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Purpose: Metabolic dysfunction-associated steatotic liver disease (MASLD) may have distinctive pathophysiological features in type 1 diabetes (T1D). We evaluated the independent role of blood glucose control on MASLD in T1D. Methods: In a cross-sectional study on 659 T1D adult patients, MASLD was assessed by the Fatty Liver Index (FLI) and the Hepatic Steatosis Index (HSI). Anthropometric, biochemical, and clinical parameters were retrieved from electronic records. Blood glucose control status was evaluated by dividing participants into subgroups according to the median value of HbA1c [7.6% (60 mmol/mol)], and this analysis was repeated excluding overweight/obese patients. Results: Patients with HbA1c above 7.6% (60 mmol/mol) showed significantly higher MASLD indices (HSI 38 ± 6 vs. 36 ± 5, p < 0.001; FLI 26 ± 26 vs.19 ± 19, p < 0.001), and higher proportions of MASLD identified by HSI (57 vs. 44%, p < 0.001) and FLI (14 vs. 7%, p < 0.001) than patients with HbA1c below 7.6% (60 mmol/mol). Similar results were obtained for HSI after the exclusion of overweight/obese patients. Stepwise linear regression analysis confirmed that HbA1c was independently associated with HSI (r = 0.496, p = 0.009) and FLI (r = 0.722, p = 0.007); waist circumference with HSI (r = 0.492, p < 0.001); and waist circumference (r = 0.700, p < 0.001), HDL cholesterol (r = 0.719, p < 0.001), and LDL cholesterol (r = 0.712, p < 0.001) with FLI. Conclusions: Blood glucose control is a main factor associated with MASLD in adults with T1D, also independently of overweight and obesity. Appropriate therapeutic strategies focused on tight blood glucose control may also be needed for the prevention and treatment of MASLD in T1D.

Gadolinium retention in the brain measured with MRI longitudinal relaxation rate mapping and laser ablation inductively coupled plasma mass spectrometry yielded different results, indicating that some forms of retained gadolinium may escape detection with MRI.

Fish consumption is associated with a reduced risk of cardiovascular diseases (CVDs) partly ascribed to the high content of long-chain (LC) n–3 PUFAs; however, not all fish types are equally rich in these components. To date, it is not clear whether the beneficial effects of fish consumption are shared by fatty and lean fish. Therefore, the aim of this meta-analysis was to synthesize knowledge regarding the relation between the intake of fatty fish or lean fish and the risk of cardiovascular events and all-cause mortality. We conducted a systematic search in PubMed, Web of Science, and Embase until May 2021 for full text with a prospective design involving humans providing data for the highest compared with the lowest fish consumption categories. Summary risk ratios (RRs) and 95% CIs were estimated using a random-effects model. Out of 1902 articles retrieved from the literature search, 19 reports met the criteria for inclusion in the meta-analysis. Altogether, studies on fatty fish comprised 1,320,596 person-years of follow-up, 20,531 incident coronary heart disease (CHD) cases, 9256 incident CVD cases, and 104,763 total deaths. Studies on lean fish comprised 937,362 person-years of follow-up, 21,636 incident CHD cases, 7315 incident CVD cases, and 16,831 total deaths. An inverse association was present for fatty fish with CHD incidence (RR: 0.92; 95% CI: 0.86, 0.97), CHD mortality (RR: 0.83; 95% CI: 0.70, 0.98), and total mortality (RR: 0.97; 95% CI: 0.94, 0.99). This was not the case for lean fish. The summary estimates for CVD incidence and mortality did not show significant association with both fatty fish and lean fish consumption. The study findings are innovative in highlighting that the health benefits so far linked to fish consumption are, in fact, driven by fatty fish.

Infection-neutralizing antibody responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 vaccination are an essential component of antiviral immunity. Antibody-mediated protection is challenged by the emergence of SARS-CoV-2 variants of concern (VoCs) with immune escape properties, such as omicron (B.1.1.529), which is rapidly spreading worldwide. Here we report neutralizing antibody dynamics in a longitudinal cohort of coronavirus disease 2019 convalescent and infection-naive individuals vaccinated with mRNA BNT162b2 by quantifying SARS-CoV-2 spike protein antibodies and determining their avidity and neutralization capacity in serum. Using live-virus neutralization assays, we show that a superior infection-neutralizing capacity against all VoCs, including omicron, developed after either two vaccinations in convalescents or a third vaccination or breakthrough infection of twice-vaccinated, naive individuals. These three consecutive spike antigen exposures resulted in an increasing neutralization capacity per anti-spike antibody unit and were paralleled by stepwise increases in antibody avidity. We conclude that an infection-plus-vaccination-induced hybrid immunity or a triple immunization can induce high-quality antibodies with superior neutralization capacity against VoCs, including omicron.

Bacterial cells present a wide diversity of saccharides that decorate the cell surface and help mediate interactions with the environment. Many Gram-negative cells express O-antigens, which are long sugar polymers that makeup the distal portion of lipopolysaccharide (LPS) that constitutes the surface of the outer membrane. This review highlights chemical biology tools that have been developed in recent years to facilitate the modulation of O-antigen synthesis and composition, as well as related bacterial polysaccharide pathways, and the detection of unique glycan sequences. Advances in the biochemistry and structural biology of O-antigen biosynthetic machinery are also described, which provide guidance for the design of novel chemical and biomolecular probes. Many of the tools noted here have not yet been utilized in biological systems and offer researchers the opportunity to investigate the complex sugar architecture of Gram-negative cells.

Objective: To evaluate intravenous immune globulin (IVIG) for autoimmune heparin-induced thrombocytopenia (aHIT), including platelet recovery, IVIG dose, dosing weight, IVIG product used, and complications reported.Data Sources: PubMed and EMBASE were searched from inception through June 21, 2020. Search terms included heparin-induced thrombocytopenia, HIT, intravenous immune globulin, IVIG, autoimmune HIT, aHIT, and immune globulin.Study Selection and Data Extraction: Patients administered IVIG for HIT and diagnosed by immunoassay (optical density ≥2) or positive activation assay were included.Data Synthesis: Twenty-four cases were reviewed; 92% had persistent aHIT. Time to IVIG administration post–nonheparin anticoagulant initiation was 9 days (median). Most common IVIG cumulative dose was 2 g/kg (dosed as 1 g/kg/d for 2 consecutive days); 75% had a favorable platelet increase (≥50 × 109/L) within 5 days of initial IVIG dosing.Relevance to Patient Care and Clinical Practice: aHIT is characterized by critically low platelets, thrombosis, and a persistent delay in platelet recovery despite treatment with a nonheparin anticoagulant. An immunoassay and subsequent confirmatory activation assay (at low, high, and 0 IU/mL unfractionated heparin levels) is recommended to confirm diagnosis. Patients nonresponsive to nonheparin anticoagulants within 5 days of initiation should be evaluated for IVIG treatment (2 g/kg cumulative dose). More data are needed to clarify appropriate IVIG dosing weight, although based on current published literature, it is recommended to use actual body weight.Conclusions: Data reported support use of IVIG as adjunctive therapy for patients with aHIT. Judicious IVIG use based on key clinical and laboratory findings is critical.

Repeated exposure to intravenous gadopentetate dimeglumine, a linear gadolinium-based contrast agent, is associated with nonhomogeneous retention of gadolinium in rat and human cerebral cortex.

Peptidoglycan glycosyltransferases are highly conserved bacterial enzymes that catalyze glycan strand polymerization to build the cell wall. Because the cell wall is essential for bacterial cell survival, these glycosyltransferases are potential antibiotic targets, but a detailed understanding of their mechanisms is lacking. Here we show that a synthetic peptidoglycan fragment that mimics the elongating polymer chain activates peptidoglycan glycosyltransferases by bypassing the rate-limiting initiation step.

The recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlighted a critical need to discover more effective antivirals. While therapeutics for SARS-CoV-2 exist, its nonstructural protein 13 (Nsp13) remains a clinically untapped target. Nsp13 is a helicase responsible for unwinding double-stranded RNA during viral replication and is essential for propagation. Like other helicases, Nsp13 has two active sites: a nucleotide binding site that hydrolyzes nucleoside triphosphates (NTPs) and a nucleic acid binding channel that unwinds double-stranded RNA or DNA. Targeting viral helicases with small molecules, as well as the identification of ligand binding pockets, have been ongoing challenges, partly due to the flexible nature of these proteins. Here, we use a virtual screen to identify ligands of Nsp13 from a collection of clinically used drugs. We find that a known ion channel inhibitor, IOWH-032, inhibits the dual ATPase and helicase activities of SARS-CoV-2 Nsp13 at low micromolar concentrations. Kinetic and binding assays, along with computational and mutational analyses, indicate that IOWH-032 interacts with the RNA binding interface, leading to displacement of nucleic acid substrate, but not bound ATP. Evaluation of IOWH-032 with microbial helicases from other superfamilies reveals that it is selective for coronavirus Nsp13. Furthermore, it remains active against mutants representative of observed SARS-CoV-2 variants. Overall, this work provides a new inhibitor for Nsp13 and provides a rationale for a recent observation that IOWH-032 lowers SARS-CoV-2 viral loads in human cells, setting the stage for the discovery of other potent viral helicase modulators.

A significant proportion of patients with T1DM free of chronic complications showed delayed GE associated with a longer time to peak glucose.

Patients with PAD have lower vitamin D levels than control subjects, and both vitamin D deficiency and vitamin D insufficiency are associated with PAD.

Background: Psoriatic arthritis is a chronic inflammatory arthropathy that affects 14%- 30% of patients with skin and/or nail psoriasis, leading to severe physical limitations and disability. It has been included in the group of spondyloarthropathy with which it shares clinical, radiologic, and serologic features in addition to familial and genetic relationship. Beyond skin and joint involvement, psoriatic arthritis is characterized by a high prevalence of extra-articular manifestation and comorbidities, such as autoimmune, infectious and neoplastic diseases. In particular, an increased risk of cardiovascular comorbidity has been observed in psoriatic arthritis patients. Methods: A systematic search was performed in the electronic databases (PubMed, Web of Science, Scopus, EMBASE) up until January 2017. Studies were included if they contained data on CV disease and/or risk factors in PsA and each article was then reviewed for quality and clinical relevance. After completing the literature search all screened literature was summarized and discussed in our study group (CaRDDs study group). All literature and comments were included in the systematic review. Results: The initial search produced 278 abstracts, which were narrowed to 83 potentially relevant articles by preliminary review of the titles and by excluding review articles and case report (n = 195). Thirty articles were deemed ineligible after examining the abstracts. Full texts of the remaining 53 articles were retrieved. The majority of articles excluded were due to only providing data on patients with psoriasis or due to being not relevant to the CV risk in PsA. In the end, 32 articles were deemed eligible for this review. Conclusion: Psoriatic arthritis appeared significantly associated with subclinical atherosclerosis and endothelial dysfunction and, in turn, with an increased cardiovascular risk. Thus, patients with psoriatic arthritis may benefit from a periodic assessment of surrogate markers of cardiovascular risk. This could help to establish more specific cardiovascular prevention strategies for these patients.

Context:Subclinical hypothyroidism (SH) is associated with some abnormalities in primary and secondary hemostasis.Objective:The objective of the study was to evaluate changes in primary and secondary hemostasis induced by levothyroxine (L-T4) treatment in SH patients.Design:This was a prospective cohort study with a 6-month follow-up.Study Setting:Outpatients were referred to “Federico II” University of Naples.Patients:Subjects with a SH without previous/ongoing L-T4 therapy participated in the study.Main Outcome Measure:Changes in major hemostatic/fibrinolytic variables and platelet reactivity [mean platelet volume (MPV), arachidonic acid (AA), or ADP concentrations inducing a ≥ 50% irreversible aggregation (AC-50%)] in SH patients before and after a 6-month L-T4 treatment.Results:At baseline, 41 SH patients showed higher levels of factor VII activity (123.9 ± 20.4 vs 107.7 ± 12.2, P< .001), plasminogen activator inhibitor-1 (33.6 ± 13.9 vs 22.5 ± 5.74, P< .001) and tissue plasminogen activator (5.56 ± 2.22 vs 4.75 ± 1.61, P= .010), with lower levels of D-dimer (220.3 ± 67.1 vs 252.1 ± 72.4, P= .017) compared with healthy controls. SH patients also showed a higher MPV (9.92 ± 1.15 vs 8.9 ± 0.9, P< .001) and AC-50% to AA (0.18 ± 0.12 vs 0.36 ± 0.10, P< .001) and to ADP (1.5 ± 0.6 vs 1.9 ± 1.3, P= .024). After a 6-month L-T4 therapy, a reduction of factor VII activity (from 123.9 ± 20.4 to 102.6 ± 14.3, P< .001), plasminogen activator inhibitor-1 (33.6 ± 13.9 to 19.4 ± 7.6, P< .001), and tissue plasminogen activator (5.56 ± 2.22 to 1.91 ± 4:43, P= .002) was found in SH subjects, with a marginal increase in D-dimer (from 220.3 ± 67.1 to 245.2 ± 103.1, P= .053). AC-50% to AA (from 0.18 ± 0.12 to 0.54 ± 0.3, P< .001) and to ADP (from 1.5 ± 0.6 to 1.86 ± 0.3, P= .042) were reduced, paralleled by a significant reduction of MPV (from 9.92 ± 1.15 to 9.10 ± 1.23, P= .016).Conclusions:SH patients exhibit a prothrombotic status, which is reverted by a 6-month L-T4 treatment.

We studied the impact of vitamin D deficiency on subclinical atherosclerosis and found that it is associated with higher carotid intima-media thickness and increased prevalence of carotid plaques.

In this study, we evaluated the impact of obesity and/or overweight on the achievement of minimal disease activity (MDA) in patients with psoriatic arthritis (PsA) and patients with rheumatoid arthritis (RA) receiving an anti-rheumatic treatment. Obesity can be considered a low-grade, chronic systemic inflammatory disease and some studies suggested that obese patients with rheumatic diseases exhibit a lower rate of low disease activity achievement during treatment with anti-rheumatic drugs. A systematic search was performed in major electronic databases (PubMed, Web of Science, Scopus, Embase) to identify studies reporting MDA achievement in obese and/or overweight patients with RA or PsA and in normal-weight RA or PsA control subjects. Results were expressed as Odds Ratios (ORs) with pertinent 95% Confidence Intervals (95%CIs). We included 17 studies (10 on RA and 7 on PsA) comprising a total of 6693 patients (1562 with PsA and 5131 with RA) in the analysis. The MDA achievement rate was significantly lower in obese patients than in normal-weight subjects (OR 0.447, 95% CI 0.346–0.577, p< 0.001, I2= 62.6%, p< 0.001). Similarly, overweight patients showed a significantly lower prevalence of MDA achievement than normal-weight subjects (OR 0.867, 95% CI 0.757–0.994, p= 0.041, I2= 64%, p= 0.007). Interestingly, the effect of obesity on MDA was confirmed when we separately analyzed data on patients with RA and patients with PsA. In contrast, when we evaluated the effect of overweight, our results were confirmed for PsA but not for RA. A meta-regression analysis showed that follow-up duration, age, male sex, and treatment duration are covariates significantly affecting the effect of obesity/overweight on MDA achievement. The results of our meta-analysis suggest that obesity and overweight reduce the chances to achieve MDA in patients with rheumatic diseases receiving treatment with traditional or biologic disease-modifying antirheumatic drugs.

OBJECTIVE: To evaluate the prevalence of chronic autoimmune thyroiditis or Hashimoto’s thyroiditis (HT) in a group of patients with spondyloarthritis (SpA). METHODS: We evaluated serum levels of thyroid-stimulating hormone, free triiodothyronine, and free thyroxine, and titers of antithyroglobulin and antithyroid peroxidase (anti-TPO) antibodies in 357 consecutive patients with SpA. We also recruited 318 healthy age-matched controls. Ultrasonography of the thyroid gland was performed in all subjects and rheumatic activity was evaluated. RESULTS: Indices of thyroid autoimmunity were significantly more frequent in patients with SpA than in controls (24.09% vs 10.69%, respectively; p < 0.05). In the SpA group, a higher prevalence of HT was found in patients with an active disease than in those with low-moderate disease levels. Also in the SpA group, patients with a disease duration > 2 years had a higher prevalence of HT and anti-TPO antibodies positivity than patients with a disease duration ≤ 2 years. Ultrasonography detected a significantly higher frequency of thyroid nodules and hypoechoic pattern in patients with SpA than in controls. Among patients with SpA, HT and anti-TPO antibodies positivity were significantly more frequent in patients with peripheral involvement (68.6%) than in patients with axial involvement (31.4%; p < 0.05). CONCLUSION: Our study shows a significantly higher prevalence of thyroid autoimmunity in patients with SpA as compared to controls. Thyroiditis occurs more frequently in patients with longer disease duration and active rheumatic disease. We suggest that thyroid function tests be part of the clinical evaluation in patients with SpA.

Bacteria synthesize hundreds of bacteria-specific or “rare” sugars that are absent in mammalian cells and enriched in 6-deoxy monosaccharides such as l-rhamnose (l-Rha). Across bacteria, l-Rha is incorporated into glycans by rhamnosyltransferases (RTs) that couple nucleotide sugar substrates (donors) to target biomolecules (acceptors). Since l-Rha is required for the biosynthesis of bacterial glycans involved in survival or host infection, RTs represent potential antibiotic or antivirulence targets. However, purified RTs and their unique bacterial sugar substrates have been difficult to obtain. Here, we use synthetic nucleotide rare sugar and glycolipid analogs to examine substrate recognition by three RTs that produce cell envelope components in diverse species, including a known pathogen. We find that bacterial RTs prefer pyrimidine nucleotide-linked 6-deoxysugars, not those containing a C6-hydroxyl, as donors. While glycolipid acceptors must contain a lipid, isoprenoid chain length, and stereochemistry can vary. Based on these observations, we demonstrate that a 6-deoxysugar transition state analog inhibits an RT in vitroand reduces levels of RT-dependent O-antigen polysaccharides in Gram-negative cells. As O-antigens are virulence factors, bacteria-specific sugar transferase inhibition represents a novel strategy to prevent bacterial infections.

Bacterial glycomes are rich in prokaryote-specific or “rare” sugars that are absent in mammals. Like common sugars found across organisms, rare sugars are typically activated as nucleoside diphosphate sugars (NDP-sugars) by nucleotidyltransferases. In bacteria, the nucleotidyltransferase RmlA initiates the production of several rare NDP-sugars, which in turn regulate downstream glycan assembly through feedback inhibition of RmlA via binding to an allosteric site. In vitro, RmlA activates a range of common sugar-1-phosphates to produce NDP-sugars for biochemical and synthetic applications. However, our ability to probe bacterial glycan biosynthesis is hindered by limited chemoenzymatic access to rare NDP-sugars. We postulate that natural feedback mechanisms impact nucleotidyltransferase utility. Here, we use synthetic rare NDP-sugars to identify structural features required for regulation of RmlA from diverse bacterial species. We find that mutation of RmlA to eliminate allosteric binding of an abundant rare NDP-sugar facilitates the activation of noncanonical rare sugar-1-phosphate substrates, as products no longer affect turnover. In addition to promoting an understanding of nucleotidyltransferase regulation by metabolites, this work provides new routes to access rare sugar substrates for the study of important bacteria-specific glycan pathways.

Background/Objectives:: Several studies confirmed a significantly increased carotid intima-media thickness (IMT) and impaired flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) in obese subjects, but few data are available on the effects of bariatric surgery on these markers of cardiovascular (CV) risk. We performed a meta-analysis of studies evaluating changes in IMT, FMD and NMD in obese patients after bariatric surgery. Methods:: A systematic search was performed in the PubMed, Web of Science, Scopus and EMBASE databases without any language or publication year restriction. The last search was performed in January 2015. In addition, the reference lists of all retrieved articles were manually reviewed. Prospective studies evaluating the impact of bariatric surgery on the markers of CV risk were included. Changes in IMT, FMD and NMD after bariatric surgery were expressed as mean differences (MD) with pertinent 95% confidence intervals (95% CIs). IMT has been expressed in millimeters (mm); FMD and NMD as percentage (%). Impact of clinical and demographic features on effect size was assessed by meta-regression. Results:: Ten articles (314 obese patients) were included in the analysis. Six studies contained data on IMT (7 data sets; 206 patients), 8 studies on FMD (9 data sets; 269 patients) and 4 on NMD (4 data sets; 149 patients). After bariatric surgery, there was a significant reduction of IMT (MD: -0.17?mm; 95% CI: -0.290, -0.049; P=0.006) and a significant improvement in FMD (MD: 5.65%; 95% CI: 2.87, 8.03; P&lt;0.001), whereas NMD did not change (MD: 2.173%; 95% CI: -0.796, 5.142; P=0.151). Interestingly, percentage of changes in the body mass index were associated with changes in IMT (Z=11.52, P&lt;0.001), FMD (Z=-4.26, P&lt;0.001) and NMD (Z=-3.81, P&lt;0.001). Conclusions:: Despite heterogeneity among studies, bariatric surgery is associated with improvement of subclinical atherosclerosis and endothelial function. These effects may significantly contribute to the reduction of the CV risk after bariatric surgery.

Context:Idiopathic reactive hypoglycemia (IRH) is characterized by recurrent episodes of symptomatic hypoglycemia occurring within 4 hours after meals. The underlying mechanisms remain obscure.Objective:This study aimed to investigate the response of the glucoregulatory and gastrointestinal hormones to an oral glucose load (OGTT) in individuals with documented IRH.Design and Setting:This was a cross-sectional study composed of outpatients referred to “Federico II” University of Naples.Patients:We enrolled subjects with IRH documented by a mixed meal under ordinary life conditions and healthy subjects as controls.Main Outcome Measure:We measured plasma glucose, insulin, glucagon-like peptide 1 (GLP-1), GIP, and glucagon response to a 75-g OGTT in cases and controls.Results:Ten IRH and eight control subjects were enrolled. During the OGTT, mean plasma glucose tended to be lower in IRH than in control subjects, reaching a statistically significant difference at 240 minutes (T240) (43 ±1.6 vs 72 ± 0.3 mg/dL; P= .001). Accordingly, the insulin response was higher in IRH than in control subjects (P< .019) with a statistically significant difference (46%) at T90 (P= .045) and was associated with significantly lower glucagon levels in the late phase of the OGTT: at T120 (P= .031) and T180 (P= .048) in IRH than in control subjects. A greater GLP-1 response was found among IRH compared with control subjects (P= .005); GLP-1 peak was 2-fold higher in IRH individuals (9.77 ± 2.52 pmol/L) than in the control group (4.19 ± 0.53 pmol/L; P= .041). In the IRH group, GLP-1 peak inversely correlated with the nadir of plasma glucose (r = −0.66; P= .039). A multivariate analysis confirmed that GLP-1 peak independently predicted the plasma glucose nadir (β = −0.593; P= .026).Conclusions:GLP-1 may play a significant role in the pathogenesis of idiopathic IRH.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor derived from parafollicular cells. At present, surgery is the most important treatment for MTC. We describe the current approaches of MTC treatment (surgery, chemotherapy, radiation therapy, and biologic therapy). MTC is currently approached surgically in the main part through total thyroidectomy and compartment-oriented microdissection of cervicomediastinal lymph nodes. Substitutive l-thyroxine administration together with close clinical monitoring and the measurement of basal and stimulated serum calcitonin are subsequently performed. Radiotherapy and chemotherapy play a marginal role in advanced MTC. Recently, it has been found that somatostatin analogs and type I interferon are able to control the neuroendocrine symptoms induced by advanced MTC and that they provide clinical benefit by improving the lifestyle of these patients. Although these agents are poorly active in inducing a shrinkage in tumor mass, the combined use of different biologic agents and cytotoxic drugs needs to be explored in advanced MTC. However, at present, surgery is the only curative treatment for MTC. Cancer 2001;91:1797–808. © 2001 American Cancer Society.

Spondyloarthritis represents a heterogeneous group of articular inflammatory diseases that share common genetic, clinical and radiological features. The therapy target of spondyloarthritis relies mainly in improving patients’ quality of life, controlling articular inflammation, preventing the structural joints damage and preserving the functional abilities, autonomy and social participation of patients. Among these, traditional disease-modifying antirheumatic drugs have been demonstrated to be effective in the management of peripheral arthritis; moreover, in the last decade, biological therapies have improved the approach to spondyloarthritis. In patients with axial spondyloarthritis, tumor necrosis factor α inhibitors are currently the only effective therapy in patients for whom conventional therapy with nonsteroidal anti-inflammatory drugs has failed. The aim of this review is to summarize the current experience and evidence about the pharmacological approach in spondyloarthritis patients.

A artrite idiopática juvenil (AIJ) é a doença reumática mais frequente na infância. Sem terapia efetiva, os pacientes podem evoluir rapidamente para incapacidade funcional. Recentemente, a depleção dos linfócitos B surgiu como nova abordagem para o tratamento de doenças autoimunes, incluindo a AIJ.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. Without an effective therapy, patients may progress quickly to functional disability. Recently, depletion of B cells emerged as a new approach for the treatment of autoimmune diseases, including JIA.

Staphylococcus aureusis a Gram-positive pathogen with an unusual mode of cell division in that it divides in orthogonal rather than parallel planes. Through selection using moenomycin, an antibiotic proposed to target peptidoglycan glycosyltransferases (PGTs), we have generated resistant mutants containing a single point mutation in the active site of the PGT domain of an essential peptidoglycan (PG) biosynthetic enzyme, PBP2. Using cell free polymerization assays, we show that this mutation alters PGT activity so that much shorter PG chains are made. The same mutation in another S. aureusPGT, SgtB, has a similar effect on glycan chain length. Moenomycin-resistant S. aureusstrains containing mutated PGTs that make only short glycan polymers display major cell division defects, implicating PG chain length in determining bacterial cell morphology and division site placement.

Objective.To prospectively evaluate the effect of tumor necrosis factor (TNF)-α inhibitors on hemostatic and fibrinolytic variables in subjects with psoriatic arthritis (PsA).Methods.Among subjects with PsA who were taking traditional disease-modifying antirheumatic drugs (DMARD), 98 patients with active disease who switched to treatment with TNF-α inhibitors were enrolled in this study (Group 1). In parallel, 98 matched subjects with minimal disease activity (MDA) and treated with DMARD were enrolled (Group 2). In all patients, hemostatic and fibrinolytic variables were evaluated at enrollment and after a 6-month followup. Results were stratified according to treatment and to MDA achievement.Results.Seventy-six Group 1 and 80 Group 2 subjects completed the 6-month followup. During the followup, significant changes in hemostatic and fibrinolytic variables were found in Group 1, but not in Group 2 subjects. At the end of the followup, patients treated with TNF-α inhibitors showed significantly lower levels of hemostatic and fibrinolytic variables as compared to those treated with traditional DMARD. Among Group 1 subjects, changes in hemostatic and fibrinolytic variable levels were significantly higher in those who achieved MDA versus in those who did not. Multivariate analyses showed that a treatment with TNF-α blockers affected fibrinolytic variables [plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (t-PA)] and some acute-phase proteins (D-dimer, coagulation factor VIII, and von Willebrand factor). In contrast, the MDA achievement during treatment with TNF-α blockers maximally affected fibrinolytic variables (PAI-1 and t-PA).Conclusion.TNF-α inhibitors brought about a significant improvement of hemostatic and fibrinolytic balance in subjects with PsA. Maximal changes were found in patients achieving MDA.

Measurement of lead in breast milk is an important public health consideration and can be technically quite challenging. The reliable and accurate determination of trace lead in human breast milk is difficult for several reasons including: potential for contamination during sample collection, storage, and analysis; complexities related to the high fat content of human milk; and poor analytic sensitivity at low concentrations. Breast milk lead levels from previous published studies should therefore be reviewed with caution. Due to the difficulty in identifying a method that would successfully digest samples with 100% efficiency, we evaluated three different digestion procedures including: (1) dry ashing in a muffle furnace, (2) microwave oven digestion, and (3) digestion in high pressure asher. High temperature, high pressure asher digestion was selected as the procedure of choice for the breast milk samples. Trace lead analysis was performed using isotope dilution (ID) inductively coupled plasma mass spectrometry (ICP-MS). Measured lead concentrations in breast milk samples (n= 200) from Mexico ranged from 0.2 to 6.7 ng ml−1. The precision for these measurements ranged from 0.27–7.8% RSD. Use of strict contamination control techniques and of a very powerful digestion procedure, along with an ID-ICP-MS method for lead determination, enables us to measure trace lead levels as low as 0.2 ng ml−1in milk (instrument detection limit = 0.01 ng ml−1).

Lantibiotics are ribosomally synthesized and post-translationally modified peptide natural products that contain the thioether structures lanthionine and methyllanthionine and exert potent antimicrobial activity against Gram-positive bacteria. At present, detailed modes-of-action are only known for a small subset of family members. Lacticin 481, a tricyclic lantibiotic, contains a lipid II binding motif present in related compounds such as mersacidin and nukacin ISK-1. Here, we show that lacticin 481 inhibits PBP1b-catalyzed peptidoglycan formation. Furthermore, we show that changes in potency of analogues of lacticin 481 containing non-proteinogenic amino acids correlate positively with the potency of inhibition of the transglycosylase activity of PBP1b. Thus, lipid II is the likely target of lacticin 481, and use of non-proteinogenic amino acids resulted in stronger inhibition of the target. Additionally, we demonstrate that lacticin 481 does not form pores in the membranes of susceptible bacteria, a common mode-of-action of other lantibiotics.

OBJECTIVE: Little is known about tumor necrosis factor-α (TNF-α) blockers, disease activity, and liver steatosis (hepatic steatosis; HS) in subjects with psoriatic arthritis (PsA). We prospectively evaluated changes in HS during treatment with TNF-α blockers. METHODS: In 48 patients with PsA who had evidence of HS before the beginning of TNF-α blocker treatment, an ultrasound followup examination was performed after a 12-month treatment period with TNF-α blockers. All subjects were stratified according to minimal disease activity (MDA) or not (n-MDA), during treatment with TNF-α blockers. Changes in grade of HS were evaluated in parallel in 42 controls with HS and without PsA. RESULTS: At baseline, no significant difference in HS score was found between PsA subjects and controls (HS scores 1.46 ± 0.65 vs 1.62 ± 0.66, respectively; p = 0.249). At 12-month followup, a worsening HS score was found in 20 (41.7%) patients with PsA and in 6 (14.3%) controls (p = 0.005). Overall, the grade of HS worsening was higher in patients with PsA (0.37 ± 0.70) than in controls (0.09 ± 0.43; p = 0.028). A significantly lower prevalence of worsening HS was found among patients with PsA with MDA, compared with n-MDA subjects (16.7% vs 66.7%, respectively; p = 0.001). Laboratory measures of liver function behaved similarly. The risk of worsening HS in patients with PsA who had MDA was similar to that in controls (HR 1.20, 95% CI 0.34–4.33, p = 0.77), and higher in patients who did not have MDA (HR 4.46, 95% CI 1.73–11.47, p = 0.001, regression analysis). CONCLUSION: Compared with patients with MDA, those with active disease after 12-month treatment with TNF-α blockers exhibited significantly higher incidence of worsening liver steatosis.

Bacterial DnaK belongs to the Hsp70 chaperone family, which plays a critical role in maintaining proteostasis by catalyzing protein folding, and is a proposed antibacterial target in the pathogen Mycobacterium tuberculosis. Here, we describe an experimental toolbox for evaluating inhibitors against the mycobacterial DnaK chaperone network: a coupled-enzymatic assay to monitor ATPase activity, a proteolytic cleavage assay to study DnaK conformational changes upon ligand addition, as well as a protein renaturation assay to assess chaperone function.

To review and discuss the role of temporomandibular dysfunction (TMD) as a cause of chronic headaches and facial pain.

Background & aims: In underweight elderly subjects it is important to estimate body composition and particularly fat-free mass (FFM). Bioelectrical impedance analysis (BIA) is a non-invasive method in determining FFM, but its usefulness in these frail subjects should be verified. The aim of this study is to verify in underweight elderly people the reliability of previously published BIA formulas in detecting FFM.

This study investigated the incorporation of cis-9,trans-11 conjugated linoleic acid (c9,t11 CLA) and trans-10,cis-12-CLA (t10,c12 CLA) into plasma and peripheral blood mononuclear cell (PBMC) lipids when consumed as supplements highly enriched in these isomers. Healthy men (n = 49, age 31 ± 8 years) consumed one, two, and four capsules containing ∼600 mg of either c9,t11 CLA or t10,c12 CLA per capsule for sequential 8 week periods followed by a 6 week washout before consuming the alternative isomer. Both isomers were incorporated in a dose-dependent manner into plasma phosphatidylcholine (PC) (c9,t11 CLA r= 0.779, t10,c12 CLA r= 0.738; P< 0.0001) and cholesteryl ester (CE) (c9,t11 CLA r= 0.706, t10,c12 CLA r= 0.788; P< 0.0001). Only t10,c12 CLA was enriched in plasma nonesterified fatty acids. Both c9,t11 CLA and t10,c12 CLA were incorporated linearly into PBMC total lipids (r= 0.285 and r= 0.273, respectively; P< 0.0005). The highest concentrations of c9,t11 CLA and t10,c12 CLA in PBMC lipids were 3- to 4-fold lower than those in plasma PC and CE.

The aim of this study was to investigate the direct involvement of hyperinsulinaemia, DHEA and DHEA-S [DHEA(S)] in severe obesity in early carotid atherosclerosis, measured as intima-media thickness (IMT). Seventeen normotensive premenopausal women with very high BMI (43.5±1.6 kg/m2) were recruited for the study. Six women were also evaluated 12 months after laparoscopic adjustable silicone gastric banding (LASGB). Dietary intake, fasting plasma lipid profile, glycemic and insulinemic response to the OGTT, adrenal secretion, at baseline and after ACTH stimulation test, were measured. IMT, common carotid diameter (CD) and left ventricular mass index (LVMi) were measured by B-mode echotomography. All obese subjects showed higher fasting and stimulated insulin levels, but lower DHEA(S) levels than controls, showing a negative correlation between both fasting and stimulated insulin and DHEA(S), either at baseline or after ACTH testing. IMT was higher (p<0.05) than controls, with a positive correlation with stimulated insulin (p<0.05) and a strong negative correlation with DHEA(S) (p<0.001). In a multiple linear regression analysis, insulin response to OGTT maintained an association with DHEA(S) independent of fasting insulin, while DHEA maintained the association with IMT independent of stimulated insulin (p<0.0001). In the six patients evaluated 12 months after LASGB, fasting insulin levels decreased, while DHEA(S) levels increased (p<0.05). In conclusion, an early cardiovascular involvement was detected in this group of severe obese with hyperinsulinaemia and low DHEA(S), even in the absence of other well known CVD risk factors.

OBJECTIVE: Despite the increasing evidence that primary hyperparathyroidism (PHPT) contributes to greater risk of cardiovascular morbidity and mortality, its exact role in the development of cardiovascular changes and its clinical significance are still controversial. Given the multiple influence of PHPT on the cardiovascular system, this study aimed to assess the effects of PHPT on blood pressure profile, and on features of the heart and arterial vessels in normotensive symptomless patients. DESIGN: Twenty patients (8 males and 12 females) with a median age of 51.5 years (range 44 to 65 years) were evaluated and the results were compared with those of 20 controls matched for age, gender and body mass index. Patients' parathyroid hormone levels ranged from 172 to 454 pg/ml and Ca levels ranged from 11.4 to 13.5 mg/dl. Fasting levels of glucose, insulin, total and high density lipoprotein cholesterol and triglycerides were within the normal range in all subjects recruited. METHODS: Twenty-four-hour blood pressure profile, left ventricle (LV) dimension and carotid artery anatomy were investigated, the latter two by ultrasonography. RESULTS: No difference was found between the patients and controls in blood pressure profile, when the following parameters were considered: supine systolic/diastolic pressure, average 24-h systolic, diastolic and mean arterial pressure, day-time mean arterial pressure and fall in nocturnal blood pressure (-17% and -18% respectively). Heart rate and all parameters of LV mass were similar in patients and controls. The only alteration found in patients was in significantly greater carotid intimal-medial thickness (IMT) (P<0.001). Atherosclerotic plaques were more frequent in patients than in controls, with a difference reaching a trend (40% vs 10%, chi(2)=4.8; P=0.091). Considering that the carotid IMT is considered to be a marker of systemic atherosclerosis, our finding suggests early atherosclerotic changes in PHPT. No correlation was found between the severity and cardiovascular manifestation of PHPT. CONCLUSIONS: Vascular changes may occur due to a combination of structural and functional impairments in PHPT patients, likely as a result of altered calcium metabolism and impaired equilibrium of other factors regulating vascular function. Both extent and duration of PHPT can play a relative role in the development of cardiovascular complications. Considering that PHPT is now recognized as a quite common and often symptomless endocrine disorder, the evidence of cardiovascular manifestation in normotensive patients, found by this morphological study, suggests a possible implication for the management of such patients. In this light, screening for abnormalities in cardiovascular system function should be recommended in all PHPT subjects.

OBJECTIVE: Despite the increasing evidence that primary hyperparathyroidism (PHPT) contributes to greater risk of cardiovascular morbidity and mortality, its exact role in the development of cardiovascular changes and its clinical significance are still controversial. Given the multiple influence of PHPT on the cardiovascular system, this study aimed to assess the effects of PHPT on blood pressure profile, and on features of the heart and arterial vessels in normotensive symptomless patients. DESIGN: Twenty patients (8 males and 12 females) with a median age of 51.5 years (range 44 to 65 years) were evaluated and the results were compared with those of 20 controls matched for age, gender and body mass index. Patients' parathyroid hormone levels ranged from 172 to 454 pg/ml and Ca levels ranged from 11.4 to 13.5 mg/dl. Fasting levels of glucose, insulin, total and high density lipoprotein cholesterol and triglycerides were within the normal range in all subjects recruited. METHODS: Twenty-four-hour blood pressure profile, left ventricle (LV) dimension and carotid artery anatomy were investigated, the latter two by ultrasonography. RESULTS: No difference was found between the patients and controls in blood pressure profile, when the following parameters were considered: supine systolic/diastolic pressure, average 24-h systolic, diastolic and mean arterial pressure, day-time mean arterial pressure and fall in nocturnal blood pressure (-17% and -18% respectively). Heart rate and all parameters of LV mass were similar in patients and controls. The only alteration found in patients was in significantly greater carotid intimal-medial thickness (IMT) (P<0.001). Atherosclerotic plaques were more frequent in patients than in controls, with a difference reaching a trend (40% vs 10%, chi(2)=4.8; P=0.091). Considering that the carotid IMT is considered to be a marker of systemic atherosclerosis, our finding suggests early atherosclerotic changes in PHPT. No correlation was found between the severity and cardiovascular manifestation of PHPT. CONCLUSIONS: Vascular changes may occur due to a combination of structural and functional impairments in PHPT patients, likely as a result of altered calcium metabolism and impaired equilibrium of other factors regulating vascular function. Both extent and duration of PHPT can play a relative role in the development of cardiovascular complications. Considering that PHPT is now recognized as a quite common and often symptomless endocrine disorder, the evidence of cardiovascular manifestation in normotensive patients, found by this morphological study, suggests a possible implication for the management of such patients. In this light, screening for abnormalities in cardiovascular system function should be recommended in all PHPT subjects.

We present a prospective study on the long-term efficacy of percutaneous ethanol injection (PEI) treatment of a large series of symptomatic thyroid cystic nodules (STCN). Ninety-eight patients (72 females and 26 males) were treated. The mean basal volume of the STCN was 35.3 mL. In 92 of 98 patients PEI treatment induced a greater than 50% nodule shrinkage, only 6 of 92 responder patients relapsed at a follow-up of 9 years. Moreover, all the patients had a significant clinical benefit because a significant reduction of the cyst-associated symptoms was recorded. Furthermore, a limited number of sessions was required for the treatment of cysts larger than 40mL (mean ± standard deviation [SD]:2.7 ± 0.75) demonstrating the feasibility of the procedure also in the treatment of large cysts. In conclusion, PEI is an effective and inexpensive procedure with a high patient compliance and long-lasting effects in the treatment of cysts larger than 40mL.

Changes in the metabolism of nutrients by the portal-drained viscera (PDV) and liver may contribute to the reduction in dry matter intake (DMI) and other production responses generally observed in lactating dairy cows fed supplemental long-chain fatty acids (LCFA). In the present study, effects of a 7-d abomasal infusion of vegetable oil on arterial concentration and splanchnic (PDV and liver) metabolism of nutrients were measured in six cows at 55 (early lactation [ELAC]) and 111 (midlactation [MLAC]) d postpartum. Cows were fed for ad libitum DMI at 8-h intervals, and blood samples for measurement of splanchnic metabolism were obtained over 8h beginning 2h before feeding at 0830h. Blood flow for the PDV and liver was increased by oil infusion and was greater in ELAC, despite similar-feed DMI during blood sampling. Increased blood flow in ELAC was associated with greater liver oxygen removal and glucose release that accompanied greater milk yield. In contrast, oil infusion had no effect on splanchnic oxygen use. Greater blood flow during oil infusion may have been due to specific effects of intestinal LCFA supply on PDV blood flow. Net PDV release and liver removal of branched-chain volatile fatty acids (VFA) and ammonia were increased by oil infusion. Net PDV release of longer-chain (4 and 5C) VFA and NEFA was greater in ELAC, but net PDV flux of other nutrients was not affected by lactation stage, possibly due to the similarity of feed DMI. Oil infusion increased arterial concentration and net PDV release and liver removal of NEFA, and it decreased net liver release and arterial concentration of glucose. Effects of oil infusion on liver glucose release were associated with decreased daily DMI. In ELAC, arterial concentration and net liver removal of NEFA were also increased, but liver release of glucose was greater than in MLAC. Oil infusion and ELAC both increased net liver removal of l-lactate. The resulting decrease in net total splanchnic release of l-lactate in ELAC reflects decreased tissue energy balance of the cows. Generally, stage of lactation and relative milk yield had greater effects on metabolism of the liver than the PDV, in which metabolism was largely dictated by DMI. In the present study, there was little evidence to suggest an effect of stage of lactation on the metabolic response of the PDV and liver to postruminal LCFA supply.

OBJECTIVE: To characterize cardiac structure and function and cardiac autonomic control in patients with subclinical and overt hyperthyroidism. DESIGN: Thirty patients with subclinical hyperthyroidism and 30 with overt disease were selected from patients never previously treated for endocrinological disease in the outpatient clinic of our institution. Twenty normal individuals were studied as control group. METHODS: Left ventricular structure and function and cardiac autonomic control were evaluated, respectively, by two-dimensional Doppler echocardiography and by 24-h Holter recording with heart rate variability analysis. RESULTS: Patients with overt hyperthyroidism showed greater values of left ventricular end-diastolic volume (P<0.05) and left ventricular mass (P<0.05) than patients with subclinical disease. In addition, the mean velocity of left ventricular fibre shortening (P<0.05) and left ventricular ejection fraction (P<0.05) were greater in patients with overt hyperthyroidism than in patients with subclinical disease. No difference in any of these parameters was detectable between normal subjects and patients with subclinical disease. The isovolumic relaxation period was shorter in patients with subclinical hyperthyroidism than in control individuals (P<0.05) and in patients with overt hyperthyroidism (P<0.05). As regards cardiac autonomic control, all time and frequency domain measures decreased progressively from control individuals to patients with subclinical hyperthyroidism and those with overt disease (P<0.001). CONCLUSIONS: Thyrotoxic patients show changes in left ventricular structure and increased echocardiographic indexes of myocardial contractility, whereas the only echocardiographic feature detectable in patients with subclinical hyperthyroidism is an increased velocity of left ventricular relaxation. Cardiac parasympathetic withdrawal is evident in patients with overt hyperthyroidism and in patients with subclinical disease.

AIM: Autonomous thyroid nodules are conventionally treated by surgery or radioiodine. Percutaneous ethanol injection is a recognized alternative approach. An assessment of the long-term success and safety was conducted. MATERIALS AND METHODS: Thirty-four patients (seven men and 27 women; age range: 32–80 years; mean: 56±13 years) with an autonomous thyroid nodule (ATN)>40ml (volume range 41–180ml; mean: 63.6±34.5ml) were treated with ultrasound-guided percutaneous ethanol injection (PEI). All patients were hyperthyroid with increased radionuclide uptake in the nodule at scintigraphy. Serial serum (free T3, free T4 and thyroid-stimulating hormone (TSH)) and ultrasound studies were performed at 3, 6, 12, 18, 24 and 36 months after the first PEI session. Scintigraphy was performed before treatment and 1 month after the serum TSH became detectable or alternatively after 6 months, even if the TSH was still undetectable. RESULTS: Each patient had 1–11 sessions of PEI, with an injection of 3–14ml of ethanol per session (total amount of ethanol per patient: 20–125ml). Within 3 months from the end of the treatment, the recovery of extranodular uptake on isotope scan and the normalization of TSH levels were observed in 30/34 patients. A reduction (average: 62.9%) of nodule volume was recorded in all patients and only 4/34 patients were refractory to PEI. The responsiveness of ATN to PEI appeared to be dependent on the initial nodule volume (3/4 failures in patients had nodule volumes>60ml). Side-effects were always self-limiting. During follow-up (6–36 months) no recurrence was observed. CONCLUSION: In conclusion, the treatment of ATN>40ml with PEI would appear to be a valid alternative approach to traditional methods of treatment. It is safe, well tolerated and inexpensive. Its acceptability when compared with surgery and radiodioine has still to be assessed. Del Prete, S.et al. (2001). Clinical Radiology56, 895–901.