Stereochemical features of the envelope protein Domain III of dengue virus reveals putative antigenic site in the five-fold symmetry axis.

We bring to attention a characteristic parasitic pattern present in the dengue virus: it undergoes several intensive thermodynamic variations due to host environmental changes, from a vector's digestive tract, through the human bloodstream and intracellular medium. Comparatively, among the known dengue serotypes, we evaluate the effects that these medium variations may induce to the overall structural characteristics of the Domain III of the envelope (E) protein, checking for stereochemical congruences that could lead to the identification of immunologic relevant regions. We used molecular dynamics and principal component analysis to study the protein in solution, for all four dengue serotypes, under distinct pH and temperature. We stated that, while the core of Domain III is remarkably rigid and effectively unaffected by most of the mentioned intensive variations, the loops account for major and distinguishable flexibilities. Therefore, the rigidity of the Domain III core provides a foothold that projects specifically two of these high flexible loop regions towards the inner face of the envelope pores, which are found at every five-fold symmetry axis of the icosahedron-shaped mature virus. These loops bear a remarkable low identity though with high occurrence of ionizable residues, including histidines. Such stereochemical properties can provide very particular serotype-specific electrostatic surface patterns, suggesting a viral fingerprint region, on which other specific molecules and ions can establish chemical interactions in an induced fit mechanism. We assert that the proposed regions share enough relevant features to qualify for further immunologic and pharmacologic essays, such as target peptide synthesis and phage display using dengue patients' sera.

The role of disulfide bridges in the 3-D structures of the antimicrobial peptides gomesin and protegrin-1: a molecular dynamics study.

Some antimicrobial peptides have a broad spectrum of action against many different kinds of microorganisms. Gomesin and protegrin-1 are examples of such antimicrobial peptides, and they were studied by molecular dynamics in this research. Both have a beta-hairpin conformation stabilized by two disulfide bridges and are active against gram-positive and gram-negative bacteria, as well as fungi. In this study, the role of the disulfide bridge in the maintenance of the tertiary peptide structure of protegrin-1 and gomesin is analyzed by the structural characteristics of these peptides and two of their respective variants, gomy4 and proty4, in which the four cysteines are replaced by four tyrosine residues. The absence of disulfide bridges in gomy4 and proty4 is compensated by overall reinforcement of the original hydrogen bonds and extra attractive interactions between the aromatic rings of the tyrosine residues. The net effects on the variants with respect to the corresponding natural peptides are: i) maintenance of the original beta-hairpin conformation, with great structural similarities between the mutant and the corresponding natural peptide; ii) combination of positive Phi and Psi Ramachandran angles within the hairpin head region with a qualitative change to a combination of positive (Phi) and negative (Psi) angles, and iii) significant increase in structural flexibility. Experimental facts about the antimicrobial activity of the gomesin and protegrin-1 variants have also been established here, in the hope that the detailed data provided in the present study may be useful for understanding the mechanism of action of these peptides.

Osteoporotic fractures: mortality and quality of life.

Osteoporosis is a widespread disease, affecting about 75 million people, mostly postmenopausal women. It is called ''the silent disease'', since there are very few associated symptoms: anyway osteoporotic fractures are the chief clinical feature, with an enormous burden on health related quality of life and mortality. The aim of this study was to review the literature on the evaluation of mortality and health related quality of life as consequences of osteoporotic fractures. Fractures, the clinical manifestation of osteoporosis, are extremely common and are devastating both to affected patients and to society that must bear the enormous cost of fracture treatment and subsequent disability. Hip and spine fractures are linked with increased mortality, and all fractures may lead to disability and reduced quality of life. Since patients with osteoporosis usually have no symptoms before fracture, early diagnosis and treatment of the disease are of great importance to the quality of life in these patients. To reduce mortality, attention must focus on optimising health status preoperatively, preventing postoperative complications, and, when these complications develop, providing optimal specialist medical care.

Improving outcomes in tumour necrosis factor a treatment: comparison of the efficacy of the tumour necrosis factor a blocking agents etanercept and infliximab in patients with active rheumatoid arthritis.

AIM: The aim of this study was to evaluate the differences between infliximab and etanercept, in terms of clinical efficacy and rapidity of action. METHODS: We selected 32 patients with rheumatoid arthritis (RA) with an incomplete response to disease modifying anti-rheumatic drugs (DMARDs), and randomly assigned them to etanercept or infliximab. We evaluated the efficacy after 14, 22, 54 weeks of treatment, using the American College of Rheumatology (ACR) 20, 50 and 70 criteria, and the improvement of quality of life using the Health Assessment Question-naire (HAQ). RESULTS: After 14 weeks, the 54.4% of patients was considered ACR-responders in the etanercept group, whereas, in the infliximab group, the percentage of responders was 74.4%: infliximab gave better results for the tender joint count and for physician's global assessment. After 22 weeks, no significant difference was present. After 54 weeks, etanercept resulted more effective than infliximab for tender joint count (TJC) value, for visual analogic scale (VAS) for pain score, for global disease assessment value, with 74.4% of patients considered ACR-responders in the group treated with etanercept and 60% in the group treated with infliximab. As regards HAQ, patients in the infliximab group presented higher scores at week 14, but in weeks 22 and 54, patients in the etanercept group showed better results. Therefore, both infliximab and etanercept are efficacious in RA, but infliximab is more efficacious than etanercept in week 14. Vice versa, in week 54 etanercept is the most efficacious drug. CONCLUSIONS: Physicians have 2 weapons in their armamentarium, with the same target but distinct clinical, pharmacokinetic and pharmacodynamic properties.

[Muscle activation patterns and gait biomechanics in patients with ankylosing spondylitis]. / Pattern di attivazione muscolare e biomeccanica del passo in pazienti con spondilite anchilosante.

UNLABELLED: Patients with ankylosing spondylitis (AS) may experience a progressive spinal kyphosis, which induces a forward and downward displacement of the centre of mass (COM) of the trunk with consequent use of mechanisms to compensate for the displacement of the trunk. The analysis of patterns of movement gives an important opportunity for follow-up of patients and is an useful tool to plan a therapeutic and rehabilitative program. OBJECTIVE: The aim of our study was to contribute to the description of abnormalities of gait biomechanics in patients with AS and to individualize, if existing, a typical pattern of these patients. METHODS: Five patients with AS (3 men, 2 women) were evaluated by gait analysis. Each patient was assessed with dynamic electromyography, with survey of phases of gait cycle and 3D video-analysis of gait related to data of platform (Digivec) which allows to display real time the force vector of reaction foot-ground overlapping the screen image of patient. RESULTS: The dynamometric platform located the following problems: increasing of the medium-lateral component of the reaction force on the ground in the mild and terminal stance. The anterior-posterior reaction force is diminished in both the initial and the terminal component. The timing of activation of the tibialis anterior results prolonged while the timing of activation of the gastrocnemius medialis results delayed. CONCLUSION: The patients with AS prefer therefore an eccentric contraction of the tibial anterior in comparison to a concentric contraction of the gastrocnemius medialis, "opting" for a gait strategy that confers greater stability but limited power.

[Comparation of levels of anxiety and depression in patients with autoimmune and chronic-degenerative rheumatic: preliminary data]. / Comparazione dei livelli di ansia e depressione in soggetti affetti da patologie reumatiche su base autoimmune e cronico-degenerative: dati preliminari.

UNLABELLED: Scientific research on rheumatic diseases was often focused on the link between psychological features and disease. Depression and anxiety are frequently observed with an higher incidence among rheumatic patients in comparison to general population. In autoimmune diseases, such as rheumatoid arthritis, an important role for psychiatric symptoms could be played by the alteration of cytokines levels. In the chronic-degenerative diseases, psychological factors such as stress and depression, can be involved in perception of pain. OBJECTIVE: We aimed at evaluating in a sample of 50 patients (25 with rheumatoid arthritis and 25 with osteoarthritis) levels of pain, anxiety and depression. METHODS: We evaluated two group of patients with rheumatic disease, group A (25 with Rheumatoid Arthritis, mean age = 45.1; DS =15.24) and group B (25 with osteoarthritis, mean age = 54.3; DS =14.74) by clinic examination and with the following tests, SF-MPQ, HAQ, HAM-A, HAM-D. RESULTS: We found in group A higher levels of depression and anxiety but lower levels of pain, which was more expressed in group B. CONCLUSION: Depression and anxiety were observed with an higher prevalence in patients with autoimmune disease, whereas pain was stronger in patients with osteoarthritis, a degenerative disease. We could explain this phenomenon considering the aetiopathology of the two conditions. As regard to autoimmune disorders, these symptoms may reflect the direct effect of cytokines on the central nervous system. As far as it concerns chronic-degenerative diseases, anxiety and depression are usually considered "reactive" to pain, not "constitutive".

Rheumatic symptoms in patients with human immunodeficiency virus are related to levels of tumor necrosis factor-alpha but not to viral load.

Infection with human immunodeficiency virus (HIV) can lead to osteoarticular involvement, usually in the late stages. The pathogenesis of these symptoms has usually been attributed to viral load or to dysregulated cytokine production. We evaluated the presence of rheumatic symptoms and levels of tumor necrosis factor (TNF)-alpha viral load and CD4 count in 46 patients with HIV from southern Italy. The prevalence of rheumatic symptoms was 23.9%; CD4 count and viral load presented no statistically significant differences between patients with rheumatic symptoms and patients without osteoarticular involvement, whereas TNF-alpha levels were increased in HIV patients with arthralgias compared with those in patients without arthralgias (p = 0.02). Evidence that TNF-alpha is increased in patients with osteoarticular or soft tissue involvement is a clear index of the pivotal role this cytokine plays in the pathogenesis of these manifestations.

Ultrasonography in the early diagnosis of psoriasis-associated enthesopathy.

The aim of the present study was to detect entheseal abnormalities by means of ultrasonography (US) in patients with psoriasis. We evaluated 24 patients with psoriasis who underwent clinical and ultrasonographic examination of both lower limbs at the calcaneal insertions of the Achilles tendons and at the flexor and extensor tendons of all fingers of the hand. Fourteen patients with psoriatic arthritis were used as controls. US was performed using a real-time scanner (ATL SDI 3000) with a 5-12 MHz linear array transducer. Longitudinal and transverse scans of the talocrural joints, Achilles tendons and both the flexor and extensor tendons of the fingers of both hands were obtained at rest and during active and passive movements. On clinical examination no entheseal site was abnormal, but on US examination 33% of patients showed abnormalities. In particular, six psoriasis patients (25%) who were asymptomatic showed effusion around the extensor tendon of the first digit of the left hand and around the extensor tendon of the third and fourth digits of both hands; two patients (8.3%) showed a hypoechoic nodular formation of the flexor tendon sheath of the left hand. We conclude that entheseal abnormalities not detected at clinical examination were present in 33% of patients with psoriasis who underwent US examination. Therefore, we suggest the routine use of ultrasonography in the early diagnosis and in treatment and follow-up of patients with tendon enthesopathy, since these factors may have implications for therapy.

Steric constraints as folding coadjuvant.

Through the analyses of the Miyazawa-Jernigan matrix it has been shown that the hydrophobic effect generates the dominant driving force for protein folding. By using both lattice and off-lattice models, it is shown that hydrophobic-type potentials are indeed efficient in inducing the chain through nativelike configurations, but they fail to provide sufficient stability so as to keep the chain in the native state. However, through comparative Monte Carlo simulations, it is shown that hydrophobic potentials and steric constraints are two basic ingredients for the folding process. Specifically, it is shown that suitable pairwise steric constraints introduce strong changes on the configurational activity, whose main consequence is a huge increase in the overall stability condition of the native state; detailed analysis of the effects of steric constraints on the heat capacity and configurational activity are provided. The present results support the view that the folding problem of globular proteins can be approached as a process in which the mechanism to reach the native conformation and the requirements for the globule stability are uncoupled.

Clinical improvement and serum amino acid levels after mud-bath therapy.

Spa therapy is an ancient approach to degenerative diseases such as osteoarthritis, but until today this tradition has been predominantly empiric and intuitive and few studies have focused on the biological changes derived from this treatment. We assessed the clinical efficacy and variations in amino acid concentrations in serum samples from patients with knee osteoarthritis who underwent spa therapy and put forward an explanation of their role in clinical improvement. Thirty-one patients with knee osteoarthritis who underwent spa therapy underwent a clinical evaluation, and serum amino acid levels were assayed before and after a cycle of balneotherapy and mud-pack therapy. The thermal treatments were carried out in Sciacca. Analysis of the data showed a significant reduction in pain and improvement in joint motility. Serum concentrations of tryptophan, cysteine and citrulline were significantly higher than at baseline. No significant differences were observed in serum levels of the remaining free amino acids. The results of this study confirm the efficacy of spa therapy in the treatment of osteoarthritis. A possible role for changes in serum amino acid concentration is discussed.

Factors influencing pain, physical function and social functioning in patients with osteoarthritis in southern Italy.

The aim of this study was to assess factors influencing bodily pain (BP), physical function (PF) and social functioning (SF) in patients with osteoarthritis (OA) from southern Italy A total of 1,782 patients (mean age 66.08 years, 570 men and 1,212 women) with knee, hip, spine or hand OA underwent a structured assessment comprising demographic data and the Short Form 36 (SF-36) BP, PF and SF scales. Separate multiple linear regression models were employed for statistical analysis. The mean disease duration was 9.18 years and the mean body mass index (BMI) was 27.06. The mean BP, PF and SF scores of 34.93 (SD 19.37), 63.58 (SD 26.53) and 47.89 (SD 21.83) for the study subjects were substantially lower than those expected for the general Italian population. Subjects who were younger with a shorter disease duration and lower BMI had better PF and SF Younger subjects with a lower BMI and a longer disease duration had less BP. Female sex was associated with more BP, worse SF and better PF. In conclusion, demographic and disease-related factors influence BP, PF and SF in southern Italian patients with OA.

[Epidemiology and risk factors in osteoarthritis: literature review data from "OASIS" study]. / Epidemiologia e fattori di rischio dell'osteoartrosi: review della letteratura e dati dal progetto OASIS.

Ostheoarthritis (OA) is a social disease characterized by pain, inflammation and stiffness due to an involvement of articular cartilage, soft tissues and bone. OA is the most common rheumatic disease, every age can be affected but prevalence increases dramatically with age with a greater incidence in subjects between 40 and 50 years of age. Hip OA has an important correlation with weight, genetic factors, sex, previous traumas, occupational factors and age. People older than 35 have a prevalence of hip OA of 10.8% that becomes 35.4% in people older than 85. Knee OA has a great correlation with weight ,life style and physical activity. An Italian study demonstrated that the prevalence of this kind of OA is highest in subjects older than 65 that becomes 44% in people older than 80. In this report we explain the results of a study conducted in the South of Italy called the OstheoArtrithis Southern Italy Study (OASIS) that involved 456 doctors and 1782 patients of three different regions. The mean age of these patients was 66.3 years and we evaluated prevalence of hip, knee, hand and spine OA and correlated it to sex, age, weight and BMI. We also evaluated what kind of drugs were used for these patients. Knee OA is the most common subset of OA, the one that requires the highest number of examinations and the one that causes the greatest disability. The most common used drugs are Fans and Coxibs. Condroprotectors were not used much, probably because they are not considered to be very effective.

Usefulness of gait analysis for rehabilitation and follow-up in a patient with neurolupus. A case report.

Neuropsychiatric symptoms are very common in patients with systemic lupus erythematosus (SLE) and can lead to a severe impairment of quality of life. Among neurological manifestations of SLE, altered gait patterns are common but usually not studied. Gait analysis allows us to evaluate the patients' skills, and in this way to plan a specific therapeutic-rehabilitative intervention. We describe the gait pattern of a patient with neurolupus, whose gait was characterized by a diminished propulsion capacity, a diminished load acceptance, a diminished progression of the pressure centre in a posterior-anterior sense, a diminished myoelectric activity in the swing and stence phases. We suggest that gait analysis may be a sensitive indicator of cerebral dysfunction and can be also an useful tool for the follow up of patients with neuropsychiatric SLE.

Effect of local thermal fluctuations on folding kinetics: a study from the perspective of nonextensive statistical mechanics.

The search through the proteins conformational space is thought as an early independent stage of the folding process, governed mainly by the hydrophobic effect. Because of the nanoscopic size of proteins, we assume that the effects of local thermal fluctuations work like folding assistants, managed by the nonextensive parameter q. Using a 27-mer heteropolymer on a cubic lattice, we obtained--by Monte Carlo simulations--kinetic and thermodynamic amounts (such as the characteristic folding time and the native stability) as a function of temperature T and q for a few distinct native targets. We found that for each native structure, at a specific system temperature T, there exists an optimum q* that minimizes the folding characteristic time τ(min); for T=1, it is found that q* lies in the interval 1.15±0.05, even for native structures presenting significantly different topological complexities. The distribution of τ(min) obtained for specific q>1 (nonextensive approach) and temperature T can be fully reproduced for q=1 (Boltzmann approach), but only at higher temperatures T'>T. However, assuming that the complete set of proteins of each organism is optimized to work in a narrow range of temperature, we conclude that--for the present problem--the two approaches, namely, (T,q>1) and (T>T',q=1), cannot be equivalent; it is not a simple matter of reparametrization. Finally, by associating the nonextensive parameter q with the instantaneous degree of compactness of the globule, q becomes a dynamic variable, self-adjusted along the simulation. The results obtained through the q-variable approach are utterly consistent with those obtained by using a target-tuned parameter q*. However, in the former approach, q is automatically adjusted by the chain conformational evolution, eliminating the need to seek for a specific optimized value of q for each case. Besides, using the q-variable approach, different target structures are promptly characterized by inherent distributions of q, which reflect the overall complexity of their corresponding native topologies and energy landscapes.

Topology-dependent protein folding rates analyzed by a stereochemical model.

It is an experimental fact that gross topological parameters of the native structure of small proteins presenting two-state kinetics, as relative contact order chi, correlate with the logarithm of their respective folding rate constant kappa(f). However, reported results show specific cases for which the (chi,log kappa(f)) dependence does not follow the overall trend of the entire collection of experimental data. Therefore, an interesting point to be clarified is to what extent the native topology alone can explain these exceptional data. In this work, the structural determinants of the folding kinetics are investigated by means of a 27-mer lattice model, in that each native is represented by a compact self-avoiding (CSA) configuration. The hydrophobic effect and steric constraints are taken as basic ingredients of the folding mechanism, and each CSA configuration is characterized according to its composition of specific patterns (resembling basic structural elements such as loops, sheets, and helices). Our results suggest that (i) folding rate constants are largely influenced by topological details of the native structure, as configurational pattern types and their combinations, and (ii) global parameters, as the relative contact order, may not be effective to detect them. Distinct pattern types and their combinations are determinants of what we call here the "content of secondary-type" structure (sigma) of the native: high sigma implies a large kappa(f). The largest part of all CSA configurations presents a mix of distinct structural patterns, which determine the chixlog kappa(f) linear dependence: Those structures not presenting a proper chi-dependent balance of patterns have their folding kinetics affected with respect to the pretense linear correlation between chi and log kappa(f). The basic physical mechanism relating sigma and kappa(f) involves the concept of cooperativity: If the native is composed of patterns producing a spatial order rich in effective short-range contacts, a properly designed sequence undertakes a fast folding process. On the other hand, the presence of some structural patterns, such as long loops, may reduce substantially the folding performance. This fact is illustrated through natives having a very similar topology but presenting a distinct folding rate kappa(f), and by analyzing structures having the same chi but different sigma.

The predictive power of r(0) in an epidemic probabilistic system.

An important issue in theoretical epidemiology is the epidemic thresholdphenomenon, which specify the conditions for an epidemic to grow or die out.In standard (mean-field-like) compartmental models the concept of the basic reproductive number, R(0), has been systematically employed as apredictor for epidemic spread and as an analytical tool to study thethreshold conditions. Despite the importance of this quantity, there are nogeneral formulation of R(0) when one considers the spread of a disease ina generic finite population, involving, for instance, arbitrary topology ofinter-individual interactions and heterogeneous mixing of susceptible andimmune individuals. The goal of this work is to study this concept in ageneralized stochastic system described in terms of global and localvariables. In particular, the dependence of R(0) on the space ofparameters that define the model is investigated; it is found that near ofthe `classical' epidemic threshold transition the uncertainty about thestrength of the epidemic process still is significantly large. Theforecasting attributes of R(0) for a discrete finite system is discussedand generalized; in particular, it is shown that, for a discrete finitesystem, the pretentious predictive power of R(0) is significantlyreduced.