Real-world effectiveness of long acting aripiprazole: Treatment persistence and its correlates in the Italian clinical practice.

OBJECTIVES: To identify the variables that are associated with persistence to Aripiprazole-Long Acting (A-LAI), in adult patients with schizophrenia. METHODS: Observational, retrospective, non-interventional study involving 261 patients with schizophrenia. RESULTS: Eighty-six percent of study subjects were persistent for at least 6 months. All subjects with baseline CGI-S of 1 or 2, 95% of subjects with CGI-S of 3, 86% with CGI-S of 4, 82% of subjects with CGI-S of 5, 73% of subjects with CGI of 6 and 90% of subjects with CGI of 7 were persistent. A-LAI treatment continuation rate was higher in patients with: 1) baseline CGI score ≤ 4; 2) schizophrenia dimension (LDPS) mania score ≤ 5; 3) psychotic spectrum schizoid score ≤ 11. CONCLUSIONS: A relatively high number of patients (n = 225, 86%) were persistent to A-LAI for at least 6 months. Not surprisingly, very severe patients were more unlikely to be persistent. However, it is noteworthy that a large number of subjects with high CGI score at the time when A-LAI was started (82% of subjects with CGI-S of 5, 73% of subjects with CGI of 6 and 90% of subjects with CGI of 7) were persistent. Larger, controlled, prospective and longer studies are warranted.

Magnetic resonance of the temporomandibular joint: experience at an Italian university center.

AIM: The aim of this investigation was to suggest criteria in order to evaluate magnetic resonance imaging (MRI) of the temporomandibular joint (TMJ). Such criteria have been discussed on the basis of our experience at the Section of Prosthetic Dentistry, Department of Neurosciences, University of Pisa. METHODS: The study sample was constituted by 135 patients. All subjects underwent bilateral MRI of the TMJs to evaluate disc structure and position, bony structure abnormalities, joint effusion localization and entity. RESULTS: MRI allowed depiction of the articular disc in 98.9% of the TMJs, showing a normal disc structure in 91.1% of the cases and abnormal in 7.7%. The disc-condyle relationship was normal in 46.6% TMJs, while a disc displacement with reduction was revealed in 35.5% cases, a disc displacement without reduction in 16.7% and a posterior disc displacement in 1.5% joints. In the coronal images, the disc was positioned lateral to the condyle in 8.9% of the TMJs and medial in 6.7%. Osseous abnormalities have been found in 177 joints (65.5%), with cases of bony flattening (condyle and/or tuberculum), erosions, subchondral cysts, osteophytosis and sclerosis. T2 sequences showed effusion in 26.7% of the TMJs. CONCLUSIONS: These findings suggest that standardized methodology application and well-defined criteria can facilitate MR imaging observations and interpretation as well as the diagnosis of intra-articular pathologies.

Is clinical assessment valid for the diagnosis of temporomandibular joint disk displacement?

AIM: The aim of this work was to evaluate the predictive value of clinical examination for magnetic resonance imaging (MRI) findings of temporomandibular joint (TMJ) disk position abnormalities. METHODS: Participants in this study were 51 consecutive patients with signs and symptoms of temporomandibular disorders (TMD). All 102 temporomandibular joints (TMJ) were evaluated to detect disk position abnormalities by means of a standardized clinical assessement according to Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) and MRI performed by a blinded radiologist at the Section of Prosthetic Dentistry, University of Pisa, Italy. The accuracy of clinical assessment was evaluated with respect to MRI. RESULTS: Clinical assessment showed a good predictive value (PV) for the diagnosis of normal disk position (86.2%) and an acceptable PV for the diagnosis of disk displacement with reduction (70.3%), while it seems less accurate in predicting MRI diagnosis of disk displacement without reduction. The overall agreement between clinical RDC/TMD examination and MRI for the evaluation of disk position was 77.3%. CONCLUSION: Clinical RDC/TMD examination proved to be accurate in detecting normal disk position and disk displacement with reduction but not reliable in predicting MRI diagnosis of disk displacement without reduction in the temporomandibular joint.

Occlusal features are not a reliable predictor of bruxism.

AIM: The aim of this investigation was to estimate the contribution of occlusion to differentiate bruxers from non-bruxers. METHODS: Participants in the study were 160 patients consecutively selected among 20-30 year old patients attending the Section of Prosthetic Dentistry for conservative care. The presence of bruxism was clinically and anamnestically investigated. In each patient the following occlusal features were recorded: retruded contact position-intercuspal position slide length, vertical overlap, horizontal overlap, unilateral posterior crossbite, incisor dental midline discrepancy, mediotrusive interferences, laterotrusive interferences. A stepwise logistic regression model was used to identify the significant associations between occlusal features and bruxism. RESULTS: Diagnosis of bruxism was made in 67/160 subjects (41.8%). Differences between sex were not significant (p=0.814). Among the 8 occlusal variables included in the logistic regression analysis, those remaining in the final model were laterotrusive interferences (OR 2.47) and anterior open-bite (OR 0.88). This model showed good specificity (87%) but an unacceptable sensitivity (26.9%) to predict bruxism (accuracy=61.6%). Therefore, multivariate analysis did not lead to an improvement in bruxism predictability with respect to univariate analysis, which revealed that the presence of bruxism was significantly associated with laterotrusive interferences alone (p=0.040), and not with unilateral cross-bite (p=0.208), anterior open-bite (p=0.202), deep-bite (p=0.572), large horizontal overlap (p=0.261), dental midline discrepancy (p=0.519), mediotrusive interferences (p=0.119), slide >or=2 mm (p=0.857). CONCLUSION: According to our findings the contribution of occlusion to differentiate bruxers from non-bruxers is very poor. Infact, only laterotrusive interferences seem to be significantly associated with bruxism.

Comparison of masticatory dysfunction in temporomandibular disorders and fibromyalgia.

AIM: Many theories have been proposed as to the relationship between fibromyalgia (FM) and temporomandibular disorders (TMD). The aim of this study was to investigate the clinical features of the involvement of the stomatognathic system in patients with fibromyalgia, and to compare signs and symptoms of masticatory dysfunction between TMD and FM patients. METHODS: The study sample consisted of 30 subjects with fibromyalgia recruited at the Rheumatology Disease Department, University of Pisa, Italy, and of 30 with temporomandibular disorders at the Section of Prosthetic Dentistry, Department of Neurosciences, University of Pisa, Italy. Masticatory dysfunction has been compared between the 2 groups by means of a clinical assessment conducted according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Patients of the TMD group underwent a rheumatologic examination to investigate for the presence of previously undiagnosed fibromyalgia. RESULTS: As regards specific clinical variables and RDC/TMD diagnoses, differences between the 2 groups appear to be not relevant, with the exception of the values of mouth opening, both voluntary and passive, and the presence of trigger points. FM patients showed a decrease in both maximum voluntary and passive mouth opening which was about 2 mm worse than that recorded in TMD patients. FM patients also showed a significantly higher number of trigger points, even though muscle palpation evoked tenderness in the same number of sites in the 2 groups. CONCLUSIONS: This study showed that most patients with fibromyalgia (86.7%) report signs and symptoms localized at the stomatognathic system; by contrast, only a minority of patients with temporomandibular disorders (10%) are actually affected by fibromyalgia.

Nimesulide as a downregulator of the activity of the neutrophil myeloperoxidase pathway. Focus on the histoprotective potential of the drug during inflammatory processes.

Neutrophils, recruited to tissue sites of inflammation, release a variety of oxidants and enzymes, which are responsible for tissue damage. Among the oxidants released are potent chlorinated compounds, such as hypochlorous acid and chloramines, which induce tissue cell damage and inactivate protease inhibitors, particularly alpha 1-antitrypsin, the specific inhibitor of neutrophil elastase. In studying a rational approach to the pharmacological control of neutrophil-mediated tissue injury, we investigated the activity of the anti-inflammatory drug nimesulide. This agent reduced the function of the myeloperoxidase pathway (which generates hypochlorous acid), by exerting a cell-directed inhibitory activity, as shown by measurement of superoxide anion and hydrogen peroxide production. Nimesulide also inactivated hypochlorous acid directly and protected alpha 1-antitrypsin from the neutrophil-mediated oxidation. Thus, neutrophil elastolytic activity may be attenuated by nimesulide-spared alpha 1-antitrypsin. The prevention of oxidative inactivation of alpha 1-antitrypsin by nimesulide strictly correlates with the drug's ability to suppress the extracellular availability of hypochlorous acid. Taken together, these data suggest that nimesulide may prevent tissue injury at sites of inflammation by maintaining natural host protective systems.

bcl-2 gene expression in hematopoietic cell differentiation.

Nonrandom translocations with breakpoint at band q21 on chromosome 18 might cause bcl-2 gene deregulation and might contribute to neoplastic transformation in human lymphomas. As the pattern of expression of bcl-2 in hematopoietic cells is still unclear, we have measured the level of the corresponding messenger RNA (mRNA) in a variety of myeloid and lymphoid cell malignancies not usually associated with the t(14;18) translocation. Molecular genetic analysis showed that bcl-2 was rearranged in only 2 of 77 patients: one was affected by hairy cell leukemia and one by diffuse small cleaved cell lymphoma with peripheral blood invasion. Although in rare cases of myeloid leukemia fairly high levels can be found, the expression of bcl-2 appears to be typical of certain lymphoid malignancies. High levels of bcl-2 mRNA had been found, previously, in established pre-B-cell lines. However, in fresh specimens, the peak level of bcl-2 expression shifts to a more differentiated cell type, represented by the long-living B lymphocytes that are found in most cases of chronic lymphocytic leukemia. bcl-2 gene product might have a role in prolonging cell survival and, even in the absence of translocations, might contribute to some of the biologic features that are typical of this disorder.

Natural killer cells and lymphocyte subsets in active MS and acute inflammation of the CNS.

Cerebrospinal fluid (CSF) and peripheral blood (PB) lymphocyte subsets were determined by flow cytometry (FCM) in 15 patients with active multiple sclerosis (MS) and 15 patients with acute inflammatory diseases (ID) of the central nervous system (CNS) in order to establish correlations between the two groups of diseases, as well as between the CSF and PB subsets distribution. A panel of monoclonal antibodies was applied to all the samples: Leu3 (CD4), Leu4 (CD3), Leu2 (CD8), Anti-HLA-DR, Leu11 (CD16). Statistical analysis did not show differences in CD3+ nor in CD3+ DR+ T-cells both in the CSF and PB in the two groups of patients. CD4+ cells were significantly higher in the CSF than in the PB, while CD8+, DR+ CD3- and CD16+ cells were constantly lower in the CSF without differences between the two groups of diseases.

Age-related expansion of functionally inefficient cells with markers of natural killer activity in Down's syndrome.

Peripheral blood lymphocyte subsets of two groups of patients affected by Down's syndrome (DS), ie, 28 children and nine adults of relatively advanced age (greater than 34 years), were investigated and compared with those of age- and sex-matched healthy controls (13 children and 20 adults). Particular attention was devoted to cells with markers of natural killer (NK) activity. Double- and triple-color cytofluorimetric analysis was used to better characterize the phenotypic features of the different subsets. Apart from a reduced number of T lymphocytes (CD3+) in DS children and of B lymphocytes (CD19+) in both DS groups, the major alteration we found was a marked age-related increase of the percentage of cells bearing markers associated with NK activity, such as CD16, CD56, and CD57. These DS cells were apparently severely defective as far as their function was concerned, because NK activity was significantly reduced in comparison with age-matched controls, but still capable of responding to cytokines such as interleukin-2, interferon-beta, and interferon-gamma, and to the modulation of lytic activity exerted by the anti-CD16 monoclonal antibody. On the whole, our data stress the importance of studying DS subjects of different ages to fully appreciate the immunologic derangement characteristic of this syndrome.

Kappa light chain gene rearrangement in a T-cell lymphoma.

Forty-three patients were studied to determine whether light chain gene rearrangements may occur in hematopoietic cells not pertaining to the B-lineage. In only one patient, affected by T-cell lymphoblastic lymphoma, one kappa light chain allele was rearranged. Neither at the protein level nor at the RNA level the rearranged gene was expressed. These data confirm that, although rarely, kappa light chain gene rearrangements may occur in neoplastic T-cells. Furthermore, as in our patient Ig heavy chain genes retained a germline configuration, the present data demonstrate that kappa light chain gene rearrangements may occur regardless of Ig heavy chain gene arrangement.

Post-marketing survey of nimesulide in the short-term treatment of osteoarthritis.

A multicentric trial was carried out to assess the therapeutic efficacy and tolerability of nimesulide in the treatment of patients with osteoarthritis. The trial involved 1600 general practitioners, 80 orthopedists and 88 specialists in internal medicine. A total of 22,938 ambulatory patients was admitted to the trial. Patients were given nimesulide tablets (40%) or granules (60%) from 100 to 400 mg/day for a length of time ranging from 1 to 3 weeks. The treatment was effective in relieving spontaneous pain and morning stiffness. The level of patients with adverse reactions, presumably related to nimesulide and mostly involving the gastro-intestinal tract, was 8%. The results of this study suggest that nimesulide is effective and well tolerated in the short-term treatment of a large number of patients with osteoarthritis.

Atypical pattern of light chain gene rearrangement in hairy cell leukemia.

Molecular genetic analysis was exploited to determine the lineage of the neoplastic cells in nine patients affected by hairy cell leukemia (HCL). In all cases the B-lineage of the cells was confirmed at the molecular level. In four cases a relatively advanced maturation stage was suggested by the expression of lambda light chain genes. Surprisingly, in two patients lambda light chain gene rearrangement was observed in spite of a germ-line kappa light chain gene. In at least one case the rearrangement was productive, as a full length messenger RNA (mRNA) was shown by Northern blot analysis and lambda light chain-restricted surface immunoglobulins (sIg) were found. These data suggest that exceptions to the hierarchy that regulates light chain gene rearrangements are not uncommon in this type of leukemia and that molecular genetic analysis should include lambda gene locus to determine more precisely the lineage origin of some leukemic cell populations.

LAK activity is inducible in blood mononuclear cells from human fetus.

Lymphocyte subpopulations, NK and LAK activities have been studied in blood mononuclear cells from two human fetuses, the first affected by Down's syndrome, the other showing a normal karyotype. Fetuses presented similar subsets, with a scarcity of CD57+ lymphocytes but an appropriate amount of CD16+ and CD56+ cells, while negligible NK activity was detectable. After 18 h of incubation with human recombinant interleukin-2 (rIL-2), significant enhancement of the cytotoxic capability was observed. This stresses the role of IL-2 as a regulatory molecule during the development of the immune system in the human fetus.

Is myelopathy of unknown origin related with tropical spastic paraparesis and myelopathy associated with human T cell lymphotropic virus type I?

Paired cerebrospinal fluid (CSF) and serum samples from 52 Italian patients affected by myelopathy of unknown origin (MUO) were tested for the presence of antibodies to human T cell lymphotrophic virus type I (HTLV-I) by an enzyme-linked immunosorbent assay, in an attempt to demonstrate a common retroviral origin of MUO, tropical spastic paraparesis (TSP) and HTLV-I-associated myelopathy (HAM). All the patients complained of weakness to the legs, while weakness to the arms, mild sensory disturbances, impaired bladder and bowel functions, and impotence were present in different percentages. All CSF and serum samples were devoid of HTLV-I antibodies. The possible relations between MUO, TSP and HAM are discussed.

Precocious aging of the immune system in Down syndrome: alteration of B lymphocytes, T-lymphocyte subsets, and cells with natural killer markers.

Phenotype and proliferative ability of peripheral blood lymphocytes from 15 noninstitutionalized children affected with Down Syndrome (DS), in apparently good health, were studied and compared with those of 16 healthy control children of the same age. A complex derangement of all the major peripheral blood cell subsets, i.e., B cells, T cells, and natural killer (NK) cells, was present in DS children. A significant decrease of the absolute number of circulating lymphocytes, a marked and significant decrease of B lymphocyte absolute number and percentage, and dramatic modifications of the T-cell subsets were observed. The absolute number of CD4+ cells was significantly decreased, whereas CD8+ cells increased significantly in percentage but not in absolute number. A derangement of cells bearing markers associated with NK activity, such as CD57, CD16, and CD56, was observed. Among the most important alterations, the presence of a high number of CD57+, CD16- cells, of CD57+, CD8+ lymphocytes, and of CD3+, CD56+ lymphocytes was seen. Many of these alterations are similar to those characteristic of chromosomally normal subjects of advanced age. The hypothesis that the reduced thymic endocrine activity and the zinc deficiency characteristic of DS are responsible for the derangement of T and NK subsets is discussed.

Presence of ACTH and beta-endorphin immunoreactive molecules in the freshwater snail Planorbarius corneus (L.) (Gastropoda, Pulmonata) and their possible role in phagocytosis.

The presence of ACTH and beta-endorphin immunoreactive molecules in the cell-free hemolymph and in the hemocytes of the freshwater snail Planorbarius corneus were demonstrated by immunocytochemistry and RIA tests. Only spreading phagocytic hemocytes were positive, in contrast with other hemocytes devoid of phagocytic activity, i.e., round hemocytes. These data were confirmed by flow cytometry. Another cell type with marked phagocytic activity, i.e., digestive cells of digestive gland, were also positive to anti-ACTH. Corticotropin-releasing factor immunoreactive molecules were found in the cell-free hemolymph and hemocytes, by RIA. Our data suggest that cells with phagocytic activity, the oldest immune response, may represent a suitable model to unravel the tangled web of the common ancestor of the immune and the neuroendocrine systems.

Immunodetection of haemocyte subpopulations by N-acetylmuramic acid antibody in Planorbarius corneus (L.) (Gastropoda, Pulmonata).

The cell subpopulations in the haemolymph of Planorbarius corneus were distinguished by means of flow cytometry. An antibody against N-acetylmuramic acid was prepared and used as a cellular marker to recognize the cell types forming the subpopulations. The spreading haemocytes showed a positive reaction for anti-N-acetylmuramic acid; round haemocytes gave a negative reaction.

T-cell receptor genes expression in B-cell leukaemias.

Using Northern-blot analysis we have studied the expression of T-cell receptor (TCR) alpha, beta and gamma chain genes in primary cells obtained from 36 leukaemic patients. Fifteen patients had myeloid leukaemias, two had T-cell leukaemias, and 19 leukaemias corresponding to various stages of B-lymphocyte differentiation. We observed that truncated TCR beta mRNAs were produced in B-cells at relatively high levels even in the absence of detectable gene rearrangements. Ti alpha mRNAs of abnormal size were also frequently found. Such transcripts were not detectable in total RNA extracted from leukaemic myeloid cells. Factors allowing Ti alpha and beta gene transcription must be active in leukaemic pre-B and B cells but not in myeloid cells. Neither B-lineage nor myeloid leukaemias expressed TCR gamma gene at detectable levels.

Efficacy and tolerability of nimesulide in elderly patients with osteoarthritis: double-blind trial versus naproxen.

A double-blind trial was carried out to assess the therapeutic efficacy and tolerability of nimesulide versus naproxen in the treatment of elderly patients with osteoarthritis. A total of 40 elderly female patients with osteoarthritis of the hip and/or knee were entered into the study and treated with either 200 mg/day nimesulide or 500 mg/day naproxen for 28 days. Both treatments were very effective in alleviating spontaneous pain, pain on movement, morning stiffness and joint mobility. Nimesulide was better tolerated than naproxen with fewer and less serious side-effects being reported. The results of this study show nimesulide to be effective and well tolerated in the treatment of elderly patients with osteoarthritis.

Extremely low frequency pulsed electromagnetic fields increase interleukin-2 (IL-2) utilization and IL-2 receptor expression in mitogen-stimulated human lymphocytes from old subjects.

The effects of the exposure of mitogen-stimulated human lymphocytes from aged subjects to low-frequency pulsed electromagnetic fields (PEMFs) were studied by measuring the production of interleukin-2 (IL-2) and the expression of IL-2 receptor. PEMF-exposed cultures that presented increased [3H]thymidine incorporation showed lower amounts of IL-2 in their supernatants, but higher percentages of IL-2 receptor-positive cells and of T-activated lymphocytes. Taken together, these data suggest that PEMFs were able to modulate mitogen-induced lymphocyte proliferation by provoking an increase in utilization of IL-2, most likely acting on the expression of its receptor on the plasma membrane.