PARP1 allows proper telomere replication through TRF1 poly (ADP-ribosyl)ation and helicase recruitment.

Telomeres are nucleoprotein structures at eukaryotic chromosome termini. Their stability is preserved by a six-protein complex named shelterin. Among these, TRF1 binds telomere duplex and assists DNA replication with mechanisms only partly clarified. Here we found that poly (ADP-ribose) polymerase 1 (PARP1) interacts and covalently PARylates TRF1 in S-phase modifying its DNA affinity. Therefore, genetic and pharmacological inhibition of PARP1 impairs the dynamic association of TRF1 and the bromodeoxyuridine incorporation at replicating telomeres. Inhibition of PARP1 also affects the recruitment of WRN and BLM helicases in TRF1 containing complexes during S-phase, triggering replication-dependent DNA-damage and telomere fragility. This work unveils an unprecedented role for PARP1 as a "surveillant" of telomere replication, which orchestrates protein dynamics at proceeding replication fork.

Locomotion performance for oscillatory swimming in free mode.

Oscillatory swimming of a fishlike body, whose motion is essentially promoted by the flapping tail, has been studied almost exclusively in axial mode under an incoming uniform stream or, more recently, self-propelled under a virtual body resistance. Obviously, both approaches do not consider the unavoidable recoil motions of the real body which have to be necessarily accounted for in a design procedure for technological means. Actually, once combined with the prescribed kinematics of the tail, the recoil motions lead to a remarkable improvement on the resulting swimming performance. An inviscid impulse model, linear in both potential and vortical contributions, is a proper tool to obtain a deeper comprehension of the physical events with respect to more elaborated flow interaction models. In fact, at a first look, the numerical results seem to be quite entangled, since their trends in terms of the main flapping parameters are not easy to be identified and a fair interpretation is obtained by means of the model capability to separate the effects of added mass and vortex shedding. Specifically, a prevailing dependence of the potential contribution on the heave amplitude and of the vortical contribution on the pitch amplitude is instrumental to unravel their combined action. A further aid for a proper interpretation of the data is provided by accounting separately for a geometrical component of the recoil which is expected to follow from the annihilation of any spurious rigid motion in case no fluid interactions occur. The above detailed decomposition of the recoil motions shows, through the numerical results, how the single components are going to influence the main flapping parameters and the locomotion performance as a guide for the design of biomimetic swimmers.

The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.

Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in the front-line setting. Thereafter, two other proteasome inhibitors (carfilzomib and ixazomib), designed to overcome resistance to bortezomib, have been approved for treatment-experienced patients, and a variety of novel inhibitors are currently under preclinical and clinical investigation not only for haematological malignancies but also for solid tumours. However, since UPS collapse leads to toxic misfolded proteins accumulation, proteasome is attracting even more interest as a target for the care of neurodegenerative diseases, which are sustained by UPS impairment. Thus, conceptually, proteasome activation represents an innovative and largely unexplored target for drug development. According to a multidisciplinary approach, spanning from chemistry, biochemistry, molecular biology to pharmacology, this review will summarize the most recent available literature regarding different aspects of proteasome biology, focusing on structure, function and regulation of proteasome in physiological and pathological processes, mostly cancer and neurodegenerative diseases, connecting biochemical features and clinical studies of proteasome targeting drugs.

Evaluation of biological and antimicrobial properties of freeze-dried whey fermented by different strains of Lactobacillus plantarum.

The aim of this study was to evaluate the biological and antimicrobial activities of commercial freeze-dried whey fermented by lactic acid bacteria in order to valorize this high polluting liquid waste of the dairy industry. Freeze-dried whey was fermented by different strains of Lactobacillus plantarum (CECT 220, 221, 748) at three different times of fermentation (24, 48, 72 h). Afterwards, the extract was purified on centricon amicon with a cut-off of 3 kDa to obtain a permeate consisting of small bioactive compounds reported in the literature to show greater bioactivity. The purified and diluted samples were subjected to the biological and antimicrobial tests for the evaluation of antioxidant, antihypertensive, iron binding, and antifungal activities and identification of phenolic compounds. The results highlighted a radical cation scavenging activity ranging from 1.415 to 2.083 mmol trolox equivalents TE per kg of dry weight, a percentage of iron binding capacity ranging between 23-55% and a percentage of ACE inhibitory activity ranging between 67-85%. The optimal biological activity was obtained from whey fermented by L. plantarum 220 for all the assays performed, except for the iron chelating activity. Furthermore, the antifungal analysis showed a good activity against the mycotoxigenic fungi belonging to Fusarium generum (F. moniliformis, F. graminearum and F. verticillioides), while a slight activity was obtained for Aspergillus and Penicillium generum. This antifungal activity could be correlated to the production of phenolic compounds during fermentation. The obtained results support the hypothesis of using whey as a functional ingredient to improve food preservation.

Tuberculosis of the eye in Italy: a forgotten extrapulmonary localization.

PURPOSE: Tuberculosis (TB) of the eye is a well-known extrapulmonary localization in high-incidence countries. Data on its relevance in developed countries are scanty. We aim to study the epidemiological and clinical pattern of ocular TB in a tertiary care institution of a western country. METHODS: From 2007 to 2010, consecutive patients with a diagnosis of isolated ocular TB or associated to extraocular TB were recruited. Patients with ophthalmological and clinical features of TB were treated with standard antitubercular therapy (ATT) and steroids in case of concomitant severe ocular inflammation. RESULTS: Seventeen cases of ocular and extraocular TB and 45 cases of isolated ocular TB were identified. The proportion of patients with ocular and extraocular TB in our local district was 8.1 %, with a proportion of 10.6 % for the isolated cases. In Cohort 1, only one patient was symptomatic for ocular impairment, and uveitis without inflammation was the most common presentation. On the contrary, in Cohort 2, all patients had visual impairment, mainly with bilateral involvement. 77.8 % of the patients showed an inflammatory pattern. ATT was administered for at least 9 months, in four cases with a short course of systemic corticosteroids. Eight cases in Cohort 2 showed recurrence after 1 year from diagnosis. CONCLUSIONS: TB of the eye should not be forgotten, even in geographical areas not considered among endemic countries. Ocular evaluation is advisable in patients with pulmonary and extrapulmonary TB, as early detection may allow ATT to preserve visual acuity.

Targeted therapy for brain tumours: role of PARP inhibitors.

The prognosis of malignant glioma and metastatic brain tumours is still extremely poor, despite recent advances in therapeutic strategies with molecular-targeted agents. Poly(ADP-ribose) polymerase (PARP) inhibitors are a promising, novel class of anticancer drugs to be used either as single agents or in combination with chemotherapy and radiotherapy. PARP-1 and PARP-2 are the only PARP proteins that bind to DNA single strand breaks (SSBs), facilitating the repair process by the base excision repair. For this reason, PARPs have been extensively investigated as targets of novel drugs that may be used to enhance the antitumour activity of SSBs inducing agents, such as the methylating compound temozolomide, which is the drug of choice for glioblastoma, or ionizing radiations. Moreover, PARP inhibitors exert cytotoxic effects in monotherapy in BRCA mutated tumours, which are defective in the homologous recombination (HR) repair. Finally, recent studies have shown that inhibition of PARP function might also induce anti-angiogenic effects which might contribute to impair tumour growth. Many clinical trials with PARP inhibitors are ongoing for the treatment of a variety of advanced solid tumours, including primary or secondary brain tumours. This review discusses the implications of targeting PARP on the design of new treatment regimens.

Chagas disease in Italy: breaking an epidemiological silence.

Chagas disease, a neglected tropical disease that due to population movements is no longer limited to Latin America, threatens a wide spectrum of people(travellers, migrants, blood or organ recipients,newborns, adoptees) also in non-endemic countries where it is generally underdiagnosed. In Italy, the available epidemiological data about Chagas disease have been very limited up to now, although the country is second in Europe only to Spain in the number of residents from Latin American. Among 867 at-risk subjectsscreened between 1998 and 2010, the Centre for Tropical Diseases in Negrar (Verona) and the Infectious and Tropical Diseases Unit, University of Florence found 4.2% patients with positive serology for Chagas disease (83.4% of them migrants, 13.8% adoptees).No cases of Chagas disease were identified in blood donors or HIV-positive patients of Latin American origin. Among 214 Latin American pregnant women,three were infected (resulting in abortion in one case).In 2005 a case of acute Chagas disease was recorded in an Italian traveller. Based on our observations, we believe that a wider assessment of the epidemiological situation is urgently required in our country and public health measures preventing transmission and improving access to diagnosis and treatment should be implemented.

Expression of the soluble vascular endothelial growth factor receptor-1 in cutaneous melanoma: role in tumour progression.

BACKGROUND: Vascular endothelial growth factor (VEGF)-A, placenta growth factor (PlGF) and their corresponding membrane receptors are involved in autocrine and paracrine regulation of melanoma growth and metastasis. Besides the membrane receptors, a soluble form of the VEGF receptor (VEGFR)-1 (sVEGFR-1) has been identified, that behaves both as a decoy receptor, sequestering VEGF-A and PlGF, and as an extracellular matrix (ECM) molecule, promoting endothelial cell adhesion and migration through the interaction with α5ß1 integrin. OBJECTIVES: To analyse whether sVEGFR-1 plays a role during melanoma progression. METHODS: sVEGFR-1 expression was evaluated in a panel of 36 melanoma cell lines and 11 primary human melanocyte cultures by quantitative real-time polymerase chain reaction analysis and in specimens of primary or metastatic melanoma lesions from 23 patients by immunohistochemical analysis. RESULTS: sVEGFR-1 expression was highly upregulated in melanoma cell lines with respect to human melanocytes. Interestingly, cell lines obtained from cutaneous metastases showed a significant reduction of sVEGFR-1 expression, as compared with cell lines derived from primary tumours. These results were confirmed by immunohistochemical analysis of sections from primary skin melanomas and the corresponding cutaneous metastases, suggesting that modulation of sVEGFR-1 expression influences ECM invasion by melanoma cells and metastasis localization. Moreover, we provide evidence that adhesion of melanoma cells to sVEGFR-1 is favoured by the activation of a VEGF-A/VEGFR-2 autocrine loop. CONCLUSIONS: Our data strongly suggest that sVEGFR-1 plays a role in melanoma progression and that low sVEGFR-1/VEGF-A and sVEGFR-1/transmembrane VEGFR-1 ratios might predict a poor outcome in patients with melanoma.

PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy.

New anti-telomere strategies represent important goals for the development of selective cancer therapies. In this study, we reported that uncapped telomeres, resulting from pharmacological stabilization of quadruplex DNA by RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate), trigger specific recruitment and activation of poly-adenosine diphosphate (ADP) ribose polymerase I (PARP1) at the telomeres, forming several ADP-ribose polymers that co-localize with the telomeric repeat binding factor 1 protein and are inhibited by selective PARP(s) inhibitors or PARP1-specific small interfering RNAs. The knockdown of PARP1 prevents repairing of RHPS4-induced telomere DNA breaks, leading to increases in chromosome abnormalities and eventually to the inhibition of tumor cell growth both in vitro and in xenografts. More interestingly, the integration of a TOPO1 inhibitor on the combination treatment proved to have a high therapeutic efficacy ensuing a complete regression of the tumor as well as a significant increase in overall survival and cure of mice even when treatments started at a very late stage of tumor growth. Overall, this work reveals the unexplored link between the PARP1 and G-quadruplex ligands and demonstrates the excellent efficacy of a multi-component strategy based on the use of PARP inhibitors in telomere-based therapy.

Gitelman syndrome: pathophysiological and clinical aspects.

Giltelman syndrome (GS) is a recessive salt-losing tubulopathy of children or young adults caused by a mutation of genes encoding the human sodium chloride cotransporters and magnesium channels in the thiazide-sensitive segments of the distal convoluted tubule. The plasma biochemical picture is characterized by hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis and hypereninemic hyperaldosteronism. However, patients with GS present some clinical and biochemical alterations resembling that observed in thiazide diuretics abuse. On the pathophysiological point of view, GS represents a useful and interesting human model to better understand the clinical consequences of plasma hydro-electrolytes and acid-base derangements, associated with multiple hormonal alterations. The impact of this complex disorder involves cardiovascular, muscle-skeletal and some other physiological functions, adversely affecting the patient's quality of life. This review tries to summarize and better explain the linkage between the electrolytes, neurohormonal derangements and clinical picture. Moreover, the differential diagnosis between other similar electrolyte-induced clinical disorders and GS is also discussed.

Pharmacological inhibition of poly(ADP-ribose) polymerase (PARP) activity in PARP-1 silenced tumour cells increases chemosensitivity to temozolomide and to a N3-adenine selective methylating agent.

We recently demonstrated that poly(ADP-ribose) polymerase (PARP)-1 is involved in angiogenesis and tumour aggressiveness. In this study we have compared the influence of abrogation of PARP-1 expression by stable gene silencing to that of the pharmacological inhibition of cellular PARP activity using PARP-1/-2 inhibitors on the chemosensitivity of tumour cells to the wide spectrum methylating agent temozolomide (TMZ) and to the N3-adenine selective methylating agent {1-methyl-4-[1-methyl-4-(3-methoxysulfonylpropanamido)pyrrole-2-carboxamido]-pyrrole-2-carboxamido}propane (Me-Lex). Silencing of PARP-1 in melanoma or cervical carcinoma lines enhanced in vitro sensitivity to TMZ and Me- Lex, and induced a higher level of cell accumulation at the G2/M phase of cell cycle with respect to controls. GPI 15427, which inhibits both PARP-1 and PARP-2, increased sensitivity to TMZ and Me-Lex both in PARP-1-proficient and - deficient cells. However, it induced different cell cycle modulations depending on PARP-1 expression, provoking a G2/M arrest only in PARP-1 silenced cells. Treatment of PARP-1 silenced cells with TMZ or Me-Lex resulted in a more extensive phosphorylation of Chk-1 and p53 as compared to PARP-1 proficient cells. The combination of the methylating agents with GPI 15427 increased Chk-1 and p53 phosphorylation both in PARP-1 proficient or deficient cells. When mice challenged with PARP-1 silenced melanoma cells were treated with the TMZ and PARP inhibitor combination there was an additional reduction in tumour growth with respect to treatment with TMZ alone. These results suggest the involvement of PARP-2 or other PARPs, in the repair of DNA damage provoked by methylating agents, highlighting the importance of targeting both PARP-1 and PARP-2 for cancer therapy.

Impact of clinical data on chest radiography sensitivity in detecting pulmonary abnormalities in immunocompromised patients with suspected pneumonia.

PURPOSE: Chest radiography (CXR) of immunocompromised patients has low sensitivity in the early evaluation of pulmonary abnormalities suspected to be infectious. The purpose of the study was to evaluate whether the knowledge of clinical data improves the diagnostic sensitivity of CXR in the particular setting of immunocompromised patients after hematopoietic stem cell transplantation (HSCT). MATERIALS AND METHODS: Sixty-four CXRs of immunocompromised patients with clinically suspected pneumonia were retrospectively and independently evaluated by two radiologists to assess the presence of radiological signs of pneumonia, before (first reading) and after (second reading) the knowledge of clinical data. A chest computed tomography (CT) performed within 3 days was assumed as the standard of reference. For each reading, sensitivity of both radiologists was calculated. RESULTS: Readers showed a sensitivity of 39% and 58.5% for the first reading, and 43.9% and 41.5% for the second reading, respectively. For both readers, these values were not significantly different from those obtained at first reading (McNemar's test, p>0.05). Interobserver agreement at second reading was fair (Cohen test, k=0.33). CONCLUSIONS: The sensitivity of CXR is too low to consider it a stand-alone technique for the evaluation of immunocompromised patients after HSCT with suspected pneumonia, even if the radiologist knows detailed clinical data. For these patients, an early chest CT evaluation is therefore recommended.

[Pathophysiology and prevention of contrast-induced acute renal failure]. / Fisiopatologia e prevenzione della insufficienza renale acuta da mezzo di contrasto.

Although the infusion of iodinated contrast media in diagnostic and interventional procedures may cause acute renal failure (ARF) especially in older or diabetic patients with preexisting nephropathy, these procedures are often unavoidable. Contrast medium-induced ARF is defined as an increase in serum creatinine of 0.5 mg/dL or a 25% or greater relative increase from baseline within 72 hours of iodinated contrast medium infusion. Because it is often very difficult to employ alternative diagnostic procedures, it is mandatory to adopt prophylactic protocols to prevent radiocontrast nephropathy. Renal hemodynamic lesions leading to medullary hypoxia, oxygen free radicals inducing tubular cell alterations, and parenchymal vasoconstriction are the main factors in the pathogenesis of contrast-induced ARF. Among the many proposed protocols to prevent contrast-induced renal toxicity, the most effective procedure is hydration with 1 mL/kg/h of isotonic saline solution in the 12 hours before and after contrast medium infusion. Promising results in terms of cardiac and renal protection have been reported in a recent trial with the use of high-dose N-acetylcysteine acting as an oxygen free radical scavenger: an intravenous bolus of 1200 mg N-acetylcysteine was given before coronary angiography followed by 1200 mg orally twice a day for 48 hours after the procedure. The protective effect seemed to involve not only the kidney: the drug was found to induce a significant reduction of the necrotic area in myocardial infarction.

Anti-TNF-alpha therapy in seven patients with Behcet's uveitis: advantages and controversial aspects.

Behcet's disease (BD) is a chronic, relapsing, multisystem disease. In some patients, ocular involvement can lead to severe vision impairment despite immunosuppressive therapy. Since high levels of circulating TNF-alpha have been found both in peripheral blood and aqueous humor of patients with active BD, we evaluated the efficacy of anti-TNF-alpha therapy in seven patients with severe ocular involvement resistant to previous treatment. Seven patients with sight-threatening relapsing uveitis refractory to immunosuppressive regimens received intravenously infliximab, at a dose of 3-5 mg/kg, on week 0-2-4 and then every 6-8 weeks, in combination with low-dose prednisone and methotrexate or azathioprine. Efficacy was assessed in terms of number and severity of relapses of posterior uveitis, visual acuity, and reduction of corticosteroids and immunosuppressive drugs. After a mean follow-up period of 23 months, the total number of relapses dropped to 6, compared to the 21 observed in an equivalent period of time before treatment. The visual acuity improved in 4 eyes, while it remained stable in 9. Therapy with infliximab considerably reduced the required daily dose of both corticosteroids and immunosuppressive drugs. In our experience infliximab proved to be safe and effective in controlling both the number and intensity of cases of posterior uveitis and the extraocular manifestations of BD. It also allowed a reduction of corticosteroids and immunosuppressive drugs required to control the disease. However, ocular and systemic manifestations tended to recur after drug withdrawal or when the interval between infliximab courses was longer than 8 weeks. Moreover, infliximab administration is costly and requires hospital admission.

[Sepsis, acute renal failure and multiple organ dysfunction syndrome]. / Sepsi, insufficienza renale acuta e "multiple organ dysfunction syndrome".

The so-called systemic inflammatory response syndrome (SIRS ) represents the cellular inflammatory and neuroendocrine systemic reaction in response to many adverse events. epsis is defined as IR induced by bacterial, mycotic or viral toxins. The circulating toxins deriving from the bacterial wall can activate the septic cascade that induces many systemic reactions involving the activation of the cellular immunity, complement and coagulation system. The endothelial cell is the target of the systemic phlogistic reaction; its stimulation is followed by the production of many vasoactive paracrine and systemic agents. In this context, local and systemic cytokine production plays a major role in inducing the septic cascade, which although meant to be a phlogistic defense reaction, can often become an uncontrolled and dangerous inflammatory reaction. The sepsis-derived lesions can involve many organs and apparatus leading to the picture of sepsis syndrome. Sepsis syndrome often induces severe pulmonary lesions with a picture of acute respiratory distress syndrome (ARDS ). The combination of acute renal failure and sepsis is associated with a high mortality rate, namely in patients with a nitric oxide-induced systemic reduction in peripheral vascular resistances and septic shock. The toxinemia can also induce myocardial damage with a reduction in cardiac performance. Therefore, septic patients who have a combination of pulmonary, cardio-vascular, renal and cerebral lesions present with the picture of multiple organ dysfunction syndrome, that can increase mor-tality to > 0%.

[Polymyxin-B direct hemoperfusion (PMX-DHP) in gram negative sepsis]. / L'moperfusione diretta con Polimixina-B (PMX-DHP) nel trattamento della sepsi da gram negativi.

UNLABELLED: Severe sepsis and septic shock have a mortality rate that may range between 28 and 50%. It is estimated that approximately 200,000 patients die per annum in the USA as a consequence of sepsis. The reduction of plasma endotoxin levels to achieve a favourable outcome for septic patients has been previously demonstrated but the effectiveness of treatments targeting single inflammatory mediators during established sepsis has been disappointing. Furthermore,some clinical study clinically showed valuable reduction in cytokine levels by hemofiltration alone. The prompt removal of endotoxins could be an effective way to reduce the immunological activation and the amount of NO produced by endotoxin-activated inducible NO-synthase in many tissues and cells. The polymyxin B cartridge is an extracorporeal hemoperfusion device (PMX-DHP) known to remove circulating endotoxins. Open-label clinical trials testing PMX-DHP have demonstrated its safety in the septic shock treatment while the overall survival rate significantly improved in comparison with the control groups. The purpose of this study was to investigate the effects of PMX-DHP on redox status, inflammatory cytokine profile, monocytes and PMN leukocyte activation in Gram-negative sepsis. Prospective study: six patients, 2 males and 4 females 60.5+/-24.5 years old, in ICU for severe Gram-negative sepsis (emergency surgery for intra abdominal infection). Two PMX-DHP runs, at T0 and T1; 2 hours each; the first within 24 hours from sepsis diagnosis or 12 hours after emergency surgery, the first PMX-DHP at T0, the second after 24 hours.; APACHE II score at T0: 20.1+/-3.7; SOFA score 14.2+/-2.5; organ failure: 3+/-1.5; norepinephrine(Ne) in 1 patient; Ne + dopamine (DA) in 4 patients; DA in 1 patient only. Mean dosage: Ne 0.24 mcg/kg/min; DA 8.9 mcg/kg/min. Four patients in CRRT (continuous veno-venous hemofiltration, AN69 hemofilter) for the entire length of the study. QB 100+/-10 ml/min. Pre and post PMX-DHP, plasma endotoxins as well as anti-IL 1-beta, IL2, IL4, IL5, IL6, IL8, IL10, TNF-alpha, GM-CSF, IFN-gamma levels were measured. Expression of CD64 on monocytes and PMN leukocytes and I -2r CD25 on CD4+ T cells by flow cytometry. Total and reduced plasma cysteine, homocysteine, glutathione (GSH); plasma glutathione peroxidase (GSH-Px) and reductase (GSH-Rx); erythrocyte GSH (eGSH), eGSH-Px and eGSH-Rx; NADP and NADPH and their ratio assessed pre and post PMX-DHP, all compared with 15 age and gender-matched healthy subjects for complete REDOX characterization. RESULTS: We observed a significant reduction of endotoxin levels post PMX-DHP; CD64 monocytes and PMN leukocytes overexpression returned to normal; pro-inflammatory cytokines Il6, Il 10 and TNF-alpha were significantly reduced. We detected no differences in plasma levels of anti-IL 1-beta, IL2, IL4, IL5, IL8, GM-CSF, IFN-gamma pre versus post PMX-DHP. SOFA score from 14.2+/-2.5 to 8.9+/-2.1 post PMX-DHP runs. Four out of six patients survived and were discharged; mortality was 33% versus the anticipated 51%. CONCLUSION: PMX-DHP reduces circulating endotoxins, down-activates monocytes and PMN leukocytes, reduces pro-Inflammatory cytokines and corrects the redox environment imbalance preventing oxidative damage to endothelial cells and the metabolic and functional microvascular derangements that usually lead to multi-organ failure and septic shock.

A randomized controlled trial on the efficacy of physical exercise in patients braced for instability of the lumbar spine.

AIM: Spinal instability is often disregarded as a cause of chronic low back pain and until now there has been no agreement as to its definition and on its nosologic importance or as to a conservative therapeutic protocol. The authors aim to verify whether possible symptomatological characteristics are reflected in radiological findings and, although there is no univocal opinion on the utilization of orthoses of containment for unstable segments, they also aim to verify their efficacy on pain control and neuromotor performance when employed in isolation or in association with the most reliable rehabilitation techniques. METHODS: Forty-eight patients between the ages of 30 and 50 were entered in the study, selected with special exclusion criteria and appropriately randomized to a group following kinesitherapy (KT) and orthoses (O) (O+KT group) and to a control group (orthoses [O] group); the symptomatological and instrumental characteristics were studied at time intervals 0 (t0), 3 months (t3), 6 months (t6), and 12 months (12t). RESULTS: The samples examined present homogeneous characteristics. Lumbar instability pain is related to the presence of shift and not to hypermobility, when the latter is guided by efficient neuromotor feedback. In the O+KT group, treatment achieves the two-fold results of reducing shift and increasing mobility in the absence of pain. Both groups tend to increase the utilization of a brace over time. Furthermore, in the O+KT group, a marked reduction in the use of medicine is noticed. CONCLUSIONS: Following treatment both groups report a decrease in pain even though the results of neuromotor performance prove to be better in the group following KT.

Apple polyphenol extracts prevent damage to human gastric epithelial cells in vitro and to rat gastric mucosa in vivo.

BACKGROUND: Fresh fruit and vegetables exert multiple biological effects on the gastrointestinal mucosa. AIM: To assess whether apple extracts counteract oxidative or indomethacin induced damage to gastric epithelial cells in vitro and to rat gastric mucosa in vivo. METHODS: Apple extracts were obtained from freeze dried apple flesh of the "Annurca" variety. Cell damage was induced by incubating MKN 28 cells with xanthine-xanthine oxidase or indomethacin and quantitated by MTT. In vivo gastric damage was induced by indomethacin 35 mg/kg. Intracellular antioxidant activity was determined using the (2,2'-azinobis (3-ethylbenzothiazolin-6-sulfonate) method. Malondialdehyde intracellular concentration, an index of lipid peroxidation, was determined by high pressure liquid chromatography with fluorometric detection. RESULTS: (1) Apple extracts decreased xanthine-xanthine oxidase or indomethacin induced injury to gastric epithelial cells by 50%; (2) catechin or chlorogenic acid (the main phenolic components of apple extracts) were equally effective as apple extracts in preventing oxidative injury to gastric cells; and (3) apple extracts (i) caused a fourfold increase in intracellular antioxidant activity, (ii) prevented its decrease induced by xanthine-xanthine oxidase, (iii) counteracted xanthine-xanthine oxidase induced lipid peroxidation, and (iv) decreased indomethacin injury to the rat gastric mucosa by 40%. CONCLUSIONS: Apple extracts prevent exogenous damage to human gastric epithelial cells in vitro and to the rat gastric mucosa in vivo. This effect seems to be associated with the antioxidant activity of apple phenolic compounds. A diet rich in apple antioxidants might exert a beneficial effect in the prevention of gastric diseases related to generation of reactive oxygen species.