Perceived stress and reported cognitive symptoms among Georgia patients with systemic lupus erythematosus.

Objective To examine associations of perceived stress with cognitive symptoms among adults with systemic lupus erythematosus (SLE). Methods Among 777 adult (≥18 years) SLE patients, the association of Perceived Stress Scale (PSS) scores with two self-reported cognitive symptoms was examined: forgetfulness (severe/moderate vs. mild/none; from the Systemic Lupus Activity Questionnaire) and difficulty concentrating (all/most vs. some/little/none of the time; from the Lupus Impact Tracker). The study used multivariable logistic regression to estimate the odds ratios (ORs) per minimal important difference (MID = 0.5*SD) of PSS score and cognitive symptoms. Results Forgetfulness and difficulty concentrating were reported by 41.7% and 29.5%, respectively. Women and those with less education and high disease activity had higher PSS scores and were more likely to report cognitive symptoms than their counterparts. With adjustment for age, race, sex, education, and disease activity, each MID increase in PSS score was associated with higher prevalence of forgetfulness (OR = 1.43, 95% CI 1.29-1.47) and difficulty concentrating (OR = 2.19, 95% CI 1.90-2.52). No substantial differences in this association by age, race, sex, or disease activity were noted. Conclusions SLE patients, particularly those with high disease activity, report a high burden of cognitive symptoms, for which stress may be a modifiable risk factor.

Dialysis facility and network factors associated with low kidney transplantation rates among United States dialysis facilities.

Variability in transplant rates between different dialysis units has been noted, yet little is known about facility-level factors associated with low standardized transplant ratios (STRs) across the United States End-stage Renal Disease (ESRD) Network regions. We analyzed Centers for Medicare & Medicaid Services Dialysis Facility Report data from 2007 to 2010 to examine facility-level factors associated with low STRs using multivariable mixed models. Among 4098 dialysis facilities treating 305 698 patients, there was wide variability in facility-level STRs across the 18 ESRD Networks. Four-year average STRs ranged from 0.69 (95% confidence interval [CI]: 0.64-0.73) in Network 6 (Southeastern Kidney Council) to 1.61 (95% CI: 1.47-1.76) in Network 1 (New England). Factors significantly associated with a lower STR (p < 0.0001) included for-profit status, facilities with higher percentage black patients, patients with no health insurance and patients with diabetes. A greater number of facility staff, more transplant centers per 10 000 ESRD patients and a higher percentage of patients who were employed or utilized peritoneal dialysis were associated with higher STRs. The lowest performing dialysis facilities were in the Southeastern United States. Understanding the modifiable facility-level factors associated with low transplant rates may inform interventions to improve access to transplantation.

The association of state and national legislation with living kidney donation rates in the United States: a national study.

The effect of state legislation and federal policies supporting living donors on living kidney donation rates in the United States is unknown. We studied living kidney donation rates from 1988 to 2006, and we assessed changes in donation before and after the enactment of state legislation and the launch of federal initiatives supporting donors. During the study, 27 states enacted legislation. Among states enacting legislation, there was no statistically significant difference in the average rate of increase in overall living kidney donations after compared to before state legislation enactment (annual increase in donations per 1 000 000 population [95% confidence interval] 2.39 [1.94-2.84] compared to 1.68 [0.89-2.47] respectively, p > 0.05). Among states not enacting legislation, there was a statistically significantly greater annual increase in overall donation rates from 1997 to 2002 compared to before 1997 when federal initiatives commenced, but there was no growth in annual rates after 2002. State and federal legislation were associated with increases in living-unrelated donation. These findings suggest that although existing public policies were not associated with improvements in the majority of donations from living-related donors, they may have had a selective effect on barriers to living-unrelated kidney donation.

Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: a longitudinal study.

Elevated bone mineral parameters have been associated with mortality in dialysis patients. There are conflicting data about calcium, parathyroid hormone (PTH), and mortality and few data about changes in bone mineral parameters over time. We conducted a prospective cohort study of 1007 incident hemodialysis and peritoneal dialysis patients. We examined longitudinal changes in bone mineral parameters and whether their associations with mortality were independent of time on dialysis, inflammation, and comorbidity. Serum calcium, phosphate, and calcium-phosphate product (CaP) increased in these patients between baseline and 6 months (P<0.001) and then remained stable. Serum PTH decreased over the first year (P<0.001). In Cox proportional hazards models adjusting for inflammation, comorbidity, and other confounders, the highest quartile of phosphate was associated with a hazard ratio (HR) of 1.57 (1.07-2.30) using both baseline and time-dependent values. The highest quartiles of calcium, CaP, and PTH were associated with mortality in time-dependent models but not in those using baseline values. The lowest quartile of PTH was associated with an HR of 0.65 (0.44-0.98) in the time-dependent model with 6-month lag analysis. We conclude that high levels of phosphate both at baseline and over follow-up are associated with mortality in incident dialysis patients. High levels of calcium, CaP, and PTH are associated with mortality immediately preceding an event. Promising new interventions need to be rigorously tested in clinical trials for their ability to achieve normalization of bone mineral parameters and reduce deaths of dialysis patients.

Upregulation of B50/GAP-43 protein mRNA in rat dorsal root ganglia during cisplatin intoxication.

Expression of the growth-associated protein B50 (GAP-43) mRNA in dorsal root ganglia (DRG) of rats was studied by in situ hybridization. In response to treatment with the neurotoxic agent cisplatin, B50 mRNA expression was significantly enhanced following a cumulative cisplatin dose of 14 mg/kg. In the untreated age-matched control animals, only half of the ganglion cells exhibited expression of B50 mRNA (mean hybridization signal, 10 times background), whereas at a cumulative cisplatin dose of 14 mg cisplatin every neuron exhibited well above background expression (mean hybridization signal, 34 times background). Cotreatment with a neuroprotective ACTH4-9 analog known to prevent cisplatin neuropathy in rats did not affect the overall expression of B50 mRNA. However, in the subpopulation of large sensory neurons, B50 mRNA content was significantly higher in the group cotreated with the ACTH4-9 analog as compared with the saline-cotreated group after 14 mg/kg of cisplatin. We conclude that in analogy with the well-known upregulation of B50 mRNA following mechanical nerve lesions, treatment with the neurotoxic drug cisplatin also leads to an increase in B50 mRNA expression. This observation lends strength to the hypothesis that in neuropathies an imbalance between regenerative and degenerative mechanisms exists. The ability of the larger sensory neurons to retain an increased B50 mRNA expression better after cotreatment with the peptide than without may be related to stimulation of regenerative processes by this ACTH4-9 analog.

Pharmacological evidence for the involvement of endogenous alpha-MSH-like peptides in peripheral nerve regeneration.

The possible involvement of alpha-MSH-like peptides in the regenerative response of peripheral nerves was investigated with a competitive antagonist of alpha-MSH, the synthetic hexapeptide [D-Trp7,Ala8,D-Phe10)alpha-MSH(6-11)-amide. Subcutaneous administration of the alpha-MSH antagonist during the first 10 days following sciatic nerve crush significantly decreased functional recovery as measured by the foot flick withdrawal test and the walking pattern analysis. Hypophysectomy delayed both the initial sprouting response and the outgrowth rate after major caudal nerve crush. When hypophysectomized rats were treated with the alpha-MSH antagonist, a further delay in initial sprouting was observed, whereas the outgrowth rate of nerve fibers was not affected. These results suggest that 1) endogenous alpha-MSH-like peptides stimulate nerve outgrowth following peripheral nerve injury and 2) alpha-MSH-like peptides derived from a source other than the pituitary may contribute to the physiological stimulus leading to sprouting.

B-50/GAP-43 mRNA expression in cultured primary Schwann cells is regulated by cyclic AMP.

Following peripheral nerve crush or transection, B-50 mRNA expression increased dramatically in the distal nerve stump. This increase has been fully attributed to an up-regulation of B-50 synthesis in reactive Schwann cells. Here we describe that B-50 mRNA expression in primary Schwann cell cultures is strongly down-regulated by cyclic AMP. Treatment of neonatal Schwann cell cultures with as low as 20 nM forskolin decreased B-50 mRNA expression. We show that B-50 promoter P2, but not P1, is active in Schwann cells and that the activity of P2 is inhibited 2.5 fold by forskolin. P2 does not contain a consensus sequence of a known cyclic AMP responsive element suggesting that the effect of forskolin is indirect.

The neurotrophic peptide Org 2766 does not influence the expression of the immediate early gene c-fos following sciatic nerve crush in the rat.

The neurotrophic peptide Org 2766 accelerates the regeneration of peripheral nerves. Although the mechanism of action of this neuropeptide is not yet understood, functional, pharmacological, and morphological evidence has demonstrated that Org 2766 exerts its beneficial effect during the early stages of nerve regeneration. The induction of some members of the Immediate Early Gene (IEG) family such as c-jun and c-fos is one of the first molecular events following peripheral nerve damage. The Fos and Jun proteins act as a transcription factor and may stimulate the expression of a number of genes implicated in nerve regeneration. We examined whether Org 2766 stimulates nerve regeneration by enhancing or prolonging the expression of c-fos mRNA. Following a crush lesion of the sciatic nerve, the expression of c-fos mRNA was induced in the spinal cord and in the damaged nerve at 30 min following injury in untreated animals as demonstrated with Northern blot. No effect of the crush lesion was observed in dorsal root ganglia (DRG). The induction of c-fos mRNA in the damaged nerve was more robust as compared to the relatively small induction observed in the spinal cord. With in situ hybridization an increase in c-fos mRNA expression both in the dorsal and in the ventral horn of the spinal cord was demonstrated at 30 min post-lesion. In the distal sciatic nerve portion the expression of c-fos mRNA was predominantly localized around Schwann cell nuclei at 30 min after nerve crush. The effect of Org 2766 treatment on the expression of c-fos mRNA was investigated using semiquantitative dot blots.(ABSTRACT TRUNCATED AT 250 WORDS)

The expression of B-50/GAP-43 in Schwann cells is upregulated in degenerating peripheral nerve stumps following nerve injury.

We have detected mRNA for B-50 (GAP-43, pp46, F1, neuromodulin), which was originally believed to be a neuron-specific protein, in non-neuronal cells in the rat sciatic nerve. In control rats, the level of B-50 mRNA in sciatic nerve tissue was much lower than in dorsal root ganglia. Following nerve crush or transection, the expression of B-50 mRNA in the distal nerve stump increased dramatically between 1 and 2 days post-injury. The B-50 mRNA levels in the distal stump of crushed nerves remained elevated for up to 4 weeks and subsequently returned to control levels after 7 weeks. In contrast, after nerve transection B-50 mRNA levels in the distal nerve portion continued to increase up to 7 weeks post-lesion. No changes in the levels of the B-50 transcript were observed in the proximal portion of either crush-lesioned or transected sciatic nerves. In situ hybridization demonstrated B-50 mRNA associated with Schwann cells in the distal nerve stump. The observation that Schwann cells are capable of producing B-50 mRNA was confirmed by Northern blot analysis of total RNA isolated from primary Schwann cell cultures. Taken together, these data show the expression of B-50 mRNA by Schwann cells and the up-regulation of B-50 mRNA in reactive Schwann cells upon loss of axonal contact.

Upregulation of B-50/GAP-43 in Schwann cells at denervated motor endplates and in motoneurons after rat facial nerve crush.

Crush or transection of peripheral nerves of the adult rat is accompanied by changes in protein expression, including the growth associated protein (GAP-43) B-50. Following peripheral nerve crush in rat enhanced B-50 immunoreactivity was observed in regenerating nerve fibres and in newly formed axon terminals. However, before reinnervation was apparent, an unexpected transient increase in B-50 immunoreactivity was observed at denervated motor endplates [J. Neurosci. 8 (1988) 1759]. This study was performed to clarify this observation. Four days following facial nerve crush B-50 immunoreactivity was detected by double immunofluorescence microscopy in Sl00-positive Schwann cells covering the denervated endplates. Using diluted polyclonal and monoclonal B-50 antibodies we found that B-50 immunoreactivity at the denervated motor endplates was strongly increased in comparison to innervated motor endplates in which B-50 immunoreactivity was hardly detectable. However, when a high concentration of B-50 antibodies was applied the normal innervated motor endplates were also B-50 immunoreactive. Muscle fibres did not display B-50 immunoreactivity. Northern blot analysis revealed elevated B-50 mRNA in denervated muscle and in degenerating nerve with respect to the controls. The B-50 mRNA levels in these non-neuronal tissues were very low compared to the intact and injured facial nucleus containing the neuronal cell bodies. Electron microscopy demonstrated that the B-50 protein was localized in the processes of Schwann cells covering axon terminals of intact and vacant motor endplates and in axon varicosities of sympathetic nerves. This study has confirmed that prior to reinnervation B-50 immunoreactivity is increased at denervated motor endplates and shows that B-50 is co-localized with S100 in Schwann cells. Therefore, upregulation of B-50 expression in Schwann cells may explain the early occurrence of B-50 immunoreactivity at the motor endplate.

Expression of the pro-opiomelanocortin gene in dorsal root ganglia, spinal cord and sciatic nerve after sciatic nerve crush in the rat.

Neuropeptides related to alpha-melanocyte-stimulating hormone (alpha-MSH) stimulate nerve outgrowth following peripheral nerve injury and may play an important physiological role in peripheral nerve regeneration. The mechanism of action underlying the neurotrophic effect of pharmacologically administered alpha-MSH is unknown. Here we investigate the hypothesis that reexpression of the proopiomelanocortin (POMC) gene, the prohormone of alpha-MSH/adrenocorticotropic hormone (ACTH)-like peptides, is part of the endogenous repertoire of peripheral nerve responses following injury. The effect of sciatic nerve crush on the expression of POMC mRNA between 0.5 h and 14 days after crush was investigated using polymerase chain reaction (PCR) and Northern blot analysis. The presence of a POMC transcript in dorsal root ganglia (DRG), spinal cord and in the sciatic nerve at the crush site could be demonstrated in both control and lesioned animals by PCR using primers located in exon 1 and 3 of the POMC gene. Minute quantities of two POMC transcripts (1200 nt and 800 nt) could be detected by Northern blot analysis of total RNA prepared from DRG, spinal cord and the sciatic nerve of control animals and of animals subjected to nerve crush. POMC mRNA expression was, however, not increased following nerve crush. Probes specific for exons 1 and 2 or specific for exon 3 of the POMC gene were employed to demonstrate that the 800 nt transcript represents the truncated POMC mRNA previously shown to be present in extra-pituitary tissue. The larger 1200 nt transcript comigrates with the full length POMC mRNA expressed in the pituitary gland. The present results demonstrate the expression of small amounts of POMC mRNA in all compartments of the sciatic nerve. The absence of an induction of POMC expression in response to nerve crush suggests that the stimulating effect of exogenously applied alpha-MSH does not mimic a POMC derived neurotrophic peptide induced in the nerve following nerve injury.