Greater Epoetin alfa Responsiveness Is Associated With Improved Survival in Hemodialysis Patients

Background and objectives: Among hemodialysis patients, achieved hemoglobin is associated with Epoetin alfa dose and erythropoietin responsiveness. A prospective erythropoietin responsiveness measure was developed and its association with mortality evaluated.Design, setting, participants, & measurements: Data from 321 participants were used and randomized to the hematocrit normalization arm of the Normal Hematocrit Cardiac Trial. Subjects were to receive a 50% Epoetin alfa dose increase at randomization. The prospective erythropoietin responsiveness measure was defined as the ratio of weekly hematocrit change (over the 3 wk after randomization) per Epoetin alfa dose increase (1000 IU/wk) corresponding to the mandated 50% dose increase at randomization. The distribution of responsiveness was divided into quartiles. Over a 1-yr follow-up, Cox proportional hazard modeling evaluated associations between this responsiveness measure and mortality.Results: Erythropoietin responsiveness values ranged from −2.1% to 2.4% per week per 1000 IU. Although subjects were similar across response quartiles, mortality ranged between 14% and 34% among subjects in the highest and lowest response quartiles (P = 0.0004), respectively. After adjusting for baseline prognostic indicators, highest versus lowest responsiveness was associated with a hazard ratio of 0.41 (95% confidence interval, 0.20 to 0.87).Conclusion: Lower erythropoietin responsiveness is a strong, independent predictor of mortality risk and should be considered when evaluating associations between clinical outcomes and potential prognostic indicators, such as Epoetin alfa dose and achieved hemoglobin values.More than 90% of end-stage renal disease patients require exogenous erythropoietin or transfusion to achieve and maintain target hemoglobin values (1,2) because of decreased endogenous erythropoietin production. The ability to achieve and maintain target hemoglobin levels is complicated by a variety of mediating factors that impact responsiveness to erythropoietin, including comorbidities, inflammation, and malnutrition. These factors are independently associated with poor clinical outcomes (3–9).The impact of erythropoietin responsiveness on mortality is not well understood. Although higher hemoglobin levels have been associated with reduction in mortality in observational studies (10,11), evidence from randomized clinical trials of hemodialysis patients does not suggest a mortality benefit (12). Paradoxically, in the Normal Hematocrit Cardiac Trial (13), the largest randomized trial conducted to date in hemodialysis patients, survival rates were higher among those achieving higher hematocrit values, but targeting a higher hematocrit was associated with a 1.3-fold increased risk of mortality or nonfatal myocardial infarction (95% confidence interval [CI], 0.9 to 1.9). This suggests that unknown/unmeasured patient characteristics associated with the ability to achieve greater hemoglobin values may confound analyses assessing mortality risks among dialysis patients.Achieved hemoglobin level is associated with both the Epoetin alfa doses administered and patient responsiveness to erythropoietin. Greater survival among patients with higher hemoglobin values may be partly due to greater erythropoietin responsiveness (14) in addition to a direct result of anemia correction. Likewise, lower survival among those with lower achieved hemoglobin values may be partly the result of lower relative erythropoietin responsiveness. Patients who require higher Epoetin alfa doses to achieve a given hemoglobin level, that is, who are less responsive to erythropoietin, may experience poorer outcomes at any achieved hemoglobin value (15).In this study, data from the hematocrit normalization arm of the Normal Hematocrit Cardiac Trial (13) were used to develop a prospective measure of erythropoietin responsiveness, which was then evaluated in relation to mortality.     

Nonlinear Optical Limiting and Radiation Shielding Characteristics of Sm2O3 Doped Cadmium Sodium Lithium Borate Glasses

Strong nonlinear absorption (NLA), reduced optical limiting (OL) thresholds, and high radiation shielding parameters are required for the effective use of glasses in the laser radiation and nuclear radiation protecting materials. In view of this, the efficacy of Sm₂O₃ on the nonlinear optical (NLO) and OL properties were ascertained (at 532 nm) along with radiation shielding characteristics. The open and closed aperture Z-scan profiles revealed the presence of positive NLA and nonlinear refraction (NLR) phenomena respectively. OL measurements showed the existence of limiting behavior in the studied glasses. The NLA and NLR coefficients were improved while the OL thresholds were decreased as the doping of Sm₂O₃ elevated to a higher doping level. These improvements in NLA, NLR coefficients and OL efficiencies were attributed to the non-bridging oxygens and high polarizable Sm³⁺ ions. The NLA and OL results clearly suggest the high (5 mol %) Sm₂O₃ doped glass (Sm5CNLB) glass is beneficial to protect the delicate devices and human eye by suppressing the high energy laser light. The theoretical linear attenuation coefficients (LAC) values of the presented SmxCNLB glasses were obtained with the help of Phy-X software between 0.284 and 1.333 MeV. At 0.284 MeV, the maximum values occur and take values between 0.302 (for Sm0CNLB) and 0.409 cm⁻¹ (for Sm5CNLB). We found that the LAC for the presented SmxCNLB glasses is a function of Sm₂O₃ content, where the LAC tends to increase, corresponding to the high probabilities of interaction, as the content of Sm₂O₃ changes from 0 to 5 mol %. The effective atomic number (Z_eff) for the presented SmxCNLB glasses was examined between 0.284 and 1.333 MeV. As the amount of Sm₂O₃ is added, the Z_eff increases, and this was observed at any energy.     

Supplemental maxillomandibular fixation with miniplate osteosynthesis��required or not?

Aim

To compare outcomes of open reduction and internal fixation of mandible fractures followed by either immediate mobilization or 5?days of maxillomandibular fixation.

Material and methods

We analyzed our use of supplemental maxillomandibular fixation with miniplate osteosynthesis during a 2.5-year period in 118 patients with 180 mandible fractures. A retrospective, matched pairing of identical fractures fixated with identical plating schemes was carried out. Thirty-five pairs of patients undergoing monocortical plating were identified. Patients in group 1 were treated with supplemental maxillomandibular fixation after surgery, whereas patients in group 2 (immediate release group) were treated without postoperative maxillomandibular fixation.

Results

The total rate of complications was 17% with supplemental maxillomandibular fixation and 14% without supplemental maxillomandibular fixation (p?>?0.05). No statistically significant outcome advantage could be attributed to the use of maxillomandibular fixation.

Conclusion

The current retrospective study shows no significant differences in treating isolated mandible fractures with open reduction and internal fixation and immediate release versus open reduction and internal fixation with 5?C7?days of MMF.     

Surgical closure of atrial septal defect in children under two years of age

Infants with atrial septal defects are seldom symptomatic and usually require elective surgery between 2 and 4 years of age. However a small minority is symptomatic and management at this age has been controversial. This study evaluated surgical closure of atrial septal defect below 2 years of age. Eighteen infants with a mean age of 13.4 +/- 5.7 months were operated on for secundum atrial septal defect from 1994 to 2001. Fourteen patients were symptomatic with failure to thrive in 7 and recurrent respiratory infections in 7, one had increasing cardiomegaly, and 3 were operated on early for social reasons. The defect was isolated in 11 patients (61%) and the other 7 (39%) had minor associated lesions requiring additional procedures such as ductal ligation, direct closure of a tiny ventricular septal defect, and inspection of the mitral valve. There were no early or late deaths. The postoperative course was complicated by pulmonary problems in 4 cases. Of the 16 patients available for follow-up, 14 were asymptomatic and 2 were symptomatically improved. Most showed a dramatic improvement in growth and development. These gratifying results indicate that consideration should be given to early surgical closure of atrial septal defect in symptomatic infants.     

Basic fibroblast growth factor induces TGF-beta release in an isoform and glioma-specific manner

The aim of the current study was to determine whether basic fibroblast growth factor (bFGF), regulates the release of transforming growth factor-beta1 (TGF-beta1) from C6 glioma cells. The results of the study show that bFGF (2, 5 and 10 ng/ml) dose dependently induced the release of TGF-beta1 from C6 glioma cells, with the 10 ng/ml dose inducing a 2- to 3-fold increase of TGF-beta1 levels. This effect was evident as early as 6 h following treatment, with maximal levels observed at 18 h. The effect of bFGF was largely on latent TGF-beta1, and was isoform specific, as bFGF had no effect on TGF-beta2 release. The bFGF effect on TGF-beta1 was also glioma specific, as no such stimulatory effect was observed in rat cortical astrocytes.     

Factors influencing pre-stroke and post-stroke quality of life among stroke survivors in a lower middle-income country

Quality of life (QOL) reflects the individual’s perception of the position within living contexts. This study was done to describe pre- and post-stroke QOLs of stroke survivors. A prospective longitudinal study was done among stroke survivors admitted to 13 hospitals in the western province of Sri Lanka. The calculated sample size was 260. The pre-stroke and post-discharge one-month QOL was gathered using short form-36 (SF-36) QOL tool. SF-36 includes questions on eight domains: general health, physical functioning, pain, role limitation due to physical problems, social functioning, vitality, role limitations due to emotional problems, and mental health. Univariate analysis was followed by determining the independent risk factors through multivariate analysis. The response rate was 81%. The disability was measured by the modified Rankin scale which ranges from 0 (no symptoms) to 6 (fatal outcome). The median (IQR) disability score was 4 (3 to 5). The post-discharge QOL scores were significantly lower than pre-stroke values (p < 0.05). With a higher pre-stroke QOL, younger age was significantly associated in six domains and higher income and better health infrastructure in two domains (p < 0.05). Six factors were determined to be independent risk factors for lower post-discharge QOL scores of SF-36: younger age (for general health and role limitation-physical domains), female gender (for physical functioning and pain domains), lower health infrastructure (for general health, vitality, and mental health domains), lower education (for pain domain), higher disability (for general health, physical functioning, vitality, social functioning, and mental health domains), and hypercholesterolemia (for role limitation-emotional domain). Stroke survivors have not regained their pre-stroke QOL at 1 month following the hospital discharge irrespective of income level and pre-stroke QOL. Higher pre- and post-stroke QOLs are associated with better statuses of social determinants of health.     

Neurokinin-1 Receptor (NK1-R) Expression in the Brains of SIV-Infected Rhesus Macaques : Implications for Substance P in NK1-R Immune Cell Trafficking into the CNS

Recent studies suggest a link between neuropsychiatric disorders and HIV/SIV infection. Most evidence indicates that monocytes/macrophages are the primary cell type infected within the CNS and that they contribute to CNS inflammation and neurological disease. Substance P (SP), a pleotropic neuropeptide implicated in inflammation, depression, and immune modulation via interaction with its cognate receptor, the neurokinin 1 receptor (NK1-R), is produced by monocyte/macrophages. While the presence of NK1-R on neurons is well known, its role on cells of the immune system such as monocyte/macrophages is just beginning to emerge. Therefore, we have examined the expression of SP and NK1-R and their relationship to SIV/HIV encephalitis (SIVE/HIVE) lesions and SIV-infected cells. These studies demonstrated intense expression of SP and NK1-R in SIVE lesions, with macrophages being the principal cell expressing NK1-R. Interestingly, all of the SIV-infected macrophages expressed NK1-R. Additionally, we examined the functional role of SP as a proinflammatory mediator of monocyte activation and chemotaxis. These studies demonstrated that treatment of monocytes with SP elicited changes in cell-surface expression for CCR5 and NK1-R in a dose-dependent manner. Moreover, pretreatment with SP enhanced both SP- and CCL5-mediated chemotaxis. All of these findings suggest that SP and NK1-R are important in SIV infection of macrophages and the development of SIVE lesions.The neuropathogenesis of HIV infection is complex and has led to the development of nonhuman primate models using infection of macaques with the simian immunodeficiency virus (SIV). The human and simian immunodeficiency viruses are closely related and produce nearly identical conditions in their respective hosts, thus the rhesus macaque infected with SIV is the premier animal model for the study of AIDS pathogenesis in general and of the neuropathogenesis of AIDS in particular. Additionally, nonhuman primates are widely used in neuroscience research, including neurophysiologic and neurobehavioral studies. Recent studies suggest a link between psychiatric disorders like stress and depression and the neuropathogenesis of HIV and/or its progression to AIDS.^1,2 Neuroinvasion by SIV and HIV occurs early in infection at the time of peak viremia. The virus most likely enters the brain within cells of monocyte/macrophage lineage, and the perivascular macrophage is the primary cell type productively infected within the CNS.^3,4Approximately 25 to 30% of untreated HIV-infected adult humans develop a debilitating neurological disorder termed AIDS dementia complex (ADC).^5,6,7 A wide variety of cytokines, which include IL-1beta, IL-6, and TNF-α, chemokines (CCL2, CCL3, CCL4 and CCL5), adhesion molecules, and other molecules such as Substance P (SP) produced by different cell types have been implicated in this process.^1,4,8,9 Microscopic evaluation of brains from individuals with ADC reveals a broad spectrum of pathological features including neuronal changes, multifocal encephalitis, accumulation of inflammatory macrophages and multinucleated giant cells (MNGCs), cerebral cortical atrophy, and white matter pallor.^5,10 The histopathological substrate of ADC, referred to as HIV encephalitis (HIVE), is characterized by perivascular accumulation of macrophages and MNGCs in the CNS with abundant infection of brain macrophages.^4,11 In addition to the pathological manifestations within the brains of individuals with ADC, extensive neurobehavioral effects have been characterized and include impaired fine motor control and memory, altered emotional control, motor slowing, and possibly depression. Compelling data from recent studies reveal the significance of inflammatory mediators including the neuropeptide SP in the neuropathogenesis of AIDS^12,13,14 as well as in clinical neurobehavioral effects of depression.^2,3,4 Such findings suggest that SP participates in important aspects of immune-neural communication and likely contributes to immune modulation in HIV/SIV infection.SP is an 11-aa neuropeptide and is the most extensively studied and most abundant member of the tachykinin family. SP is synthesized mainly by primary sensory neurons, however recent studies have demonstrated that immune cells also express SP mRNA and protein during SIV/HIV-infection,^1,8 suggesting that it may contribute to neurological disease by acting on its preferred receptor, NK1-R, a G-protein–coupled receptor expressed on T-cells, B-cells, monocyte/macrophages, NK cells, astrocytes, and neurons.⁹ Activation of NK1-R by SP results in increased phagocytic response in macrophages, enhanced inflammatory cytokine production by immune cells, and possible induction of a chemotactic response in monocyte macrophages, thus facilitating immune cell trafficking at sites of inflammation or infection.^{16,17,18,19,20} SP has a role in AIDS, and results from recent in vivo studies^1,8,15,21,22 revealed that NK1-R antagonists have an antiviral effect,²³ likely through down-regulation of CCR5⁹ as well as immunomodulatory and antidepressive effects.^23,24 The major focus of existing work on SP (and its receptor-NK1-R) in macaques, however, has focused on its role as a neurotransmitter or neuromodulator and therefore the distribution of SP and NK1-R on neurons is well known, while little data exists on the in vivo distribution of SP and NK1-R on other cell types.Because the cellular expression of SP and its receptor NK1-R is not fully characterized in normal or SIV-infected macaques, we examined the cellular distribution/location and phenotype of SP and NK1-R expressing cells in the CNS in vitro and in vivo using multiple techniques and at various stages of infection in animals with or without SIVE. Such analysis allowed us to assess spatial correlations between the presence of SIV-infected cells and cells positive for SP and NK1-R. Additionally, we examined the functional aspects of SP/NK1-R signaling in monocyte activation and chemotaxis. Data from our immunofluorescence and in situ hybridization studies show that while NK1-R is expressed in astrocytes and neurons, it is intensely expressed in SIVE lesions. NK1-R expression was detected in all SIV-infected cells associated with SIVE lesions, of which macrophages were the predominant cell type and also the primary cell type expressing NK1-R. T-cells were found in small numbers in SIVE lesions and were rarely infected but were shown to express NK1-R when present. Our quantitative flow cytometric analysis demonstrates that SP functionally regulates NK1-R and CCR5 expression on macaque monocytes. Furthermore, pretreatment of monocytes with SP enhanced SP-mediated chemotaxis as well as CCL5-mediated chemotaxis. The enhancement of SP-mediated chemotaxis in the presence of CCL5 demonstrates cross talk between NK1-R and CCR5 signaling pathways. These findings suggest that SP contributes to SIV-associated neurological disease and suggest that SP also has a role in augmented cellular trafficking across the blood-brain barrier and thus the development of SIVE lesions. This insight into the function of SP and NK1-R allows for a better understanding of the interaction between the immune and nervous systems, and may lead to advancements in treatment of neurological and neuropsychiatric disease.