Wall Talk, a community-based, peer-led HIV prevention education program implemented in 36 Texas State prison units. Peer educators completed questionnaires prior to receipt of a 40-hour intensive training (N = 590) and at 9-month follow-up (N = 257). Students (N = 2506) completed questionnaires pre- and post-receipt of peer educator-led HIV education sessions. Peer educators and their students showed significant increases in HIV-related knowledge. Peer educators showed significant increases in assessment of their skills as educators. For both peer educators and students, significant differences in HIV-related knowledge were indicated across categories of prior educational level attained and race/ethnicity; no such differences were indicated at follow-up. Compared with baseline, a significantly greater proportion of peer educators reported ever having had an HIV test. After receiving peer-led education, a significantly smaller proportion of students reported they knew their HIV status and more indicated plans to take an HIV test. Additionally, in months 12 and 18 following program implementation, the numbers of HIV tests at the five units that implemented the peer education program were roughly twice that of five, matched comparison units without the peer education program. Based on peer educator reports, we projected that peer educators (N = 257) may have as many as 84,000 or more annual opportunities to share HIV-related knowledge with other prisoners outside the classroom.     

The changing face of paediatric hydrocephalus: a decade's experience.

All 253 children receiving neurosurgical intervention for hydrocephalus (HCP) at a single British Neurosurgical Unit over a decade were investigated by retrospective case note review. Referral rates and mean age at presentation remained stable throughout, as did proportions of children presenting due to myelomeningocoele or meningitis. Comparing the first and second halves of the decade, the predominant aetiologies (intraventricular haemorrhage [IVH] at <1 year and brain tumour at 1-16 years) reduced from comprising half (70/129) of all cases to just over one-third (43/124). Other significant changes included a 45% reduction in neonatal IVH and a 179% increase in rare miscellaneous disorders. Outcome after 4 years of follow-up for all patients showed 44.4% without deficit, 11.9% with non-cognitive neurological deficits only, 11.5% with cognitive impairment only, 13.5% with both cognitive and neurological impairments, and 15.5% mortality.     

Effects of cocaine, exercise, and resting conditions on plasma corticosterone and catecholamine concentrations in the rat

Cocaine and exercise are both known as stressors, but little is known about the combined effects of these two treatments. In this study, rats under the influence of cocaine (12.5 mg/kg, intraperitoneally [IP]) or saline were exposed to a variety of resting conditions, as well as exercise (running, 26 m/min, 10% grade, for 30 minutes), to evaluate the amount of stress imposed by these conditions as determined by the changes in the plasma concentrations of corticosterone (C) and catecholamines (norepinephrine [NE], epinephrine [E], dopamine [DA]). After injection of saline, resting near the operating treadmill for 30 minutes caused the concentration of C to increase from 0.07 +/- 0.03 to 0.30 +/- 0.05 microgram/mL (P less than .05), compared to the increase to only 0.15 +/- 0.04 micrograms/mL after resting in a cage. This increase due to proximity to the treadmill subsided after 50 minutes. After cocaine, the 30-minute resting values were 0.70 +/- 0.15 (treadmill) and 0.55 +/- 0.13 (cage) (P less than .05), and did not subside after 50 minutes. Cocaine also increased levels of E, NE, and DA above those in saline under all rest conditions. With exercise, the value for C in saline increased to 0.61 +/- 0.18, but, in cocaine, the value went to 0.93 +/- 0.05 (P less than .05). The concentrations of E (946 +/- 74 v 603 +/- 101 pg/mL, cocaine v saline) and NE (1,027 +/- 102 v 440 +/- 153, cocaine v saline) during exercise also were exaggerated by cocaine treatment (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

A Randomized Pilot Study of Behavioral Treatment to Increase Calorie Intake in Toddlers With Cystic Fibrosis

This pilot study examined a behavioral treatment to increase calorie intake in toddlers with cystic fibrosis. Eight toddlers were randomly assigned to behavioral plus nutrition (BEH) or nutrition intervention (NTR) conditions. Calorie intake and weight were measured at pre- and posttreatment. The BEH group showed a trend for changes in calorie intake pre- to posttreatment (p = .07; 40% increase). Results for the BEH and NTR groups did not differ significantly. Most participants achieved weight gains consistent with normal growth. Seventy-five percent had not shown this pattern during the year prior to intervention. These results support the feasibility and potential for behavioral interventions in this age group.