Dissecting the genetic make-up of North-East Sardinia using a large set of haploid and autosomal markers

Sardinia has been used for genetic studies because of its historical isolation, genetic homogeneity and increased prevalence of certain rare diseases. Controversy remains concerning the genetic substructure and the extent of genetic homogeneity, which has implications for the design of genome-wide association studies (GWAS). We revisited this issue by examining the genetic make-up of a sample from North-East Sardinia using a dense set of autosomal, Y chromosome and mitochondrial markers to assess the potential of the sample for GWAS and fine mapping studies. We genotyped individuals for 500K single-nucleotide polymorphisms, Y chromosome markers and sequenced the mitochondrial hypervariable (HVI-HVII) regions. We identified major haplogroups and compared these with other populations. We estimated linkage disequilibrium (LD) and haplotype diversity across autosomal markers, and compared these with other populations. Our results show that within Sardinia there is no major population substructure and thus it can be considered a genetically homogenous population. We did not find substantial differences in the extent of LD in Sardinians compared with other populations. However, we showed that at least 9% of genomic regions in Sardinians differed in LD structure, which is helpful for identifying functional variants using fine mapping. We concluded that Sardinia is a powerful setting for genetic studies including GWAS and other mapping approaches.     

Prevalence of Infections After In-Office Hysteroscopy in Premenopausal and Postmenopausal Women

Study Objective

To estimate the incidence of infection after diagnostic and operative hysteroscopic procedures performed in an in-office setting with different distension media (saline solution or CO₂).

A Modified Post-Transplant Cyclophosphamide Regimen,for Unmanipulated Haploidentical Marrow Transplantation,in Acute Myeloid Leukemia: A Multicenter Study

We report a modified post-transplant cyclophosphamide (PT-CY) regimen, for unmanipulated haploidentical marrow transplants, in 150 patients with acute myeloid leukemia (AML). All patients received a myeloablative regimen, cyclosporine A (CsA) on day 0, mycophenolate on day +1, and PT-CY 50?mg/kg on days +3 and +5. The median age was 51 (range, 17–74) years, 51 (34%) patients had active disease at transplant, and the median follow-up of surviving patients 903 (range, 150-1955) days. The cumulative incidence (CI) of engraftment, acute graft-versus-host disease (GVHD) grade II to IV, and moderate/severe chronic GVHD was 92%, 17%, and 15%, respectively. The 4-year CI of transplant-related mortality (TRM) and relapse was 20% and 24%, respectively. Four-year survival for remission patients was 72% (74% versus 67% for <60 or ≥60 years of age) and 26% for advanced patients (17% versus 41% for <60 or ≥60 years of age). In a multivariate analysis, active disease at transplant was the only negative predictor of survival, TRM and relapse. The original PT-CY regimen can be modified with CsA on day 0, still providing protection against GVHD, low toxicity, and encouraging low relapse incidence in AML patients, also over 60 years of age.     

Successful Treatment with Cyclosporine A of HCV-Driven Chronic Liver Disease Mimicking Autoimmune Hepatitis in a Patient with Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is the commonest primary immunodeficiency disease characterized by defective antibody production and various degrees of T cell numbers abnormality or impaired proliferation to mitogens. Clinical features include recurrent bacterial sinopulmonary and gastrointestinal infections. Autoimmunity is very common in CVID, occurring in approximately 25% of the patients particularly with autoimmune thrombocytopenia, hemolytic anemia, inflammatory bowel disease, and rheumatoid arthritis. Persistent antigen stimulation, secondary to a defective eradication of pathogens followed by a compensatory exaggerated chronic inflammatory response, is the primary cause leading to autoimmunity. Here we describe a girl with CVID in whom a chronic liver disease mimicking autoimmune hepatitis developed after hepatitis C virus infection. The immunosuppressive treatment with cyclosporine A proved effective in reversing liver disease.     

Metallothionein (I+II) confers, via c-myc, immune plasticity in oldest mice: model of partial hepatectomy/liver regeneration

Because of its similarity to ageing in impaired immune efficiency 48 h after surgical procedures on young partially hepatectomised mice, partial hepatectomy/liver regeneration (pHx) provides a good model for the study of inflammation in ageing. In old age, high metallothionein (I+II) (MT) sequesters a substantial number of intracellular zinc ions consequently leading to low zinc ion bioavailability for an adequate immune response. Corticosterone and IL-6 affect MTmRNA induction in inflammation and after pHx against oxidative damage. The aim of this study was to investigate the role played by MT in conferring immune plasticity in ageing and in very old age using the pHx model. 48 h after their partial hepatectomy, the crude zinc balance was negative in young, old and very old mice coupled with increased MT, corticosterone, sIL-6R and IL-6. Concomitantly, Natural Killer (NK) cell activity and IL-2 production decreased. Complete restoration of the nutritional-endocrine-immune parameters occurred 15 days from the surgical procedures in young and very old mice, but not in old or transgenic mice overexpressing MT. A significant positive or inverse correlation among nutritional-endocrine-immune parameters exists in young and very old mice, but not in old mice during liver regeneration. Since MT also affects c-myc, the gene expression of c-myc declines from 48 h to days 7 and 15 after pHx in young and very old mice, but remains constantly high in old pHx mice for the same days. This circumstance leads to the appearance of tumours in the long run in old pHx mice and survival times that are shorter than old sham controls. Because complete remodelling also occurs in IL-6 and in sIL-6R in very old mice during liver regeneration, the pre-existing inflammation is not detrimental in very old age. As such, very old mice are still responsive to large inflammation, such as pHx, thanks to correct MT homeostasis. Correct MT homeostasis, via c-myc, is therefore pivotal in both suitable liver regeneration and in conferring immune plasticity with subsequent successful ageing. High MT plays an extremely harmful role in ageing: on one hand it lowers zinc ion bioavailability levels required for immune efficiency and on the other hand it increases c-myc expression. The combination of immune depression and enhanced c-myc, via high MT, may trigger the appearance of age-related degenerative diseases.     

Hysteroscopic Findings in Women With Menorrhagia

Study ObjectiveTo describe the hysteroscopic findings in patients complaining of menorrhagia to establish any significant association between menorrhagia and benign/malignant intrauterine disorders.DesignProspective cohort study (Canadian Task Force classification II).SettingUniversity La Sapienza, Rome, Italy.PatientsOne hundred eighteen premenopausal women undergoing office hysteroscopy for menorrhagia (group A) and 344 premenopausal patients undergoing office hysteroscopy for other indications (noncyclic abnormal uterine bleeding, infertility, ultrasonographic abnormalities, etc) (group B).InterventionsOffice hysteroscopy.Measurement and Main ResultsData on the prevalence of hysteroscopic findings (cervical polyps, endometrial polyps, submucous myomas, low-grade hyperplasia and high-grade hyperplasia/endometrial carcinoma) were compared between group A and group B. The total prevalence, as well as the prevalence of type 0 and type I myomas (totally or >50% intracavitary, respectively), and the mean number per patients with submucous myomas was significantly higher in group A compared with group B (p = .0001, p = .024, and p = .017, respectively). Multivariable logistic regression analysis showed a statistically significant association between age (odds ratio 4.15, 95% confidence interval 1.55–11.1 in the 40- to 49-year age group), presence of submucous myomas (odds ratio 2.76, 95% confidence interval 1.52–5.00), and menorrhagia.ConclusionsMenorrhagia seems to be associated with aging, the presence and number of submucous myomas, and with the degree of their intracavitary development.     

Usefulness and limitations of edema of the small intestine in malabsorption syndromes

Malabsorption syndrome is a clinical condition that can be determined by several situations which can ensue by many etiopathogenetic mechanisms. While the diagnostic approach is, for this reason, complex and uses a lot of clinical, laboratory and instrumental techniques, the therapeutic approach could be surgical or medical. The aim of our research is to establish the diagnostic utility of the radiologic examination of the small intestine by enteroclysis, on the basis of our personal experience and the data referred in literature. We took particular care of the radiological study of primitive malabsorption.     

Allogeneic hematopoietic stem cell transplantation for neuromyelitis optica

Neuromyelitis optica is a rare neurological autoimmune disorder characterized by a poor prognosis. Immunosuppression can halt disease progression, but some patients are refractory to multiple treatments, experiencing frequent relapses with accumulating disability. Here we report on durable clinical remissions after allogeneic hematopoietic stem cell transplantation in 2 patients suffering from severe forms of the disease. Immunological data evidenced disappearance of the pathogenic antibodies and regeneration of a naive immune system of donor origin. These findings correlated with evident clinical and radiological improvement in both patients, warranting extended clinical trials to investigate this promising therapeutic option. ANN NEUROL 2014;75:447–453     

The ILAILL study: iloprost as adjuvant to surgery for acute ischemia of lower limbs: a randomized, placebo-controlled, double-blind study by the italian society for vascular and endovascular surgery

SUMMARY BACKGROUND DATA: High rate of complications has been reported following revascularization for acute limb ischemia (ALI). No adjuvant pharmacologic treatment, apart from anticoagulation and standard perioperative care, has been shown clinically effective. OBJECTIVE: Aim of this study was to evaluate the effects of the prostacyclin analog iloprost as adjuvant to surgery for ALI. METHODS: A total of 300 patients were randomly assigned to receive perioperative iloprost (intra-arterial, intraoperative bolus of 3000 ng, plus intravenous infusion of 0.5-2.0 ng/kg/min for 6 hours/day for 4-7 days following surgery), or placebo. The primary endpoint was the combined incidence of death and amputation at 3-month follow-up. Secondary endpoints were the incidence of each single major complication, total event rate, symptomatology, and tolerability. RESULTS: The combined incidence of death and amputation was 19.9% in the placebo and 14.1% in the iloprost group (relative risk, 1.56; 95% confidence interval, 0.89-2.75, P = 0.12, Cox regression analysis). A statistically significant lower mortality (4.7%) was reported in patients receiving iloprost, compared with controls (10.6%; relative risk, 2.61; 95% confidence interval, 1.07-6.37, P = 0.03). The overall incidence of fatal plus major cardiovascular events was 33.1% and 22.8% in placebo and iloprost groups, respectively (relative risk, 1.61; 95% confidence interval, 1.04-2.49, P = 0.03). No serious adverse reactions occurred after iloprost administration, nor differences in the incidence of bleeding or hypotension between treatment groups. CONCLUSIONS: Although at lower levels than previously reported, our results confirm the severity of ALI. Iloprost as adjuvant to surgery significantly reduced mortality and overall major event rate. Further data are needed to support this finding, and to face a still open medical issue.     

Effects of intra-aortic balloon pump on coronary artery bypass grafts blood flow: differences by graft type and coronary target

The intra-aortic balloon pump (IABP) is used worldwide as an anti-ischemic strategy. However, little is known about the modifications of the graft blood flow during IABP. A retrospective study aimed at analyzing transit-time flow measurements during 1:1 IABP and during its cessation in 401 consecutive patients receiving IABP before coronary artery bypass grafting (n = 880 graft segments) was reported. All normally functioning grafts were considered. Mean diastolic and mean blood flow improved significantly during 1:1 IABP compared with during IABP cessation (P < 0.001), although mean and end-diastolic arterial pressures were significantly lower (P = 0.001). Arterial and sequential saphenous vein (SV) grafts showed greater improvements in mean diastolic and mean flow compared with single venous grafts. Higher flows were also observed in the grafts directed to the circumflex territory. Surplus graft flow (SGF, defined as mean flow during 1:1 IABP/mean flow with IABP off) was recruited (SGF >1) during 1:1 IABP, with higher values in single arterial or sequential SV grafts versus single venous grafts (both P < 0.001). Y-conduit radial artery (RA) grafts showed higher maximum diastolic flow, mean flow, and SGF compared to aortocoronary RA or SV grafts. In this retrospective analysis, IABP was associated with improved diastolic and mean blood flow in bypass grafts. Arterial, sequential, and Y-conduit grafts were associated with greater improvements in blood flow and SGF than aortocoronary SV grafts.