Circulating microRNAs in extracellular vesicles as potential biomarkers for psoriatic arthritis in patients with psoriasis.

BACKGROUND: Psoriatic arthritis (PsA) develops in ~30% of patients with psoriasis. The diagnosis of PsA is challenging, and there are no reliable molecular markers in clinical use. MicroRNAs are short non-coding regulatory RNAs, which can be actively packaged into extracellular vesicles (EVs) and secreted to the circulation. OBJECTIVES: To explore whether plasma-derived EV microRNAs may serve as biomarkers for PsA in patients with psoriasis. METHODS: Plasma samples were obtained from patients with cutaneous-only psoriasis (PsC) and patients with psoriasis and PsA. Plasma EVs were isolated using miRCURY™ Exosome Isolation Kit. RNA sequencing was used to identify differentially expressed EV miRNAs in the discovery phase (PsC, n = 15; PsA, n = 14). In the validation phase (PsC, n = 29; PsA, n = 28), 41 selected miRNAs were analysed in plasma EVs by qPCR. The association of the identified miRNAs with PsA was assessed by logistic regression analysis. RESULTS: RNA sequencing identified 19 plasma EV miRNAs with significantly different levels between PsA and PsC in the discovery cohort. Significantly lower levels of plasma EV let-7b-5p and miR-30e-5p in PsA vs. PsC were confirmed in the validation cohort, and their decreased levels were found to be associated with the presence of PsA. ROC analysis revealed an AUC of 0.68 (95% CI 0.53-0.83) for let-7b-5p and 0.69 (95% CI 0.55-0.84) for miR-30e-5p. CONCLUSIONS: Circulating EV microRNA levels are altered in patients with PsA as compared with PsC. Findings of this exploratory study suggest that circulating EV microRNAs may serve as biomarkers for arthritis in psoriasis patients.

Quantitative resonant soft x-ray reflectivity from an organic semiconductor single crystal.

Resonant soft X-ray reflectivity at the carbon K-edge was applied to a trigonal tetracene single crystal. The angular resolved reflectivity was quantitatively simulated describing the tetracene crystal in terms of its dielectric tensor, which was derived from the anisotropic absorption cross section of the single molecule, as calculated by density functional theory. A good agreement was found between the experimental and theoretically predicted reflectivity. This allows us to assess the anisotropic optical constants of the organic material, probed at the carbon K-edge, in relation to the bulk/surface structural and electronic properties of the crystal, through empty energy levels.

Quantitative resonant soft x-ray reflectivity of ultrathin anisotropic organic layers: Simulation and experiment of PTCDA on Au.

Resonant soft X-ray reflectivity at the carbon K edge, with linearly polarized light, was used to derive quantitative information of film morphology, molecular arrangement, and electronic orbital anisotropies of an ultrathin 3,4,9,10-perylene tetracarboxylic dianhydride (PTCDA) film on Au(111). The experimental spectra were simulated by computing the propagation of the electromagnetic field in a trilayer system (vacuum/PTCDA/Au), where the organic film was treated as an anisotropic medium. Optical constants were derived from the calculated (through density functional theory) absorption cross sections of the single molecule along the three principal molecular axes. These were used to construct the dielectric tensor of the film, assuming the molecules to be lying flat with respect to the substrate and with a herringbone arrangement parallel to the substrate plane. Resonant soft X-ray reflectivity proved to be extremely sensitive to film thickness, down to the single molecular layer. The best agreement between simulation and experiment was found for a film of 1.6 nm, with flat laying configuration of the molecules. The high sensitivity to experimental geometries in terms of beam incidence and light polarization was also clarified through simulations. The optical anisotropies of the organic film were experimentally determined and through the comparison with calculations, it was possible to relate them to the orbital symmetry of the empty electronic states.

Growth dynamics of L-cysteine SAMs on single-crystal gold surfaces: a metastable deexcitation spectroscopy study.

We report on a metastable deexcitation spectroscopy investigation of the growth of L-cysteine layers deposited under UHV conditions on well-defined Au(110)- (1 × 2) and Au(111) surfaces. The interaction of He(*) with molecular orbitals gave rise to well-defined UPS-like Penning spectra which provided information on the SAM assembly dynamics and adsorption configurations. Penning spectra have been interpreted through comparison with molecular orbital DFT calculations of the free molecule and have been compared with XPS results of previous works. Regarding adsorption of first-layer molecules at room temperature (RT), two different growth regimes were observed. On Au(110), the absence of spectral features related to orbitals associated with SH groups indicated the formation of a compact SAM of thiolate molecules. On Au(111), the data demonstrated the simultaneous presence, since the early stages of growth, of strongly and weakly bound molecules, the latter showing intact SH groups. The different growth mode was tentatively assigned to the added rows of the reconstructed Au(110) surface which behave as extended defects effectively promoting the formation of the S-Au bond. The growth of the second molecular layer was instead observed to proceed similarly for both substrates. Second-layer molecules preferably adopt an adsorption configuration in which the SH group protrudes into the vacuum side.

Long-term follow-up of 106 multiple sclerosis patients undergoing interferon-beta 1a or 1b therapy: predictive factors of thyroid disease development and duration.

BACKGROUND: Conflicting data have been reported on the association between interferon (IFN)-beta therapy of multiple sclerosis (MS) patients and thyroid disease development. AIMS: The goals of this study are as follows: to assess the actual occurrence of thyroid dysfunction and autoimmunity during long-term IFN-beta therapy; to establish the possible presence of predictive factors for thyroid dysfunction development and duration; and to suggest an effective follow-up protocol for patients receiving long-term IFN-beta therapy. STUDY PROTOCOL: A total of 106 MS patients (76 women) underwent IFN-beta 1a or 1b therapy for up to 84 months (median, 42 months). Thyroid function and autoimmunity were assessed at baseline and every 3-6 months throughout the treatment course. RESULTS: Baseline thyroid autoimmunity was detected in 8.5% of patients and hypothyroidism in 2.8%. Thyroid dysfunction (80% hypothyroidism, 92% subclinical, 56% transient) developed in 24% (68% with autoimmunity) of patients and autoimmunity in 22.7% (45.5% with dysfunction), without significant differences between the two cytokines; 68% of dysfunctions occurred within the first year. Autoimmunity emerged as the only predictive factor for dysfunction development (relative risk, 8.9), whereas sustained disease was significantly associated with male gender (P < 0.003). CONCLUSIONS: Both incident thyroid autoimmunity and dysfunction frequently occur in MS patients during IFN-beta therapy, particularly within the first year of treatment. Thyroid dysfunction is generally subclinical and transient in over than half of cases; preexisting or incident autoimmunity emerged as the only significant predictive factor for thyroid dysfunction development. Thyroid function and autoimmunity assessment is mandatory within the first year of IFN-beta therapy; thereafter, serum TSH measurement only in patients with thyroid disease could be sufficient.

Facioscapulohumeral muscular dystrophy type 1A in northwestern Tuscany: a molecular genetics-based epidemiological and genotype-phenotype study.

Facioscapulohumeral muscular dystrophy type 1A (FSHD1A) is an autosomal dominant inherited disorder characterized by early involvement of facial and scapular muscles with eventual spreading to pelvic and lower limb muscles. A high degree of clinical variability with respect to age at onset, severity, and pattern of muscle involvement, both between and within families, is present. For this reason, diagnosis of FSHD1A can be sometimes difficult and molecular diagnosis is then necessary. A clinical and molecular genetic-based epidemiological investigation has been carried out in the territory of northwestern Tuscany in central Italy to calculate the prevalence rate of FSHD1A as of March, 2004. The molecular diagnosis has been based on the detection of large deletions of variable size of kpnI repeat units on chromosome 4q35. Results have been compared to those of a previous study conducted in the same area in 1981 (in the premolecular diagnosis era). The minimum prevalence rate was 4.60 x 10(-5) inhabitants, a value four times higher compared to our previous study. No significant correlation between fragment size and clinical severity has been observed. This study confirms in an Italian population a prevalence rate of FSHD1A similar to that observed in other populations. Furthermore, it underlines the usefulness of routine adoption of the genetic testing in confirming clinical suspicion of FSHD1A as well as in correctly diagnosing atypical and otherwise misclassified cases.

Vitrectomy and Whipple's disease.

We diagnosed Whipple's disease from the vitreous aspirate of two patients who underwent vitrectomies . In one case, the vitrectomy specimen would have indicated the diagnosis three years before the jejunal biopsy was performed had the appropriate PAS stain been used. In the second case, the PAS-positive macrophages were identified at the time of surgery.

Neurophysiological evaluation of vigilance in epileptic patients on monotherapy with lamotrigine.

OBJECTIVE: Limited research has focused to date on daytime sleepiness in epileptic patients treated with either conventional or newer antiepileptic drugs. We evaluated the level of vigilance in 15 consecutive, newly diagnosed and never medicated adult epileptic patients, receiving initial monotherapy with lamotrigine (LTG). METHODS: Patients underwent the Multiple Sleep Latency Test (MSLT), visual reaction times (VRT) and Stanford Sleepiness Scale (SSS) on two separate occasions, i.e. before and 2 months after LTG treatment. A group of 15 age-matched healthy volunteers was taken as control. RESULTS: At baseline, mean sleep latencies on the MSLT were comparable in epileptic patients and in controls. In patients, 2 months after monotherapy with LTG 200 mg/day, MSLT scores did not significantly change as compared with pre-treatment values. Accordingly, subjective evaluation of vigilance by the SSS and psychomotor performance by VRT were superimposable in controls and in untreated patients, and did not change in patients after LTG treatment. CONCLUSIONS: These results suggest that in adult, newly diagnosed epileptic patients initial monotherapy with LTG does not impair vigilance.

Impaired oxidative metabolism in exercising muscle from ALS patients.

The pathogenic mechanism of selective loss of motor neurones in amyotrophic lateral sclerosis (ALS) is still poorly understood. Recently, research evidence has suggested that mitochondrial dysfunction occurs in central nervous system as well as in peripheral tissues from ALS patients. The aim of our study was to indirectly investigate in vivo oxidative metabolism of exercising muscle in a case history of patients affected by ALS. To this purpose 11 patients, 8 male and 3 female, mean age+/-SD: 52.4+/-11.1 years, performed a bicycle incremental test for the assessment of lactate production. At rest, there was increased lactate concentration in patients: 2.77+/-0.79 vs. 1.48+/-0.49 mmol/l in normal controls (normal range: 0.67-2.47 mmol/l). Analysis of lactate curve during exercise showed a lactate production increase compared to controls. Furthermore, anaerobic lactate threshold was detected at 40-50% of the predicted normal power output, anticipated with respect to both normal subjects and non-ALS chronically denervated controls with comparable motor impairment (60-70%), suggesting that mitochondrial dysfunction can occur in exercising skeletal muscle from ALS patients.

Gastric emptying in myotonic dystrophic patients.

BACKGROUND: Myotonic dystrophy is often associated with digestive symptoms that can precede the clinical appearance of skeletal muscle involvement. Although motility disorders may be observed in these patients at any level of the gastrointestinal tract, upper gastrointestinal symptoms have up to now usually been considered to be due to oesophageal rather than gastric dysmotility. AIMS: To evaluate: a) gastric emptying in myotonic dystrophic patients without dyspeptic symptoms, and b) relationship between gastric emptying and severity and duration of the disease. PATIENTS AND METHODS: Gastric emptying was evaluated in 11 non-dyspeptic dystrophic patients and in 22 healthy volunteers by means of computerised ultrasound scan, assessing the variation in the antral area over time after ingestion of a meal. RESULTS: The final emptying time was higher in patients than in healthy volunteers (373' +/- 35' vs 270' +/- 47'; p < 0.001). Basal and maximal post-prandial antral areas were similar in the two groups. There was a significant correlation between gastric emptying and the duration of the disease (rs = 0.62; p = 0.04). No relationship was found between gastric emptying and severity of the disease. CONCLUSIONS: Gastric emptying may be abnormally delayed in myotonic dystrophy patients, even in absence of dyspeptic symptoms. This delay is correlated with duration but not with severity of the disease. However there is no difference in either basal or maximal postprandial antral areas between myotonic dystrophy patients and healthy volunteers.

The relationship between probing attachment loss and computerized radiographic analysis in monitoring progression of periodontitis.

This study attempted to evaluate quantitative changes in radiographic density as an indicator of progression of periodontitis. Twenty-one subjects with a history of periodontitis were monitored at baseline, 3, 6, and 9 months using duplicate probing attachment level (PAL) measurements from stents and computer assisted densitometric image analysis (CADIA) of standardized radiographs. Results indicate that the majority of sites exhibited no PAL change during the 9-month period; however, the percentage of sites with loss increased with time. A mean of 6.1% of the sites/patient exhibited probing attachment loss during the study, as compared to a mean of 38.3% of the sites/patient that exhibited a loss of radiographic density. Due to the two dimensional nature of radiographs, density analysis was calculated in terms of radiographic "complexes" of multiple probing sites. There was significantly more density loss at complexes with greater than or equal to 2 mm of attachment loss than at sites with no change in PAL at 9 months; there was no such difference noted at 3 and 6 months. Also, density loss tended to increase as more sites within each complex experienced PAL. Although there was a significant correlation between mean density and PAL changes during the same time interval, there were wide variations at individual sites. This study suggests that there is a complex relationship between density change on radiographs and PAL change. The difficulties inherent in comparing highly sensitive new technologies to relatively imprecise clinical measurements of the attachment level are discussed.(ABSTRACT TRUNCATED AT 250 WORDS)

[Reconstructive and non-reconstructive procedures in the treatment of the threatened limb]. / Procedure ricostruttive e non ricostruttive nel trattamento dell'arto critico.

Limb threatening ischemia is an acute step in the chronic course of peripheral arterial obstructive disease that requires some form of intervention. The objective of this study is to prove that reconstructive surgery as well as non reconstructive approaches are associated with positive results. Ours is a retrospective analysis of a ten year experience in the treatment of limb threatening ischemia. In the period 1983-93, 139 patients under-went 164 procedures. 67% of patients were diabetics. Early in the observation period the therapeutic strategy was non reconstructive, the procedure of choice was sympathectomy. Later vascular reconstructions have been recognized as the procedures of choice. In the cases not amenable to reconstructive procedures according to our group criteria (absence of a tibial vessel in continuity with a patent pedal arch), we have employed procedures such as prostanoid infusion; thrombolysis and epidural spinal cord stimulation. Reconstructive procedures have been associated with a decrease in the number of major amputations. Alternative procedures, employed in patients not amenable to reconstruction have proven worthwhile in terms of limb salvage even if this trend is limited to a short period of observation.

Effects of intrauterine growth and gestational age upon infants' early psychomotor development in Brazil.

In a sample of 245 Brazilian infants, the effects of intrauterine growth and gestational age upon psychomotor development were studied through ages 4 to 18 mo. Gestational age was more important than intrauterine growth in determining psychomotor development in the first 18 mo. of life. Intrauterine growth had a significant but smaller and more stable effect than gestational age upon psychomotor development at all ages. Maternal parity, interval between the birth of the child studied and the next oldest sibling, 5-min. Apgar score, and socioeconomic status were also relevant to psychomotor development at these early ages.

Is motor development really more advanced in Third World infants?

Motor and adaptive development were studied longitudinally at 4, 8, 12, and 18 mo. in Brazilian infants of low and middle socioeconomic status. No significant differences were found between these two groups. Gesell Developmental Quotients were similar to those found in American infants, which did not confirm precocious motor development in Brazilian infants.

Psychometric properties of the Brazilian Health Locus of Control Scale.

Based on social learning theory, the construct of health locus of control has proven valuable in predicting a wide variety of health-related behaviors. In studying this concept among Brazilians, the psychometric properties of the Multidimensional Health Locus of Control Scale translated into Brazilian Portuguese were investigated in a sample of 280 middle-class persons. Three types of health locus of control were verified, internal, powerful others, and chance. Further refinement of subscales is needed to improve internal consistency reliabilities.

Lipid profile of nutrition students and its association with cardiovascular disease risk factors.

OBJECTIVE: To describe the lipid profile and to verify its relationship with cardiovascular disease risk factors in students at a public university in São Paulo. METHODS: After obtaining clinical, anthropomorphic, and lipid profile data from 118 students, variables of the lipid profile were related to other risk factors. RESULTS: The mean age of the students was 20.3 years (SD = 1.5). The risk of cardiovascular disease was characterized by a positive family history of ischemic heart disease in 38.9%; sedentariness in 35.6%; limiting and increased total and LDL-C cholesterol levels in 17.7% and 10.2%, respectively; decreased HDL-C levels in 11.1%; increased triglyceride levels in 11.1%; body mass index > 25 in 8.5%, and smoking in 6.7% of the subjects. Students' diet was found to be inadequate regarding protein, total fat, saturated fat, sodium, and fiber contents. A statistically significant association between cholesterol and contraceptive use, between HDL-C and contraceptive use, age and percent body fat, and triglycerides and percent lean weight was observed. CONCLUSION: A high prevalence of some risk factors of cardiovascular disease as well as the association between these factors with altered lipid profiles was observed in the young population studied.

Proximity effects and exchange bias in Co/MnF2(111) heterostructures studied by x-ray magnetic circular dichroism.

Cobalt nano-structured ultrathin films were grown on orthorhombic MnF(2) by molecular beam epitaxy on CaF(2) epitaxial layers deposited on Si(111) substrates. The Co film was grown at room temperature. It was found to be polycrystalline, forming nano-islands with height≈diameter≤10 nm. X-ray absorption evidences the chemical stability of the Co/MnF(2) interface. Remarkably, x-ray magnetic circular dichroism (XMCD) demonstrates that the Co induces a net magnetization on the Mn ions close to the interface. The magnetic moments of these Mn ions couple antiparallel to the Co and rotate upon field reversal following the magnetization of the Co both below and high above the Néel temperature of MnF(2) (T(N) = 67 K). The density of coupled Mn moments is found to be temperature dependent, with an equivalent thickness of ~1.5 MnF(2) monolayers at 20 K, decreasing to about ~0.5 ML as the temperature is raised to 300 K. Interestingly, the intensity of the Mn XMCD signal appears to be related to the coercivity of the Co layer. This behavior is interpreted in terms of the competition between thermal fluctuations, exchange coupling between Co and Mn at the interface and, at low temperature, the antiferromagnetic order in MnF(2).

Parallel manifestations of neuropathologies in the enteric and central nervous systems.

BACKGROUND: Neurodegenerative diseases may extend outside the central nervous system (CNS) and involve the gastrointestinal (GI) tract. The gut would appear to be a pathological marker for neurodegeneration, as well as a site for studying the pathophysiology of neurodegeneration. In fact, both in the ENS and CNS, misfolded proteins are likely to initiate a process of neurodegeneration. For example, the very same protein aggregates can be detected both in the ENS and CNS. In both systems, misfolded proteins are likely to share common cell-to-cell diffusion mechanisms, which may occur through a parallel prion-like diffusion process. Independently from the enteric or central origin, misfolded proteins may proceed along the following steps, they: (i) form aggregates; (ii) are expressed on plasma membrane; (iii) are secreted extracellularly; (iv) are glycated to form advanced glycation end-products (AGEs); (v) are internalized through specific receptors placed on neighboring cells (RAGEs); (vi) are cleared by autophagy; and (vii) are neurotoxic. These features are common for a-synuclein (in Parkinson's disease and other synucleinopathies), ß-amyloid and tau (in degenerative dementia), SOD-1 and TDP43 (in amyotrophic lateral sclerosis), and PrPsc (in prion diseases). While in some diseases these features are common to both ENS and CNS, in others this remains a working hypothesis. PURPOSE: This review analyzes GI alterations from a pathological perspective to assess whether the enteric nervous system (ENS) mirrors the neuropathology described in the CNS. We discuss the potential mechanisms that lead to the onset and spread of neurodegeneration within the gut, from the gut to the brain, and vice versa.

Atomic and electronic structure of ultrathin fluoride barrier layers at the oxide/Si interface.

A SrF(2) ultrathin barrier layer on Si(001) is used to form a sharp interface and block reactivity and intermixing between the semiconductor and a Yb(2)O(3) overlayer. Yb(2)O(3)/Si(001) and Yb(2)O(3)/SrF(2)/Si(001) interfaces grown in ultra high vacuum by molecular beam epitaxy are studied by photoemission and x-ray absorption fine structure. Without the fluoride interlayer, Yb(2)O(3)/Si(001) presents an interface reacted region formed by SiO(x) and/or silicate compounds, which is about 9 Å thick and increases up to 14-15 Å after annealing at 500-700 °C. A uniform single layer of SrF(2) molecules blocks intermixing and reduces the oxidized Si region to 2.4 Å after deposition and to 3.5 Å after annealing at 500 °C. In both cases we estimate a conduction band offset and a valence band offset of ∼ 1.7 eV and 2.4 eV between the oxide and Si, respectively. X-ray absorption fine structure measurements at the Yb L(III) edge suggest that the Yb oxide films exhibit a significant degree of static disorder with and without the fluoride barrier. Sr K edge measurements indicate that the ultrathin fluoride films are reacted, with the formation of bonds between Si and Sr; the Sr-Sr and Sr-F interatomic distances in the ultrathin fluoride barrier film are relaxed to the bulk value.

Clinical trials for neuroprotection in ALS.

Owing to uncertainty on the pathogenic mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) riluzole remains the only available therapy, with only marginal effects on disease survival. Here we review some of the recent advances in the search for disease-modifying drugs for ALS based on their putative neuroprotective effetcs. A number of more or less established agents have recently been investigated also in ALS for their potential role in neuroprotection and relying on antiglutamatergic, antioxidant or antiapoptotic strategies. Among them Talampanel, beta-lactam antibiotics, Coenzyme Q10, and minocycline have been investigated. Progress has also been made in exploiting growth factors for the treatment of ALS, partly due to advances in developing effective delivery systems to the central nervous system. A number of new therapies have also been identified, including a novel class of compounds, such as heat-shock protein co-inducers, which upregulate cell stress responses, and agents promoting autophagy and mitochondriogenesis, such as lithium and rapamycin. More recently, alterations of mRNA processing were described as a pathogenic mechanism in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations. This knowledge is expected to improve our understanding of the pathogenetic mechanism in ALS and developing more effective therapies.