Undifferentiated Spondyloarthritis: A Longterm Followup

Objective. To analyze the longterm followup of a series of Brazilian patients with undifferentiated spondyloarthritis (uSpA). Methods. Prospective study analyzing a group of 111 patients with the diagnosis of uSpA, fulfilling the European Spondylarthropathy Study Group and the Amor criteria, who were followed for 5 to 10 years in a single university referral center. Patients had their outcome analyzed at 5, 7, and 10 years. Results. There was a predominance of men (81.1%), white ethnicity (78.4%), and positive HLA-B27 (61.3%), with a mean age at onset of 27.2 years. Twenty-seven patients presented development to ankylosing spondylitis (AS; 24.3%) and 3 to psoriatic arthritis (PsA; 2.7%), while 25 patients (22.5%) went into remission during the followup. Univariate logistic regression analysis revealed that ethnicity, HLA-B27, buttock pain, inflammatory low back pain, ankle involvement, grade I sacroiliitis at the beginning of the study, and the use of sulfasalazine were statistically associated with progression to AS. Multivariate logistic regression analysis revealed that HLA-B27 (p = 0.035, OR 6.720.95% CI 11.45-39.43) and buttock pain (p = 0.009, OR 6.211, 95% CI 1.591-24.25) were statistically associated with progression to AS. Conclusion. In a longterm followup of 111 Brazilian patients with uSpA, HLA-B27 and buttock pain were significant predictors of progression to a definite disease. (First Release May 1 2010; J Rheumatol 2010;37:1195-9; doi:10.3899/jrheum.090625)

Non-pharmacological approach to neuropathic pain: the use of repetitive transcranial magnetic stimulation

Neuromodulation is the branch of neurophysiology related to the therapeutic effects of electrical stimulations of the nervous system. There are currently different practical applications of neuromodulation techniques for the treatment of various neurological disorders, such as deep brain stimulation for Parkinson`s disease and repetitive transcranial magnetic stimulation (rTMS) for major depression. An increasing number of studies have been devoted to the analgesic effects of rTMS in chronic pain patients. RTMS has been used either as a therapeutic tool per se, or as a preoperative test in patients undergoing epidural precentral gyrus stimulation. High-frequency rTMS (a parts per thousand yen5 Hz) is considered to be excitatory, while low-frequency stimulation (a parts per thousand currency sign1 Hz) is considered to exert an inhibitory effect over neuronal populations of the primary motor cortex. However, other parameters of stimulation may play a central role on its clinical effects such as the type of coil, its orientation over the scalp, and the total number of rTMS sessions performed. Experimental data from animals, healthy volunteers, and neuropathic pain patients have suggested that stimulation of the primary motor cortex by rTMS is able to activate brain regions implicated in the processing of the different aspects of chronic pain, and influence brain regions involved in the endogenous opioid system. Over twenty prospective randomized sham-controlled trials have studied the analgesic effects of rTMS on chronic pain. Most of the patients included in these trials had central or peripheral neuropathic pain. Although most studies used a single session of stimulation, recent studies have shown that the analgesic effects of rTMS may outlast the stimulation period for many days when repetitive sessions are performed. This opens the possibility to use rTMS as a therapeutic tool of its own in the armamentarium against neuropathic pain.

Effects of biomass burning on nasal mucociliary clearance and mucus properties after sugarcane harvesting

Objective: Biofuel from sugarcane is widely produced in developing countries and is a clean and renewable alternative source of energy. However, sugarcane harvesting is mostly performed after biomass burning. The aim of this study was to evaluate the effects of harvesting after biomass burning on nasal mucociliary clearance and the nasal mucus properties of farm workers. Methods: Twenty seven sugarcane workers (21-45 years old) were evaluated at the end of two successive time-periods: first at the end of a 6-month harvesting period (harvesting), and then at the end of a 3-month period without harvesting (non-harvesting). Nasal mucociliary clearance was evaluated by the saccharine transit test, and mucus properties were analyzed using in vitro mucus contact angle and mucus transportability by sneeze. Arterial blood pressure, heart rate, respiratory rate, pulse oximetry, body temperature, associated illness, and exhaled carbon monoxide were registered. Results: Data are presented as mean values (95% confidence interval). The multivariate model analysis adjusted for age, body-mass index, smoking status and years of working with this agricultural practice showed that harvesting yielded prolonged saccharine transit test in 7.83 min (1.88-13.78), increased mucus contact angle in 8.68 degrees (3.18-14.17) and decreased transportability by sneeze in 32.12 mm (-44.83 to -19.42) compared with the non-harvesting period. No significant differences were detected in any of the clinical parameter at either time-period. Conclusion: Sugarcane harvesting after biomass burning negatively affects the first barrier of the respiratory system in farm workers by impairing nasal mucociliary clearance and inducing abnormal mucus properties. (C) 2011 Elsevier Inc. All rights reserved.

Autoimmune bullous dermatoses

Autoimmune bullous dermatoses are diseases in which blisters and vesicles are the primary and fundamental types of skin lesion. Their classification is based on the location of the blister; intraepidermal and subepidermal. Patients produce autoantibodies against self-specific structures of the skin detectable by immunofluorescence techniques, immunoblotting and ELISA. Recent advances in molecular and cellular biology have brought to knowledge these self-antigens, against which patients are sensitized, and which are found in epidermis or in the dermo-epidermal junction. These are low incidence, but high morbidity diseases that may be fatal. The aim of this article is to review and describe the progress of four autoimmune vesiculobullous disorders; endemic pemphigus foliaccous (wild fire), pemphigus vulgaris, bullous pemphigoid and dermatitis herpetiformis.

Biological markers and prognosis in recurrent oral cancer after salvage surgery

Objective: To analyze the prognostic effect of epidermal growth factor receptor (EGFR), matrix metalloproteinases 2 and 9, and vascular endothelial growth factor expression in patients with locally recurrent oral carcinoma after salvage surgery. Design: Retrospective cohort study. Settings: Tertiary center cancer hospital. Patients: The charts of 111 patients with local recurrence of oral carcinomas were retrospectively analyzed. The previous treatment consisted of surgery in 33 patients (30.0%), radiotherapy with or without chemotherapy in 46 patients (41.0%), and surgery with adjuvant radiotherapy in 32 patients (29.0%). The expression of EGFR, matrix metalloproteinases 2 and 9, and vascular endothelial growth factor was analyzed with a tissue microarray immunohistochemical technique. Main Outcome Measures: Overall survival and cancer-specific survival (CSS). Results: The recurrences were diagnosed in less than 1 year in 69 patients (62.2%) and in more than 1 year in 42 patients (37.8%). The prognosis was worse in the group with the disease-free interval of less than 1 year (P=.01). Patients with more advanced disease (clinical stage of recurrence, III/IV) had worse rates of CSS (P=.04). Cases that were positive for EGFR had a 3-year CSS of 27.2%, while EGFR-negative cases had a 3-year CSS of 64.3% (P=.001). The expression of matrix metalloproteinases 2 (P=.83) and 9 (P=.15) and vascular endothelial growth factor (P=.86) was not significant in this group. In multivariate analysis, only the disease-free interval and the overexpression of EGFR were associated with a higher risk of cancer death. Conclusions: Local recurrence in oral carcinomas carries a poor prognosis. A disease-free interval of more than 1 year and a EGFR-negative expression are the main prognostic factors related to better CSS in patients treated with salvage surgery.

In vivo electrochemical characterization and inflammatory response of multiwalled carbon nanotube-based electrodes in rat hippocampus

Stimulating neural electrodes are required to deliver charge to an environment that presents itself as hostile. The electrodes need to maintain their electrical characteristics (charge and impedance) in vivo for a proper functioning of neural prostheses. Here we design implantable multi-walled carbon nanotubes coating for stainless steel substrate electrodes, targeted at wide frequency stimulation of deep brain structures. In well-controlled, low-frequency stimulation acute experiments, we show that multi-walled carbon nanotube electrodes maintain their charge storage capacity (CSC) and impedance in vivo. The difference in average CSCs (n = 4) between the in vivo (1.111 mC cm(-2)) and in vitro (1.008 mC cm(-2)) model was statistically insignificant (p > 0.05 or P-value = 0.715, two tailed). We also report on the transcription levels of the pro-inflammatory cytokine IL-1 beta and TLR2 receptor as an immediate response to low-frequency stimulation using RT-PCR. We show here that the IL-1 beta is part of the inflammatory response to low-frequency stimulation, but TLR2 is not significantly increased in stimulated tissue when compared to controls. The early stages of neuroinflammation due to mechanical and electrical trauma induced by implants can be better understood by detection of pro-inflammatory molecules rather than by histological studies. Tracking of such quantitative response profits from better analysis methods over several temporal and spatial scales. Our results concerning the evaluation of such inflammatory molecules revealed that transcripts for the cytokine IL-1 beta are upregulated in response to low-frequency stimulation, whereas no modulation was observed for TLR2. This result indicates that the early response of the brain to mechanical trauma and low-frequency stimulation activates the IL-1 beta signaling cascade but not that of TLR2.

Prevalence of Insulin Resistance and Related Risk Factors for Cardiovascular Disease in Patients With Essential Hypertension

BACKGROUND There is evidence that the subgroup of patients with essential hypertension who are also insulin resistant is at increased risk of cardiovascular disease (CVD). We are unaware of the frequency of insulin resistance in patients with essential hypertension as well as the CVD risk in this subgroup of patients. This analysis was aimed at providing the prevalence of insulin resistance and associated CVD risk factors in treated and untreated patients with essential hypertension. METHODS The study population consisted of 126 patients with hypertension: 56 untreated and 70 in a stable treatment program. Body mass index (BMI), blood pressure, plasma glucose and insulin responses to an oral glucose challenge, lipid and lipoprotein concentrations, and steady-state plasma glucose (SSPG) concentration during the insulin suppression test were measured. Insulin resistance was defined operationally as a SSPG concentration >180 mg/dl. RESULTS Demographic characteristics and metabolic CVD risk factors were comparable in both groups, with 30-50% of both treated and untreated patients having abnormalities of all risk factors measured. Approximately 50% of patients met the criteria for insulin resistance in both groups, and the prevalence of abnormal CVD risk factors in this group was increased two to threefold as compared to the other half of the subjects. CONCLUSIONS Approximately 50% of patients with essential hypertension, both treated and untreated, appear to be insulin resistant, and CVD risk factors are greatly accentuated in this subset of patients.

Creatine Supplementation Prevents the Accumulation of Fat in the Livers of Rats Fed a High-Fat Diet

The aim of the present study was to examine the effects of creatine supplementation on liver fat accumulation induced by a high-fat diet in rats. Rats were fed 1 of 3 different diets for 3 wk: a control liquid diet (C), a high-fat liquid diet (HF), or a high-fat liquid diet supplemented with creatine (HFC). The C and HF diets contained, respectively, 35 and 71% of energy derived from fat. Creatine supplementation involved the addition of 1% (wt:v) of creatine monohydrate to the liquid diet. The HF diet increased total liver fat concentration, liver TG, and liver TBARS and decreased the hepatic S-adenosylmethionine (SAM) concentration. Creatine supplementation normalized all of these perturbations. Creatine supplementation significantly decreased the renal activity of L-arginine:glycine amidinotransferase and plasma guanidinoacetate and prevented the decrease in hepatic SAM concentration in rats fed the HF diet. However, there was no change in either the phosphatidylcholine:phosphatidylethanolamine (PE) ratio or PE N-methyltransferase activity. The HF diet decreased mRNA for PPAR as well as 2 of its targets, carnitine palmitoyltransferase and long-chain acylCoA dehydrogenase. Creatine supplementation normalized these mRNA levels. In conclusion, creatine supplementation prevented the fatty liver induced by feeding rats a HF diet, probably by normalization of the expression of key genes of beta-oxidation. J. Nutr. 141: 1799-1804, 2011.

Frequency of HLA-B27 alleles in Brazilian patients with psoriatic arthritis

This prospective study analyzed the frequency of HLA-B27 and its alleles in 102 Brazilian patients with psoriatic arthritis (PsA). The association of the HLA-B27 alleles with these variants was compared to a control healthy HLA-B27 positive group of 111 individuals. There was a predominance of male gender (59.8%), Caucasian race (89.2%), and negative HLA-B27 (79.4%) patients. Asymmetric oligoarthritis (62.7%) was the most frequently observed clinical PsA subgroup, followed by spondylitis (16.7%), and polyarthritis (15.7%). Male gender and the spondylitis subgroup were statistically associated to the positive HLA-B27, and the oligoarthritis subgroup was associated to the negative HLA-B27. Among the 21 HLA-B27-positive PsA patients, there was a significant prevalence of the HLA-B*2705 allele (90.5%), similar to that observed in the control group (80.2%); HLA-B*2703 and HLA-B*2707 were statistically associated to the control group.

Frequency of HLA-B27 and its alleles in patients with Reiter syndrome: comparison with the frequency in other spondyloarthropathies and a healthy control population

This retrospective study analyzed the HLA-B*27 alleles in a group of 20 consecutive patients with the diagnosis of Reiter syndrome (RS) followed in a tertiary referral university hospital in Brazil, during the period 1990-2006, and compared the data with that observed in other patients with spondyloarthropathies followed at the same institution. Eight cases were associated to gastrointestinal infection, eight cases to previous urethritis, and four cases presented no established preceding infection. HLA-B*27 alleles were typed by polymerase chain reaction-amplified DNA hybridized with sequence-specific oligonucleotide probes (HLA-B*2701 to HLA-B*2721). They were compared to a group of 108 patients with ankylosing spondylitis (AS), 40 with undifferentiated spondyloarthropathy (uSpA) and 111 healthy controls. Among the 20 patients, 17 were HLA-B*27 positive (85%). Two HLA-B*27 alleles were observed: HLA-B*2705 (65%) and HLA-B*2702 (35%). In the other spondyloarthropathies, the observed alleles were HLA-B*2705 (90% in AS and 92.5% in uSpA), HLA-B*2702 (8% in AS and 5% in uSpA), HLA-B*2704 (1% in AS and 2.5% in uSpA) and HLA-B*2713 (1% in AS). Among the 111 healthy controls, 80% presented HLA-B*2705, followed by HLA-B*2702 in 10%, HLA-B*2703 in 6%, HLA-B*2707 in 3% and HLA-B*2713 in 1%. Concluding, in the HLA-B*27 positive patients with RS in this study there was predominance of HLA-B*2705 allele, in a lower frequency than that observed in patients with other spondyloarthropathies and healthy controls.

Local profile of cytokines and nitric oxide in patients with bacterial vaginosis and cervical intraepithelial neoplasia

Objective: To evaluate the local immune response in patients with bacterial vaginosis (BV) and cervical intraepithelial neoplasia (CIN), as assessed by cytokine and nitric oxide (NO) concentrations. Study design: Patients attending for routine gynaecological examination were prospectively enrolled in groups: BV (n = 25) diagnosed by clinical criteria, CIN graded I to III (n = 35, 6 CIN 1, 8 CIN 11 and 21 CIN 111) by histological analysis, and controls (n = 15) without clinical and cytological findings. Randomly selected patients within CIN group at grades 11 or III (n = 15) were re-evaluated at 60 days after surgical treatment. Endocervical (EC) and vaginal secretion samples were collected by cytobrush and the levels of cytokines (ELISA) and NO metabolite (Griess reaction) were assayed. Results: NO was assessed in all subjects, and cytokines in all controls, 15 BV and 30 CIN patients. Interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10) and nitrite levels were higher in EC than in vaginal secretions in BV and CIN groups. In CIN group, IL-8, IL-10 and nitrite concentrations were greater in EC and/or vaginal secretions than in BV or controls. Surgical treatment reduced IL-8 levels in EC and vaginal secretions. Conclusion: A similar local immune profile was found in BV and CIN groups. The increased local production of IL-8, IL-10 and NO in CIN suggests a role for these mediators in the immune response against tumour or tumour development. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Lipoxin A(4) attenuates zymosan-induced arthritis by modulating endothelin-1 and its effects

BACKGROUND AND PURPOSE Lipoxin A(4) (LXA(4)) is a lipid mediator involved in the resolution of inflammation. Increased levels of LXA(4) in synovial fluid and enhanced expression of the formyl peptide receptor 2/lipoxin A(4) receptor (FPR2/ALX) in the synovial tissues of rheumatoid arthritis patients have been reported. Endothelins (ETs) play a pivotal pro-inflammatory role in acute articular inflammatory responses. Here, we evaluated the anti-inflammatory role of LXA(4), during the acute phase of zymosan-induced arthritis, focusing on the modulation of ET-1 expression and its effects. EXPERIMENTAL APPROACH The anti-inflammatory effects of LXA(4), BML-111 (agonist of FPR2/ALX receptors) and acetylsalicylic acid (ASA) pre- and post-treatments were investigated in a murine model of zymosan-induced arthritis. Articular inflammation was assessed by examining knee joint oedema; neutrophil accumulation in synovial cavities; and levels of prepro-ET-1 mRNA, leukotriene (LT)B(4), tumour necrosis factor (TNF)-alpha and the chemokine KC/CXCL1, after stimulation. The direct effect of LXA(4) on ET-1-induced neutrophil activation and chemotaxis was evaluated by shape change and Boyden chamber assays respectively. KEY RESULTS LXA(4), BML-111 and ASA administered as pre- or post-treatment inhibited oedema and neutrophil influx induced by zymosan stimulation. Zymosan-induced preproET-1 mRNA, KC/CXCL1, LTB(4) and TNF-alpha levels were also decreased after LXA(4) pretreatment. In vitro, ET-1-induced neutrophil chemotaxis was inhibited by LXA4 pretreatment. LXA(4) treatment also inhibited ET-1-induced oedema formation and neutrophil influx into mouse knee joints. CONCLUSION AND IMPLICATION LXA(4) exerted anti-inflammatory effects on articular inflammation through a mechanism that involved the inhibition of ET-1 expression and its effects.

Involvement of the prelimbic prefrontal cortex on cannabidiol-induced attenuation of contextual conditioned fear in rats

Rationale: Systemic administration of cannabidiol (CBD), a non-psychotomimetic component of Cannabis sativa, is able to attenuate cardiovascular and behavioral (freezing) changes induced by re-exposure to a context that had been previously paired with footshocks. The brain sites mediating this effect, however, remain unknown. The medial prefrontal cortex (mPFC) has been related to contextual fear conditioning. Objectives: (1) To verify, using c-Fos immunocytochemistry, if the mPFC is involved in the attenuation of contextual fear induced by systemic administration of CBD; (2) to investigate if direct microinjections of CBD into mPFC regions would also attenuate contextual fear. Results: Confirming previous results systemic administration of CBD (10 mg/kg) decreased contextual fear and associated c-Fos expression in the prefrontal cortex (prelimbic and infralimbic regions). The drug also attenuated c-Fos expression in the bed nucleus of the stria terminalis (BNST). Direct CBD (30 nmol) microinjection into the PL prefrontal cortex reduced freezing induced by re-exposure to the aversively conditioned context. In the infralimbic (IL) prefrontal cortex, however, CBD (30 nmol) produced an opposite result, increasing the expression of contextual fear conditioning. This result was confirmed by an additional experiment where the conditioning session was performed under a less aversive protocol. Conclusion: These results suggest that the PL prefrontal cortex may be involved in the attenuation of contextual fear induced by systemic injection of CBD. They also support the proposition that the IL and PL play opposite roles in fear conditioning. A possible involvement of the BNST in CBD effects needs to be further investigated. (C) 2009 Elsevier B.V. All rights reserved.

Renal structure and function evaluation of rats from dams that received increased sodium intake during pregnancy and lactation submitted or not to 5/6 nephrectomy

Adult rats submitted to perinatal salt overload presented renin-angiotensin system (RAS) functional disturbances. The RAS contributes to the renal development and renal damage in a 5/6 nephrectomy model. The aim of the present study was to analyze the renal structure and function of offspring from dams that received a high-salt intake during pregnancy and lactation. We also evaluated the influence of the prenatal high-salt intake on the evolution of 5/6 nephrectomy in adult rats. A total of 111 sixty-day-old rat pups from dams that received saline or water during pregnancy and lactation were submitted to 5/6 nephrectomy (nephrectomized) or to a sham operation (sham). The animals were killed 120 days after surgery, and the kidneys were removed for immunohistochemical and histological analysis. Systolic blood pressure (SBP), albuminuria, and glomerular filtration rate (GFR) were evaluated. Increased SBP, albuminuria, and decreased GFR were observed in the rats from dams submitted to high-sodium intake before surgery. However, there was no difference in these parameters between the groups after the 5/6 nephrectomy. The scores for tubulointerstitial lesions and glomerulosclerosis were higher in the rats from the sham saline group compared to the same age control rats, but there was no difference in the histological findings between the groups of nephrectomized rats. In conclusion, our data showed that the high-salt intake during pregnancy and lactation in rats leads to structural changes in the kidney of adult offspring. However, the progression of the renal lesions after 5/6 nephrectomy was similar in both groups.

Sonographic evaluation of endothelial function in letrozole and tamoxifen users

Objectives: Studies have shown that women previously treated for breast cancer present fewer cardiovascular events, indicating a possible protective effect of tamoxifen treatment. The effects of these aromatase inhibitors on cardiovascular protection remain controversial. The aim of this study was to compare some cardiovascular risk markers among breast cancer survivors following treatment with tamoxifen group (TMXg), letrozole group (LTZg) or no endocrine treatment group (NETg). Methods: A total of 103 breast cancer survivors: 35 using TMXg, 34 using letrozole group (LTZg) and 34 using no endocrine treatment group (NETg) were evaluated. Ultrasonographic evaluation of brachial artery flow-mediated dilation (FMD), carotid intima-media thickness (IMT) and stiffness index (beta); blood total cholesterol, HDL and triglycerides were assessed. Results: All three groups presented similar values of HDL and IMT. TMXg showed the lowest total cholesterol (219.29 +/- 36.31 mg/dL vs. 250.59 +/- 38.37 mg/dL vs. 245.09 +/- 35.35 mg/dL; TMXg vs. LTZg vs. NETg, respectively; p < 0.01-ANOVA), the highest triglycerides (139.34 +/- 41.82 mg/dL vs. 111.35 +/- 28.22 mg/dL vs.122.09 +/- 33.42 mg/dL; p < 0.01), the highest FMD (6.32 +/- 2.33% vs. 4.10 +/- 2.06% vs. 4.66 +/- 2.52%; p < 0.01) and the lowest stiffness index (beta) (5.08 +/- 1.68 vs. 6.28 +/- 1.75 vs. 5.99 +/- 1.86; p=0.01). LTZg did not differ significantly from NETg on any evaluated parameter. Conclusions: We did not observe any effect of LTZg on the evaluated cardiovascular risk parameters compared to NETg. As such, the observed difference on lipid values, stiffness index (beta) and FMD between women receiving tamoxifen anti letrozole might be best attributed to the beneficial effect of tamoxifen than to a detrimental effect of letrozole. (C) 2008 Elsevier Ireland Ltd. All rights reserved.