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Unlabelled: Staphylococcus aureus (S. aureus) is an independent risk factor for orthopaedic surgical site infection (SSI). To determine whether a preoperative decolonization protocol reduces S. aureus SSIs, we conducted a prospective observational study of patients undergoing elective total joint arthroplasty (TJA) at our institution, with two control groups. The concurrent control group comprised patients of surgeons who did not participate in the intervention study. The preintervention control group comprised patients of participating surgeons who had undergone elective TJA during the year before the study. Patients in the intervention group were screened preoperatively for S. aureus by nasal swab cultures. S. aureus carriers were decolonized with mupirocin ointment to the nares twice daily and chlorhexidine bath once daily for 5 days before surgery. All 164 of 636 participants (26%) who tested positive completed the decolonization protocol without adverse events and had no postoperative S. aureus SSIs at 1-year followup. In contrast, 1330 concurrent control patients had 12 S. aureus infections. If these infections had occurred in the 26% of patients expected to be nasal carriers of S. aureus at a given time, the infection rate would have been 3.5% (12 of 345) in the control group. In addition, the overall infection rate of the participating surgeons, including nonstaphylococcal infections, decreased from 2.6% during the preintervention period to 1.5% during the intervention period, translating to an adjusted economic gain of $231,741 for the hospital. The data suggest a preoperative decolonization protocol reduces S. aureus SSIs in patients undergoing TJA.Level Of Evidence: Level II, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Heat shock proteins (Hsps) interact with the immune system and have been shown to contribute to immunoregulation. As efficient chaperones, Hsps bind many peptides and these complexes have many yet-to-be-clarified functions. We have shown that Hsp70 is complexed within the mouse CNS with peptide CLAFHDISPQAPTHFLVIPK derived from histidine triad nucleotide-binding protein-1 (HINT1₃₈₋₅₇/Hsp70). Only this complex, in contrast to other peptides complexed with Hsp70, was able to prevent experimental autoimmune encephalomyelitis (EAE) by induction of immunoregulatory mechanisms dependent on NK cells. Pretreatment of proteolipid protein peptide ₁₃₉₋₁₅₁(PLP₁₃₉₋₁₅₁) sensitized SJL/J mice with HINT1₃₈₋₅₇/Hsp70 prevented the development of EAE, suppressed PLP₁₃₉₋₁₅₁-induced T-cell proliferation, and blocked secretion of IL-17. HINT1₃₈₋₅₇ /Hsp70 stimulation of NK cells depended on synergistic activation of two NK-cell receptors, CD94 and NKG2D. NK cells with depleted CD94 or with blocked NKG2D did not inhibit PLP₁₃₉₋₁₅₁-induced spleen cell (SC) proliferation. The HINT1₃₈₋₅₇/Hsp70 complex enhanced surface expression of the NKG2D ligand-H60. Downstream signaling of CD94 and NKG2D converged at the adaptor proteins DAP10 and DAP12, and in response to HINT1₃₈₋₅₇ /Hsp70 stimulation, expression of DAP10 and DAP12 was significantly increased in NK cells. Thus, we have shown that the HINT1₃₈₋₅₇ /Hsp70 complex affects NK-cell function by enhancing NK-cell-dependent immunoregulation in the EAE model of autoimmune demyelination., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The present study explored parallel changes in the physiology and structure of myelinated (Adelta) and unmyelinated (C) small diameter axons in the cavernous nerve of rats associated with streptozotocin-induced hyperglycemia. Damage to these axons is thought to play a key role in diabetic autonomic neuropathy and erectile dysfunction, but their pathophysiology has been poorly studied. Velocities in slow conducting fibers were measured by applying multiple unit procedures; histopathology was evaluated with both light and electron microscopy. To our knowledge, these are the initial studies of slow nerve conduction velocities in the distal segments of the cavernous nerve. We report that hyperglycemia is associated with a substantial reduction in the amplitude of the slow conducting response, as well as a slowing of velocities within this very slow range (< 2.5 m/s). Even with prolonged hyperglycemia (> 4 months), histopathological abnormalities were mild and limited to the distal segments of the cavernous nerve. Structural findings included dystrophic changes in nerve terminals, abnormal accumulations of glycogen granules in unmyelinated and preterminal axons, and necrosis of scattered smooth muscle fibers. The onset of slowing of velocity in the distal cavernous nerve occurred subsequent to slowing in somatic nerves in the same rats. The functional changes in the cavernous nerve anticipated and exceeded the axonal degeneration detected by morphology. The physiologic techniques outlined in these studies are feasible in most electrophysiologic laboratories and could substantially enhance our sensitivity to the onset and progression of small fiber diabetic neuropathy.

The cytokine receptor interleukin (IL)-4R, expressed by lymphocytes, is well known for its role in immunomodulatory signaling and has also been documented on oligodendrocytes, suggesting involvement in glial cell interactions. In the present study, we investigated the clinical course and pathology of experimental autoimmune encephalomyelitis in mice demonstrating deletion of IL-4R and found a correlation with cytokine expression during acute and chronic disease. Wild-type (WT) littermates served as controls. Although IL-4R(-/-) mice displayed a milder course throughout, they showed comparable pathology to WT in the acute phase. However, during the chronic phase, IL-4R(-/-) mice exhibited extensive remyelination and an apparent increase in oligodendrocytes. Cytokine patterns were examined by immunocytochemistry, fluorescence-activated cell sorting, and enzyme-linked immunosorbent assay and were strongly proinflammatory within the central nervous system during the acute phase in WT mice whereas IL-4R(-/-) animals expressed higher levels of IL-6 and IL-10 that became more pronounced with time. The milder experimental autoimmune encephalomyelitis and enhanced remyelination in IL-4R(-/-) mice appeared to be related to a shift toward a Th-2 pattern involving mainly IL-6 and IL-10. These data suggest that IL-4R exerts a negative regulatory role on oligodendrocytes that when deleted results in enhanced myelin repair.

To determine whether TNF and TRAIL death receptors (DR), and decoy receptors (DcR), play a role in oligodendrocyte depletion in the lesions of chronic multiple sclerosis (MS), we investigated the presence and functionality of these molecules on oligodendrocytes in MS and non-MS brain tissue and on human oligodendrocytes in vitro. For this, we performed immunocytochemistry, Western blotting, TUNEL and FACS analysis for the presence of DR and apoptosis in sections of fresh frozen CNS tissue from cases of chronic MS, other neurologic diseases and normals, and in fetal human oligodendrocytes in vitro. The results showed that although oligodendrocytes demonstrated both DR and DcR, particularly in vitro, there was no predilection of the phenomenon for MS and apoptosis of oligodendrocytes, common in cultures after ligation with TRAIL, was negligible in CNS tissue in situ. Thus, death of oligodendrocytes by apoptosis was an infrequent event in all human CNS samples examined. We postulate that while oligodendrocyte apoptosis might prevail during the initial stages of MS, from our findings other mechanisms probably account for their loss in the established lesion and decoy receptors may play a protective role in oligodendrocyte survival.

Objective: To illustrate the ultrastructural fibre composition of the rat cavernosal nerve at serial levels, from its origin in the main pelvic ganglion to its termination in the corpus cavernosum of the distal penile shaft, and to develop a technique that permits repeated electrophysiological recording from the fibres that form the cavernosal nerve distinct from the axons of the dorsal nerve of the penis (DNP)., Materials and Methods: For the light microscope and ultrastructural studies, Sprague-Dawley rats were anaesthetized and the pelvic organs and lower limbs were perfused with glutaraldehyde through the distal aorta. Tissue samples were embedded in epoxy resin and prepared for light and electron microscopy. Frozen tissue was used for the immunohistochemical studies and sections were stained with rabbit anti-nitric oxide synthetase 1 (NOS1). For the electrophysiology, anaesthetized rats were used in sterile conditions. Nerve conduction velocity for the cavernosal nerve was assessed from a point 2 mm below the main (major) pelvic ganglion after stimulating the nerve at the crus penis; multi-unit averaging techniques were used to enhance the recording of slow-conduction activity. Recordings from the DNP were obtained over the proximal shaft after stimulation at the base of the penis., Results: Step-serial sections of the cavernosal nerve revealed numerous ganglion cells in the initial segments and gradually fewer myelinated fibres at distal levels. At the point of crural entry, the nerve contained almost exclusively unmyelinated axons. As it descended the penile shaft, the nerve separated into small fascicles containing only one to four axons at the level of the distal shaft. In the corpus cavernosum, vesicle-filled presynaptic axon preterminals were close to smooth muscle fibres, but did not seem to be in direct contact. Immunohistochemical evaluation of NOS1 activity showed intense staining of the fibres of the DNP and most of the neurones in the main pelvic ganglion. There was also scattered NOS1 activity in the nerve bundles of the corpus cavernosum. Electrophysiology identified activity in C fibres on the cavernosal nerve and in Aalpha-Adelta fibres in the DNP., Conclusion: These results show that it is possible to perform integrated cavernosal pressure monitoring and ultrastructural and electrophysiological studies in this model. These yielded accurate data about the erectile status of the penis, and the state of unmyelinated and myelinated fibres in the DNP and cavernosal nerves of the same animal. This study provides a useful template for future studies of experimental diabetic autonomic neuropathy.

Introduction: This study examined the self-reported fears of school-age children living in the United States and in Nepal., Method: Thirty school-age children from each country, matched by sex and age, participated in this study. The revised version of the Child Medical Fear Scale was used to identify medical fears of children., Results: Among 17 feared items, the result showed getting a shot to be the most feared item reported by both groups. Nepalese children reported higher fear scores than did American children. It also was found that there was a significant difference in fear scores between Nepalese boys and girls, with girls reporting higher fear scores than boys. There was no difference in fear scores between American boys and girls., Discussion: The findings of this study are important to nurse practitioners in understanding children's fears of medical experiences across different cultures. Nurses can support children in dealing with their fears of medical experiences by recognizing these fears and taking into consideration the child's family, sex, and culture when planning care. Nursing implications are discussed.

The integrin VLA-4 has been shown to play a key role in the entry of antigen-specific T cells into the CNS during autoimmune demyelination. Treatment of animals with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, with antibodies to VLA-4 is known to suppress acute disease. In the present study, a synthetic antagonist of VLA-4 (TBC 3486) was injected subcutaneously into mice adoptively sensitized for chronic relapsing EAE. TBC 3486 was administered daily for 14 days at early (before acute signs) and late time points (during chronic disease). Early treatment led to marked delay in disease onset and reduction in clinical severity and demyelination. After termination of treatment, clinical severity remained lower than in controls for more than 1 week. TBC 3486-treated animals showing no clinical signs (at the height of disease in controls) displayed moderate levels of inflammation but little damage to myelin. Late administration of TBC 3486 to animals with chronic EAE had no effect clinically. Immunocytochemistry and Western blotting of CNS tissue from acutely treated animals supported a moderate shift toward a Th2-type cytokine profile after treatment. Thus, TBC 3486 effectively delayed and reduced the acute (but not chronic) phase of EAE, and this amelioration correlated with changes in the inflammatory molecule profile., (Copyright 2002 Wiley-Liss, Inc.)

Chemokines are low molecular weight cytokines which act as chemoattractants for infiltrating cells bearing appropriate receptors (CCR) to sites of inflammation. It has been proposed that CCR2 on monocytes is responsible for their recruitment into the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, and two previous reports have described resistance of CCR2(-/-) mice to EAE. The present study examined three different mouse strains with CCR2 deletions for susceptibility to EAE. Animals were studied up to 4 months post-sensitization and were examined by neuropathology, RNase protection assay, in situ hybridization, and in vitro assays. All three strains were found to be susceptible to EAE: C57BL/6 x J129 and Balb c strains, 100%; and C57BL/6, 67%. Unusual in CNS lesions of CCR2(-/-) mice was an overabundance of neutrophils versus monocytes in wild-type animals. An attempt of the immune system to develop compensatory mechanisms for the lack of CCR2 was evidenced by a corresponding increase in mRNA for other chemokines and CCR. Inasmuch as neutrophils replaced monocytes and led to demyelination, our findings support the concept that promiscuity of chemokines and CCR was able to surmount the deletion of CCR2, still resulting in full expression of this autoimmune disease.

Microarray analysis of multiple sclerosis (MS) lesions obtained at autopsy revealed increased transcripts of genes encoding inflammatory cytokines, particularly interleukin-6 and -17, interferon-gamma and associated downstream pathways. Comparison of two poles of MS pathology--acute lesions with inflammation versus 'silent' lesions without inflammation--revealed differentially transcribed genes. Some products of these genes were chosen as targets for therapy of experimental autoimmune encephalomyelitis (EAE) in mice. Granulocyte colony-stimulating factor is upregulated in acute, but not in chronic, MS lesions, and the effect on ameliorating EAE is more pronounced in the acute phase, in contrast to knocking out the immunoglobulin Fc receptor common gamma chain where the effect is greatest on chronic disease. These results in EAE corroborate the microarray studies on MS lesions. Large-scale analysis of transcripts in MS lesions elucidates new aspects of pathology and opens possibilities for therapy.

Previous studies have shown that insulin-like growth factor-1 (IGF-1) has beneficial effects, both clinically and histopathologically, on experimental autoimmune encephalomyelitis (EAE), although results vary depending on species and treatment regimen. The present study investigated whether IGF-1, delivered at different time points during the acute and chronic phases of adoptively transferred EAE in SJL mice, had the ability to affect or enhance myelin regeneration. Central nervous system tissue sampled at different stages of treatment was subjected to detailed neuropathological, immunocytochemical and molecular analysis. The results revealed some transient clinical amelioration and low level remyelination after IGF-1 administration during the acute phase of EAE. However, central nervous system tissue from acute phase treated animals sampled at chronic time points and from animals given IGF-1 during the chronic phase revealed no enhancing effect on remyelination in comparison to vehicle-treated controls. Examination of oligodendrocyte progenitor populations also revealed no differences between IGF-1- and vehicle-treated groups. At the cytokine level, the immunomodulatory molecules TGF-beta2 and TGF-beta3 displayed significant decreases that may have contributed to the transient nature of the effect of IGF-1 on EAE. Together with evidence from previous studies, it appears doubtful that IGF-1 is a good candidate for treatment in multiple sclerosis, for which EAE serves as a major model.

Susceptibility to multiple sclerosis (MS) is associated with the human histocompatibility leukocyte antigen (HLA)-DR2 haplotype, suggesting that major histocompatibility complex class II-restricted presentation of central nervous system-derived antigens is important in the disease process. Antibodies specific for defined HLA-DR2-peptide complexes may therefore be valuable tools for studying antigen presentation in MS. We have used phage display technology to select HLA-DR2-peptide-specific antibodies from HLA-DR2-transgenic mice immunized with HLA-DR2 molecules complexed with an immunodominant myelin basic protein (MBP) peptide (residues 85-99). Detailed characterization of one clone (MK16) demonstrated that both DR2 and the MBP peptide were required for recognition. Furthermore, MK16 labeled intra- and extracellular HLA-DR2-MBP peptide complexes when antigen-presenting cells (APCs) were pulsed with recombinant MBP. In addition, MK16 inhibited interleukin 2 secretion by two transfectants that expressed human MBP-specific T cell receptors. Analysis of the structural requirement for MK16 binding demonstrated that the two major HLA-DR2 anchor residues of MBP 85-99 and the COOH-terminal part of the peptide, in particular residues Val-96, Pro-98, and Arg-99, were important for binding. Based on these results, the antibody was used to determine if the HLA-DR2-MBP peptide complex is presented in MS lesions. The antibody stained APCs in MS lesions, in particular microglia/macrophages but also in some cases hypertrophic astrocytes. Staining of APCs was only observed in MS cases with the HLA-DR2 haplotype but not in cases that carried other haplotypes. These results demonstrate that HLA-DR2 molecules in MS lesions present a myelin-derived self-peptide and suggest that microglia/macrophages rather than astrocytes are the predominant APCs in these lesions.

For all hospitalized patients admitted in the first six months of 1999, we recorded the data relative to antibiotic therapy (TA) administered, establishing the period of treatment in days and the dosage, including any variations during the period in question. We calculated the prescribed daily dose (PDD) and were thus able to establish the expense incurred in antibiotic therapy, comparing the real overall cost per product used. For all patients, the discharge diagnosis was reported, and the whole case-study was aggregated into homogeneous groups. PDD was compared with DDD (defined daily doses). The Pareto curve was used to highlight the antibiotics with higher overall cost. Besides cotrimoxazole, ceftriaxone and ciprofloxacin were the antibiotics most frequently prescribed, while ceftriaxone, imipenem-cilastatine and vancomycin were the antibiotics incurring the greatest expense. With reference to the average duration of the treatment cycle, ceftriaxone (9.75 dd) and ciprofloxacin tbl (6.75 dd) were the only antibiotics (in monotherapy) used for less than 10 treatment days. Special attention was paid to analysing the TA costs in treating pneumonia, which accounted for the highest percentage of cases (50 cases). Ceftriaxone, especially pulmonary infections, was the most commonly used drug. In hospitalized subjects treated who show good therapeutic response, we recommend early discharge and continuation of the therapy at home (switch therapy). This strategy will allow the patient to return to his/her family in good time, also thereby reducing hospital management costs.