The association of plasma IL-6 levels with functional disability in community-dwelling elderly

BACKGROUND: IL-6 is a multifunctional cytokine that has been shown to increase with age. METHODS: Plasma IL-6 was measured by ELISA in 1,727 community-dwelling elderly subjects whose blood was drawn during the third in-person survey of the Duke Established Populations for Epidemiologic Studies of the Elderly (EPESE). Demographics, functional status (disability), and disease states were determined. Correlations of these factors with IL-6 were analyzed with Spearman's Rho while differences between groups were assessed by Wilcoxon test. RESULTS: IL-6 levels were higher with age (p = .0001) even in this older population (> 70 years). There was a positive correlation between IL-6 and functional disability for each of the functional status measures (p = .0001), as well as a correlation between self-rated health and IL-6. Significantly higher median levels of IL-6 were found in subjects reporting prevalent cancer, heart attack, and high blood pressure, but not diabetes or arthritis. The association between age and functional status with high IL-6 remained when all other variables were controlled, in multivariable analysis. CONCLUSIONS: This association between increased plasma IL-6 levels and functional status suggests that dysregulation of IL-6 may be related to the functional disability seen with aging, and that IL-6 may be useful as a component of an overall marker of health.     

Primary intraosseous meningioma of the vault

Primitive intra-osseous meningioma is a rare benign tumor. We report a case with a temporal localization and antro-attical extension into the petrous bone.     

A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo

Agouti-related protein (Agrp) is present in rat and human hypothalamus and is structurally related to agouti protein. Overexpression of either of these proteins results in obesity. However the effect of exogenous Agrp and its in vivo interaction with alpha-melanocyte stimulating hormone (alphaMSH), the likely endogenous melanocortin 3 and 4 receptor (MC3-R and MC4-R) agonist, have not been demonstrated. We report that 1 nmol of Agrp(83-132), a C-terminal fragment of Agrp, when administered intracerebroventricularly (ICV) into rats, increased food intake over a 24-h period (23.0+/-1.4 g saline vs 32.9+/-2.3 g Agrp, p<0.05). The hyperphagia was similar to that seen when 1 nmol of the synthetic MC3-R and MC4-R antagonist SHU9119 was given i.c.v. (19.6+/-1.8 g saline vs 32.5+/-1.7 g SHU9119, p<0.001). Both Agrp(83-132) and SHU9119 blocked the reduction in 1-h food intake of i.c.v. alphaMSH at the beginning of the dark phase. This effect occurred independently of whether the antagonists were administered simultaneously, or nine hours prior, to the alphaMSH. We have also shown Agrp(83-132) is an antagonist at the MC3-R and MC4-R, with similar inhibition of cAMP activation to that previously reported for the full length peptide. In conclusion, Agrp(83-132) administered i.c.v. increases feeding with long lasting effects and is able to inhibit the action of alphaMSH. This interaction may be mediated by the MC3-R and/or MC4-R.     

Neurofilament phosphorylation is increased in ventral horn neurons of neonatal rat spinal cord exposed to cerebrospinal fluid from patients with amyotrophic lateral sclerosis

Aberrant neurofilament (NF) phosphorylation in the soma of the ventral horn neurons of neonatal rat spinal cord is observed following exposure to cerebrospinal fluid (CSF) of patients suffering from Amyotrophic Lateral Sclerosis (ALS). CSF samples from ALS and non-ALS neurological patients were injected into the spinal subarachnoid space of 3 day old rat pups. After 48 h, sections of spinal cords were stained for the presence of phosphorylated NF epitopes with SMI-31 antibody. The number of neuronal soma staining with this antibody in the ventral and dorsal horns sides of the spinal cord was counted. There was a significant 3-fold increase in the number of soma stained with SMI-31 antibody in the ventral horns of rat spinal cords exposed to CSF of patients with ALS compared to cords from rats exposed to CSF of non-ALS patients and those which were not exposed to any CSF samples. Such an increase in staining of neuronal soma was not observed in the dorsal horns. Hyperphosphorylation of neuronal soma suggests an initial stage of degenerative changes occurring in the motor (ventral horn) neurons following exposure to circulating factor(s) in the CSF of patients with ALS.     

Inhalable Antibiotics Manufactured Through Use of Near-Critical or Supercritical Fluids

The development of unit-dose, inhalable, antibiotic microparticles for use in primary and combined therapy approaches to treating tuberculosis (TB), multi-drug-resistant (MDR-TB), and extensively drug-resistant TB is explored using the gentle drying process of Carbon-dioxide Assisted Nebulization with a Bubble Dryer (CAN-BD). The microparticles produced using this method contain capreomycin, kanamycin, and isoniazid, respectively, imbedded in L-leucine. Antibiotics were developed into inhalable antibiotic formulations for their utility in both first line and second line antibiotic treatment regimens. Capreomycin and kanamycin are typically administered by injection making them desirable candidates for the development of a needle-free delivery system that addresses the Grand Challenges in Global Health Initiative #3. In response to this challenge, unit-dose packaging that preserves powder properties by protecting them from moisture, oxidants, and UV exposure, and a low cost “active” dry powder inhaler, the PuffHaler, were developed and used as a prototype device, in addition to the Aerolizer, to disperse the microparticle antibiotic formulations. Antibiotic formulations show yields above 50% in small-scale powder production by CAN-BD. Capreomycin and kanamycin show improved powder yields in scale up experiments. The particle properties were characterized using scanning electron microscopy, Karl Fischer moisture analysis, Anderson Cascade Impaction studies, and X-ray diffraction. The inhalable antibiotic formulations are within a respirable size range (1–5 μm), and have less than 3% residual moisture. Unit-dose dry powder antibiotics have the potential to provide easy-to-use, stable products with improved safety profiles.     

Activation and adherence of lyophilized human platelets on canine vessel strips in the Baumgartner perfusion chamber

The Baumgartner perfusion technique was used to test the ability of rehydrated lyophilized human platelets to adhere to the thrombogenic surface of a denuded arterial vessel segment and to undergo platelet activation under conditions of high shear. Twenty preparations of washed platelets were stabilized by 1-hour or 2-hour exposure to paraformaldehyde before freeze-drying in a Virtis 600 lyophilizer. The response of these fixed-dried preparations was compared with that of non-fixed platelets in fresh citrated whole blood. The outcome of each perfusion experiment was quantified in photomicrographs by morphometric estimation of the percent area of the vessel segment covered by adherent platelets after immunofluorescent staining with monoclonal antibodies to glycoprotein Ib (CD42) or glycoprotein IIbIIIa (CD41a). Evidence of activation in nonadherent platelets was examined by flow cytometry for CD62 and GP53 expression. In addition, thromboxane B2 was measured by radioimmunoassay as an index of platelet responsiveness to activation conditions during perfusion. The percent vessel coverage observed with lyophilized platelets in recombined whole blood was somewhat less than that of platelets in fresh whole blood (39% vs 73%, respectively). In other perfusion experiments performed with non-denuded vessel segments, the percent coverage was reduced by half or more for both types of platelet preparation. Scanning electron microscopy confirmed that the lyophilized platelets did not adhere to areas of intact endothelium. Furthermore, the lyophilized platelets showed a small-but-significant rise in CD62 or CD63 activation antigen expression and generated thromboxane B2 at about one third the rate of fresh platelets in these perfusion experiments. The thromboxane generation during perfusion was inhibited in fresh or lyophilized platelet preparations by pretreatment with indomethacin or PGE-1. We interpret these data as evidence of the ability of our lyophiilized platelet preparations to respond at least partially to physiologic stimuli and to adhere to appropriate thrombogenic sites to support hemostasis.     

Functional Interdependence and Product Similarity Based on Customer Needs

In this paper, related product functions are determined for a group of approximately 70 consumer products. Using customer need data, a new matrix approach is introduced to identify these relationships. Techniques are then created for determining product similarity. These techniques are clarified and validated through three case studies, including beverage brewers and material-removal products. The results of these case studies are argued to have significant impact on design-by-analogy procedures, benchmarking methods, mass customization strategies and modular design. The paper concludes with a discussion of applications and related procedures for product development.     

The Challenges of Ensuring Participant Consent in Internet-based Sex Studies: A Case Study of the Men's INTernet Sex (MINTS-I and II) Studies

This study documents our experience in designing, testing, and refining human subjects' consent protocol in 3 of the first NIH-funded online studies of HIV/STI sexual risk behavior in the USA. We considered 4 challenges primary: a) designing recruitment and enrollment procedures to ensure adequate attention to subject considerations; b) obtaining and documenting subjects' consent; c) establishing investigator credibility through investigator-participant interactions; d) enhancing confidentiality during all aspects of the study. Human consent in online studies appears more relative, continuous, inherent, tenuous, and diverse than in offline studies. Reasons for declining consent appear related to pragmatic concerns not human subjects' risks. Reordering the consent process, and short, chunked, stepwise, tailored consent procedures may enhance communicating information and documenting consent.     

Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar)

A potential mechanism of chemotherapy resistance in acute myeloid leukemia (AML) is the multidrug resistance (MDR-1) gene product P-glycoprotein (P-gp), which is often overexpressed in myeloblasts from refractory or relapsed AML. In a multicenter phase II clinical trial, 37 patients with these poor risk forms of AML were treated with PSC 833 (Valspodar; Novartis Pharmaceutical Corporation, East Hanover, NJ), a potent inhibitor of the MDR-1 efflux pump, plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). Pharmacokinetic (PK) interactions of etoposide and mitoxantrone with PSC were anticipated, measured in comparison with historical controls without PSC, and showed a 57% decrease in etoposide clearance (P =.001) and a 1.8-fold longer beta half-life for mitoxantrone in plasma (P <.05). The doses of mitoxantrone and etoposide were substantially reduced to compensate for these interactions and clinical toxicity and in Cohort II were well tolerated at dose levels of 4 mg/m2 mitoxantrone, 40 mg/m2 etoposide, and 1 g/m2 C daily for 5 days. Overall, postchemotherapy marrow hypoplasia was achieved in 33 patients. Twelve patients (32%) achieved complete remission, four achieved partial remission, and 21 failed therapy. The PK observations correlated with enhanced toxicity. The probability of an infectious early death was 36% (4 of 11) in patients with high PK parameters for either drug versus 5% (1 of 20) in those with lower PK parameters (P =.04). P-gp function was assessed in 19 patients using rhodamine-123 efflux and its inhibition by PSC. The median percentage of blasts expressing P-gp was increased (49%) for leukemic cells with PSC-inhibitable rhodamine efflux compared with 17% in cases lacking PSC-inhibitable efflux (P =.004). PSC-MEC was relatively well tolerated in these patients with poor-risk AML, and had encouraging antileukemic effects. The Eastern Cooperative Oncology Group is currently testing this regimen versus standard MEC chemotherapy in a phase III trial, E2995, in a similar patient population.     

Uterine rhabdomyosarcoma metastatic to mediastinal lymph nodes: diagnosis by transbronchial needle aspiration

An inherited tendency to hypercoagulability has been suggested as a cause of vascular thrombosis resulting in Legg-Calvé-Perthes disease (LCPD). Here we carried out an investigation of the most common inherited risk factors for hypercoagulability including the mutation in the factor V gene (factor V Leiden), the transition 20.210G-->A in the prothrombin gene, and also the homozygosity for the 677C-->T transition in the methylenetetrahydrofolate reductase gene (MTHFR). The investigation was carried out among 61 Brazilian children with LCPD, who were compared with 296 individuals from the general population. The prevalence of the factor V Leiden mutation was higher in LCPD patients than in the controls (4.9 vs. 0.7%; p = 0.03). However, no patient had the prothrombin gene variant, and no difference was found between patients and controls when homozygosity for MTHFR-T (3.2 vs. 2.6%: p = 0.64) was determined. These data suggest that in our population, the heterozygosity for factor V Leiden was the only inherited risk factor associated with the development of LCPD.