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Climate change is increasing the occurrence of the so-called heatwaves with a trend that is expected to worsen in the next years due to global warming. The growing intensity and duration of these extreme weather events are leading to a significant number of power system failures, especially in urban areas. This is drastically affecting the reliability and normal operation of power distribution grids around the world, with high financial costs and huge negative impacts on people's life. Typically, the response to these failure events is approached by post-event analysis, aimed at identifying the grid areas that require resources to increase the resilience of the system and prevent future outages. Nevertheless, understanding the nature of heatwaves and forecasting their impact on power distribution systems can be useful to anticipate them and accelerate a reaction, possibly avoiding negative impacts on power systems and customers. In this study, a structured method to predict distribution grid disruptions caused by heatwaves is defined. The proposed method relies on machine learning to analyze previous failure data and forecast power grid outages using operational and meteorological information. The method is evaluated using real failure data from a large power distribution network located in southern Italy.

Listeriosis is an infective complication that primarily affects pregnant women, patients at extremes of age or those with weakened immune systems. Ingestion of food contaminated with Listeria monocytogenesis the most common source of infection, causing self-limiting illness in immunocompetent hosts but associated with invasive infection and high mortality in high-risk patient groups. Milder illness presents as gastroenteritis with fever, diarrhoea, nausea and vomiting common in the 7 days post exposure. Invasive infection, characterised by bacteraemia and encephalitis, can develop in high-risk patients. Fetal loss is a major complication of listeriosis during pregnancy. Penicillin-based therapy (high dose penicillin or amoxicillin) in combination with gentamicin is advised for invasive infection; co-trimoxazole may be considered for patients intolerant to penicillin. Vulnerable individuals, notably pregnant women, should be counseled on appropriate preventative strategies including avoiding foods commonly contaminated with L. monocytogenes, such as soft ripened cheeses, pate, cooked chilled meats, unpasteurised milk, and ready to eat poultry unless thoroughly cooked.

Over 25 years ago, GNASmutations were discovered associated with McCune–Albright syndrome (MAS) and pituitary tumors. The mutant gene, encoding the heterotrimeric Gs protein, was named ‘derived from Gs Protein’ (gsp) oncogene.For a long time, gspremained associated with specific endocrine tumors. Recently, high frequencies of gspwere reported for a rapidly growing number of neoplasms in the gastrointestinal tract. Will heterotrimeric G-proteins follow small G-proteins and become recognized as cancer biomarkers and therapeutic targets?

Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder, characterized by severe organ complication. Sickle bone disease (SBD) affects a large part of the SCD patient population, and its pathogenesis has been only partially investigated. Here, we studied bone homeostasis in a humanized mouse model for SCD. Under normoxia, SCD mice display bone loss and bone impairment, with increased osteoclast and reduced osteoblast activity. Hypoxia/reperfusion (H/R) stress, mimicking acute vaso-occlusive crises (VOCs), increased bone turnover, osteoclast activity (RankL), and osteoclast recruitment (Rank) with upregulation of IL-6as proresorptive cytokine. This was associated with further suppression of osteogenic lineage (Runx2, Sparc). To interfere with the development of SBD, zoledronic acid (Zol), a potent inhibitor of osteoclast activity/osteoclastogenesis and promoter of osteogenic lineage, was used in H/R-exposed mice. Zol markedly inhibited osteoclast activity and recruitment, promoting osteogenic lineage. The recurrent H/R stress further worsened bone structure, increased bone turnover, depressed osteoblastogenesis (Runx2, Sparc), and increased both osteoclast activity (RankL, Cathepsin k) and osteoclast recruitment (Rank) in SCD mice compared with either normoxic or single-H/R-episode SCD mice. Zol used before recurrent VOCs prevented bone impairment and promoted osteogenic lineage. Our findings support the view that SBD is related to osteoblast impairment, and increased osteoclast activity resulted from local hypoxia, oxidative stress, and the release of proresorptive cytokine such as IL-6. Zol might act on both the osteoclast and osteoblast compartments as multimodal therapy to prevent SBD.

Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder, characterized by severe organ complication. Sickle bone disease (SBD) affects a large part of the SCD patient population, and its pathogenesis has been only partially investigated. Here, we studied bone homeostasis in a humanized mouse model for SCD. Under normoxia, SCD mice display bone loss and bone impairment, with increased osteoclast and reduced osteoblast activity. Hypoxia/reperfusion (H/R) stress, mimicking acute vaso-occlusive crises (VOCs), increased bone turnover, osteoclast activity (RankL), and osteoclast recruitment (Rank) with upregulation of IL-6 as proresorptive cytokine. This was associated with further suppression of osteogenic lineage (Runx2, Sparc). To interfere with the development of SBD, zoledronic acid (Zol), a potent inhibitor of osteoclast activity/osteoclastogenesis and promoter of osteogenic lineage, was used in H/R-exposed mice. Zol markedly inhibited osteoclast activity and recruitment, promoting osteogenic lineage. The recurrent H/R stress further worsened bone structure, increased bone turnover, depressed osteoblastogenesis (Runx2, Sparc), and increased both osteoclast activity (RankL, Cathepsin k) and osteoclast recruitment (Rank) in SCD mice compared with either normoxic or single-H/R-episode SCD mice. Zol used before recurrent VOCs prevented bone impairment and promoted osteogenic lineage. Our findings support the view that SBD is related to osteoblast impairment, and increased osteoclast activity resulted from local hypoxia, oxidative stress, and the release of proresorptive cytokine such as IL-6. Zol might act on both the osteoclast and osteoblast compartments as multimodal therapy to prevent SBD.

Epilepsy is a common disorder but diagnosis remains largely clinical. Although MRI and EEG significantly aid the diagnosis of epilepsy, these techniques may also be misleading and indicate abnormalities not related to phenomenology. Consequences of erroneous diagnosis of epilepsy may lead to aggressive and escalating pharmacotherapy with potentially serious side effects. Metabolic disorders, which may mimic epilepsy, should always be considered as they are potentially curable and may be fatal if untreated. We report a case of an insulinoma, misdiagnosed as temporal lobe epilepsy. We highlight the risks associated with misinterpretation of neuroimaging and EEG and outline an approach to differentiate between symptoms of insulinoma or neuroglycopenia and temporal epileptic seizures.

Epilepsy is a common disorder but diagnosis remains largely clinical. Although MRI and EEG significantly aid the diagnosis of epilepsy, these techniques may also be misleading and indicate abnormalities not related to phenomenology. Consequences of erroneous diagnosis of epilepsy may lead to aggressive and escalating pharmacotherapy with potentially serious side effects. Metabolic disorders, which may mimic epilepsy, should always be considered as they are potentially curable and may be fatal if untreated. We report a case of an insulinoma, misdiagnosed as temporal lobe epilepsy. We highlight the risks associated with misinterpretation of neuroimaging and EEG and outline an approach to differentiate between symptoms of insulinoma or neuroglycopenia and temporal epileptic seizures.

Background and aims:Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase. hTERT expression and telomerase activity are elevated in most human tumors. Bisphosphonates play an important role in the management of tumors with the secondary involvement of bone. Methods:We investigated the effect on hTERT gene expression of clodronate, alendronate, and pamidronate (from 10- 6M to 10- 5M) on MCF-7 and T47D human breast cancer cells, using real time RT-PCR. Results:At 10- 5M, amino-bisphosphonates (alendronate and pamidronate) inhibited breast cancer cell viability and induced a significant decrease in hTERT gene expression with respect to controls (82% and 71% in MCF-7 cells; 74% and 60% in T47D, p<0.0001). No effect was observed with clodronate. Conclusions:Amino-bisphosphonates down-regulate hTERT gene expression. The role of hTERT is a new finding, which gives an alternative explanation for the direct effect of bisphosphonates on tumor cells.

Presurgical evaluation for patients with drug‐resistant epilepsy requires the definition of various zones that have a variable spatial relationship with the epileptogenic zone. All the available mehods to directly measure the actual seizure‐onset zone and to define “the minimum amount of cortical tissue that must be resected to produce seizure‐freedom” have significant limitations. We report on the case of a patient with dual pathology (hippocampal sclerosis and a post‐traumatic scar) and discuss the contribution of the various presurgical investigations that led to surgery and seizure‐freedom.

Paroxysmal motor phenomena and arousals during sleep are frequent. The differential diagnoses between benign hypnic transient events, epileptic and non‐epileptic seizures represent a common clinical problem. Video‐EEG monitoring during sleep, recording several episodes in the same patient, is essential in order to characterize these phenomena. It offers the possibility to compare electro‐clinical data, to demonstrate the eventual stereotyped pattern of motor phenomena and their progression in time, and to study EEG‐polygraphic correlates. The recently described double split‐screen synchronized display (DSSSD) technique represents a useful tool for comparing particular clinical patterns of epileptic seizures when dealing with complex, hypermotor phenomena observed in frontal lobe epilepsy. We reviewed the data of 24 patients admitted during a two‐year period (2002‐2003) to our epilepsy sleep unit for isolated paroxysmal sleep motor events. Four patients presented with very brief paroxysmal arousals without daytime fits. Three of our patients presented isolated paroxysmal arousals, whereas in one, the events were associated with hypermotor seizures. We present a simplified variant of the DSSSD method (modified DSSSD) that can be used to study episodes of paroxysmal arousals in order to confirm their stereotyped motor pattern. The clinical aspects and the EEG‐polygraphy patterns were informative, with the absence of asymmetrical tonic or dystonic posturing of the limbs. Scalp EEG alone does not usually provide much information in patients with isolated paroxysmal arousals. Coupled to the modified DSSSD technique, it may allow confirmation of the diagnosis of frontal epilepsy, as was the case in our four patients. [Published with video sequences] Content available: Video

Single photon emission computed tomography (SPECT) is currently used in the presurgical evaluation of medically intractable partial epilepsies, but not very often, in generalized epilepsy. In the present study, we used the SISCOM procedure, which represents the fusion of MRI and ictal‐interictal difference SPECT images using 99mTc‐ECD, to study cerebral blood flow changes during the ictal and postictal phases of typical childhood absence seizures. The study was performed on four children with typical, difficult to treat absence seizures, aged 10‐13 years at the time of scan. The delay between the onset of absence seizures and the injection of 99mTc‐ECD was carefully noted. One scan was performed during the ictal phase and showed diffuse blood flow decreases, while the three other scans performed during the postictal phase, showed generalized blood flow increase. These data are consistent with most previous data reporting generalized changes in functional activity, not limited to the thalamo‐cortical circuit in which absence seizures originate, and a decrease in cerebral blood flow during the ictal phase. Our data are concordant with the hypothesis that neuronal activity underlying the occurrence of spike‐and‐wave discharges does not seem to require an increase in metabolic demand and blood flow rates. [Published with videosequences] Content available: Video

Reading epilepsy (RE) is a form of reflex epilepsy currently classified as an idiopathic localization‐related epilepsy (ILAE, 1989). We describe a 30 year‐old right‐handed male who suffered since the age of 8 from nocturnal partial motor seizures. Clinical features were typical of BECT. We reviewed the EEG recorded at that time which showed centrotemporal spike and waves. He was seizure‐free from the age of 12 to the age of 17 when seizures evoked only by reading appeared. No other stimuli provoked seizures. Neurological and neuroradiological (CT and MR) investigations were normal. Baseline video‐polygraphic EEG recordings were normal while reading aloud provoked myoclonic jerks in the facial muscles related to bilateral spike and wave discharges. Therapy with carbamazepine and valproic acid strongly reduced seizure frequency. Recent papers have debated the difficulties in classifying RE among the generalized or focal syndromes. Literature reports describe an association with RE and juvenile myoclonic epilepsy, supporting the hypothesis of an idiopathic generalized form. We report the first documented case with a clear‐cut idiopathic localization‐related epilepsy evolving to a primary reading epilepsy. Content available: Video

A quantitatively and/or qualitatively abnormal duodenogastric reflux (DGR) could be involved in the pathogenesis of nonulcer dyspepsia (NUD). The aims of this prospective study were to look for (1) a pathological DGR profile during fasting and (2) an eventual correlation between DGR profile and clinical symptoms. Twenty-six NUD patients were investigated. Seven other operated patients with a surgical procedure facilitating DGR episodes and 27 healthy volunteers served as control groups. A clinical score was determined for each patient from a standardized questionnaire. Gastric aspiration was performed for 6 hr in fasting subjects. The aspirates were pooled into 17 samples. In each sample the concentration and the output of total bile acids was determined. If the concentration was larger than 30 µmol/liter in pooled samples, the concentrations of free bile acids and the distribution of the conjugated bile acids was determined. The percentage of aliquots with a total bile acid concentration larger than 50 µmol/liter (without upper limit), and the percentage with a concentration larger than 2500 µmol/liter was also obtained. No significant difference was demonstrated between the healthy volunteers and NUD patients, whatever the parameter considered. However, there was a significant increase in each of the quantitative parameters for the group of operated patients in comparison with the NUD patient group. No significant correlation was found between the clinical score and the DGR profile in NUD patients. Apparently, DGR episodes do not play a primary role in the pathogenesis of NUD.

A comparative analysis of the differentiation pattern, the proliferative behaviour, and the level of apoptosis between human benign and malignant neoplasms of smooth-muscle (SM) tissue is lacking. The clinical, histopathological, immunochemical, and immunocytochemical features of leiomyomas (LM) and leiomyosarcomas (LMS) were investigated by a panel of monoclonal antibodies specific for some differentiation markers of SM tissue (SM myosin and α-actin, desmin, and SM22) and for markers of non-muscle tissue (vimentin and non-muscle myosin). Proliferating normal and neoplastic cells were identified by proliferating-cell nuclear antigen (PCNA)/Ki67 immunostainings and the apoptotic cells were revealed by means of the terminal-deoxynucleotidyltransferase-mediated dUTP nick-end labelling technique. Gel electrophoresis and Western blotting, performed with anti-(SM1/SM2 myosin isoform) antibody, indicated quantitative differences between LMS and LM, which mirrored higher positive to negative nuclear ratios for PCNA, Ki67 and apoptosis in malignant as opposed to benign neoplasms. With LM, however, a similar SM1 to SM2 ratio could be associated with different proliferation levels. Uterine, gastric and intestinal LMS displayed specific patterns of SM1/SM2 and/or non-muscle myosin expression that were not paralled by different levels of proliferation/apoptosis. While the level of PCNA/Ki67 correlated with the level of apoptosis in normal SM tissues and LM, that of LMS did not. In vivo at the cellular level, LM and uterine LMS displayed a near-uniform SM tissue differentiation, whereas the other LMS displayed a lesser or a heterogeneous immunoreactivity. In vitro, cultured LMS cells showed a limited and peculiar expression of SM myosin. In conclusion, there is no reciprocal relationship between degree of differentiation and the level of proliferation, as exemplified by the finding that the less differentiated intestinal LMS displays the lowest proliferative behaviour and that the relatively more differentiated gastric LMS/metastasis is more proliferative.A comparative analysis of the differentiation pattern, the proliferative behaviour, and the level of apoptosis between human benign and malignant neoplasms of smooth-muscle (SM) tissue is lacking. The clinical, histopathological, immunochemical, and immunocytochemical features of leiomyomas (LM) and leiomyosarcomas (LMS) were investigated by a panel of monoclonal antibodies specific for some differentiation markers of SM tissue (SM myosin and α-actin, desmin, and SM22) and for markers of non-muscle tissue (vimentin and non-muscle myosin). Proliferating normal and neoplastic cells were identified by proliferating-cell nuclear antigen (PCNA)/Ki67 immunostainings and the apoptotic cells were revealed by means of the terminal-deoxynucleotidyltransferase-mediated dUTP nick-end labelling technique. Gel electrophoresis and Western blotting, performed with anti-(SM1/SM2 myosin isoform) antibody, indicated quantitative differences between LMS and LM, which mirrored higher positive to negative nuclear ratios for PCNA, Ki67 and apoptosis in malignant as opposed to benign neoplasms. With LM, however, a similar SM1 to SM2 ratio could be associated with different proliferation levels. Uterine, gastric and intestinal LMS displayed specific patterns of SM1/SM2 and/or non-muscle myosin expression that were not paralled by different levels of proliferation/apoptosis. While the level of PCNA/Ki67 correlated with the level of apoptosis in normal SM tissues and LM, that of LMS did not. In vivo at the cellular level, LM and uterine LMS displayed a near-uniform SM tissue differentiation, whereas the other LMS displayed a lesser or a heterogeneous immunoreactivity. In vitro, cultured LMS cells showed a limited and peculiar expression of SM myosin. In conclusion, there is no reciprocal relationship between degree of differentiation and the level of proliferation, as exemplified by the finding that the less differentiated intestinal LMS displays the lowest proliferative behaviour and that the relatively more differentiated gastric LMS/metastasis is more proliferative.

Benign neonatal sleep myoclonus (BNSM), characterized by myoclonic jerks of the extremities only in non-REM sleep, occurs in the first months of life with spontaneous disappearance within 3–4 months. We examined five siblings with typical BNSM, at the 3–10 years follow-up neurological examination. Psychomotor development, cognitive functions and EEG were completely normal. These cases confirm that BNSM is a self limited and nonepileptic disorder.

Erythropoiesis is a dynamic and multistep process, resulting in generation of red cells from hematopoietic stem cells. Aging is characterized by increased oxidation and reduced efficiency of cytoprotective mechanisms. Nrf2 is a key transcription factor that participates in acute response to oxidative stress and controls the expression of anti-oxidant and cytoprotective systems. We previously documented activation of Nrf2 during β-thalassemic erythropoiesis. In addition, a previous study reported a mild chronic hemolytic anemia as a result of increased erythrophagocytosis in mice genetically lacking Nrf2 (PNAS, 2004). Here, we show an age-dependent worsening of anemia in Nrf2-/-mice characterized by accelerated senescence of circulating erythrocytes in association with reticulocytopenia, suggesting a perturbation of erythroblast maturation. Indeed, we found ineffective erythropoiesis in 12 months-old Nrf2-/-mice with extramedullary erythropoiesis, increased ROS levels, reduction in the expression of Nrf2 related anti-oxidant proteins and apoptosis of erythroid precursor cells. In agreement, we observed an age dependent sensitivity of Nrf2-/-mice to stress erythropoiesis induced by either phenyhydrazine (PHZ) or doxorubicine. In 12-month-old mice we observed (i) activation of the unfoldeld protein response system (UPR) due to endosomal reticulum stress and (ii) impaired autophagy. The cytoprotective processes were unable to fully counteract oxidation re-directing cells towards apoptosis as supported by the increased activity of caspase-3. To understand the impact of oxidation in this model of accelerated senescence, we treated Nrf2-/-mice with astaxanthin, a powerful anti-oxidant but with low oral bioavailability, by administrating it in the form of PLGA loaded nanoparticles (ATS-NP). Treatment of Nrf2-/-mice with ATS-NP ameliorated the age-dependent anemia and decreased ineffective erythropoiesis through (i) inactivation of UPR system; (ii) improvement of autophagy and (iii) reduction in caspase-3 activity. In future studies, we plan to evaluate the impact of ATS-NP administration in other models of pathologic erythropoiesis. In summary, we propose that Nrf2, a key transcriptional factor plays a key protective role in regulating aged related oxidation and ensures normal erythroid maturation and growth.

No relevant conflicts of interest to declare.

Le syndrome FIRES correspond à une encéphalopathie épileptique survenant chez l’enfant. Nous rapportons les observations de deux femmes adultes ayant présentées un tableau clinique proche à celui décrit chez l’enfant.

La stéréo-électroencéphalographie (SEEG) est une méthode d’exploration invasive de l’épilepsie focale pharmacorésistante ayant pour buts d’identifier la zone épileptogène (ZE) et d’évaluer des possibilités de résection chirurgicale.

No relevant conflicts of interest to declare.

Sickle bone disease (SBD) is a severe and invalidating complication related to recurrent bone vaso-occlusive events affecting patients with sickle cell disease (SCD). In a humanized mouse model for SCD, we previously showed that SBD is sustained by impaired osteoblast function and increased osteoclast activity associated with local up-regulation of pro-inflammatory cytokines and anti-oxidant systems (Dalle Carbonare L., Blood 2015;126:2320-2328). Growing evidence supports a role of ω-3 fatty acid supplementation in improving bone homeostasis (Fallon EM, et al J Surg Res 2014;191:148-155.). A diet enriched with ω-3 fatty acids beneficially impacts SCD inflammatory vasculopathy, and blunts the acute and chronic SCD-related organ damage in humanized SCD mice (Kalish BT et al Haematologica 2015;100:870-880). Here, we sought to compare the dietary effects of ω-6 (soybean oil-based, SD)- vsω-3 (fish oil-based, FD)-enriched diets on SBD in SCD mice (Hbatm1(HBA)TowHbbtm2(HBG1,HBB*)Tow). Treated SCD and control healthy mice (AA, Hbatm1(HBA)TowHbbtm3(HBG1,HBB)Tow) (n=6 animals in each group) were exposed to recurrent hypoxia/reoxygenation (rH/R) stress, which closely mimics SBD natural history (Dalle Carbonare L., Blood 2015). In SCD mice, FD prevented rH/R-induced bone loss compared to animals exposed to SD by decreasing osteoclast and increasing osteoblast activities. Up-regulation of molecular osteogenic markers such as Runx2and Sparcand down-regulation of Rankand RankL, molecular markers of osteoclast recruitment and activity were observed in FD SCD mice exposed to rH/R compared to SD SCD animals. Similar changes, but to a lesser extent, were also observed in AA control mice exposed to rH/R stress. Expression of IL-6 (Il6) and matrix-metalloproteinase-9 (Mmp9) regulators which interact with RankL on osteoclastic activity and bone resorption were studied. In SCD mice, FD markedly reduced the up-regulation of both genes compared to SD SCD animals in conjunction with down-regulation of peroxiredoxin-2 (Prx2) gene expression, an important cytoprotective and antioxidant system. We also evaluated bone adipogenesis, which is believed to be an important contributor to bone impairment in SBD. Bone immunohistochemistry for Peripilin-1 which coats storage lipid droplets revealed increased adipogenesis in SD SCD mice compared to either FD SCD animals or AA controls, in association with downregulation of miR205, which decreases adipogenesis and enhances osteogenic activity. Our data thus indicate that in SCD exposed to rH/R, FD (i) improves osteoblastogenesis; (ii) decreases osteoclast activity; (iii) modulates the bone inflammatory response; iv) reduces adipogenesis. These findings provide new insights on the mechanism of action of ω-3 fatty acid supplementation on the pathogenesis of SBD and strengthen the rationale for ω-3 fatty acid dietary supplementation in SCD as a complementary therapeutic intervention targeting an amplified inflammatory response and sickle cell-related bone impairment.

Le stroke like migraine after radiation therapy(SMART) syndrome associe céphalées, troubles neurologiques aigus, crises épileptiques et prise de contraste corticale à l’IRM, à distance d’une radiothérapie cérébrale.

No relevant conflicts of interest to declare.

Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder, characterized by the synthesis of pathological hemoglobin S (HbS). Up to now, limited studies in SCD patients have proposed a bone loss related to recurrent acute vaso-occlusive events (VOCs). Here, we designed a study in a humanized mouse model for SCD to evaluate (i) bone structure turnover and micro-architecture by histomorphometric approach; (ii) osteoblastic differentiation by RT-PCR analysis of bone runx2, sparcand alpgene expression. We used humanized healthy control (Hbatm1(HBA)TowHbbtm3(HBG1,HBB)Tow) and SCD (Hbatm1(HBA)TowHbbtm2(HBG1,HBB*)Tow) mice. Mice were divided into different groups as detailed in the enclosed flow-chart. In steady state, we first evaluated bone-marrow erythropoiesis by FACS analysis based on CD44-TER119 strategy. No signs of ineffective erythropoiesis were detectable in SCD mice compared to controls. Bone analysis was performed by histomorphometric approach after double labelling with demeclocycline followed by calcein to evaluate the dynamic parameters of bone turnover and analyzed by a specific software (bone3.1, Explora Nova, Larochelle, France). The histomorphometric bone analysis revealed (i) reduced bone volume with associated decreased trabecular number and increased trabecular separation; (ii) increased bone-turnover measured as bone formation rate (BFR) and activation frequency (AcF); (iii) decreased number of nodes (NdN) and node termini ratio; (iv) increased marrow star volume (MSV) and fractal dimension (D) compared to healthy mice. The bone molecular analysis revealed a significant down-regulation of runx2, sparcand alpgene expression in SCD mice compared to healthy ones. These data indicate a severe osteoporosis with bone fragility associated with alteration of osteogenic differentiation in SCD mice. Zoledronic acid (Zol) is the most powerful available bisphosphonate used to reduce bone turnover and bone fragility. Since VOCs are life-threatening complication of SCD and mainly involved skeletal system, requiring multidiscliplinary approach, we exposed SCD and control mice to hypoxia/reoxygenation (H/R) stress to mimic acute VOCs (see flow-chart). Mice were exposed to hypoxia (8% oxygen, 10 hours) followed by reoxygenation (21% oxygen) for either 18 hours to carry out molecular analysis or 10 days to carry out histomorphometric analysis. In H/R exposed vehicle treated SCD mice, we found (i) a significant increase in AcF (bone turnover), without differences in bone structure and microarchitecture compared to SCD mice under normoxia; (ii) a further reduction in osteogenic differentiation molecular markers. Zol (100 μg/ Kg in a single ip injection) was administrated either 7 days before (Zol-pre) or immediately after (Zol-post) H/R stress. In SCD mice, both Zol-pre and Zol-post significantly prevented the H/R induced increased bone turnover, while no differences were detectable in bone structure and microarchitecture compared to vehicle treated H/R SCD mice. The molecular analysis showed that Zol increased the osteogenic related gene expression, indicating a positive induction of osteogenic differentiation. Our data suggest that murine SCD is characterized by a significant bone impairment related to the unbalance between osteoblastic/osteoclastic activity in favor of osteoclastic one in presence of a down-regulation of osteogenic differentiation. In SCD, Zol plays a pivotal role decreasing osteoclastic activity and promoting osteogenic differentiation, representing a powerful new therapeutic strategy to limit bone disease in SCD.

Circulating endothelial cells are increased in patients affected by systemic sclerosis (SSc) and their number strongly correlates with vascular damage. The effects of iloprost in systemic sclerosis are only partially known. We aimed at studying the gene expression profile of circulating endothelial cells and the effects of iloprost infusion and gene expression in patients with systemic sclerosis.

The purpose of this study was to evaluate the effects of risedronate (Ris) in the modulation of bone formation in rats with glucocorticoid (GC)-induced osteoporosis by histomorphometric, immunohistochemical and gene expression analyses.