Neural Stem Cells from Shank3-ko Mouse Model Autism Spectrum Disorders.

Autism spectrum disorders (ASD) comprise a complex of neurodevelopmental disorders caused by a variety of genetic defects and characterized by alterations in social communication and repetitive behavior. Since the mechanisms leading to early neuronal degeneration remain elusive, we chose to examine the properties of NSCs isolated from an animal model of ASD in order to evaluate whether their neurogenic potential may recapitulate the early phases of neurogenesis in the brain of ASD patients. Mutations of the gene coding for the Shank3 protein play a key role in the impairment of brain development and synaptogenesis in ASD patients. Experiments here reported show that NSCs derived from the subventricular zone (SVZ) of adult Shank3Δ11-/- (Shank3-ko) mice retain self-renewal capacity in vitro, but differentiate earlier than wild-type (wt) cells, displaying an evident endosomal/lysosomal and ubiquitin aggregation in astroglial cells together with mitochondrial impairment and inflammasome activation, suggesting that glial degeneration likely contributes to neuronal damage in ASD. These in vitro observations obtained in our disease model are consistent with data in vivo obtained in ASD patients and suggest that Shank3 deficit could affect the late phases of neurogenesis and/or the survival of mature cells rather than NSC self-renewal. This evidence supports Shank3-ko NSCs as a reliable in vitro disease model and suggests the rescue of glial cells as a therapeutic strategy to prevent neuronal degeneration in ASD.

Vitamin D deficiency in refugees in Italy.

The objective of the research is to determine 25[OH]D serum levels in refugees in Italy. In the following research we have taken into consideration the results of the monitoring of Vitamin D levels in 46 refugees of the Italian Service for protection of refugees and asylum seekers (SPRAR) system. The indicator of overall vitamin D status used was the circulating serum level of 25(OH)D. Data was analyzed using Microsoft Excel. In the refugees tested, the mean level of 25(OH)D resulted 9.18 ng/mL. The standard deviation was 4.8, with a minimal level of 4.3 and a maximum of 27.4. This figure indicates a clear condition of hypovitaminosis in refugees. While it is general assumption that migratory phenomena may induce the spread of tropical or infectious diseases, widely attested literature demonstrates how chronic pathologies and diseases related to altered lifestyles are the most relevant for Italian case records. Indeed, among the aforementioned diseases, Vitamin D deficiency so far lacks acknowledgement at a national level. Considering the results of lower-than-desirable vitamin D levels found in refugees in Italy, it is necessary to take this parameter into consideration when analyzing individuals who have faced migratory phenomena in order to mitigate the effects of hypovitaminosis D.

Central nervous system niche involvement in the leukemia.

Central nervous system (CNS) impairment is commonly involved in leukemia, as it can be observed upon onset or relapse of the disease. It is associated with poor prognosis and is a challenging clinical problem. The objective of this paper was to provide a characterization of the CNS niche in leukemia, to elucidate the culprits of CNS involvement, including diagnostic micro RNAs (miRs) and early leukemia prognosis. CNS niche is a proper location for homing of leukemic stem cells, thus representing a candidate target in the treatment of leukemia. Recent advances in the study of leukemia hallmarks have enlightened miRs as novel biomarkers for diagnosis and detection of CNS involvement in leukemia, thus providing the opportunity to develop novel therapeutic approaches. Given the importance of prognosis and early diagnosis of CNS involvement in leukemias as well as the severe side effects of current treatments, diagnostic and therapeutic approaches should focus on identification and inhibition of the factors contributing to CNS involvement, including CXCR3, P-selectin glycoprotein ligand-1 and MCP1. MiRs such as miR-221 and miR-222 are emerging as potential tools for an innovative non-invasive therapy of CNS in leukemia affected patients.

Murine neural stem cells model Hunter disease in vitro: glial cell-mediated neurodegeneration as a possible mechanism involved.

Mucopolysaccharidosis type II (MPSII or Hunter Syndrome) is a lysosomal storage disorder caused by the deficit of iduronate 2-sulfatase (IDS) activity and characterized by progressive systemic and neurological impairment. As the early mechanisms leading to neuronal degeneration remain elusive, we chose to examine the properties of neural stem cells (NSCs) isolated from an animal model of the disease in order to evaluate whether their neurogenic potential could be used to recapitulate the early phases of neurogenesis in the brain of Hunter disease patients. Experiments here reported show that NSCs derived from the subventricular zone (SVZ) of early symptomatic IDS-knockout (IDS-ko) mouse retained self-renewal capacity in vitro, but differentiated earlier than wild-type (wt) cells, displaying an evident lysosomal aggregation in oligodendroglial and astroglial cells. Consistently, the SVZ of IDS-ko mice appeared similar to the wt SVZ, whereas the cortex and striatum presented a disorganized neuronal pattern together with a significant increase of glial apoptotic cells, suggesting that glial degeneration likely precedes neuronal demise. Interestingly, a very similar pattern was observed in the brain cortex of a Hunter patient. These observations both in vitro, in our model, and in vivo suggest that IDS deficit seems to affect the late phases of neurogenesis and/or the survival of mature cells rather than NSC self-renewal. In particular, platelet-derived growth factor receptor-α-positive (PDGFR-α+) glial progenitors appeared reduced in both the IDS-ko NSCs and in the IDS-ko mouse and human Hunter brains, compared with the respective healthy controls. Treatment of mutant NSCs with IDS or PDGF throughout differentiation was able to increase the number of PDGFR-α+ cells and to reduce that of apoptotic cells to levels comparable to wt. This evidence supports IDS-ko NSCs as a reliable in vitro model of the disease, and suggests the rescue of PDGFR-α+ glial cells as a therapeutic strategy to prevent neuronal degeneration.

Combination of aprepitant, palonosetron and dexamethasone as antiemetic prophylaxis in lung cancer patients receiving multiple cycles of cisplatin-based chemotherapy.

Introduction: With repeated courses of chemotherapy, chemotherapy-induced nausea and vomiting (CINV) becomes progressively more difficult to control. The aim of this study was to evaluate whether the antiemetic efficacy of the triple combination aprepitant, palonosetron and dexamethasone could be sustained for up to six cycles of highly emetogenic chemotherapy (HEC) (cisplatin ≥ 50 mg/m(2) ). Methods: Chemotherapy-naive patients receiving cisplatin-based HEC, were treated with palonosetron 0.25 mg/i.v., dexamethasone 20 mg/i.v. and aprepitant 125 mg/p.o. 1 h before chemotherapy. Aprepitant 80 mg/p.o. and dexamethasone 4 mg/p.o. were administered on days 2-3. The primary endpoint was complete response (CR, no vomiting and no use of rescue medication), over 5 days following HEC in up to six cycles. Secondary endpoints were emesis-free and nausea-free rates. Safety was also evaluated. Results: One hundred and fifty six lung cancer patients were included in the study; the median age was 64 years and 76.9% were men. The minimum cisplatin dosage was 75 mg/m(2) , and in most patients was combined with another drug (87.4%). CR ranged from 74.4% (first cycle) to 82% (sixth cycle). More than 90% and 60% of patients were emesis-free and nausea-free during all chemotherapy cycles. The most commonly reported side effects were constipation and headache. Conclusions: The triple combination of aprepitant, palonosetron and dexamethasone enhanced not only the antiemetic protection during the first cycle, but its efficacy was also sustained for up to six cycles of cisplatin-based HEC in lung cancer patients.

DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression.

Ataxia-telangiectasia (A-T) is a neurodegenerative disorder caused by defects in the ATM kinase, a component of the DNA-damage response (DDR). Here, we employed an immortalized human neural stem-cell line (ihNSC) capable of differentiating in vitro into neurons, oligodendrocytes and astrocytes to assess the ATM-dependent response and outcome of ATM ablation. The time-dependent differentiation of ihNSC was accompanied by an upregulation of ATM and DNA-PK, sharp downregulation of ATR and Chk1, transient induction of p53 and by the onset of apoptosis in a fraction of cells. The response to ionizing radiation (IR)-induced DNA lesions was normal, as attested by the phosphorylation of ATM and some of its substrates (e.g., Nbs1, Smc1, Chk2 and p53), and by the kinetics of gamma-H2AX nuclear foci formation. Depletion in these cells of ATM by shRNA interference (shATM) attenuated the differentiation-associated apoptosis and response to IR, but left unaffected the growth, self-renewal and genomic stability. shATM cells generated a normal number of MAP2/beta-tubulin III+ neurons, but a reduced number of GalC+ oligodendrocytes, which were nevertheless more susceptible to oxidative stress. Altogether, these findings highlight the potential of ihNSCs as an in vitro model system to thoroughly assess, besides ATM, the role of DDR genes in neurogenesis and/or neurodegeneration.

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.

[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".

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.

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.

[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.

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.

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.

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.

Fusion and metabolism of plant cells as affected by microgravity.

Plant cell protoplasts derived from leaf tissue of two different tobacco species (Nicotiana tabacum., N. rustica L.) were exposed to short-term (sounding rocket experiments) and long-term (spacelab) microgravity environments in order to study both (electro) cell fusion and cell metabolism during early and later stages of tissue regeneration. The period of exposure to microgravity varied from 10 min (sounding rocket) to 10 d (space shuttle). The process of electro fusion of protoplasts was improved under conditions of microgravity: the time needed to establish close membrane contact between protoplasts (alignment time) was reduced (5 as compared to 15 s under 1 g) and numbers of fusion products between protoplasts of different specific density were increased by a factor of about 10. In addition, viability of fusion products, as shown by the ability to form callus, increased from about 60% to more than 90%. Regenerated fusion products obtained from both sounding-rocket and spacelab experiments showed a wide range of intermediate properties between the two parental plants. This was verified by isozyme analysis and random amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR). In order to address potential metabolic responses, more general markers such as the overall energy state (ATP/ADP ratio), the redox charge of the diphosphopyridine nucleotide system (NADH/NAD ratio), and the pool size of fructose-2,6-bisphosphate (Fru 2,6 bisp), a regulator of the balance between glycolysis and gluconeogenesis, were determined. Responses of these parameters were different with regard to short-term and long-term exposure. Shortly after transition to reduced gravitation (sounding rocket) ratios of ATP/ADP exhibited strong fluctuation while the pool size of NAD decreased (indicating an increased NADH/NAD ratio) and that of Fru 2,6 bisp increased. As similar changes can be observed under stress conditions, this response is probably indicative of a metabolic stress compensation. Samples taken for up to 7 d of exposure to microgravity showed the opposite effect. Here, the ratios of ATP/ADP and of NADH/NAD, and the pool size of Fru 2,6 bisp were decreased. We take this an an indication of metabolic relaxation, i.e. decreased metabolic turnover. As rates of protoplast regeneration and cell division were obviously similar to 1-g controls, we conclude that under conditions of microgravity regenerating tobacco mesophyll protoplasts need less metabolic energy for the same effort.