Search for Gamma-Ray Spectral Lines from Dark Matter Annihilation up to 100 TeV toward the Galactic Center with MAGIC.

Linelike features in TeV γ rays constitute a "smoking gun" for TeV-scale particle dark matter and new physics. Probing the Galactic Center region with ground-based Cherenkov telescopes enables the search for TeV spectral features in immediate association with a dense dark matter reservoir at a sensitivity out of reach for satellite γ-ray detectors, and direct detection and collider experiments. We report on 223 hours of observations of the Galactic Center region with the MAGIC stereoscopic telescope system reaching γ-ray energies up to 100 TeV. We improved the sensitivity to spectral lines at high energies using large-zenith-angle observations and a novel background modeling method within a maximum-likelihood analysis in the energy domain. No linelike spectral feature is found in our analysis. Therefore, we constrain the cross section for dark matter annihilation into two photons to ⟨σv⟩≲5×10^{-28} cm^{3} s^{-1} at 1 TeV and ⟨σv⟩≲1×10^{-25} cm^{3} s^{-1} at 100 TeV, achieving the best limits to date for a dark matter mass above 20 TeV and a cuspy dark matter profile at the Galactic Center. Finally, we use the derived limits for both cuspy and cored dark matter profiles to constrain supersymmetric wino models.

Occurrence of ticks in the subcutaneous tissue of red foxes, Vulpes vulpes in Czech Republic and Romania.

An extensive survey of parasites in red foxes (Vulpes vulpes) was independently conducted in Romania and the Czech Republic. Carcasses were examined by necropsy, and small, dark nodules apparently containing ticks were noticed in the subcutaneous tissue of several foxes. Histopathological examination was performed using hematoxylin and eosin (HE) staining. Of the 91 foxes examined from the Czech Republic, 14 (15.4%) were harboring ticks in the subcutaneous tissue. In the majority of these cases, 1-3 nodules/fox were found, with a maximum of 31 nodules/fox. In Romania a single examined fox had subcutaneous ticks. All ticks collected from subcutaneous tissue were partially engorged adults. Based on morphological features, Ixodes ricinus, I. hexagonus, I. crenulatus and Dermacentor reticulatus were identified. The histopathological examination revealed chronic granulomatous panniculitis with peripheral fibrosis and intralesional presence of the ticks. Only few data are available regarding ticks localized in the subcutaneous tissue of any host. All the ticks were dead or already decomposed and it is evident that subcutaneous location does not represent an evolutionary advantage, as the detachment and finishing the life cycle is impossible.

Mouse mesenchymal stem cells inhibit high endothelial cell activation and lymphocyte homing to lymph nodes by releasing TIMP-1.

Mesenchymal stem cells (MSC) represent a promising therapeutic approach in many diseases in view of their potent immunomodulatory properties, which are only partially understood. Here, we show that the endothelium is a specific and key target of MSC during immunity and inflammation. In mice, MSC inhibit activation and proliferation of endothelial cells in remote inflamed lymph nodes (LNs), affect elongation and arborization of high endothelial venules (HEVs) and inhibit T-cell homing. The proteomic analysis of the MSC secretome identified the tissue inhibitor of metalloproteinase-1 (TIMP-1) as a potential effector molecule responsible for the anti-angiogenic properties of MSC. Both in vitro and in vivo, TIMP-1 activity is responsible for the anti-angiogenic effects of MSC, and increasing TIMP-1 concentrations delivered by an Adeno Associated Virus (AAV) vector recapitulates the effects of MSC transplantation on draining LNs. Thus, this study discovers a new and highly efficient general mechanism through which MSC tune down immunity and inflammation, identifies TIMP-1 as a novel biomarker of MSC-based therapy and opens the gate to new therapeutic approaches of inflammatory diseases.

A novel and personalized rehabilitation program for obese kidney transplant recipients.

INTRODUCTION: Physical rehabilitation programs for kidney transplant recipients are not routinely personalized to patients' physical and emotional health, which could result in a potentially limited health impact, shorter-term participation, and an overall low success rate. MATERIALS AND METHODS: We conducted an internal review board-approved randomized prospective study involving a 12-month supervised multidisciplinary rehabilitation program (GH method) initiated after kidney transplantation in obese recipients (body mass index >30). The new method incorporates 3 major components: physical exercise, behavioral interventions, and nutritional guidance. We compared 9 patients who underwent supervised rehabilitation with 8 patients who underwent standard care. Patients were followed up after the start of the intervention, and multiple assessments were performed. RESULTS: The adherence to training and follow-up was 100% in the intervention group, compared with 25% at 12 months in the control group. There was a trend for a higher glomerular filtration rate in the intervention group compared with the control group (55.5 ± 18.6 mL/min/1.73 m(2) vs 38.8 ± 18.9 mL/min/1.73 m(2), P = .06). The quality of life (SF-36) mean score improved more in the intervention group compared with the control group (583 ± 13 vs 436 ± 22, P = .008). There was a significantly higher employment rate in the intervention group, 77.7% at 12 months compared with 12.5% in the control group (P = .02). CONCLUSIONS: Our preliminary results suggest that this comprehensive approach to physical rehabilitation can improve adherence, kidney function, quality of life, and employment rate for obese patients after kidney transplantation.

External vs. endonasal dacryocystorhinostomy: has the current view changed?

In past years, external dacryocystorhinostomy has been considered the gold standard in terms of functional outcome for treatment for nasolacrimal duct obstruction. In comparison, interest in the use of the recently developed endonasal dacyocystorhinostomy procedure has been rekindled because of advances in instrumentation. For the past 10 years, differences in the outcomes between the two techniques have been reduced; thus, currently, the choice of the type of surgery is associated with the experience of the surgeon, resources available in the healthcare system and patient preferences.

Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients.

BACKGROUND: Morphological, haemodynamic and clinical stages of cirrhosis have been proposed, although no definite staging system is yet accepted for clinical practice. AIM: To investigate whether clinical complications of cirrhosis may define different prognostic disease stages. METHODS: Analysis of the database from a prospective inception cohort of 494 patients. Decompensation was defined by ascites, bleeding, jaundice or encephalopathy. Explored potential prognostic stages: 1, compensated cirrhosis without oesophago-gastric varices; 2, compensated cirrhosis with varices; 3, bleeding without other complications; 4, first nonbleeding decompensation; 5, any second decompensating event. Patient flow across stages was assessed by a competing risks analysis. RESULTS: Major patient characteristics were: 199 females, 295 males, 404 HCV+, 377 compensated, 117 decompensated cirrhosis. The mean follow-up was 145 ± 109 months without dropouts. Major events: 380 deaths, 326 oesophago-gastric varices, 283 ascites, 158 bleeding, 146 encephalopathy, 113 jaundice, 126 hepatocellular carcinoma and 19 liver transplantation. Patients entering each prognostic stage along the disease course were: 202, stage 1; 216, stage 2; 75 stage 3; 206 stage 4; 213 stage 5. Five-year transition rate towards a different stage, for stages 1-4 was 34.5%, 42%, 65% and 78%, respectively (P < 0.0001); 5-year mortality for stages 1-5 was 1.5%, 10%, 20%, 30% and 88% respectively (P < 0.0001). An exploratory analysis showed that this patient stratification may configure a prognostic system independent of the Child-Pugh score, Model for End Stage Liver Disease and comorbidity. CONCLUSION: The development of oesophago-gastric varices and decompensating events in cirrhosis identify five prognostic stages with significantly increasing mortality risks.

Mesenchymal stem cells from Shwachman-Diamond syndrome patients display normal functions and do not contribute to hematological defects.

Shwachman-Diamond syndrome (SDS) is a rare inherited disorder characterized by bone marrow (BM) dysfunction and exocrine pancreatic insufficiency. SDS patients have an increased risk for myelodisplastic syndrome and acute myeloid leukemia. Mesenchymal stem cells (MSCs) are the key component of the hematopoietic microenvironment and are relevant in inducing genetic mutations leading to leukemia. However, their role in SDS is still unexplored. We demonstrated that morphology, growth kinetics and expression of surface markers of MSCs from SDS patients (SDS-MSCs) were similar to normal MSCs. Moreover, SDS-MSCs were able to differentiate into mesengenic lineages and to inhibit the proliferation of mitogen-activated lymphocytes. We demonstrated in an in vitro coculture system that SDS-MSCs, significantly inhibited neutrophil apoptosis probably through interleukin-6 production. In a long-term coculture with CD34(+)-sorted cells, SDS-MSCs were able to sustain CD34(+) cells survival and to preserve their stemness. Finally, SDS-MSCs had normal karyotype and did not show any chromosomal abnormality observed in the hematological components of the BM of SDS patients. Despite their pivotal role in the hematopoietic stem cell niche, our data suggest that MSC themselves do not seem to be responsible for the hematological defects typical of SDS patients.

[Atypical onset cryoglobulinemia: case report]. / Crioglobulinemia ad esordio atipico: caso clinico.

Cryoglobulinemia is a disease mediated by antibodies with the property to precipitate at temperatures below 37°C. It can be distinguished into a primitive form (also referred to as 'essential mixed cryoglobulinemia'), and a secondary form. In the essential mixed variant a key role is played by HCV infection. The pathogenesis of mixed cryoglobulinemia is mediated by immune complexes that are the most important cause of the vasculitic phenomena, typical of the disease. However, the severity of the clinical manifestations is not always related to the serum levels of cryoglobulins and immune complexes. In our case report, a 46-year old man came to our observation with asymmetric diffuse and invalidating arthralgies, with both substitutive and additive behaviour, located at pelvic girdle, inferior limbs and elbows, associated to skin lesion vascultis-like. The remote pathological anamnesis was characterized by a previous surgically treated non-Hodgkin lymphoma, and HCV infection. Despite several attempts were done, it was not possible to reveal cryoglobulins, nor reumatoid factor in the serum. Cryoglobulins resulted positive only after the third day of hospitalization, along with a new fever attack and a worsening of the vasculitic manifestations. In conclusion, this case demonstrated that cryoglobulinemia can occur with a totally atypical sequence of clinical manifestations which can be present before and in absence of the typical laboratory proofs.

University of Modena experience in HIV-positive patients undergoing liver transplantation.

INTRODUCTION: Highly effective antiretroviral therapy in the last decade has increased the survival rates of HIV-positive patients, yielding a greater number of HIV patients suffering from liver-related disease. Liver transplantation (LT) is the only curative treatment for end-stage liver disease (ESLD) associated or not with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: From June 2003 to September 2010, 23 patients underwent cadaveric donor LT for ESLD at our institution. Inclusion criteria followed the Italian Protocol for LT in HIV-positive patients. Immunosuppressive regimens were based on cyclosporine or tacrolimus, eventually switched to Rapamycin. RESULTS: The median CD4 T-cell count was 275/mmc (range=119-924). All patients were affected by ESLD, which was associated with HCC in 14 cases. Ten patients were within the Milan criteria and four patients exceeded them but were within the San Francisco criteria. Conversion from calcineurin inhibitors (CNI) to rapamycin occurred in ten cases. Hepatitis C virus (HCV) recurrence occurred in 13/21 HCV-positive patients. Acute cellular rejection occurred in eight patients with one developing chronic cellular rejection. Overall patient and graft survivals at 80 months were 50% and 45% respectively. DISCUSSION: LT in HIV-positive patients is a feasible procedure, even if in our experience was burdened by a greater incidence of complications including HCV recurrence and infection compared with HIV-negative patients.

Liver transplantation due to iatrogenic injuries: two case reports.

The transjugular intrahepatic portosystemic shunt (TIPS) is an acceptable procedure that has proven benefits in the treatment of patients who have complications from portal hypertension due to liver cirrhosis. In the literature few reports have described complications after TIPS placement. Initial surgery and local hemostasis have been needed to manage abdominal bleeding: if this treatment is insufficient, it may be necessary to perform a liver transplantation. This report describes the role of liver transplantation to manage dangerous complications in 2 patients after TIPS placement, when surgical procedures and hemostasis were unable to stop the bleeding.

Intravitreal bevacizumab vs intravitreal triamcinolone combined with macular laser grid for diffuse diabetic macular oedema.

OBJECTIVE: To evaluate the 12-month clinical outcome of patients with persistent non-ischaemic diffuse diabetic macular oedema (DME) treated with intravitreal bevacizumab (IVB) or with intravitreal injection of triamcinolone combined with macular laser grid (IVTA-MLG) from September 2005 to February 2008. METHODS: Retrospective interventional comparative study. Best-corrected visual acuity (BCVA, ETDRS LogMAR scale) and foveal thickness (FT) at optical coherence tomography (OCT) were obtained at baseline and during 12 months after first treatment. Re-treatment was based on clinical or OCT-based evidence of persistent macular oedema or deterioration in visual acuity. RESULTS: Forty-three eyes (32 patients) with DME were treated with IVB. Ninety-six eyes (52 patients) with DME were treated with combined laser grid treatment and intravitreal triamcinolone. At baseline, mean BCVA and FT were 0.92+/-0.34 LogMAR and 372+/-22 microm in the IVTA-MLG group, and 1.07+/-0.49 LogMAR and 423+/-33 microm in the IVB group, respectively. At 1- and 3-month visits, BCVA and FT had significantly improved in both groups. After 6 and 12 months, the IVB group experienced a statistically significant improvement in visual acuity (0.83+/-0.21 LogMAR, P<0.001 at 6 months; BCVA 0.86+/-0.24 LogMAR, P<0.001 at 12 months) and FT (248+/-18 microm, P<0.001 at 6 months; 262+/-28 microm, P=0.001 at 12 months) when compared with baseline, whereas the IVTA-MLG group did not show statistically significant improvement in vision and FT. An increase in intraocular pressure (IOP) was present in 10 of 96 (10.4%) eyes treated with IVTA-MLG, and in two cases it was resistant to topical treatment. No significant side effects were reported in the IVB group. CONCLUSIONS: At 6 and 12 months after first treatment for chronic DME IVB provided significant improvement of BCVA and FT, whereas improvement after IVTA-MLG was not significant. Increased IOP occurred in 10.4% of patients who received IVTA, with two patients requiring trabeculectomy.

[Is there an age limit for radical surgery in case of tumors infiltrating the duodenum?]. / Per le neoplasie infiltranti il duodeno esiste un limite di età per una chirurgia radicale?

AIM: Radical resection is the only potential cure for pancreatic malignancies and a useful treatment for other benign diseases, such as pancreatitis. Over the last two decades, medical and surgical improvements have drastically changed the postoperative outcome of elderly patients undergoing pancreatic resection, and appropriate treatment for elderly potential candidates for pancreatic resection has become an important issue. METHODS: A hundred and five consecutive patients undergoing radical pancreatic resection between 2003 and 2007 at the Surgery Unit of the University of Modena, Italy, were considered and divided into two groups according to their age, i.e., over 75-year olds (group 1, 25 patients) and under 75-year-olds (group 2, 80 patients). The two groups were compared as regards to demographic features, American Society of Anesthesiologists scores, comorbidities, previous major surgery, surgical procedure, postoperative mortality, and morbidity. RESULTS: There were no significant differences between the two groups concerning postoperative mortality, and the duration of hospital stay and days in the postoperative Intensive Care Unit were also similar. Complications such as pancreatic fistulas, wound infections, and pneumonia were more frequent in the older group, but the differences were not statistically significant. CONCLUSION: In the light of these findings and as reported for other series, old age is probably not directly related with any increase in the rate of postoperative complications, but comorbidities (which are naturally related to the patients' previous life) may have a key role in the postoperative course.

Effects of the conventional antitumor therapies surgery, chemotherapy, radiotherapy and immunotherapy on regulatory T lymphocytes in cancer patients.

BACKGROUND: Several clinical studies have clearly demonstrated that the immune status is one a major prognostic factor for the survival time in cancer patients. However the main clinical problem is to identify the most prognostically important index within the great number of immune parameters. Recently the evaluation of regulatory T (T-reg) (CD4CD25) lymphocyte count and function with respect to the T helper (TH) (CD4) number has been shown to represent the main immune parameters capable of representing the functional status of the anticancer immunity in cancer patients. This study evaluated the influence of the four main conventional anticancer therapies (surgery, chemotherapy, radiotherapy, immunotherapy) on the CD4/CD4CD25 ratio. PATIENTS AND METHODS: The study included 70 patients. The oncological treatments consisted of surgery in 14, chemotherapy in 36, radiotherapy in 12 and immunotherapy (subcutaneous low-dose, S.C.-low, interleukin, IL-2) in 8 patients. The normal value of the CD4/CD4CD25 ratio was greater then 4.0. RESULTS: Surgery induced a significant decline in the CD4/CD4CD25 mean ratio. Radiotherapy also induced also a dramatic significant decrease in the CD4/CD4CD25 ratio, whereas the effect of both chemotherapy and immunotherapy reflected the clinical response to the treatments. The CD4/CD4CD25 mean ratio was significantly enhanced in the patients who obtained control of the neoplastic growth, whereas it diminished in progressing patients. CONCLUSION: The commonly used anticancer therapies profoundly modify the levels of amounts of T-reg lymphocytes. Because of the fundamental role of T-reg cells in suppressing the anticancer immunity, thus diminishing survival, the monitoring of the CD4/CD4CD25 ratio could constitute an important clinical index during conventional anticancer therapies to predict the prognosis of cancer patients.

GMP-grade preparation of biomimetic scaffolds with osteo-differentiated autologous mesenchymal stromal cells for the treatment of alveolar bone resorption in periodontal disease.

BACKGROUND: Periodontal disease is a degenerative illness that leads to resorption of the alveolar bone. Mesenchymal stromal cells (MSC) represent a novel tool for the production of biologic constructs for the treatment of degenerative bone diseases. The preparation of MSC differentiated into osteogenic lineage for clinical use requires the fulfillment of strict good manufacturing practice (GMP) procedures. METHODS: MSC were isolated from BM samples and then cultured under GMP conditions. MSC were characterized phenotypically and for their differentiative potential. Cells were seeded onto collagen scaffolds (Gingistat) and induced to differentiate into osteogenic lineages using clinical grade drugs compared with standard osteogenic supplements. Alizarin Red S stain was used to test the deposition of the mineral matrix. Standard microbiologic analysis was performed to verify the product sterility. RESULTS: The resulting MSC were negative for CD33, CD34 and HLA-DR but showed high expression of CD90, CD105 and HLA-ABC (average expressions of 94.3%, 75.8% and 94.2%, respectively). Chondrogenic, osteogenic and adipogenic differentiation potential was demonstrated. The MSC retained their ability to differentiate into osteogenic lineage when seeded onto collagen scaffolds after exposure to a clinical grade medium. Cell numbers and cell viability were adequate for clinical use, and microbiologic assays demonstrated the absence of any contamination. DISCUSSION: In the specific context of a degenerative bone disease with limited involvement of skeletal tissue, the combined use of MSC, exposed to an osteogenic clinical grade medium, and biomimetic biodegradable scaffolds offers the possibility of producing adequate numbers of biologic tissue-engineered cell-based constructs for use in clinical trials.

Fatal necrotising fasciitis associated with intramuscular injection of nonsteroidal anti-inflammatory drugs after uncomplicated endoscopic polypectomy.

Necrotising fasciitis is a life-threatening infection of the superficial muscle fascia and the adjacent deep layer of subcutaneous tissue that is often fatal. A 46-year-old woman was admitted to the intensive care unit (ICU) three days after an uncomplicated endoscopic polypectomy because of necrotising fasciitis of left tight, buttock and retroperitoneal space and septic shock. Six hours after the polypectomy she was given an intramuscular injection of ketorolac in the left tight because of moderate low abdominal pain. Twelve and 24h later she was treated with another two intramuscular injection of diclofenac in the left tight for severe pains in the left hip joint region. The shock was unresponsive to any treatment and the fasciitis extended to the whole body even after surgical specific treatment and the patient died in four days. This is the first report of a necrotising fasciitis following intramuscular administration of nonsteroidal anti-inflammatory drugs after an endoscopic procedure.

T cells stimulated by CD40L positive leukemic blasts-pulsed dendritic cells meet optimal functional requirements for adoptive T-cell therapy.

Adoptive T-cell immunotherapy may provide complementary therapy for childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In this study, we have analyzed the functional characteristics of anti-BCP-ALL effector T cells generated by co-culturing T lymphocytes and dendritic cells (DC) from allogeneic human stem cell transplantation (HSCT) donors. After 21-day co-culture with DC pulsed with CD40L+ apoptotic BCP-ALL blasts, T cells presented with both effector and central memory phenotype, and showed high and specific cytotoxic activity against leukemic cells (average lysis = 77%), mostly mediated by CD8+ T cells. Noticeably, growth of CD4 T cells was maintained (45% of total cells), which actively produced Th1 cytokines (IFN-gamma, TNF-alpha, IL-2), but not IL-4, IL-5 and IL-10. Anti-BCP-ALL T cells expressed CD49d and CXCR4 (implicated in the recruitment to bone marrow), and CD62L and CCR7 (involved in the migration to lymphoid organs). In accordance with this profile, T cells significantly migrated in response to the chemokines CXCL12 and CCL19. In conclusion, stimulation of T cells with CD40L+BCP-ALL cells-loaded DC not only elicited the generation of potent and specific anti-leukemic cytotoxic effectors, but also the differentiation of specific and functional Th-1 CD4 lymphocytes. These effectors are fully equipped to reach leukemia-infiltrated tissues and have characteristics to support and orchestrate the anti-tumor immune-response.