Polysorbate 80 and Helicobacter pylori: a microbiological and ultrastructural study.

BACKGROUND: The frequent occurrence of chemoresistant strains reduces the chances of eradication of H. pylori infection and prompted the investigation of non-antibiotic substances active against this organism. Some surfactants enhance the effectiveness of antibiotics for their permeabilizing properties towards bacteria. We examined the antimicrobial activity to H. pylori of the surfactant polysorbate 80, used alone and in association with amoxicillin, clarithromycin, metronidazole, levofloxacin and tetracycline. We also aimed to study the ultrastructural alterations caused upon H. pylori by polysorbate 80, alone and in combination with antibiotics. Twenty-two H. pylori strains were tested using the broth dilution method. After incubation, broth from each dilution was subcultured onto agar enriched with foetal bovine serum to determine the minimum bactericidal concentration (MBC). Synergistic effect of polysorbate 80 with antibiotics was investigated by the broth dilution and disc diffusion techniques. Ultrastructural alterations of organisms treated with polysorbate 80, alone and in association with antibiotics were analyzed by transmission electron microscopy. RESULTS: MBCs of polysorbate 80 ranged from 2.6 (1.1) µg/ml to 32 (0) µg/ml. Polysorbate 80 exerted a synergistic effect when associated with metronidazole and clarithromycin: polysorbate 80 and metronidazole MBCs decreased by ≥ 4 fold; clarithromycin MBCs for two resistant strains decreased by 20 and 1000 times. The principal alteration caused by polysorbate 80 consisted in the detachment of the outer membrane of bacteria. CONCLUSIONS: The bactericidal activity of polysorbate 80 and the synergistic effect of the association with metronidazole and clarithromycin could be useful in the treatment of H. pylori infection.

Evaluation of antioxidant drugs for the treatment of ochronotic alkaptonuria in an in vitro human cell model.

Alkaptonuria (AKU) is a rare autosomal recessive disease, associated with deficiency of homogentisate 1,2-dioxygenase activity in the liver. This leads to an accumulation of homogentisic acid (HGA) and its oxidized derivatives in polymerized form in connective tissues especially in joints. Currently, AKU lacks an appropriate therapy. Hence, we propose a new treatment for AKU using the antioxidant N-acetylcysteine (NAC) administered in combinations with ascorbic acid (ASC) since it has been proven that NAC counteracts the side-effects of ASC. We established an in vitro cell model using human articular primary chondrocytes challenged with an excess of HGA (0.33 mM). We used this experimental model to undertake pre-clinical testing of potential antioxidative therapies for AKU, evaluating apoptosis, viability, proliferation, and metabolism of chondrocytes exposed to HGA and treated with NAC and ASC administered alone or in combination addition of both. NAC decreased apoptosis induced in chondrocytes by HGA, increased chondrocyte growth reduced by HGA, and partially restored proteoglycan release inhibited by HGA. A significantly improvement in efficacy was found with combined addition of the two antioxidants in comparison with NAC and ASC alone. Our novel in vitro AKU model allowed us to demonstrate the efficacy of the co-administration of NAC and ASC to counteract the negative effects of HGA for the treatment of ochronotic arthropathy.

Evaluation of anti-oxidant treatments in an in vitro model of alkaptonuric ochronosis.

OBJECTIVES: Alkaptonuria (AKU) is a rare genetic disease associated with deficient homogentisate 1,2-dioxygenase activity in the liver. This leads to the accumulation of homogentisic acid (HGA) and its oxidized/polymerized products in connective tissues, which in turn become characterized by the presence of melanin-like pigments (ochronosis). Since at present, further studies are necessary to support the use of drugs for the treatment of AKU, we investigated the effects of various anti-oxidants in counteracting melanin-like pigmentation and oxidative stress related to HGA and its metabolites. METHODS: We set up an in vitro model using human serum treated with 0.33 mM HGA and tested the anti-oxidants ascorbic acid, N-acetylcysteine, phytic acid (PHY), taurine (TAU), ferulic acid (FER) and lipoic acid (LIP) for their ability to prevent or delay the production of melanin-like pigments, as well as to reduce oxidative post-translational modifications of proteins. Monitoring of intrinsic fluorescence of HGA-induced melanin-like pigments was used to evaluate the efficacy of compounds. RESULTS: Our model allowed us to prove efficacy especially for PHY, TAU, LIP and FER in counteracting the production of HGA-induced melanin-like pigments and protein oxidation induced by HGA and its metabolites. CONCLUSIONS: Our model allows the opening of new anti-oxidant therapeutic strategies to treat alkaptonuric ochronosis.

Biochemical investigation of the effects of human platelet releasates on human articular chondrocytes.

The aim of the present study was to demonstrate the mitogenic and differentiating properties of platelet-rich plasma releasates (PRPr) on human chondrocytes in mono- and three-dimensional cultures. In order to assess if PRPr supplementation could maintain the chondrocyte phenotype or at least inhibit the cell de-differentiation even after several days in culture, we performed a proteomic study on several cell cultures independently grown, for different periods of time, in culture medium with FCS, human serum (HS), and releasates obtained from PRP and platelet-poor plasma (PPP). We found that PRP treatment actually induced in chondrocytes the expression of proteins (some of which novel) involved in differentiation.

Subcutaneous panniculitis-like T-cell lymphoma misdiagnosed as lupus erythematosus panniculitis.

We report a case of subcutaneous panniculitis-like T-cell lymphoma (SPTCL), associated with macrophage activation syndrome, mimicking a lupus erythematosus panniculitis (LEP). A 29-year-old woman presented with high fever, general malaise, nausea, vomiting, and subcutaneous nodules and ulcerating lesions located on the lower extremities. The histopathology showed an infiltration of the panniculus, mostly involving fat, and periadnexial and perivascular structures consistent with lymphocytic lobular panniculitis (LLP). LLP is a shared feature of LEP and SPTCL. The immunophenotyping of the cell infiltrate was crucial for a correct diagnosis.

Clinical presentation of osteoarthritis in general practice: determinants of pain in Italian patients in the AMICA study.

OBJECTIVE: To assess the clinical characteristics and determinants of pain observed by general practitioners (GPs) in Italian patients with osteoarthritis (OA) of the hand, hip, and knee. METHODS: The 2764 GPs participating in the study were asked to enroll 10 consecutive patients with OA diagnosed according to the American College of Rheumatology (ACR) clinical criteria. To standardize the diagnosis, the GPs received ad hoc training from musculoskeletal system specialists. A questionnaire evaluating demographic data, the clinical characteristics of OA, and previous diagnostic and therapeutic interventions was administered by the GPs. RESULTS: 25,589 evaluable patients were enrolled during a mean period of 2.8 weeks by the GPs: 17,567 women (69%) and 7878 men (31%). The most painful OA joints were the knee in 12,827 patients (54%), the hip in 5645 patients (24%), and the hand in 5467 patients (23%)--percentages calculated on the 23,939 patients for whom this information was available. The weekly incidence of referrals to GPs for OA was higher for women and for knee OA. The median age of the patients was 70 years (range 50 to 104 years) and disease duration was 8.3 +/- 7.10 years. The most frequent comorbidities were hypertension (53%), obesity (22%), osteoporosis (21%), type II diabetes mellitus (15%), and chronic obstructive pulmonary disease (13%). The median pain visual analog scale (VAS) score was higher for women than for men, for hip OA, and for generalized OA (GOA) than for knee and hand OA (P < 0.0001). Intense pain, defined as VAS readings of >60 mm, was increased in women only in the knee (OR = 1.24; 95% CI 1.15 to 1.34) and in GOA (OR = 1.17; 95% CI 1.03 to 1.33). It was also significantly increased in patients older than 70 years (OR = 1.46; 95% CI 1.39 to 1.54), those with a low educational level (OR = 1.44; 95% CI 1.36 to 1.5), a BMI of > or =30 (OR = 1.52; 95% CI 1.42 to 1.61), a disease duration of more than 7 years (OR = 1.60; 95% CI 1.52 to 1.68), comorbidities (OR = 1.61; 95% CI 1.5 to 1.73), and GOA (OR = 2.05; 95% CI 1.91 to 2.19). Manual occupations were associated with highly intense pain only in men. CONCLUSIONS: The results of this study underscore the major impact of OA on care in general practice, the high frequency of OA-associated comorbidities, and the role of different risk factors in OA pain.

Do physicians treat symptomatic osteoarthritis patients properly? Results of the AMICA experience.

OBJECTIVE: The main objective of the AMICA project was to photograph the Italian scenario of osteoarthritis (OA) and its treatment in general and specialty practice. The study was designed to evaluate their prescription modalities to determine whether they matched the recently proposed treatment guidelines for OA (ACR 2000; EULAR 2000; APS 2002). METHODS: The study involved 2764 general practitioners (GPs) and 316 specialists who enrolled a total of 25,589 patients with OA of the hand, knee, and hip. RESULTS: Pharmacological treatment alone was prescribed to 55% of the patients seen by GPs, 25% of those seen by rheumatologists, 8% of those seen by orthopedic surgeons, and 17% of those seen by physical medicine specialists (GPs versus specialists, P < 0.001). Specialists often prescribed a combined pharmacological and nonpharmacological approach (rheumatologists 51%, orthopedic surgeons 66%, physical medicine specialists 76%). Concomitant comorbidities and their treatment do not seem to influence OA prescription modalities except for peptic ulcer and anticoagulant therapy. The presence of peptic ulcer was associated with a reduction in NSAID prescriptions (OR 0.61, CI 0.53 to 0.69) and more frequent use of Coxibs (OR 1.15, CI 1.03 to 1.28) and simple analgesics (OR 1.42; CI 1.26 to 1.61), as well as physical therapy. NSAIDs and Coxibs also were less frequently prescribed if patients were receiving anticoagulant therapy (NSAIDs OR 0.86, CI 0.70 to 1.06; Coxibs: OR 0.77; CI 0.64 to 0.93). Gastroprotective therapy was more frequently used in patients treated with NSAIDs, Coxibs, and analgesics. There was no significant difference in therapies prescribed for patients with hypertension or cardiac disease (myocardial infarction and/or angina pectoris). CONCLUSIONS: The published guidelines appear to be properly used by most of the physicians in terms of the pharmacological approach; however, the increased use of Coxibs has not reduced the amount of prescribed gastroprotection. No specific precautions were observed in the treatment of patients with hypertension or cardiac problems. Nonpharmacological treatments are mainly used in conjunction with medications and did not take into account the findings of evidence-based medicine. Continuing education of GPs and specialists caring for OA patients is essential.

Long-term effects of neridronate on human osteoblastic cell cultures.

UNLABELLED: Bisphosphonates (BPs) are widely used in the treatment of a variety of bone-related diseases, particularly where the bone turnover is skewed in favor of osteolysis. The mechanisms by which BPs reduce bone resorption directly acting on osteoclasts are now largely clarified even at molecular level. Researches concerning the BP's effects on osteoblast have instead shown variable results. Many in vitro studies have reported positive effects on osteoblasts proliferation and mineralization for several BPs; however, the observed effects differ, depending on the variety of different model system that has been used. OBJECTIVES: We have investigated if neridronate, an aminobisphosphonate suitable for pulsatory parenteral administration, could have an effect on human osteoblastic proliferation and differentiation in vitro. METHODS: We have investigated whether prolonged addition of neridronate (from 10(-3) to 10(-11) M) to different human osteoblasts cultures, obtained from 14 different bone specimens, could affect the cells number, the endogenous cellular alkaline phosphatase (ALKP) activity, and the formation of mineralized nodules. RESULTS: Our results show that neridronate does not negatively affect in vitro the viability, proliferation, and cellular activity of normal human osteoblasts even after a long period addition of the drug (20 days) at concentrations equal or lower than 10(-5) mol/l (therapeutic dose). In addition, neridronate seems to enhance the differentiation of cultured osteoblasts in mature bone-forming cells. A maximum increase of alkaline phosphatase activity (+50% after 10 days; P < 0.01) and mineralized nodules (+48% after 20 days; P < 0.05) was observed in cultures treated with neridronate 10(-8) M. CONCLUSIONS: These results encourage the use of neridronate in long-term therapy of demineralizing metabolic bone disorders.

Reactivity to superficial and deep stimuli in patients with chronic musculoskeletal pain.

In this study, we evaluated pain sensitivity in patients with fibromyalgia or other types of chronic, diffuse musculoskeletal pain to establish whether fibromyalgia represents the end of a continuum of dysfunction in the nociceptive system. One hundred and forty five patients and 22 healthy subjects (HS) completed an epidemiological questionnaire to provide information about fatigue, stiffness, sleep, the intensity of pain (VAS 0-100) and its extent both at onset and at present. Algometry was performed at all American College of Rheumatology (ACR) tender points and at ten control points. Patients were divided into five main groups: fibromyalgia (FS) patients, secondary-concomitant fibromyalgia (SCFS) patients, patients with widespread pain (WP) but not reaching the ACR criterion of 11 tender points, patients with diffuse multiregional pain (MP) not reaching the ACR criteria (widespread pain, tender point counts), and patients with multiregional pain associated with at least 11 tender points (MPTE). von Frey monofilaments were used to assess superficial punctate pressure pain thresholds. Heat and cold pain thresholds were determined with a thermal stimulator. Ischemic pain was assessed by the cold pressure test and the submaximal effort tourniquet test. The scores for stiffness and present pain intensity gradually increased concomitantly with the increase in tender point count and pain extent. The pressure pain thresholds for positive tender and positive control points were significantly lower in the SCFS, FS and MPTE groups than in HS, MP and WP groups, the latter three groups displaying similar values. In all groups, there were no differences in pain thresholds between positive tender and positive control points. The heat pain threshold and the pain threshold in the cold pressure test were lower in the FS and SCFS groups than in HS. The cold pressure tolerance was lower in patients with widespread pain than in HS. In the von Frey test, all patient groups except MP had similar values, which were significantly lower than in HS. Finally, all patient groups displayed lower tourniquet tolerance than HS. In each psychophysical test, patients with widespread pain and patients with multiregional pain showed similar thresholds; however, the thresholds in the MP or MPTE groups differed from those in the FS and SCFS groups. In the FS group, pain thresholds and pain tolerance did not differ according to the presence of ongoing pain at the stimulated site and were not correlated to ongoing pain. The results indicate that dysfunction in the nociceptive system is already present in patients with multiregional pain with a low tender point count; it becomes more and more severe as the positive tender point count and pain extent increase and it is maximal in fibromyalgia patients.

Alkaptonuria, ochronosis, and ochronotic arthropathy.

OBJECTIVES: To describe the clinical presentation and course of a relatively large group of Italian adult patients screened for mutation of the homogentisate dioxygenase gene causing alkaptonuria (AKU) and ochronosis, and to review typical and atypical facets of this condition. METHODS: We reviewed the medical records of 9 patients affected by ochronotic arthropathy who were observed in our institutions between 1979 and 2001. All patients were diagnosed as having AKU through a rapid urine test with alkali. Mutation screening was performed by single-strand conformation analysis of all homogentisate dioxygenase exons, followed by sequencing of altered conformers. RESULTS: Our 9 cases had similar clinical features and they reflected those described in the literature: a progressive degenerative arthropathy mainly affecting axial and weight-bearing joints associated with extraarticular manifestation. Musculoskeletal symptoms began in most of our patients around the age of 30 years with back pain and stiffness: involvement of the large peripheral joints usually occurred several years after spinal changes. Ochronotic peripheral arthropathy generally was degenerative, but joint inflammation was observed in some cases; this could be attributed to an inflammatory reaction of the ochronotic shard in the synovial membrane. CONCLUSIONS: Ochronosis is a model of arthropathy with known etiologic factors. Over time, AKU, the genetically determined metabolic defect, leads to the accumulation of pigment and the development of this crippling condition. Most of the clinical findings may be explained by inhibition of collagen crosslinks, but some require additional interpretation. For example, inflammatory features of the ochronotic joint only occur in a minority of cases, and may be attributable to ochronotic shards. Further studies are needed to establish the genotype-phenotype correlation to identify mutations that are predictive of severe disease. For this purpose, the Italian Study Group on Alkaptonuria (www.dfc.unifi.it/aku) is enrolling affected patients in an on-line database to characterize the molecular defects and their relationship to clinical data.

A randomized, double-blind, multicenter trial of nimesulide-beta-cyclodextrin versus naproxen in patients with osteoarthritis.

BACKGROUND: Nonsteroidal anti-inflammatory drugs are the most widely used agents in the symptomatic treatment of osteoarthritis (OA). No data are presently available on the medium-term management of this disease with an on-demand treatment regimen, which nevertheless reflects medical practice. OBJECTIVES: The aim of this study was to compare nimesulide-beta-cyclodextrin and naproxen in terms of short-term (2 weeks) pain control with scheduled dosing and medium-term (5.5 months) pain control with on-demand dosing in patients with OA. METHODS: In this multicenter, randomized, double-blind, controlled study, we compared 2 weeks of scheduled treatment plus 5.5 months of on-demand treatment in patients with OA of the hip and/or knee and moderate to severe pain, with no important concomitant disorders. Treatment consisted of nimesulide-beta-cyclodextrin (400 mg BID, orally = 100 mg nimesulide BID) or naproxen (500 mg BID). The primary outcome measures for scheduled dosing were pain on movement (measured by visual analog scale), morning stiffness score, Lequesne index, and adverse events. For on-demand dosing, the measures were the same as for scheduled dosing, plus duration of treatment and global assessment of efficacy and tolerability by patient and physician. RESULTS: After 2 weeks, there was equivalent reduction from baseline in pain on movement in the 2 treatment groups (nimesulide-beta-cyclodextrin, -41.5%; naproxen, -40.5%); the reduction was significant after 1 week (P < 0.001). The findings were also similar for the morning stiffness score and Lequesne index. There were no significant differences in mean duration of on-demand treatment (nimesulide-beta-cyclodextrin, 163.03 days; naproxen, 166.3 days) or in mean consumption of study drug (nimesulide-beta-cyclodextrin, 0.85 +/- 0.61 sachets/d; naproxen, 0.74 +/- 0.42 sachets/d). Withdrawal due to intolerance occurred in 8 patients given nimesulide-beta-cyclodextrin and 13 patients given naproxen, with no significant difference between groups; 3 and 12 patients, respectively, withdrew due to gastrointestinal intolerance, a finding that was significantly different between groups (P < 0.01). Global assessment of efficacy by patient and physician was similar for both drugs. Assessment of tolerability significantly favored nimesulide-beta-cyclodextrin on the physician assessments (P < 0.05) but was similar for the 2 drugs on the patient assessments (physicians, 46.9% vs 30.9%; patients, 43.5% vs 33.3%). CONCLUSIONS: The results suggest that nimesulide-beta-cyclodextrin provides similar pain relief to naproxen in the management of OA of the hip and/or knee and is associated with fewer gastrointestinal adverse reactions. On-demand dosing may be an effective and well-tolerated low-dose regimen of nonsteroidal anti-inflammatory drugs for the maintenance of pain control in OA in the medium term.

Linear scleroderma associated with progressive brain atrophy.

Linear scleroderma (LS) is characterized by scleroatrophic lesions affecting limbs and legs, unilaterally. Neurological involvement may be associated with ipsilateral facial and skull involvement in disorders referred to clinically as LS 'en coup de sabre', and Parry-Romberg syndrome. We report a child with LS presenting with a severe neurological disorder characterized by epilepsy, progressive mental deterioration and a rapid process of atrophy involving the ipsilateral cerebral hemisphere, but not associated with an overlying facial structure involvement. Functional brain studies showed a reduction in the diameter of the left internal carotid and of the left middle cerebral artery. Our observations suggest that neuroimaging studies should be considered in all patients with linear scleroderma, and such studies become necessary when neurological symptoms occur.

Chromosome aberrations in Raynaud's phenomenon.

We evaluated the occurrence of spontaneous chromosome damage in cultured peripheral lymphocytes of subjects with idiopathic and pre-scleroderma Raynaud's phenomenon, by means of molecular cytogenetic analysis. Using the micronucleus assay as a marker of chromosome alteration, we studied 30 patients with pre-scleroderma Raynaud's phenomenon, 30 patients with idiopathic Raynaud's phenomenon and 30 healthy subjects. All subjects were classified as ANA-, ACA+ or Scl 70+. To identify the mechanism of micronucleus formation, fluorescence in situ hybridisation analysis was also performed. Pre-scleroderma Raynaud's phenomenon subjects showed significantly higher micronucleus frequencies than idiopathic Raynaud's phenomenon subjects and controls (37.0 +/- 11.5 vs. 11.1 +/- 3.2 and 10.7 +/- 2.7 respectively p < 0.0001). Interestingly, subjects with idiopathic Raynaud's phenomenon displayed micronucleus frequency comparable to that of healthy controls. Furthermore, ACA+ subjects showed the highest micronucleus frequencies (41.0 +/- 7.6) as compared to subjects with Scl 70+ antibody (25.0 +/- 3.5). Our results show that circulating lymphocytes of only pre-scleroderma Raynaud's phenomenon subjects undergo chromosomal damage, as detected by the micronucleus assay, at a higher rate than expected. No prevalence of aneuploidogenic or clastogenic events in micronucleus formation is revealed by fluorescence in situ hybridisation analysis.

Pregnancy in Wegener's granulomatosis: successful treatment with intravenous immunoglobulin.

We present the case of a women diagnosed with Wegener's disease at the age of 26 years, refractory to corticosteroid and cyclophosphamide therapy. Treatment with intravenous immunoglobulin (IVIg) was started, leading to partial clinical remission of disease. During IVIg treatment she became pregnant. IVIg therapy was continued, the disease went into remission, and after 40 weeks the patient delivered a healthy boy. After 6 months from the delivery, the patient became pregnant again. Now she is at the 22nd week of pregnancy and she is doing very well. This case supports the beneficial effect of IVIg in Wegener's granulomatosis and illustrates its safety and efficacy during pregnancy.

Preclinical characterization of DEKAVIL (F8-IL10), a novel clinical-stage immunocytokine which inhibits the progression of collagen-induced arthritis.

INTRODUCTION: In this article, we present a comparative immunohistochemical evaluation of four clinical-stage antibodies (L19, F16, G11 and F8) directed against splice isoforms of fibronectin and of tenascin-C for their ability to stain synovial tissue alterations in rheumatoid arthritis patients. Furthermore we have evaluated the therapeutic potential of the most promising antibody, F8, fused to the anti-inflammatory cytokine interleukin (IL) 10. METHODS: F8-IL10 was produced and purified to homogeneity in CHO cells and shown to comprise biological active antibody and cytokine moieties by binding assays on recombinant antigen and by MC/9 cell proliferation assays. We have also characterized the ability of F8-IL10 to inhibit arthritis progression in the collagen-induced arthritis mouse model. RESULTS: The human antibody F8, specific to the extra-domain A of fibronectin, exhibited the strongest and most homogenous staining pattern in synovial biopsies and was thus selected for the development of a fully human fusion protein with IL10 (F8-IL10, also named DEKAVIL). Following radioiodination, F8-IL10 was able to selectively target arthritic lesions and tumor neo-vascular structures in mice, as evidenced by autoradiographic analysis and quantitative biodistribution studies. The subcutaneous administration route led to equivalent targeting results when compared with intravenous administration and was thus selected for the clinical development of the product. F8-IL10 potently inhibited progression of established arthritis in the collagen-induced mouse model when tested alone and in combination with methotrexate. In preparation for clinical trials in patients with rheumatoid arthritis, F8-IL10 was studied in rodents and in cynomolgus monkeys, revealing an excellent safety profile at doses tenfold higher than the planned starting dose for clinical phase I trials. CONCLUSIONS: Following the encouraging preclinical results presented in this paper, clinical trials with F8-IL10 will now elucidate the therapeutic potential of this product and whether the targeted delivery of IL10 potentiates the anti-arthritic action of the cytokine in rheumatoid arthritis patients.

Dimensions of "unidimensional" ratings of pain and emotions in patients with chronic musculoskeletal pain.

The use of unidimensional scales to measure pain intensity has been criticised because of the multidimensional nature of pain. We conducted multiple linear regression analyses to determine which dimensions of pain--sensory versus affective--predicted scores on unidimensional scales measuring pain intensity and emotions in 109 Italian women suffering from chronic, non-malignant musculoskeletal pain. We then compared the results with earlier findings in two groups of cancer patients suffering from acute post-operative pain and chronic cancer-related pain, respectively. Age, physical capacity and scores on the multidimensional affect and pain survey (MAPS) were used to predict patients' ratings on one visual analogue scale (VAS) and three numerical rating scales (NRS) measuring pain intensity, anxiety and depressed mood. Unidimensional pain intensity ratings were predicted better from sensory than from affective pain predictors, and the affective predictors made no unique contribution (NRS), or only a very small one (VAS). Both sensory and emotional pain aspects were unique predictors of NRS anxiety and depression. Therefore, in contrast to earlier findings in two different types of cancer patients, in subjects affected by chronic non-malignant musculoskeletal pain, the scores on unidimensional pain intensity scales mainly reflect sensory pain dimensions, supporting the discriminant validity of the NRS and VAS used. However, the patients had some difficulty in distinguishing between sensory and emotional information. For this reason, several unidimensional scales to rate pain intensity and emotions separately should be used to obtain a complete picture of the status and needs of any given patient.

Novel therapeutic agents for bone resorption. Part 1. Synthesis and protonation thermodynamics of poly(amido-amine)s containing bis-phosphonate residues.

Two poly(amido-amine)s (oligoPAM and oligoNER) containing bis-phosphonate residues were obtained by a Michael-type polyaddition of pamidronate and neridronate to 1,4-bis(acryloyl)piperazine. The SEC (size-exclusion chromatography) and the MALDI-TOF (matrix assisted laser desorption ionization) analyses were consistent with the presence of oligomeric species (2-3 kDa) and with a narrow polydispersity index. The thermodynamic results (log Ks, -DeltaH(o) , and DeltaS(o) obtained at 25 degrees C in 0.15 M NaCl) of both the oligomers and the corresponding low molecular weight precursors were in line with a cluster structure formed during the protonation of the basic nitrogen in the pamidronate. The solubility of the oligoNER with a longer aliphatic chain was improved at high pHs, allowing the evaluation of their solution properties. Preliminary biological results show that both the oligomers do not negatively affect the in vitro viability, proliferation, and cellular activity of either normal animal or human osteoblasts.