Treg-Cell Control of a CXCL5-IL-17 Inflammatory Axis Promotes Hair-Follicle-Stem-Cell Differentiation During Skin-Barrier Repair

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Bacteria induce osteoclastogenesis via an osteoblast-independent pathway

Bacteria or their products may cause chronic inflammation and subsequent bone loss. This inflammation and bone loss may be associated with significant morbidity in chronic otitis media, periodontitis, endodontic lesions, and loosening of orthopedic implants caused by lipopolysaccharide (LPS)-contaminated implant particles. Currently, it is not clear how bacteria or endotoxin-induced bone resorption occurs and what cell types are involved. Here we report that Porphyromonas gingivalis, a periodontal pathogen, and Escherichia coli LPS induce osteoclastic cell formation from murine leukocytes in the absence of osteoblasts. In contrast, stimulation with parathyroid hormone had no effect. These multinucleated, tartrate-resistant acid phosphatase-positive cells were positive for receptor activator of NF-kappaB (RANK), the receptor for osteoprotegerin ligand (OPGL), also known as RANK ligand (RANKL). Blocking antibodies demonstrated that their formation was dependent upon expression of OPGL and, to a lesser extent, on tumor necrosis factor alpha. Mononuclear cells represented a significant source of OPGL production. In vivo, P. gingivalis injection stimulated OPGL expression in both mononuclear leukocytes and osteoblastic cells. Thus, these findings describe a pathway by which bacteria could enhance osteolysis independently of osteoblasts and suggest that the mix of cells that participate in inflammatory and physiologic bone resorption may be different. This may give insight into new targets of therapeutic intervention.     

Prophylaxis and treatment of experimental lung metastases in mice after treatment with liposome-encapsulated 6-O-stearoyl-N-acetylmuramyl-L-α-aminobutyryl-D-isoglutamine

A new lipophilic muramyl dipeptide analog, 6-O-stearoyl-N-acetylmuramyl-L--aminobutyryl-D-isoglutamine, when incorporated in liposomes, was effective in both the prevention and eradication of experimental pulmonary metastases in mice. Multilamellar vesicles composed of synthetic phospholipids (phosphatidylglycerol and phosphatidylcholine) containing saturated myristoyl or unsaturated dioleoyl acyl chains were found to potentiate the antimetastatic activity of this glycopeptide. Prophylactic and therapeutic efficacy was observed against the three murine tumors tested: FSa, an immunogenic fibrosarcoma; NFSa, a nonimmunogenic fibrosarcoma; and B16 melanoma. Neither the administration of empty liposomes or free glycopeptide, nor their coadministration, had a significant antimetastatic effect. This approach is promising for the therapy of cancer metastases in humans, particularly in the prevention of metastatic seeding and in the treatment of micrometastases.This is contribution No. 180 from the Institute of Bio-Organic Chemistry, Syntex Research.     

The middle cranial fossa approach: an anatomical study

Hearing preservation surgery has become an option for an increasing number of patients with vestibular schwannomas due to diagnosis at an earlier stage. The middle cranial fossa approach represents one such surgical approach for resection of vestibular schwannomas with hearing preservation. We have undertaken an anatomical study of the middle cranial fossa approach to the internal auditory meatus using 20 fresh temporal bones. By simulating the surgical approach it was possible to analyze critically two of the main recognized subapproaches to the internal acoustic meatus. The results confirmed that the angle subtended by the facial nerve and "blue-lined" semicircular canal was much less than 60 degrees but equally important was the degree of individual variability. Furthermore the roof of the geniculate fossa was not infrequently dehiscent. The distance measured from the inner table of the craniotomy to the superior semicircular canal was on average 22 mm, similar to previous reports and utilized by some in their approach in this challenging surgery. From this anatomical study it appears that safe dissection of this area is facilitated by observing the more acute angle between the facial nerve and superior semicircular canal and by taking advantage of the relationship between the inner table and important landmarks.     

Efficacy of chemopreventive agents for growth inhibition of Apc [+/-] 1638NCOL colonic epithelial cells

Germline mutations of the Apc tumor suppressor gene result in increased risk for gastrointestinal carcinogenesis. The Apc1638N [+/-] mouse exhibits accelerated gastrointestinal carcinogenesis that is modifiable by select pharmacological and dietary agents. Experiments in the present study were conducted on a subculturable epithelial 1638NCOL cell line established from histologically normal colon of Apc1638N [+/-] mouse to examine the effects of selected chemopreventive agents that differ in their mechanism of action. Extent of growth arrest, number of cell population doublings, cell cycle progression and aneuploid G0/G1: S + G2/M ratio represented the quantitative endpoints for the susceptibility and efficacy of chemopreventive agents. Treatment of exponentially growing 1638NCOL cells with maximum cytostatic dose of 9cisRA, DFMO or SUL (100 microM) produced a 60-70% growth arrest, that with TAM and AMF (10 microM) produced a 20-40% growth arrest, while that with OLT (100 microM) produced a 25% growth arrest. This response was associated with corresponding decrease in the number of cell population doubling. 9cisRA, SUL or AMF increased the aneuploid G0/G1: S + G2/M ratio by inducing G1 checkpoint arrest, while DFMO, TAM and OLT decreased the ratio by inducing G2 checkpoint arrest. Thus, cell cycle phase-dependent susceptibility of the Apc [+/-] 1638NCOL cell line to mechanistically distinct chemopreventive agents validates a novel colon epithelial cell culture model for mechanistic, preventive or therapeutic studies on Apc regulated colon carcinogenesis.     

APOE is a potential modifier gene in an autosomal dominant form of frontotemporal dementia (IBMPFD).

PURPOSE: Inclusion-body myopathy, Paget's disease of bone and frontotemporal dementia is an adult-onset autosomal dominant illness (IBMPFD) caused by mutations in the valosin-containing protein (VCP) on chromosome 9p21.1-p12. The penetrance of the gene is 82% for myopathy, 49% for Paget's disease, but may be as low as 30% for frontotemporal dementia. Modifier genes could account for decreased frontotemporal dementia penetrance. In this study apolipoprotein-E (APOE) was evaluated for this role in IBMPFD families based on its known modifier effect in Alzheimer's disease. METHODS: From a database of 231 members of 15 families, 174 had APOE genotype available for analysis. Logistic regressions on APOE genotype and frontotemporal dementia were performed, using appropriate covariates. RESULTS AND CONCLUSION: FTD was associated with APOE 4 genotype (P=0.0002), myopathy (P=0.0006), and age (P=0.01), but not microtubule associated protein tau (MAPT) H2 haplotype (P=0.5) or gender (0.09) after adjustment for membership in pedigrees with at least one APOE 4 genotype. These data suggest a potential link between APOE 4 genotype and the specific form of frontotemporal dementia found in IBMPFD. The molecular basis of this link bears further investigation. We did not observe an association of frontotemporal dementia and H2 MAPT haplotype.     

Chemical modification of human neutrophil membrane proteins: effect on fMet-Leu-Phe binding and function

[3H]fMet-Leu-Phe binding to human neutrophil membrane proteins was shown to be inhibited by pretreatment of membranes with the histidine-preferring reagent diethylpyrocarbonate in a concentration- and time-dependent fashion. The inhibition was partially reversed by hydroxylamine and was affected by pH. The pH profile for inhibition and the partial reversibility of the inhibition by hydroxylamine are consistent with a modification of the histidine residue by diethylpyrocarbonate. The addition of unlabeled fMet-Leu-Phe to the membrane preparation prior to diethylpyrocarbonate treatment provided protection from the binding inhibition following washout of unlabeled fMet-Leu-Phe and unreacted reagent. Cells treated with diethylpyrocarbonate were inhibited in their ability to produce superoxide anions in response to fMet-Leu-Phe, but the concentration of the chemotactic factor required to obtain 50% of the response was alike for treated or untreated cells. These results suggest that a histidine residue at or near the receptor binding site for fMet-Leu-Phe is required for binding and cell activation. Neither N-acetylimidazole, an agent that preferentially reacts with tyrosine, nor acetic anhydride, which reacts with lysyl groups, affected [3H] fMet-Leu-Phe binding to plasma membrane proteins or superoxide production by intact cells. Scatchard analysis of the binding inhibition owing to diethylpyrocarbonate was consistent with a loss of receptor number rather than a change in affinity.     

Low delay rate adaptive pacemaker using FPGA embedded piezoelectric sensor

Abstract

This paper presents the hardware implementation of low delay, power-efficient, rate-adaptive dual-chamber pacemaker (RDPM) using a piezoelectric sensor. Rate adaptive pacemaker has the ability to sense the patient’s activity by means of some special sensors and it controls the pacing rate according to the patient’s activity. Ideally, there should be no delay between sensing and the subsequent pacing operation performed by the pacemaker. However, delay in the responses of various components in the circuitry produces an accumulative delay effect in any practical circuit. Physical activity and the physiological needs of the patient can be easily adapted by the rate-responsive pacemakers using a wide range of sensor information. The piezo-electric sensor recognises the pressure on human muscles because of physical activity and converts it to an electrical signal, which is received by the pulse generator of the pacemaker. When the patient is in the rest mode, the heart rate is the only parameter that is to be detected by the pacemaker. Thus, the heart rate and the physical activity both are the inevitable parameters for the design of RDPM. Performance analysis of the proposed RDPM shows a significant reduction in the delay between sensing and pacing. Device utility analysis shows that the proposed design not only requires lesser memory but also reduces the number of components on the chip. Therefore, it becomes very clear that the proposed pacemaker design will consume much lesser power.     

Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-onset Alzheimer's disease

Mutations in the gene encoding presenilin 1 (PS-1) account for 50% of early-onset familial Alzheimer's disease (EOFAD) cases. In this study, we identified two missense mutations in the coding sequence of the presenilin (PS-1) gene in two EOFAD pedigrees. AD was confirmed in one pedigree by autopsy. Mutation analysis of PCR products amplified from genomic DNA templates showed two novel PS-1 mutations resulting in Gln222His and Tyr256Ser. The two novel mutations are located within predicted transmembrane domains five (TM-5) and six (TM-6), respectively, and are associated with very early ages of onset. The Tyr256Ser is associated with one of the youngest age of AD onset, 25 years, which is consistent with a drastic change in function of the altered PS-1 protein. A morphometric analysis of the cortical degenerative changes of the Tyr256Ser case, showed severe involvement of the primary motor cortex, which correlated well with the pyramidal changes, including tetraspasticity. Immunoblot analysis showed the Tyr256Ser case had the greatest expression of Abeta(1-40) and Abeta(1-42), which was confirmed by ELISA, compared to other PS-1 mutant FAD cases and age-matched controls and, thus, contributes to the severity of the disease pathology.