Spinal glial TLR4-mediated nociception and production of prostaglandin E2 and TNF

Background and purpose:

Toll-like receptor 4 (TLR4) expressed on spinal microglia and astrocytes has been suggested to play an important role in the regulation of pain signalling. The purpose of the present work was to examine the links between TLR4, glial activation and spinal release of prostaglandin E₂ (PGE₂) and tumour necrosis factor (TNF), and the role these factors play in TLR4-induced tactile allodynia.

Experimental approach:

Toll-like receptor 4 was activated by intrathecal (i.t.) injection of lipopolysaccharide (LPS) and KDO₂-Lipid A (KDO₂) to rats. Tactile allodynia was assessed using von Frey filaments and cerebrospinal fluid collected through spinal dialysis and lumbar puncture. PGE₂ and TNF levels were measured by mass spectometry and elisa. Minocycline and pentoxifylline (glia inhibitors), etanercept (TNF-blocker) and ketorolac (COX-inhibitor) were given i.t. prior to injection of the TLR4-agonists, in order to determine if these agents alter TLR4-mediated nociception and the spinal release of PGE₂ and TNF.

Key results:

Spinal administration of LPS and KDO₂ produced a dose-dependent tactile allodynia, which was attenuated by pentoxifylline, minocycline and etanercept but not ketorolac. Both TLR4 agonists induced the spinal release of PGE₂ and TNF. Intrathecal pentoxifylline blunted PGE₂ and TNF release, while i.t. minocycline only prevented the spinal release of TNF. The release of PGE₂ induced by LPS and KDO₂ was attenuated by i.t. administration of ketorolac.

Conclusions and implications:

Activation of TLR4 induces tactile allodynia, which is probably mediated by TNF released by activated spinal glia.     

Sugar and fat: sensory and hedonic evaluation of liquid and solid foods

Twenty-five subjects evaluated the sweetness, creaminess and fat content of liquid and solid dairy products containing between 0.1 and 52 g fat/100 g and sweetened with 0-20% sucrose weight/weight. Liquid stimuli included skim milk, whole milk, half and half, and heavy cream, while the solids included cottage cheese and cream cheese, blended and spread "jelly-roll" fashion on slices of white bread. The subjects' ratings of stimulus sweetness, creaminess, and fat content differed sharply between liquids and solids, and the assessment of fat content of solid foods appeared to be impaired. In contrast, acceptability ratings for both sets of stimuli were not substantially different: the subjects optimally preferred equivalent levels of sugar in both liquids and solids, but selected higher fat levels in solid than in liquid foods. Sensory preferences for fat in liquid stimuli may not always be indicative of preferences for fat in solid foods.     

In vitro susceptibility to pexiganan of bacteria isolated from infected diabetic foot ulcers.

During two clinical trials involving the treatment of 835 outpatients with infected diabetic foot ulcers, 2515 bacterial isolates, including 2337 aerobes and 178 anaerobes, were grown from cultures of the ulcers. The in vitro susceptibility of these isolates was determined to pexiganan, a peptide anti-infective evaluated in these clinical trials, and to other classes of antibiotics. Pexiganan demonstrated broad spectrum antimicrobial activity against Gram-positive and Gram-negative aerobes and anaerobes. The MIC90 values for the most common species among 1735 Gram-positive aerobes isolated, such as Staphylococcus aureus, coagulase-negative staphylococci, Group A streptococci, and Group B streptococci, were 16 micrograms/mL or less. Of 602 Gram-negative aerobes tested, the MIC90 values for pexiganan were 16 micrograms/mL or less for Acinetobacter, Pseudomonas, Stenotrophomonas, Citrobacter, Enterobacter, Escherichia, Klebsiella, and Flavobacterium species. Pexiganan had a MIC90 of 4 to 16 micrograms/mL against the anaerobic isolates of Bacteroides, Peptostreptococcus, Clostridium, and Prevotella species. Importantly, pexiganan did not exhibit cross-resistance with other commonly used antibiotics, including beta-lactams, quinolones, macrolides, and lincosamides. The broad spectrum in vitro antimicrobial activity of pexiganan against clinical isolates from infected diabetic foot ulcers supports its potential as a local therapy for infected diabetic foot ulcers.     

Nutrient intake and diet quality in patients with systemic lupus erythematosus on a culturally sensitive cholesterol lowering dietary program

OBJECTIVE: To evaluate the effect of a culturally sensitive cholesterol lowering dietary program on energy, protein, fiber, vitamin and mineral intake, diet quality, and hemoglobin levels in patients with systemic lupus erythematosus (SLE). METHODS: Seventeen patients with SLE were randomized to a Step II diet intervention group or a control group for 12 weeks. The diet intervention was made up of weekly group sessions during the first 6 weeks followed by telephone counseling every 2 weeks for the last 6 weeks. Food intake was assessed by 3-day food record at baseline, 6, and 12 weeks. Diet quality was assessed by expressing the nutrients as a percentage of the Dietary Reference Intakes of the US National Academy of Sciences, or as a percentage of the nutrient guidelines by the National Cholesterol Education Program, Adult Treatment Panel III. Between- and within-group changes in nutrient intakes were assessed by repeated measures ANOVA. RESULTS: The changes in nutrient intakes were not significantly different between the groups for any of the nonfat nutrients except vitamin B12 (p = 0.05), which decreased in the diet group and increased in the control group. Within-group analysis showed a significant reduction (p = 0.0003 to 0.02) in the diet group in energy and sodium intake at 6 and 12 weeks and B12 intake at 12 weeks compared to the respective baseline values (28-32%, 37-41%, and 43%, respectively). Sodium intake decreased to 66-71% of the total sodium allowance (< 2400 mg per day) in the diet group. The intervention was successful in maintaining adequate intakes or even increasing intakes of most nutrients except B12, dietary fiber, folate, calcium, and iron, which were slightly higher or below 67% of the Dietary Reference Intakes or other dietary guidelines. Anemia, as assessed by hemoglobin levels, was present throughout the study and did not correlate with iron intake. CONCLUSION: This culturally sensitive cholesterol reducing diet program was successful in decreasing sodium intake and maintaining adequate intakes of most nutrients except B12, dietary fiber, iron, calcium, and folate. Future intervention studies in patients with SLE need to pay special attention to these nutrients and the presence of anemia.     

Delineation of the functional capacity of human neonatal lymphocytes.

Neonatal T cell-B cell collaboration was investigated utilizing a system of T cell-dependent polyclonal B cell activation and Ig secretion. In this system, T cells activated by immobilized anti-CD3 provide a potent stimulus for Ig production by adult lymphocytes. By contrast, anti-CD3 stimulation of cord blood lymphocytes generated minimal numbers of Ig-secreting cells. Ig production by neonatal lymphocytes was enhanced by the addition of Staphylococcus aureus or secreted factors from mitogen-stimulated adult T cells. Supplementation with IL-2 resulted in the production of large amounts of IgM and small amounts of IgG and IgA, with less Ig produced than by comparable cultures of adult lymphocytes. Neonatal T cells proliferated and produced IL-2 in response to immobilized anti-CD3, and supported B cell proliferation and Ig secretion by adult B cells, although not as effectively as adult T cells. Supernatants from activated neonatal T cells were markedly limited in their capacity to support Ig production by adult B cells. Neonatal B cells could be induced to differentiate in response to anti-CD3-stimulated adult T cells. However, the amounts of IgG and IgA secreted were small compared to adult levels. These studies indicate a relative, but not absolute, functional deficiency of both neonatal B and T cells.     

BDNF Polymorphism-Dependent OFC and DLPFC Plasticity Differentially Moderates Implicit and Explicit Bias

This study examined the role of orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) plasticity in controlling implicit and explicit social biases. Normal controls and patients with varied OFC and DLPFC lesion size and single nucleotide polymorphisms (SNPs) in the brain-derived neurotrophic factor (BDNF) gene, which promotes (methionine-valine [Met/Val] SNP) or stifles (valine-valine [Val/Val] SNP) plasticity in damaged PFC regions, completed measures of implicit and explicit social bias. Patients and controls demonstrated comparable levels of implicit bias, but patients with Met/Val SNPs exhibited less implicit bias when they had smaller OFC lesions compared with Val/Val patients with similar size lesions and those with large OFC lesions. Both patients and controls demonstrated patterns of explicit bias consistent with hypotheses. Patients with Met/Val SNPs exhibited less explicit bias when they had smaller DLPFC lesions sizes compared with Val/Val patients with similar size lesions and those with large DLPFC lesions. OFC lesion size and BDNF SNP type did not moderate explicit bias; DLPFC lesion size and BDNF SNP type did not moderate implicit bias (nor did other medial or lateral regions). Findings suggest that plasticity within specific PFC regions modulates the type and degree of social bias that individuals' exhibit.     

Definitions and criteria for diabetic foot disease

Multiple disciplines are involved in the management of diabetic foot disease, and a common vocabulary is essential for clear communication. Based on the systematic reviews of the literature that form the basis of the International Working Group on the Diabetic Foot (IWGDF) Guidelines, the IWGDF has developed a set of definitions and criteria for diabetic foot disease. This document describes these definitions and criteria. We suggest these definitions be used consistently in both clinical practice and research to facilitate clear communication between professionals.     

Treatment limitations in nursing homes in northwest Ohio

Eighty-eight nursing homes in northwest Ohio were surveyed by telephone regarding the acceptance of "do not resuscitate" (DNR) and "do not hospitalize" (DNH) orders. Written protocols addressing these issues were requested, if available. Eighty-three of the 88 homes participated in the survey. Seventy-five percent of nursing homes accept DNR orders, while 35% accept DNH orders. The most common qualifying condition for a DNR/DNH order was the approval of the family. Although 32 homes stated that they have written protocols, only eight were made available for review. The authors concluded that DNR orders are widely accepted in nursing homes in northwestern Ohio. However, DNH orders are less likely to be accepted in northwest Ohio long-term facilities and the use of written protocols is even more limited.