Prevalence of ankylosing spondylitis in Spain: EPISER2016 Study.

Objective: The aim of this study was to estimate the prevalence of ankylosing spondylitis (AS) in Spain.Method: This is a cross-sectional, population-based study of people aged 20 years or older in Spain. Randomly selected individuals were contacted by telephone and rheumatic disease screening was performed. If the first screening was positive, medical records were then reviewed and/or a telephone questionnaire was conducted by a rheumatologist, followed by an appointment if necessary. Cases had to fulfil the modified New York (mNY) criteria.Results: In total, 4916 individuals were included, of whom 355 had a positive screening result for AS. Of these, 11 were classified as AS. An additional individual who reported a prior diagnosis of rheumatoid arthritis had a diagnosis of AS confirmed on review of the medical records. Estimated prevalence was 0.26% (95% CI 0.14-0.49).Conclusion: EPISER2016 is the first population-based study to estimate the prevalence of AS in Spain, which has been estimated as being similar to that in other European countries.

Systemic blockade of TNF-α does not improve insulin resistance in humans.

The purpose of this study was to determine whether long-term modulation of inflammatory activity by tumor necrosis factor (TNF)-α inhibitors has some influence on insulin resistance (IR). 16 active rheumatoid arthritis (RA) patients without CV risk factors treated with anti-TNF-α agents were included in this study. RA activity by disease activity score 28, IR by HOMA2-IR, body composition by impedance analysis, physical activity by accelerometry, abdominal fat distribution by magnetic resonance imaging, and serum level of key adipokines by ELISA were measured at baseline and during a 1-year follow-up period. Patient body mass index increased significantly (26.94 ± 3.88 vs. 28.06 ± 4.57 kg/m2, p=0.02) after 1 year of treatment. Body composition, in terms of fat and fat-free mass, remained unchanged except for a significant elevation in body cell mass (25.50 ± 4.60 vs. 26.60 ± 3.17 kg, p=0.02). Basal levels of IR in the RA patients included in this study were significantly higher than healthy controls (1.6 ± 0.8 vs. 1.11 ± 0.56, p=0.011) but did not change during the follow-up. Nor did basal concentrations of adiponectin, visfatin, leptin, ghrelin, resistin, and apelin in response to anti-TNF-α treatment; only retinol-binding protein 4, showed a significant increase (51.7 ± 32.7 vs. 64.9 ± 28.4 µg/ml, p=0.03) at the end of the study. IR, adiposity distribution, and serum levels of most adipokines are not significantly affected by long-term inhibition of TNF-α in RA patients. Our data suggest that although systemic blockade of TNF-α exerts an anticachectic effect in RA patients, it does not seem to play a major role in IR.

An open-label pilot study of infliximab therapy in diffuse cutaneous systemic sclerosis.

AIM: The safety and potential efficacy of a chimaeric anti-tumour necrosis factor alpha monoclonal antibody (infliximab) were examined in diffuse cutaneous systemic sclerosis (dcSSc). METHODS: A 26-week open-label pilot study in which 16 cases of dcSSc received five infusions of infliximab (5 mg/kg). Clinical assessment included skin sclerosis score, scleroderma health assessment questionnaire, self-reported functional score and physician global visual analogue scale. Collagen turnover, skin biopsy analysis and full safety evaluation were performed. RESULTS: There was no significant change in skin score at 26 weeks but a trend for lower modified Rodnan skin score at 22 weeks (OR 17, 95% CI 6 to 46) compared with peak value (OR 29, 95% CI 11 to 44; p = 0.10). Serum aminoterminal propeptide of type III collagen level was significantly lower at week 26 compared with baseline (p = 0.03). Secretion of type I collagen by dermal fibroblasts was reduced at 26 weeks compared with baseline (p = 0.02). There were no deaths during the study and no suspected unexpected serious adverse reactions. 21 serious adverse events (AE) occurred in seven subjects, mostly attributable to dcSSc. 127 distinct AE occurred in 16 subjects. Of these, 19 AE (15%) were probably or definitely related to infliximab treatment. Eight (50%) patients prematurely discontinued infliximab. Anti-infliximab antibodies developed during the study in five subjects and were significantly associated with suspected infusion reactions (p = 0.025). CONCLUSION: In dcSSc infliximab did not show clear benefit at 26 weeks but was associated with clinical stabilisation and a fall in two laboratory markers of collagen synthesis. The frequency of suspected infusion reactions may warrant additional immunosuppression in any future studies in systemic sclerosis.

Permanent neonatal diabetes caused by a homozygous nonsense mutation in the glucokinase gene.

Glucokinase deficiency is an unfrequent cause of permanent neonatal diabetes (PND), as only seven patients have been reported, either homozygous for a missense or frameshift mutation or compound heterozygous for both of them. We report here the first known case caused by a homozygous nonsense mutation (Y61X) in the glucokinase gene (GCK) that introduces a premature stop codon, generating a truncated protein that is predicted to be completely inactive as it lacks both the glucose- and the adenosine triphosphate-binding sites. The proband, born to consanguineous parents, was a full-term, intra-uterine growth-retarded male newborn who presented with a glycaemia of 129 mg/dL (7.16 mmol/L) on his second day of life, increasing thereafter up to 288 mg/dL (15.98 mmol/L) and 530 mg/dL (29.41 mmol/L) over the next 24 h, in the face of low serum insulin (<3 muIU/mL; <20.83 pmol/L). He was put on insulin on the third day of life. Insulin has never been discontinued since then. The patient was tested negative for anti-insulin and islet cell antibodies at age 5 months. His father had non-progressive, impaired fasting glucose for several years. The mother was found to be mildly hyperglycaemic only when her glucose was checked after the child was diagnosed. In conclusion, biallelic GCK loss should be considered as a potential cause of PND in children born to consanguineous parents, even if they are not known to be diabetic at the time of PND presentation.

Contralateral lymph neck node metastasis of primary squamous cell carcinoma of the tongue: a retrospective analytic study of 203 patients.

In primary squamous cell carcinoma (SCC) of the oral cavity, many clinical and histopathological factors have been described as predictive for cervical lymph-node metastasis, but there are no data available on this association for surgical resection of lateral tongue primary SCC. The aim of this study was to analyse factors related to contralateral neck relapse in a series of 203 consecutive patients with SCC of the lateral aspect of the tongue treated by surgery with or without adjuvant radiotherapy. Several clinical features were analyzed. Histological study included pTNM classification, tumour size, surgical margins, extracapsular spread of lymph-node metastasis, perineural infiltration, peritumoral inflammation and bone involvement. The mean duration of follow up for surviving patients was 70.9+/-49.6 months; 47 patients eventually died of the disease and 116 patients are alive with no evidence of recurrence. The mean disease-specific survival time was 149+/-7 months. Twenty (9.8%) patients developed ipsilateral and nine (4.4%) contralateral neck recurrence. The mean period of time from surgery to contralateral neck recurrence was 11.4 months (range 3-27 months). Fourteen of the 20 ipsilateral and 8 of the 9 contralateral neck relapse patients eventually died of the disease. Histopathological grading and peritumoral inflammation were found to be statistically significant (P<0.05). Clinical and pathological lymph neck node status was not found to be associated with the appearance of contralateral lymph neck node relapse. Due to the increased risk of contralateral neck relapse within the first 2 years of surgery, close surveillance is mandatory at this time.

Radial forearm free flap for reconstruction of the oral cavity: clinical experience in 55 cases.

OBJECTIVE: Since the advent of modern microvascular techniques, the radial forearm free flap (RFFF) has become a reliable method for reconstruction of defects within the oral cavity. The purpose of the present study was to evaluate our experience with the use of the RFFF for the reconstruction of oral cavity defects after tumor resection. STUDY DESIGN: During a 9-year period, 103 consecutive patients were treated in our department for the reconstruction of oral defects after tumoral ablation by means of microvascularized free flaps. Fifty-five patients were reconstructed by means of the RFFF. Patients were treated for benign (n = 1) and malignant (n = 54) entities. All the patients underwent an abdominal split-thickness skin graft for the closure of the donor site. RESULTS: Fifty-five patients underwent reconstruction by means of the RFFF after resection of the oral cavity. Squamous cell carcinoma was present in 54 patients. A mean age of 55.5 years was observed (range 16-78). Thirty-nine patients (70.9%) were men and 16 (29.1%) women. Primary reconstruction was achieved in 52 patients (96.3%). A fasciocutaneous graft was used in all of the cases, with a mean size of 7.39 x 5.17 cm. The mean flap ischemic time was 56.02 minutes. During the immediate follow-up period, revision of the vascular anastomosis was necessary in 18.9% of the cases owing to flap ischemia. CONCLUSION: Our results revealed that the RFFF is a reliable method for reconstructing a wide range of oral cavity defects with an acceptable low morbidity rate. It provides adequate bulkiness and pliability, resulting in adequate reconstruction of a wide variety of defects within the oral cavity.

Dual positivity for cytoplasmic and perinuclear anti-neutrophil antibodies in a patient with Henoch-Schönlein purpura.

We herein describe the case of a 60-year-old man who presented clinical and histopathological evidence of Henoch-Schönlein purpura. Antineutrophil antibodies (ANCA) showed positive results on an enzyme-linked immunosorbent assay and immunofluorescence for anti-myeloperoxidase and anti-proteinase 3 antibodies. Dual positivity for both cytoplasmatic (C-ANCA) and perinuclear (P-ANCA) antineutrophil antibodies has been found previously in a small number of reports, but to our knowledge this is the first time the simultaneous presence of C-ANCA and P-ANCA has been observed in Henoch-Schönlein purpura.

Intraoral mandibular distraction osteogenesis: special attention to treatment planning.

PURPOSE: To demonstrate our experience using internal devices for unidirectional distraction osteogenesis in treating different mandibular hypoplasias (with or without maxillary deformities). An algorithmic table for diagnosis, and treatment planning is presented. PATIENTS AND METHODS: Twenty internal distraction devices were used in 16 patients with mandibular hypoplasia. Deficiency in length of the mandible was calculated on three-dimensional computed tomography scans. The device was activated by a transcutaneous pin on the fifth postoperative day. Distraction was achieved at rates of 0.5 mm/12 h. After a variable period of consolidation the devices were removed. Mean follow-up was 18 months. RESULTS: Successful distraction osteogenesis was achieved in all patients. No premature consolidation or pseudoarthrosis was observed. Improvement of facial aesthetics was produced in all cases. Final occlusion was excellent in those cases where no simultaneous maxillary deformity was present. Orthodontic treatment was applied in all cases. Results remained stable one year postoperatively. CONCLUSIONS: The occlusal results obtained in this series show that we can plan distraction as a definitive treatment in cases with isolated mandibular hypoplasia. When an additional maxillary deformity is present, mandibular distraction must be performed first if indicated, but a maxillary procedure will be necessary later.

Vascularized free fibular flap for mandibular reconstruction: a report of 26 cases.

PURPOSE: Mandibular reconstruction represents a challenge to the oral and maxillofacial surgeon and has been revolutionized by the modern microvascular techniques. Rehabilitation using techniques such as reconstruction plates frequently produce a functional and cosmetic defect. The primary objective of the current study was to evaluate the usefulness of the osteomuscular free fibular flap for this purpose. PATIENTS AND METHODS: The results of 26 vascularized free fibula flaps with or without a skin paddle that were used for mandibular reconstruction is presented. The "double barrel" technique was used in 6 cases. The donor site was closed directly in 2 cases and with an abdominal full-thickness skin graft in 24 cases. RESULTS: All flaps except 1 were viable. There was partial necrosis of the skin island in 1 patient. The average length of the fibula graft was 10.96 cm, and the number of osteotomies ranged from 0 to 3. In the donor site, the most significant problem was unsatisfactory scarring related to the use of a skin graft. There were no long-term functional complications in the lower leg. Two patients have been secondarily rehabilitated with osseointegrated implants. CONCLUSION: The fibula flap provides a successful bone graft for mandibular restoration with an acceptably low complication rate. This method meets most of the requirements for oral and mandibular replacement.

Down-regulation of L-selectin expression in neutrophils by nonsteroidal anti-inflammatory drugs: role of intracellular ATP concentration.

L-selectin is an adhesion molecule that plays an essential role in the early events of the inflammatory response. Our group has recently described that several nonsteroidal anti-inflammatory drugs (NSAIDs) are able to induce both in vivo and in vitro the shedding of L-selectin in neutrophils through an unknown mechanism. In this work, we have studied potential mechanisms involved in the shedding of L-selectin induced by NSAIDs. This effect of NSAIDs did not involve any detectable intracellular calcium flux. Pretreatment of neutrophils either with Ro 31-8220 and H7, 2 specific inhibitors of protein kinase C (PKC), or with inhibitors of protein tyrosine kinases such as tyrphostin A25 or herbimycin A did not prevent the NSAID-mediated L-selectin shedding. However, the KD-IX-73-4, an inhibitor of L-selectin proteolysis was able to block the effect of NSAIDs on L-selectin expression. Remarkably, NSAIDs caused a variable reduction in the neutrophil intracellular ATP concentration that highly correlated with the differential ability of NSAIDs to trigger L-selectin shedding (r = 0.8, P <.01). In agreement with this finding, azide plus 2-deoxy-D-glucose, 2 metabolic blockers, also induced a rapid L-selectin shedding (65% +/- 8%) without affecting the neutrophil viability, activation, or expression level of other surface molecules with soluble isoforms such as CD16 and CD59. These data indicate that the maintenance of L-selectin on the neutrophil surface requires energy consumption, which suggests that L-selectin is shed in neutrophils by default. Interestingly, NSAIDs seem to cause the shedding of L-selectin, at least in part, through the reduction of the intracellular ATP concentration.

Distraction osteogenesis of the ascending ramus for mandibular hypoplasia using extraoral or intraoral devices: a report of 8 cases.

PURPOSE: This report presents the results of distraction osteogenesis using unidirectional extraoral and intraoral devices in 8 patients with different grades of vertical mandibular ramus hypoplasia. PATIENTS AND METHODS: Eight patients with hypoplastic mandibles underwent unilateral lengthening of the ascending ramus using unidirectional extraoral or intraoral devices. Intraoral mandibular distraction was performed on 5 patients with deficiencies of the vertical ramus up to 24 mm. External devices were used in 3 patients with more severe hypoplasias. An intraoral osteotomy was performed, and progressive distraction at rates of 0.5 mm/12 hours was initiated after 5 days. Once the desired length was reached, the device was maintained in place for 8 to 12 weeks. Three-dimensional computed tomography scans were taken in all the patients to plan the procedure and to compare the changes postoperatively. RESULTS: Successful distraction osteogenesis was achieved in all patients. The amount of mandibular lengthening ranged from 17 to 32 mm. Complications with the external devices such as rotation of the proximal bony fragment (2 cases) and loosening of the external screws at the end of the consolidation period (1 case) were observed. CONCLUSIONS: The results suggest that the intraoral device can be used as the method of choice for distraction osteogenesis of the ascending ramus of the mandible in patients with large deficiencies. Preoperative and postoperative 3-dimensional computed tomographic scans are essential in treatment planning.

Prevention of alphaII(b)beta3 activation by non-steroidal antiinflammatory drugs.

We have studied the effect of non-steroidal antiinflammatory drugs (NSAIDs) on alphaII(b)beta3 integrin activation and platelet aggregation. NSAIDs such as meloxicam, piroxicam, indomethacin and aspirin, but not aceclofenac or diclofenac interfered with the activation state of alphaII(b)beta3. NSAIDs that inhibited alphaII(b)beta3 activation were also able both to partially inhibit platelet primary aggregation and to accelerate platelet deaggregation. These effects of NSAIDs were not dependent on cyclooxygenase inhibition. The results obtained indicate that some NSAIDs exert a specific action on alphaII(b)beta3 activation, and provide an additional mechanism that accounts for their beneficial effects in diseases in which platelet activation is involved.

A new transfacial approach for lesions of the clivus and parapharyngeal space: the partial segmented Le Fort I osteotomy.

Tumors of the clival and parapharyngeal areas are a challenge because of their location. They used to be considered inaccessible because the aggressive approaches employed caused elevated levels of morbidity. This fact led to more conservative approaches that attempted to preserve the exposure of the lesion. These approaches were a combination of cranial and facial procedures, thus utilizing a combined effort between neurosurgeons and maxillofacial surgeons. We described our experience with a partial segmented Le Fort I osteotomy added to a transmandibular approach to expose a chordoma of the clivus and left parapharyngeal space. A three-dimensional imaging was used as a diagnostic tool and to plan the optimal surgical approach. The operative technique was described in this case study. Some important technical details of the approach are described. The global outcome was favorable.

Interference of nonsteroidal antiinflammatory drugs with very late activation antigen 4/vascular cells adhesion molecule 1-mediated lymphocyte-endothelial cell adhesion.

OBJECTIVE: To study the effect of nonsteroidal antiinflammatory drugs (NSAIDs) on the adhesion of peripheral blood lymphocytes (PBL) to activated human umbilical vein endothelial cells (HUVEC) under conditions that resemble blood flow. METHODS: Assays of adhesion of PBL to HUVEC or recombinant vascular cell adhesion molecule 1 (rVCAM-1), intercellular adhesion molecule 1 (ICAM-1), and E-selectin were performed under continuous rotation at 37 degrees C. The phenotype of PBL subpopulations attached was characterized by flow cytometry. Lymphocytes were pretreated with different doses (5-100 microg/ml) of aceclofenac, diclofenac, indomethacin, or piroxicam or with inhibitory monoclonal antibodies (MAb) prior to the adhesion assays. The effect of NSAIDs on lymphocyte adhesion molecules was assessed by flow cytometry. To determine whether NSAIDs interfere with the affinity state of very late activation antigen 4 (VLA-4) integrin, we studied the effect of these drugs on the appearance of a beta1 activation-dependent epitope recognized by the HUTS21 MAb both on human T lymphoblasts and on synovial fluid lymphocytes (SFL). RESULTS: In the flow-resembling model, PBL-HUVEC adhesion was mainly mediated by the VLA-4/ VCAM-1 adhesion pathway. The major PBL subset attached was the CD3+, CD45RO+ memory T cell, with CD49d(high) expression. Aceclofenac, diclofenac, and indomethacin, but not piroxicam, were able to inhibit PBL adhesion to HUVEC or rVCAM-1. However, the quantitative expression of VLA-4 was not affected by treatment of PBL with any of the NSAIDs studied. On T lymphoblasts and SFL, mostly CD45RO+ cells, the expression of the beta1 activation-dependent epitope detected by HUTS21 MAb was significantly decreased by aceclofenac, diclofenac, and indomethacin. CONCLUSION: Some NSAIDs are able to inhibit the adhesion of PBL to HUVEC under conditions that resemble blood flow by interfering with the conformational change in VLA-4 that increases its affinity for VCAM-1.

Tumor DNA content as a prognostic indicator in squamous cell carcinoma of the oral cavity and tongue base.

BACKGROUND: Nuclear deoxyribonucleic acid (DNA) content is a prognostic factor in several tumors, and decisions regarding treatment have been made using this parameter. Nevertheless, there is no agreement in head and neck cancer. The purpose of the present study was to ascertain whether tumor DNA content correlated with prognosis in cases of primary squamous cell carcinoma (SCC) of the oral cavity and tongue base. METHODS: A retrospective study of formalin-fixed, paraffin-embedded tissue from patients with histologically confirmed SCC of the oral cavity and tongue base was performed using flow cytometry. Tumor DNA content was studied in 109 sets of specimens from previously untreated patients. All of them underwent surgical resection at the University "Hospital de La Princesa" between 1982 and 1992. Clinical parameters (age, sex, site of primary tumor, clinical stage, adjuvant therapy received, and disease-free and overall survival) and histologic parameters (histopathologic stage, tumor differentiation, type of inflammatory infiltration, presence of perineural invasion) were recorded in all cases. An exhaustive statistical analysis was applied. RESULTS: Only the histograms of 93 patients were adequate for consideration. In flow cytometric analysis, DNA aneuploidy was observed in 51 tumors (55%). The proportion of aneuploid tumors was significantly higher in advanced-stage carcinomas (p < .05), tumors with perineural invasion (p < .05) and in men (p < .05). In the 24 patients with lymph node metastasis, the incidence of aneuploidy was 82% (19 of 24) (p < .05). The rate of metastasis and aneuploidy increased as the degree of differentiation decreased (p < .05 for both). Patients with aneuploid carcinomas in both early and advanced stages had shorter relapse-free and overall survival periods than did the patients with diploid tumors (p < .001 for both). A Cox regression analysis demonstrated that ploidy was the single most important prognostic factor in determining relapse and death (p < .001 for both). CONCLUSIONS: The results indicate that tumor DNA analysis by flow cytometry appears to be useful as a supplement to clinical and histologic evaluation in predicting the tendency of SCC of the oral cavity and tongue base to metastasize to regional lymph nodes and to predict the outcome of the disease.

Inhibition of leukocyte adhesion: an alternative mechanism of action for anti-inflammatory drugs.

It has been widely accepted that the mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) is the inhibition of prostaglandin synthesis. However, a significant body of evidence suggests that NSAIDs have additional anti-inflammatory mechanisms of action. Here, Federico Díaz-González and Francisco Sánchez-Madrid discuss novel effects of NSAIDs on leukocyte adhesion pathways that may help in the development of new anti-inflammatory agents that selectively block cell adhesion molecules.

Adhesion molecules in inflammatory diseases.

Cell adhesion molecules (CAM) have a key role in the inflammatory response. Selectins, integrins and immunoglobulin (Ig) gene superfamily adhesion receptors mediate the different steps of the migration of leucocytes from the blood-stream towards inflammatory foci. The activation of endothelial cells (EC) upregulates the expression of several CAM and triggers the interaction of these cells with leucocytes. Selectins are involved in the initial interactions (tethering/rolling) of leucocytes with activated endothelium, whereas integrins and Ig superfamily CAM mediate the firm adhesion of these cells and their subsequent extravasation. During rolling, leucocytes are activated through the intracellular signals generated by CAM and chemokine receptors. Blockade of the function or expression of CAM has emerged as a new therapeutic target in inflammatory diseases. Different drugs are able to interfere with cell adhesion phenomena. In addition, new antiadhesion therapeutic approaches (blocking monoclonal antibodies, soluble receptors, synthetic peptides, peptidomimetics, etc.) are currently in development.