Effect of transcutaneous electrical nerve stimulation (TENS) on knee pain and physical function in patients with symptomatic knee osteoarthritis: the ETRELKA randomized clinical trial.

OBJECTIVE: To determine the effectiveness of TENS at relieving pain and improving physical function as compared to placebo TENS, and to determine its safety, in patients with knee osteoarthritis. METHODS: Multi-centre, parallel, 1:1 randomized, double-blind, placebo-controlled clinical trial conducted in six outpatient clinics in Switzerland. We included 220 participants with knee osteoarthritis recruited between October 15, 2012, and October 15, 2014. Patients were randomized to 3 weeks of treatment with TENS (n = 108) or placebo TENS (n = 112). Our pre-specified primary endpoint was knee pain at the end of 3-weeks treatment assessed with the WOMAC pain subscale. Secondary outcome measures included WOMAC physical function subscale and safety outcomes. RESULTS: There was no difference between TENS and placebo TENS in WOMAC pain at the end of treatment (mean difference -0.06; 95%CI -0.41 to 0.29; P = 0.74), nor throughout the trial duration (P = 0.98). Subgroup analyses did not indicate an interaction between patient/treatment characteristics and treatment effect on WOMAC pain at the end of treatment (P-interaction ≥0.22). The occurrence of adverse events was similar across groups, with 10.4% and 10.6% of patients reporting events in the TENS and placebo TENS groups, respectively (P = 0.95). No relevant differences were observed in secondary outcomes. CONCLUSIONS: TENS does not improve knee osteoarthritis pain when compared to placebo TENS. Therapists should consider other potentially more effective treatment modalities to decrease knee osteoarthritis pain and facilitate strengthening and aerobic exercise. Our findings are conclusive and further trials comparing TENS and placebo TENS in this patient population are not necessary.

Temporal expression of inflammatory mediators in brain basilar artery vasculitis and cerebrospinal fluid of rabbits with coccidioidal meningitis.

Strokes due to transmural vasculitis associated with coccidioidal meningitis result in significant morbidity and mortality. The immunological and inflammatory processes responsible are poorly understood. To determine the inflammatory mediators, i.e. cytokines, chemokines, iNOS, matrix metalloproteinase-9 (MMP-9), that possibly contribute to vasculitis, temporal mRNA expression in brain basilar artery samples and MMP-9 protein in the CSF of male NZW rabbits infected intracisternally with 6.5 x 10(4) arthroconidia of Coccidioides immitis were assessed. Five infected and 3 sham-injected rabbits at each time point were euthanized 4, 9, 14 and 20 days post infection. All infected rabbits had neurological abnormalities and severe vasculitis in the basilar arteries on days 9-20. In basilar arteries of infected animals versus controls, mRNAs encoding for IL-6, iNOS, IFN-gamma, IL-2, MCP-1, IL-1beta, IL-10, TNF-alpha, CCR-1, MMP-9, TGF-beta, as well as MMP-9 protein in CSF, were found to be significantly up-regulated. Thus, this study identified inflammatory mediators associated with CNS vasculitis and meningitis due to C. immitis infection. Assessment of the individual contribution of each mediator to vasculitis may offer novel approaches to the treatment of coccidioidal CNS infection. This study also provides unique methodology for immunology studies in a rabbit model.

In pneumococcal meningitis a novel water-soluble inhibitor of matrix metalloproteinases and TNF-alpha converting enzyme attenuates seizures and injury of the cerebral cortex.

Matrix metalloproteinases (MMPs) and TNF-alpha converting enzyme (TACE) contribute to the pathophysiology of bacterial meningitis. To date, MMP-inhibitors studied in models of meningitis were compromised by their hydrophobic nature. We investigated the pharmacokinetics and the effect of TNF484, a water-soluble hydroxamate-based inhibitor of MMP and TACE, on disease parameters and brain damage in a neonatal rat model of pneumococcal meningitis. At 1 mg/kg q6h TNF484 reduced soluble TNF-alpha and the collagen degradation product hydroxyproline in the cerebrospinal fluid. Clinically, TNF484 attenuated the incidence of seizures and was neuroprotective in the cortex. Water-soluble MMP-inhibitors may hold promise in the therapy of bacterial meningitis.

Authorship and teamwork around the Cimento Academy: mathematics, anatomy, experimental philosophy.

Multiple authorship is so common and pervasive in our world that it is tempting to take it for granted. Prior to the twentieth century, however, multiple authorship was exceedingly rare. This essay addresses the issue of whether in the past collaboration was less common or was acknowledged in different forms. I focus on the 1660s circle of intellectuals fluctuating around the Cimento Academy because the Cimento is generally considered the first academy devoted to experimental philosophy, this essay highlights the existence of a wide range of conventions about authorship even within a geographically and temporally limited area, and suggests that collaboration was more common than title pages would suggest.

Human eosinophils and parasitic diseases. II. Characterization of two cell fractions isolated at different densities.

A new procedure, based on centrifugation through multiple discontinuous gradients of polyvinylpyrrolidone-coated silica particles has been developed for the separation of almost pure eosinophils from blood samples of healthy donors. When this technique is employed for the purification of eosinophils from the peripheral blood of patients with parasitic diseases, two cell fractions almost pure in eosinophil granulocytes are harvested at different densities. Preliminary results, concerning the characterization of these cell fractions, indicate that in the terms of detectable membrane receptors and K cell activity, two distinct eosinophil subpopulations can be recognized.

Reversibility by L-carnitine of immunosuppression induced by an emulsion of soya bean oil, glycerol and egg lecithin.

Experimental and clinical data appear to indicate that Intralipid--an emulsion of soya bean oil, glycerol and egg lecithin--which is usually employed to improve caloric intake of parenteral nutrition regimens, may compromise human host defence mechanisms and therefore expose patients to an increased incidence of infectious diseases. Since from a biochemical point of view it has been suggested that a possible way whereby the somewhat poor reputation of Intralipid--attributable to the liver damage and the persistent lipaemia which attend its use--might be improved is to give supplementary carnitine which acts as a rate-limiting factor in the removal of the fat emulsion from blood, we hypothesized that the addition of carnitine to Intralipid could also result in a improvement of the immune responses both "in vitro" and "in vivo". Our results lend some support to the hypothesis in favour of a metabolic basis for some of the immunosuppressive properties of Intralipid and justify the inclusion of L-carnitine in parenteral nutrition regimens which, by abrogating some co-factor limitation, improves the immune responses of the host.

Vitamins and immunity: II. Influence of L-carnitine on the immune system.

Vitamin A affects the antibody responses and may affect phagocytic function and properdin levels. Pyridoxine deficiency impairs nucleic acid synthesis and depresses antibody formation, delayed hypersensitivity reactions and the ability of phagocytes to kill bacteria. Pantothenic acid deficiency impairs antibody formation. Vitamin C deficiency increases the incidence of infection, primary by a negative influence on reparative processes. Deficiencies of other vitamins either have not been sufficiently studied or have a variable effect. Moreover, even substances which for their biosynthesis require an adequate vitamin supplementation may exert immunomodulatory influences. With this respect the authors report their results on the influence of L-carnitine on the immune system. L-carnitine increases the proliferative responses of both murine and human lymphocyte following mitogenic stimulation and increase polymorphonuclear chemotaxis. Furthermore, L-carnitine, even at minimal concentrations, neutralizes the lipid induced immunosuppression.

Human peripheral eosinophils with receptors for IgM: demonstration and ultrastructural morphology.

Receptors for IgM were detected on peripheral blood human eosinophils by a rosette technique with ox red blood cells coated with the IgM fraction of the specific immunserum. Between 14% and 43% (mean 27%) FcmuR positive cells were found after an overnight incubation period at 37 degrees C by using this technique. The specificity of the receptors for IgM was assessed by studying the inhibitory capacity of purified human IgM in the rosette assay. From an ultrastructural point of view, the EAM rosette-forming cells are mature eosinophilic granulocytes characterized by a nucleus with a variable number of lobes and a certain number of "first type" granules partially or totally devoid of their content.

In vitro effect of inosiplex on T lymphocytes. I. Influence on T cells with receptors for IgG (T gamma).

Inosiplex, a complex of inosine and 2-hydroxypropyldimethyl ammonium-4-(acetylamino)benzoate, 1:3 molar ratio, originally developed for antiviral use, is now under wider investigation because of its immunopotentiating properties. This compound can have some actions on T cells at various stages of differentiation, thus promoting an enhancement of their blastogenic responses to varied mitogenic agents (PHA, Con A, PWM, MLC, tetanus toxoid, and viral antigens). Our studies demonstrated that under the influence of inosiplex human peripheral blood T lymphocytes bearing Fc IgG receptors have an augmented receptor avidity for SRBC which result in an increased E active rosette formation, and that T cells preincubated with the drug at the appropriate concentrations express more Fc IgG receptors. Even though T gamma cells exert "in vitro" immunoregulatory properties, the increase in percentage of T gamma lymphocytes do not correlate with a potentiation of the Con A-induced suppressor activity of T cells. Moreover, the lymphocytes treated with the substance in the absence of Con A exert helper functions, increasing the mitogenic responses of the second culture PHA--treated lymphocytes. These data appear to suggest a pro-proliferative inosiplex-induced effect which could mask a concomitant suppressor cell induction.

Density and size distributions of the intramembranous particles in the cytoplasmic membrane of human peripheral blood lymphocytes.

A freeze-fracture study has been carried out on human peripheral blood lymphocytes (hPBL) from healthy donors. Lymphocytes were frozen either from 37 degrees C or 4 degrees C. Quantitative analysis performed on density and size of intramembranous particles (IMPs) present on both fracture faces of the plasma membrane has revealed: a) a difference in size between IMPs on the external face (EF) and those on the protoplasmic face (PF); b) a remarkable influence of temperature either on size or density of the IMPs; c) the existence at 4 degrees C of two lymphocyte populations differing in IMP density.

[Effect of antibiotics on spontaneous and direct migration of human leukocytes. Preliminary findings]. / Effetto degli antibiotici sulla migrazione spontanea e diretta dei leucociti umani. Risultati preliminari.

Like other human blood cells, neutrophiles can travel enter tissues spontaneously. This apparently casual journeying is arrested in the presence of infection and they migrate to the site of the lesion. Experiments in vitro have shown that tetracycline, rifamycin, chloramphenicol, and cefuroxine inhibit such migration. In the present paper, it is demonstrated that ampicillin and tauglycolcillin, a new semi-synthetic penicillin, exert no significant influence on either direct or spontaneous neutrophile migration.

[Influence of antibiotics on leukocyte migration]. / Influenza degli antibiotici sulla migrazione leucocitaria.

Polymorphonuclear granulocytes play an important role in the immediate unspecific host response, and a depression of their functions can be found in many patients with severe or recurrent infections. Therefore administration of drugs causing such impairment in PMN function may be regarded as an additional risk for negative side effects to the patient. In our report the influence of 13 antibiotics--amphotericin B, ampicillin, tauglicolcillin, amoxicillin, cloxacillin, dicloxacillin, cephaloridine, cefalexin, cefuroxime, chloramphenicol, gentamicin, rifamycin, fosfomycin--on the granulocyte spontaneous and induced migration is investigated under in vitro experimental conditions. Human PMN preincubated with the antibiotics appropriately brought to the desired concentrations (therapeutic dose, 1/10 and 10X) in Hepes-Medium 199-water solution pH 7.2, were washed three times and tested for spontaneous and induced migration under agarose. Our experiments demonstrate that amphotericin B, cefalexin, cephaloridine, cefuroxime, chloramphenicol, dicloxacillin, gentamicin and rifamycin can inhibit in vitro human PMN chemotaxis and/or random migration. Inhibition of intracellular respiratory enzyme synthesis, presence of inactive metabolites of the drug, alterations of cyclic AMP and GMP or of the membrane bound divalent cations can be responsible of the phenomenon.

[Effect of vitamin B6 on some immune responses in chronic uremia (author's transl)]. / Vitamine ed immunità: effeto della vitamina B6 sull'immunocompetenza dell'uremico cronico.

Patients with chronic uremia undergoing periodic haemodialysis were found to have low levels of vitamin B6 (12 out of 18 patients). The same subjects also showed a reduction of the immunocompetence. The AA. report that the administration of pyridoxine (100 mg/die for 4 weeks) can induce a normalization of the vitamin levels and of some immunological parameters.

Human eosinophils and parasitic diseases: light and electron microscopy evidence of interaction with sheep erythrocyte.

The aim of this study was to investigate the possible formation of spontaneous rosettes between human eosinophils and sheep erythrocytes. In patients with parasitic diseases a percentage of 15.7 +/- 6 (range 6-23%), eosinophils were able to form rosettes. Each rosette showed as few as four to eight erythrocytes attached per eosinophil. Two types of interaction were observed at the electron microscope: point attachments and large surface contacts. In patients with non-parasite induced eosinophilia the formation of rosettes is decidedly below the above-mentioned percentage (less than 2%) or totally absent. It follows that during parasitic infections with blood eosinophilia, whatever the mechanism responsible, the formation of spontaneous rosettes could be diagnostic significance and might reflect qualitative or quantitative modifications in the eosinophil population.