Evidence for a pathogenic role of extrafollicular, IL-10-producing CCR6+B helper T cells in systemic lupus erythematosus.

Interleukin 10 (IL-10) is an antiinflammatory cytokine, but also promotes B cell responses and plays a pathogenic role in systemic lupus erythematosus (SLE). CD4+CCR6+IL-7R+T cells from human tonsils produced IL-10 following stimulation by naïve B cells, which promoted B cell immunoglobulin G (IgG) production. These tonsillar CCR6+B helper T cells were phenotypically distinct from follicular helper T (TFH) cells and lacked BCL6 expression. In peripheral blood, a CCR6+T cell population with similar characteristics was identified, which lacked Th17- and TFH-associated gene signatures and differentiation-associated surface markers. CD4+CCR6+T cells expressing IL-10, but not IL-17, were also detectable in the spleens of cytokine reporter mice. They provided help for IgG production in vivo, and expanded systemically in pristane-induced lupus-like disease. In SLE patients, CD4+CCR6+IL-7R+T cells were associated with the presence of pathogenic anti-dsDNA (double-stranded DNA) antibodies, and provided spontaneous help for autoantibody production ex vivo. Strikingly, IL-10-producing CCR6+T cells were highly abundant in lymph nodes of SLE patients, and colocalized with B cells at the margins of follicles. In conclusion, we identified a previously uncharacterized population of extrafollicular B helper T cells, which produced IL-10 and could play a prominent pathogenic role in SLE.

Environmental electroactive consortia as reusable biosensing element for freshwater toxicity monitoring.

The development of tools to monitor water quality is mandatory in a scenario where clean water resources are decreasing. Here, the biosensing capability of an electroactive river sediment consortium was tested towards three model contaminants (glutaraldehyde, nickel(II) and chromium(III)). The proposed biosensor is a small membrane-less single chamber Microbial Fuel Cell (MFC), fabricated by 3D printing. Its semi-continuous mode of operation resulted in long-term current profile stability and reproducibility. A linear trend of response was obtained for glutaraldehyde in a concentration range of 5-1000 ppm. After the recovery of the electroactive consortium activity, the MFC-based biosensors were shown to be sensitive towards Ni(II) and Cr(III), at concentrations above 2 mg L-1. To effectively analyze biosensor response, a novel algorithm was proposed, offering advantages for the realization of energy-saving protocols for MFC-biosensor data transmission. Implementation of the device and method, from laboratory test to real environment, can offer a low cost in situ system for detection of water contaminants.

IL-10 producing regulatory and helper T-cells in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disease characterised by the production of pathogenic autoantibodies against nuclear self-antigens. The anti-inflammatory and tolerogenic cytokine Interleukin-10 appears to play a paradoxical pathogenic role in SLE and is therefore currently therapeutically targeted in clinical trials. It is generally assumed that the pathogenic effect of IL-10 in SLE is due to its growth and differentiation factor activity on autoreactive B-cells, but effects on other cells might also play a role. To date, a unique cellular source of pathogenic IL-10 in SLE has not been identified. In this review, we focus on the contribution of different CD4+T-cell subsets to IL-10 and autoantibody production in SLE. In particular, we discuss that IL-10 produced by different subsets of adaptive regulatory T-cells, follicular helper T-cells and extra-follicular B-helper T-cells is likely to have different effects on autoreactive B-cell responses. A better understanding of the role of IL-10 in B-cell responses and lupus would allow to identify the most promising therapies for individual SLE patients in the future.

Accuracy of dielectric-dependent hybrid functionals in the prediction of optoelectronic properties of metal oxide semiconductors: a comprehensive comparison with many-body GW and experiments.

Understanding the electronic structure of metal oxide semiconductors is crucial to their numerous technological applications, such as photoelectrochemical water splitting and solar cells. The needed experimental and theoretical knowledge goes beyond that of pristine bulk crystals, and must include the effects of surfaces and interfaces, as well as those due to the presence of intrinsic defects (e.g. oxygen vacancies), or dopants for band engineering. In this review, we present an account of the recent efforts in predicting and understanding the optoelectronic properties of oxides using ab initio theoretical methods. In particular, we discuss the performance of recently developed dielectric-dependent hybrid functionals, providing a comparison against the results of many-body GW calculations, including G 0 W 0 as well as more refined approaches, such as quasiparticle self-consistent GW. We summarize results in the recent literature for the band gap, the band level alignment at surfaces, and optical transition energies in defective oxides, including wide gap oxide semiconductors and transition metal oxides. Correlated transition metal oxides are also discussed. For each method, we describe successes and drawbacks, emphasizing the challenges faced by the development of improved theoretical approaches. The theoretical section is preceded by a critical overview of the main experimental techniques needed to characterize the optoelectronic properties of semiconductors, including absorption and reflection spectroscopy, photoemission, and scanning tunneling spectroscopy (STS).

Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study.

Objective A task force of scientists at the International Congress on Antiphospholipid Antibodies recognized that phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT) might contribute to a better identification of antiphospholipid syndrome (APS). Accordingly, initial and replication retrospective, cross-sectional multicentre studies were conducted to ascertain the value of aPS/PT for APS diagnosis. Methods In the initial study (eight centres, seven countries), clinical/laboratory data were retrospectively collected. Serum/plasma samples were tested for IgG aPS/PT at Inova Diagnostics (Inova) using two ELISA kits. A replication study (five centres, five countries) was carried out afterwards. Results In the initial study ( n = 247), a moderate agreement between the IgG aPS/PT Inova and MBL ELISA kits was observed ( k = 0.598). IgG aPS/PT were more prevalent in APS patients (51%) than in those without (9%), OR 10.8, 95% CI (4.0-29.3), p < 0.0001. Sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratio of IgG aPS/PT for APS diagnosis were 51%, 91%, 5.9 and 0.5, respectively. In the replication study ( n = 214), a moderate/substantial agreement between the IgG aPS/PT results obtained with both ELISA kits was observed ( k = 0.630). IgG aPS/PT were more prevalent in APS patients (47%) than in those without (12%), OR 6.4, 95% CI (2.6-16), p < 0.0001. Sensitivity, specificity, LR + and LR- for APS diagnosis were 47%, 88%, 3.9 and 0.6, respectively. Conclusions IgG aPS/PT detection is an easily performed laboratory parameter that might contribute to a better and more complete identification of patients with APS.

Cognitive outcome as part and parcel of clinical outcome in brain tumor surgery.

Although validated tools (neuropsychological tests, patient reported outcomes, mood and psychological profile) were first introduced many years ago in clinical practice, the impact of the tumor itself on patient cognition has not been extensively studied. Furthermore, while outcome research is evolving in an attempt to adapt the use of different tools to the preoperative and postoperative phases, the standard guidelines for evaluating outcome after brain surgery, by neurological examination and complication assessment, are frequently neglected in the current literature. This article attempts to provide an appraisal of the evidence for the impact of surgical treatment on cognitive function of brain tumor patients within the context of general outcome.

Software for hepatic vessel classification: feasibility study for virtual surgery.

PURPOSE: The detection and classification of hepatic vessels in diagnostic images are essential for hepatic pre-surgery planning. Our team has developed a tool for classification, analysis, and 3D reconstruction of the hepatic and portal systems. METHODS: Our software first extracts a graphic representation of a set of connected voxels, representing both systems. It then calculates two binary volumes representing the main part of the two venous systems. Finally, it combines these results to obtain the correct vessel classification. RESULTS: Segmentation steps are semi-automatic and require about 40 min to complete. Schematization and classification steps are automatic and require about 17 min for results. CONCLUSION: The software provides a correct and detailed reconstruction even where pathologies have caused morphological and geometrical variations in the vessels. The time required for the entire procedure is compatible with clinical requirements, providing an efficient tool for diagnosis and surgical planning.

Pidotimod: a reappraisal.

Pidotimod (Polimod ) is a synthetic dipeptide molecule with biological and immunological activity on both the adaptive and the innate immune responses. In vitro studies, both from animal and human specimens, have documented a good activity on innate and adaptive immune responses and have been confirmed by in vivo studies. These activities have been applied in clinical studies demonstrating the efficacy of pidotimod in reducing the rate of recurrent infections of the upper respiratory and urinary tracts in children. The same results were obtained in recurrent respiratory tract infections in adults. Interestingly, these effects are more evident in the setting of immune defects such as senescence, Downs syndrome, and cancer.

Operative classification of brain arteriovenous malformation. Part two: validation.

SUMMARY: The most important issue when dealing with a patient with a brain AVM is the decision whether to treat or not. Only after this decision has been made, taking into consideration a number of factors depending on both the patient and the specific type of AVM, can the best option for treatment be chosen. An operative classification of brain AVMs, previously adopted in the Department of Neuroradiology and Neurosurgery of Verona (Italy) and published in this journal, was subjected to validation in a consecutive group of 104 patients clinically followed for at least three years after completion of treatment. This classification, slightly modified from the original version concerning the importance of some specific items, allowed us to assess the indication to treat in each case, whatever type of treatment was offered to the patient.

Rheumatoid arthritis: a female challenge.

Rheumatoid arthritis (RA) is two- to three-fold more frequent in women than in men and a strong association with sex hormones has been demonstrated. There is strong evidence that autoimmunity is under genetic control, and genes in sexual chromosomes can play a role in supporting the female prevalence. On the other hand, it is widely accepted that sex hormones--estrogens in particular--may regulate the immune response by favoring the survival of forbidden autoreactive clones and ultimately the prevalence of autoimmunity in women. Accordingly, estrogens have been suggested to be associated with the development of RA. Pregnancy in RA women is a common situation and most pregnant patients experience a remission. This has been closely related to a switch from Th1 to Th2 immune responses and to a decreased production of proinflammatory cytokines, at least in part supported by the changes of the hormonal profile in pregnancy. Pregnancy planning is required in RA in order to avoid unwanted complications. In particular, the need to control the disease requires safe use of antirheumatic drugs both during the pregnancy itself and in the breastfeeding period. Hormonal treatment for contraception is contraindicated in the case of positivity for antiphospholipid antibodies owing to the increased thrombophilic risk. Similarly, replacement hormonal treatment in postmenopausal women with RA to control osteoporosis is no longer recommended as a result of its ability to increase the cardiovascular risk closely associated with RA itself.

Management of the controversial aspects of the antiphospholipid syndrome pregnancies: a guide for clinicians and researchers.

BACKGROUND: Recommendations for the treatment of aPL-positive patients with pregnancy morbidity are based on a limited number of well-designed clinical trials. However, the management of pregnant aPL-positive women still displays several open questions. OBJECTIVE: To determine the practice patterns of experienced physicians in the management of the controversial aspects of aPL pregnancies. METHODS: A questionnaire reproducing debated conditions was initially sent to the Advisory Board members (ABMs) of the 12th Congress of aPL and the Fifth Conference on Sex Hormones, Pregnancy and Rheumatic Diseases (Florence, Italy, April 2007), and then the same questionnaire was posted at the Hospital for Special Surgery (www.hss.edu) website and all attendees (ATS) of the above meetings were invited to participate via e-mail. Answers have been collected and analysed in a descriptive fashion and responses of the two groups evaluated by Chi-square or Fisher's exact test. RESULTS: As a whole 75 responses from the ABMs and ATS were included in the analysis. In general, there was no significant difference between the opinions of two groups. CONCLUSIONS: Management recommendations displayed reasonable consistence: (i) for the use of low-dose aspirin and low-molecular weight heparin during pregnancy and during ovarian stimulation for in vitro fertilization; (ii) against oestrogen-containing oral contraceptives; and (iii) for the use of anticoagulants in the post-partum period.

Monitoring of motor pathways during brain stem surgery: what we have achieved and what we still miss?

Intraoperative neurophysiological monitoring (IOM) has established itself as one of the paths by which modern neurosurgery can improve surgical results while minimizing morbidity. IOM consists of both monitoring (continuous "on-line" assessment of the functional integrity of neural pathways) and mapping (functional identification and preservation of anatomically ambiguous nervous tissue) techniques. In posterior-fossa and brainstem surgery, mapping techniques can be used to identify - and therefore preserve - cranial nerves, their motor nuclei and corticospinal or corticobulbar pathways. Similarly, free-running electromyography (EMG) and muscle motor-evoked potential (mMEP) monitoring can continuously assess the functional integrity of these pathways during surgery. Mapping of the corticospinal tract, at the level of the cerebral peduncle as well as mapping of the VII, IX-X and XII cranial nerve motor nuclei on the floor of the fourth ventricle, is of great value to identify "safe entry-zones" into the brainstem. Mapping techniques allow recognizing anatomical landmarks such as the facial colliculus, the hypoglosseal and glossopharyngeal triangles on the floor of the fourth ventricle, even when normal anatomy is distorted by a tumor. On the basis of neurophysiological mapping, specific patterns of motor cranial nuclei displacement can be recognized. However, brainstem mapping cannot detect injury to the supranuclear tracts originating in the motor cortex and ending on the cranial nerve motor nuclei. Therefore, monitoring techniques should be used. Standard techniques for continuously assessing the functional integrity of motor cranial nerves traditionally rely on the evaluation of spontaneous free-running EMG in muscles innervated by motor cranial nerves. Although several criteria have been proposed to identify those EMG activity patterns that are suspicious for nerve injury, the terminology remains somewhat confusing and convincing data regarding a clinical correlation between EMG activity and clinical outcome are still lacking. Transcranial mMEPs are also currently used during posterior-fossa surgery and principles of MEP monitoring to assess the functional integrity of motor pathways are similar to those used in brain and spinal-cord surgery. Recently, current concepts in muscle MEP monitoring have been extended to the monitoring of motor cranial nerves. So-called "corticobulbar mMEPs" can be used to monitor the functional integrity of corticobulbar tracts from the cortex through the cranial motor nuclei and to the muscle innervated by cranial nerves. Methodology for this purpose has appeared in the literature only recently and mostly with regards to the VII cranial nerve monitoring. Nevertheless, this technique has not yet been standardized and some limitations still exist. In particular, with regards to the preservation of the swallowing and coughing reflexes, available intraoperative techniques are insufficient to provide reliable prognostic data since only the efferent arc of the reflex can be tested.

Neuroprotective role of neurophysiological monitoring during endovascular procedures in the brain and spinal cord.

The goal of endovascular neurosurgery is to occlude aneurysms and arteriovenous malformations (AVMs) or to reduce the vascular supply to hypervascularized tumors, while preserving function in the normal neural tissue. However, the intra-arterial injection of embolizing materials into the cerebral or spinal circulation exposes to the risk of ischemic complications. Under general anesthesia, unless a wake-up test is performed, the only way to assess the functional integrity of sensory and motor pathways is to use neurophysiological monitoring. Somatosensory (SEPs) and muscle motor evoked potentials (mMEPs) can be used in combination with pharmacological provocative tests (PTs) to predict the effects of embolization. Amytal blocks neuronal activity, while lidocaine blocks axonal conduction. Therefore, a positive Amytal or lidocaine test (i.e. more than 50% decrease in SEP amplitude and/or mMEP disappearance) indicates that the vessel distal to the tip of the microcatheter supplies the functional gray or white matter of the spinal-cord respectively and cannot be embolized. Brain and spinal-cord vascularization and hemodynamics are extremely complex and even more unpredictable in the presence of a vascular malformation, but using a combined SEPs, MEPs and PTs protocol, morbidity related to endovascular procedures is very low. Given the high sensitivity of peripheral recordings to spinal-cord ischemia, experimental and clinical studies support the concept that whenever the mechanism of spinal-cord injury is purely ischemic, recording mMEPs may suffice. Reports on the use of PTs and neurophysiological monitoring during embolization of brain AVMs in critical areas are more anecdotal and mainly limited to the use of short-acting barbiturates. Our preliminary experience using lidocaine and combining SEP and mMEP monitoring is encouraging, since no false negative results were observed. Finally, if the sensitivity of this method is very high, its specificity has not been tested because embolization is abandoned whenever PTs are consistently positive. Accordingly, the possibility of false positive results cannot be excluded.

Immune function in children born to mothers with autoimmune diseases and exposed in utero to immunosuppressants.

The administration of immunosuppressive drugs during pregnancy is often necessary in women with autoimmune diseases. Teratogenicity of immunosuppressives during pregnancy has been evaluated, only few data exist about the effects on immune systems. We therefore performed a pilot study on the influence of foetal exposure to immunosuppressives on immune function of babies born to mothers with autoimmune disorders. We investigated serological and cellular parameters as indicators of immune system status. We included in the study 14 babies (mean age 11 months, range 1-24) born to mothers with autoimmune diseases and exposed in utero to different immunosuppressants and, as controls, 14 babies whose mothers had autoimmune manifestations but did not receive immunosuppressive therapy. We evaluated: (i) complete blood count, (ii) immunoglobulin levels and IgG subclasses, (iii) antibody response to hepatitis B vaccine, (iv) leukocyte subpopulations and (v) interleukin-2 and interferon gamma in vitro production by resting or activated peripheral blood mononuclear cells. We did not find statistically significant differences between exposed and not exposed babies or among treatments for the tested parameters. Immunosuppressive regimens currently in use for controlling maternal autoimmune disorders do not significantly affect the immune status of the offspring.

Electrocardiographic abnormalities in infants born from mothers with autoimmune diseases--a multicentre prospective study.

OBJECTIVES: To assess the prevalence of congenital heart block (CHB) and electrocardiographic (ECG) abnormalities in infants of anti-Ro/SSA-positive women. METHODS: Sixty anti-Ro-positive and 36 anti-Ro-negative patients were prospectively followed before/during pregnancy and underwent weekly fetal echocardiography from 18th to 26th weeks of gestational age. Infants' ECG and/or ECG-Holter were performed at 1, 3, 6 and 12 months. ECG of 200 consecutive neonates were used as a healthy control group. RESULTS: One of 61 fetuses of anti-Ro-positive mothers developed CHB (20th week); another anti-Ro-positive baby developed second degree atrioventricular (AV) block (30th week). The prevalence of transient first degree AV block detected post-natally was significantly higher in the anti-Ro-positive group, in comparison with healthy controls (P = 0.002). No differences in corrected QT (QTc) interval prolongation prevalence (>/=440 ms) was observed between the anti-Ro-positive and -negative groups, but both were significantly higher than that of the control population (P < 0.001). ECG-Holter showed QTc prolongation in 59% of infants of anti-Ro-positive and in 60% of infants of anti-Ro-negative mothers. Holter QTc was >/=470 ms in four infants of anti-Ro-positive group and two of anti-Ro-negative group. Known acquired causes of QTc prolongation were excluded. CONCLUSIONS: This prospective study confirms the low occurrence of CHB in newborns from anti-Ro-positive mothers. ECG abnormalities (first degree AV block and QTc interval prolongation) are frequent in infants of mothers with autoimmune diseases, independently of maternal disease, autoantibody profile and treatment during pregnancy.

Diagnostic value of PRND gene expression profiles in astrocytomas: relationship to tumor grades of malignancy.

Doppel (PRND) is a paralogue of the mammalian prion (PRNP) gene. It is abundant in testis and, unlike PRNP, it is expressed at low levels in the adult central nervous system (CNS). Besides, doppel overexpression correlates with some prion-disease pathological features, such as ataxia and death of cerebellar neurons. Recently, ectopic expression of doppel was found in two different tumor types, specifically in glial and haematological cancers. In order to address clinical important issues, PRND mRNA expression was investigated in a panel of 111 astrocytoma tissue samples, histologically classified according to the World Health Organization (WHO) criteria (6 grade I pilocytic astrocytomas, 15 grade II low-grade astrocytomas, 26 grade III anaplastic astrocytomas and 64 grade IV glioblastoma multiforme). Real-time PRND gene expression profiling, after normalisation with GAPDH, revealed large differences between low (WHO I and II) and high grade (III and IV) of malignancy (P<0.001). Extensive differences in PRND gene expression were also found within each grade of malignancy, suggesting that PRND mRNA quantitation might be useful to distinguish astrocytoma subtypes, and important in disease stratification and in the assessment of specific treatment strategies.

Measurement of electrical skin impedance of dermal-visceral zones as a diagnostic tool for disorders of the immune system.

Among complementary medicine approaches, diagnostic screening tools based on neuroreflexology have been recently developed. Such techniques are based on the rationale that measurement of electrical impedance of specific dermal zones might reflect the occurrence of pathological states in the corresponding internal organs or systems. Our objective was to evaluate the reliability of a neuroreflexology-based diagnostic test in diagnosing immune-mediated diseases in a blinded single centre study. Seventy-eight patients with immune-mediated diseases (38 patients with autoimmune diseases (AD), and 40 allergic patients) were included in the study. Thirty age and sex matched healthy subjects were also evaluated as a control group. All the patients and subjects underwent conventional medical history and physical examination. We evaluated a device manufactured by Medex Screen Ltd (Arad, Israel). The Medex Test analysis was carried out by a second physician who was blinded to the previous diagnosis. A high correlation between the formal clinical diagnosis and the results of the measurement of electrical skin impedance was reported, with a specificity of 93.3% and a sensitivity of 81.2%. Both sensitivity and specificity dropped when analysing the autoimmune and the allergic group separately, but remained significant for the autoimmune diseases. Degree of activity of the allergic disorders, or specific treatment, did not affect the diagnostic properties of the described device. The Medex Test neurophysiology based technique has the potential to serve as a diagnostic tool for immune based pathologies. Future studies will define this tool place in routine evaluation and potential screening ability.

Statins and autoimmune diseases.

Besides the well-known lipid-lowering effect, statins display nonlipid-lowering pharmacological activities. In vitro and in vivo studies suggest that statins have direct anti-inflammatory, anti-thrombotic and plaque-stabilizing effects via a number of mechanisms. A direct immunomodulatory effect has been also demonstrated in in vitro and in vivo experimental models. In addition to traditional risk factors, systemic inflammation, immune-mediated responses and thrombophilia have been suggested to play a major role in sustaining the premature atherosclerosis in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. This review focuses on the anti-inflammatory and immunomodulating mechanisms of statins as demonstrated in in vitro and in vivo experimental models, providing new insights for the use of statins in treating systemic autoimmune diseases both for their anti-atherosclerotic activity and for their pleiotropic effects on inflammation, haemostasis and the immune responses.

Gamma knife radiosurgery in brain metastases from testicular tumors.

To our knowledge, there are no published reports on the effectiveness of radiosurgery in the management of brain metastases from testicular nonseminomatous germ cell tumor. The authors evaluate the results of gamma knife (GK) treatment in three patients with these unusual intracranial lesions. Between April 1995 and July 2001, three patients with brain metastasis from testicular nonseminomatous germ cell tumor underwent adjuvant radiosurgery at our department. The primary tumor had been surgically removed in all cases. At diagnosis, one patient was stage IB and two were stage III poor risk. Chemotherapy and whole brain radiotherapy were administered before radiosurgery in all cases. Pre-GK radiotherapy was administered with a daily fraction dosage of 1.8-2.0 Gy. The indications for radiosurgery were tumor volume <20 cm3, microsurgery too risky, refusal of surgery. All the lesions were located in eloquent brain areas. Post-GK high-dose chemotherapy with autologous peripheral-blood stem-cell rescue was administered in two cases due to systemic recurrence of the disease. All patients are still alive with a median and mean follow-up period after radiosurgery of 63 and 68.3 mo, respectively. They had no neurological deficits at the latest examination. Neuroradiological follow-up invariably showed tumor growth control (complete response in two cases and partial response in one) with typically delayed post-radiosurgical imaging changes (transient in two cases and long-lasting in one). In conclusion, GK seems to be highly effective and safe in brain metastases from testicular nonseminomatous germ cell tumor. In cases with diffuse metastatic brain involvement, the whole brain radiotherapy preceding radiosurgery should be delivered with 1.8 Gy daily fraction to prevent the risk of long-lasting post-radiosurgical imaging changes.