PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (132)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
more »
author:("crete, A.")
1.  The pull-through: back to the future 
Il Giornale di Chirurgia  2013;34(11-12):293-301.
SUMMARY
Background
Historically, coloanal pull-through (P-T) has been the first surgical procedure adopted to facilitate a handmade lower anastomosis. Very popular around mid twentieth century, P-T has had poor diffusion, mainly as a consequence of the technical simplifications brought by staplers. Recent literature seems poor on this specific topic, despite description of P-T appears in published series during the reconstructive phase of total laparoscopic protectomies. A comeback of P-T has also been observed as an option with deferred anastomosis, to allow and protect a coloanal anastomosis in situations at greater risk of dehiscence, avoiding a temporary faecal diversion.
After reviewing the most significant aspects of classic techniques of P-T, we report our experience with transanal laparoscopic P-T for distal rectal cancer, presenting a new, modified P-T with deferred anastomosis aimed at improving defecatory compliance.
Patients and methods
Between January 2008 and June 2011 we operated in 258 rectal cancers (0–14 cm from the anal verge), 62.79% of which by laparoscopic access (VL), with 218 restorative procedures (84.49%). The coloanal anastomoses (CAA) were globally 68 (26.35%), of which 48 in VL procedures (70.58%). In 27 of these CAAs we utilised the P-T procedure, with immediate CAA (I-CAA) in 11 cases (all VL) and delayed CAA (D-CAA) in 16 (2 VL), by selective indications. All CAAs were manually fashioned; 6 D-CAA had the addition of a transverse coloplasty. Site of tumor was the lower rectum in 24 patients, with 21 patients receiving preoperative chemoradiation.
Results
There was no operative mortality. Early morbidity: D-CAA: 3 pelvic abscesses with stoma formation. I-CAA: 1 intraoperative re-resection and coloanal anastomosis with stoma formation for defective distal vascular supply. Late morbidity: anastomotic stenosis in 5/12 I-CAA and 4/14 D-CAA controlled by mechanical dilation. Function: 4/7 D-CAA and 4/6 I-CAA nearly complete functional recovery (Kirwan’s 1 or 2).
Conclusion
There are selective indications to P-T, when resection and anastomosis is not feasible in one step, or also as a primary restorative option in elective cases when a covering stoma is refused or dangerous.
PMCID: PMC3926465  PMID: 24342154
Pull-through; Laparoscopic; Transanal; Rectal cancer; Delayed coloanal anastomosis; Sphincter function
2.  Molecularly Tagged Simian Immunodeficiency Virus SIVmac239 Synthetic Swarm for Tracking Independent Infection Events 
Journal of Virology  2014;88(14):8077-8090.
ABSTRACT
Following mucosal human immunodeficiency virus type 1 transmission, systemic infection is established by one or only a few viral variants. Modeling single-variant, mucosal transmission in nonhuman primates using limiting-dose inoculations with a diverse simian immunodeficiency virus isolate stock may increase variability between animals since individual variants within the stock may have substantial functional differences. To decrease variability between animals while retaining the ability to enumerate transmitted/founder variants by sequence analysis, we modified the SIVmac239 clone to generate 10 unique clones that differ by two or three synonymous mutations (molecular tags). Transfection- and infection-derived virus stocks containing all 10 variants showed limited phenotypic differences in 9 of the 10 clones. Twenty-nine rhesus macaques were challenged intrarectally or intravenously with either a single dose or repeated, limiting doses of either stock. The proportion of each variant within each inoculum and in plasma from infected animals was determined by using a novel real-time single-genome amplification assay. Each animal was infected with one to five variants, the number correlating with the dose. Longitudinal sequence analysis revealed that the molecular tags are highly stable with no reversion to the parental sequence detected in >2 years of follow-up. Overall, the viral stocks are functional and mucosally transmissible and the number of variants is conveniently discernible by sequence analysis of a small amplicon. This approach should be useful for tracking individual infection events in preclinical vaccine evaluations, long-term viral reservoir establishment/clearance research, and transmission/early-event studies.
IMPORTANCE Human immunodeficiency virus type 1 transmission is established by one or only a few viral variants. Modeling of limited variant transmission in nonhuman primates with a diverse simian immunodeficiency virus isolate stock may increase the variability between animals because of functional differences in the individual variants within the stock. To decrease such variability while retaining the ability to distinguish and enumerate transmitted/founder variants by sequence analysis, we generated a viral stock with 10 sequence-identifiable but otherwise genetically identical variants. This virus was characterized in vitro and in vivo and shown to allow discrimination of distinct transmission events. This approach provides a novel nonhuman primate challenge system for the study of viral transmission, evaluation of vaccines and other prevention approaches, and characterization of viral reservoirs and strategies to target them.
doi:10.1128/JVI.01026-14
PMCID: PMC4097795  PMID: 24807714
3.  Focus on emerging drugs for the treatment of patients with non-alcoholic fatty liver disease 
World Journal of Gastroenterology : WJG  2014;20(45):16841-16857.
Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disorder in Western countries and is increasingly being recognized in developing nations. Fatty liver disease encompasses a spectrum of hepatic pathology, ranging from simple steatosis to non-alcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma and end-stage liver disease. Moreover, NAFLD is often associated with other metabolic conditions, such as diabetes mellitus type 2, dyslipidemia and visceral obesity. The most recent guidelines suggest the management and treatment of patients with NAFLD considering both the liver disease and the associated metabolic co-morbidities. Diet and physical exercise are considered the first line of treatment for patients with NAFLD, but their results on therapeutic efficacy are often contrasting. Behavior therapy is necessary most of the time to achieve a sufficient result. Pharmacological therapy includes a wide variety of classes of molecules with different therapeutic targets and, often, little evidence supporting the real efficacy. Despite the abundance of clinical trials, NAFLD therapy remains a challenge for the scientific community, and there are no licensed therapies for NAFLD. Urgently, new pharmacological approaches are needed. Here, we will focus on the challenges facing actual therapeutic strategies and the most recent investigated molecules.
doi:10.3748/wjg.v20.i45.16841
PMCID: PMC4258554  PMID: 25492998
Non-alcoholic steatohepatitis; Non-alcoholic fatty liver disease; Fatty liver; Steatosis; Emerging drugs
4.  Role of vaptans in the management of hydroelectrolytic imbalance in liver cirrhosis 
World Journal of Hepatology  2014;6(11):793-799.
Ascites and hyponatremia are the most common complications in patients with liver cirrhosis and develop as a consequence of a severe impairment of liver function and portal hypertension. Increasing evidences support the central role of renal function alterations in the pathogenesis of hydroelectrolytic imbalances in cirrhotic patients, thus implying a dense cross-talk between liver and kidney in the systemic and splanchnic vascular homeostasis in such subjects. Since Arginin Vasopressin (AVP) hyperincretion occurs at late stage of cirrhosis and plays an important role in the development of refractory ascites, dilutional hyponatremia and finally hepato-renal syndrome, selective antagonists of AVP receptors V2 (vaptans) have been recently introduced in the therapeutic algorithm of advanced cirrhotic patients. Despite the promising results of earlier phase-two studies, randomized controlled trials failed to find significant results in terms of efficacy of such drugs both in refractory ascites and hyponatremia. Moreover, concerns on their safety profile arise, due to the number of potentially severe side effects of vaptans in the clinical setting, such as hypernatremia, dehydration, renal impairment, and osmotic demyelination syndrome. More robust data from randomized controlled trials are needed in order to confirm the potential role of vaptans in the management of advanced cirrhotic patients.
doi:10.4254/wjh.v6.i11.793
PMCID: PMC4243153  PMID: 25429317
Cirrhosis; Vaptans; Portal hypertension; Arginin vasopressin; Liver
5.  Allogeneic stem cell transplantation for patients with advanced rhabdomyosarcoma: a retrospective assessment 
British Journal of Cancer  2013;109(10):2523-2532.
Background:
Allogeneic haematopoietic stem cell transplantation (allo-SCT) may provide donor cytotoxic T cell-/NK cell-mediated disease control in patients with rhabdomyosarcoma (RMS). However, little is known about the prevalence of graft-vs-RMS effects and only a few case experiences have been reported.
Methods:
We evaluated allo-SCT outcomes of 30 European Group for Blood and Marrow Transplantation (EBMT)-registered patients with advanced RMS regarding toxicity, progression-free survival (PFS) and overall survival (OS) after allo-SCT. Twenty patients were conditioned with reduced intensity and ten with high-dose chemotherapy. Twenty-three patients were transplanted with HLA-matched and seven with HLA-mismatched grafts. Three patients additionally received donor lymphocyte infusions (DLIs). Median follow-up was 9 months.
Results:
Three-year OS was 20% (s.e.±8%) with a median survival time of 12 months. Cumulative risk of progression was 67% (s.e.±10%) and 11% (s.e.±6%) for death of complications. Thirteen patients developed acute graft-vs-host disease (GvHD) and five developed chronic GvHD. Eighteen patients died of disease and four of complications. Eight patients survived in complete remission (CR) (median: 44 months). No patients with residual disease before allo-SCT were converted to CR.
Conclusion:
The use of allo-SCT in patients with advanced RMS is currently experimental. In a subset of patients, it may constitute a valuable approach for consolidating CR, but this needs to be validated in prospective trials.
doi:10.1038/bjc.2013.630
PMCID: PMC3833217  PMID: 24149176
rhabdomyosarcoma; allogeneic haematopoietic stem cell transplantation; graft-vs-tumour effect; reduced intensity conditioning; myeloablative conditioning; donor lymphocyte infusion
6.  CoCo trial: Color-coded blood pressure Control, a randomized controlled study 
Background
Inadequate blood pressure (BP) control is a frequent challenge in general practice. The objective of this study was to determine whether a color-coded BP booklet using a traffic light scheme (red, >180 mmHg systolic BP and/or >110 mmHg diastolic BP; yellow, >140–180 mmHg systolic BP or >90–110 mmHg diastolic BP; green, ≤140 mmHg systolic BP and ≤90 mmHg diastolic BP) improves BP control and adherence with home BP measurement.
Methods
In this two-group, randomized controlled trial, general practitioners recruited adult patients with a BP >140 mmHg systolic and/or >90 mmHg diastolic. Patients in the control group received a standard BP booklet and the intervention group used a color-coded booklet for daily home BP measurement. The main outcomes were changes in BP, BP control (treatment goal <140/90 mmHg), and adherence with home BP measurement after 6 months.
Results
One hundred and twenty-one of 137 included patients qualified for analysis. After 6 months, a significant decrease in systolic and diastolic BP was achieved in both groups, with no significant difference between the groups (16.1/7.9 mmHg in the intervention group versus 13.1/8.6 mmHg in the control group, P=0.3/0.7). BP control (treatment target <140/90 mmHg) was achieved significantly more often in the intervention group (43% versus 25%; P=0.037; number needed to treat of 5). Adherence with home BP measurement overall was high, with a trend in favor of the intervention group (98.6% versus 96.2%; P=0.1)
Conclusion
Color-coded BP self-monitoring significantly improved BP control (number needed to treat of 5, meaning that every fifth patient utilizing color-coded self-monitoring achieved better BP control after 6 months), but no significant between-group difference was observed in BP change. A markedly higher percentage of patients achieved BP values in the normal range. This simple, inexpensive approach of color-coded BP self-monitoring is user-friendly and applicable in primary care, and should be implemented in the care of patients with arterial hypertension.
doi:10.2147/PPA.S68213
PMCID: PMC4206524  PMID: 25346595
primary care; home blood pressure measurement; hypertension; high blood pressure; general practitioner; number needed to treat
7.  APP Is Cleaved by Bace1 in Pre-Synaptic Vesicles and Establishes a Pre-Synaptic Interactome, via Its Intracellular Domain, with Molecular Complexes that Regulate Pre-Synaptic Vesicles Functions 
PLoS ONE  2014;9(9):e108576.
Amyloid Precursor Protein (APP) is a type I membrane protein that undergoes extensive processing by secretases, including BACE1. Although mutations in APP and genes that regulate processing of APP, such as PSENs and BRI2/ITM2B, cause dementias, the normal function of APP in synaptic transmission, synaptic plasticity and memory formation is poorly understood. To grasp the biochemical mechanisms underlying the function of APP in the central nervous system, it is important to first define the sub-cellular localization of APP in synapses and the synaptic interactome of APP. Using biochemical and electron microscopy approaches, we have found that APP is localized in pre-synaptic vesicles, where it is processed by Bace1. By means of a proteomic approach, we have characterized the synaptic interactome of the APP intracellular domain. We focused on this region of APP because in vivo data underline the central funtional and pathological role of the intracellular domain of APP. Consistent with the expression of APP in pre-synaptic vesicles, the synaptic APP intracellular domain interactome is predominantly constituted by pre-synaptic, rather than post-synaptic, proteins. This pre-synaptic interactome of the APP intracellular domain includes proteins expressed on pre-synaptic vesicles such as the vesicular SNARE Vamp2/Vamp1 and the Ca2+ sensors Synaptotagmin-1/Synaptotagmin-2, and non-vesicular pre-synaptic proteins that regulate exocytosis, endocytosis and recycling of pre-synaptic vesicles, such as target-membrane-SNAREs (Syntaxin-1b, Syntaxin-1a, Snap25 and Snap47), Munc-18, Nsf, α/β/γ-Snaps and complexin. These data are consistent with a functional role for APP, via its carboxyl-terminal domain, in exocytosis, endocytosis and/or recycling of pre-synaptic vesicles.
doi:10.1371/journal.pone.0108576
PMCID: PMC4172690  PMID: 25247712
8.  Three-Dimensional Imaging of HIV-1 Virological Synapses Reveals Membrane Architectures Involved in Virus Transmission 
Journal of Virology  2014;88(18):10327-10339.
ABSTRACT
HIV transmission efficiency is greatly increased when viruses are transmitted at virological synapses formed between infected and uninfected cells. We have previously shown that virological synapses formed between HIV-pulsed mature dendritic cells (DCs) and uninfected T cells contain interdigitated membrane surfaces, with T cell filopodia extending toward virions sequestered deep inside invaginations formed on the DC membrane. To explore membrane structural changes relevant to HIV transmission across other types of intercellular conjugates, we used a combination of light and focused ion beam scanning electron microscopy (FIB-SEM) to determine the three-dimensional (3D) architectures of contact regions between HIV-1-infected CD4+ T cells and either uninfected human CD4+ T cells or human fetal astrocytes. We present evidence that in each case, membrane extensions that originate from the uninfected cells, either as membrane sheets or filopodial bridges, are present and may be involved in HIV transmission from infected to uninfected cells. We show that individual virions are distributed along the length of astrocyte filopodia, suggesting that virus transfer to the astrocytes is mediated, at least in part, by processes originating from the astrocyte itself. Mechanisms that selectively disrupt the polarization and formation of such membrane extensions could thus represent a possible target for reducing viral spread.
IMPORTANCE Our findings lead to new insights into unique aspects of HIV transmission in the brain and at T cell-T cell synapses, which are thought to be a predominant mode of rapid HIV transmission early in the infection process.
doi:10.1128/JVI.00788-14
PMCID: PMC4178837  PMID: 24965444
9.  Are hematopoietic stem cells involved in hepatocarcinogenesis? 
The liver has three cell lineages able to proliferate after a hepatic injury: the mature hepatocyte, the ductular “bipolar” progenitor cell termed “oval cell” and the putative periductular stem cell. Hepatocytes can only produce other hepatocytes whereas ductular progenitor cells are considerate bipolar since they can give rise to biliary cells or hepatocytes. Periductular stem cells are rare in the liver, have a very long proliferation potential and may be multipotent, being this aspect still under investigation. They originate in the bone marrow since their progeny express genetic markers of donor hematopoietic cells after bone marrow transplantation. Since the liver is the hematopoietic organ of the fetus, it is possible that hematopoietic stem cells may reside in the liver of the adult. This assumption is proved by the finding that oval cells express hematopoietic markers like CD34, CD45, CD 109, Thy-1, c-kit, and others, which are also expressed by bone marrow-derived hematopoietic stem cells (BMSCs). Few and discordant studies have evaluated the role of BMSC in hepatocarcinogenesis so far and further studies in vitro and in vivo are warranted in order to definitively clarify such an issue.
doi:10.3978/j.issn.2304-3881.2014.06.02
PMCID: PMC4141297  PMID: 25202697
Hepatocellular carcinoma (HCC); stem cells; carcinogenesis; hematopoietic
10.  Optimized contrast-enhanced ultrasonography for characterization of focal liver lesions in cirrhosis: A single-center retrospective study 
Background
Hepatocellular carcinoma (HCC) is the leading cause of death amongst cirrhotic patients. Its diagnosis and discrimination from non-HCC malignant lesions in cirrhosis includes contrast enhanced computed tomography (CECT), contrast enhanced magnetic resonance imaging (CEMRI), or, in selected cases, liver biopsy. The role of contrast-enhanced ultrasonography (CEUS) is still controversial.
Aims
To evaluate whether, by selecting an appropriate ‘time to wash-out’ cut-off value, CEUS capability of discriminating between HCC and non-HCC malignancies in cirrhotic patients may be enhanced.
Methods
We enrolled 282 cirrhotic patients who underwent CEUS at our institute, from January 2008 to January 2012, for focal liver lesions (FLLs) detected at ultrasound (US). We used liver biopsy and subsequent histological evaluation as the gold standard for correct classification of FLLs. We calculated the area under receiver operator characteristic curves for CEUS to distinguish patients with HCC from those with non-HCC malignancies. The best ‘time to wash-out’ cut-off values were selected.
Results
Histological diagnosis of FLLs was as follows: 34 benign lesions (i.e. 25 regenerative nodules and 9 dysplastic nodules) and 248 malignant lesions (223 well-to-moderately differentiated HCCs; 7 poorly-differentiated HCCs; 5 intrahepatic colangiocellular carcinomas (ICCs); 5 primary non-Hodgkin B-cell lymphomas (NHBLs); and 8 metastatic liver tumors). A time to wash-out > 55 s identified patients with HCC with the highest level of accuracy (92.7%). Similarly, a time to wash-out ≤ 55 s correctly identified the vast majority of the non-HCC malignancies (100% sensitivity, 98.2% specificity and diagnostic accuracy of 98.3%).
Conclusions
CEUS is an accurate and safe procedure for discriminating FLLs in cirrhotic patients, especially when a cut-off time to wash-out of 55 s is chosen as a reference value.
doi:10.1177/2050640614538964
PMCID: PMC4114116  PMID: 25083285
Biopsy; cirrhosis; cholangiocellular carcinoma; contrast enhancement; focal liver lesions; hepatocellular carcinoma; liver; ultrasound
11.  Phase II Study of Everolimus in Patients With Metastatic Colorectal Adenocarcinoma Previously Treated With Bevacizumab-, Fluoropyrimidine-, Oxaliplatin-, and Irinotecan-Based Regimens 
Purpose
Dysregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is seen in 40–60% of colorectal cancer (CRC) patients. Everolimus, an oral inhibitor of mTOR, demonstrated efficacy in metastatic CRC (mCRC) patients in phase I studies.
Experimental Design
In sequential phase II studies assessing 2 dosing schedules, mCRC patients refractory to bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens received everolimus 70 mg/week (N=99) or 10 mg/d (N=100). Primary endpoints were disease control rate (DCR) and objective response rate; secondary endpoints included progression-free survival (PFS), overall survival (OS), and duration of response or stable disease (SD). Tumor tissue was collected from all patients for predefined exploratory biomarker analyses.
Results
71 patients were included in the per protocol set for each cohort. DCRs of 31.0% and 32.4% (all SD) were seen in the weekly and daily schedules, respectively. Median duration of SD was 3.9 months in each cohort. Median PFS and OS were 1.8 months and 4.9 months and 1.8 months and 5.9 months, respectively, for the weekly and daily schedules. Among patients receiving daily everolimus, those with a KRAS mutation experienced significantly shorter median OS (P = .008) and lower DCR (P = .035) compared with those with wild-type KRAS in exploratory biomarker analyses.
Conclusions
Everolimus 70 mg/week or 10 mg/day was well tolerated but did not confer meaningful efficacy in heavily pretreated mCRC patients. Future studies may consider evaluating everolimus in combination with other agents or in patients with dysregulation of the PI3K/Akt/mTOR pathway.
doi:10.1158/1078-0432.CCR-13-0027
PMCID: PMC3725595  PMID: 23743569
Clinical trial; Colorectal cancer; Everolimus; mTOR; Phase II
12.  Considerations in the Development of Nonhuman Primate Models of Combination Antiretroviral Therapy for Studies of AIDS Virus Suppression, Residual Virus, and Curative Strategies 
Current opinion in HIV and AIDS  2013;8(4):262-272.
Purpose of review
Animal models will be critical for preclinical evaluations of novel HIV eradication and/or functional cure strategies in the setting of suppressive combination antiretroviral therapy (cART). Here, the strengths, limitations, and challenges of recent efforts to develop nonhuman primate (NHP) models of cART-mediated suppression for use in studies of persistent virus and curative approaches are discussed.
Recent findings
A number of combinations of NHP species and viruses that recapitulate key aspects of human HIV infection have been adapted for cART-mediated suppression studies. Different cART regimens implementing drugs targeting multiple different steps of the viral life cycle have provided varying levels virologic suppression, dependent in part upon the host species, virus, drug regimen and timing, and virologic monitoring assay sensitivity. New, increasingly sensitive virologic monitoring approaches for measurements of plasma viral RNA, cell- and tissue-associated viral RNA and DNA, and the replication-competent residual viral pool in the setting of cART in NHP models are being developed to allow for the assessment of persistent virus on cART and to evaluate the impact of viral induction/eradication strategies in vivo.
Summary
Given the vagaries of each specific virus and host species, and cART regimen, each model will require further development and analysis to determine their appropriate application for addressing specific experimental questions.
doi:10.1097/COH.0b013e328361cf40
PMCID: PMC3939607  PMID: 23698559
nonhuman primate; antiretroviral therapy; SIV; cure
13.  The hnRNP-Q Protein LIF2 Participates in the Plant Immune Response 
PLoS ONE  2014;9(6):e99343.
Eukaryotes have evolved complex defense pathways to combat invading pathogens. Here, we investigated the role of the Arabidopsis thaliana heterogeneous nuclear ribonucleoprotein (hnRNP-Q) LIF2 in the plant innate immune response. We show that LIF2 loss-of-function in A. thaliana leads to changes in the basal expression of the salicylic acid (SA)- and jasmonic acid (JA)- dependent defense marker genes PR1 and PDF1.2, respectively. Whereas the expression of genes involved in SA and JA biosynthesis and signaling was also affected in the lif2-1 mutant, no change in SA and JA hormonal contents was detected. In addition, the composition of glucosinolates, a class of defense-related secondary metabolites, was altered in the lif2-1 mutant in the absence of pathogen challenge. The lif2-1 mutant exhibited reduced susceptibility to the hemi-biotrophic pathogen Pseudomonas syringae and the necrotrophic ascomycete Botrytis cinerea. Furthermore, the lif2-1 sid2-2 double mutant was less susceptible than the wild type to P. syringae infection, suggesting that the lif2 response to pathogens was independent of SA accumulation. Together, our data suggest that lif2-1 exhibits a basal primed defense state, resulting from complex deregulation of gene expression, which leads to increased resistance to pathogens with various infection strategies. Therefore, LIF2 may function as a suppressor of cell-autonomous immunity. Similar to its human homolog, NSAP1/SYNCRIP, a trans-acting factor involved in both cellular processes and the viral life cycle, LIF2 may regulate the conflicting aspects of development and defense programs, suggesting that a conserved evolutionary trade-off between growth and defense pathways exists in eukaryotes.
doi:10.1371/journal.pone.0099343
PMCID: PMC4051675  PMID: 24914891
14.  Ryanodine receptors: physiological function and deregulation in Alzheimer disease 
Perturbed Endoplasmic Reticulum (ER) calcium (Ca2+) homeostasis emerges as a central player in Alzheimer disease (AD). Accordingly, different studies have reported alterations of the expression and the function of Ryanodine Receptors (RyR) in human AD-affected brains, in cells expressing familial AD-linked mutations on the β amyloid precursor protein (βAPP) and presenilins (the catalytic core in γ-secretase complexes cleaving the βAPP, thereby generating amyloid β (Aβ) peptides), as well as in the brain of various transgenic AD mice models. Data converge to suggest that RyR expression and function alteration are associated to AD pathogenesis through the control of: i) βAPP processing and Aβ peptide production, ii) neuronal death; iii) synaptic function; and iv) memory and learning abilities. In this review, we document the network of evidences suggesting that RyR could play a complex dual “compensatory/protective versus pathogenic” role contributing to the setting of histopathological lesions and synaptic deficits that are associated with the disease stages. We also discuss the possible mechanisms underlying RyR expression and function alterations in AD. Finally, we review recent publications showing that drug-targeting blockade of RyR and genetic manipulation of RyR reduces Aβ production, stabilizes synaptic transmission, and prevents learning and memory deficits in various AD mouse models. Chemically-designed RyR “modulators” could therefore be envisioned as new therapeutic compounds able to delay or block the progression of AD.
doi:10.1186/1750-1326-9-21
PMCID: PMC4063224  PMID: 24902695
Ryanodine receptor; Calcium; Alzheimer disease; Endoplasmic reticulum; Neurodegeneration; Presenilin; Amyloid precursor protein; Amyloid beta
15.  An atypical Dent's disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes 
Dent's disease is an X-linked renal tubulopathy caused by mutations mainly affecting the CLCN5 gene. Defects in the OCRL gene, which is usually mutated in patients with Lowe syndrome, have been shown to lead to a Dent-like phenotype called Dent disease 2. However, about 20% of patients with Dent's disease carry no CLCN5/OCRL mutations. The disease's genetic heterogeneity is accompanied by interfamilial and intrafamilial phenotypic heterogeneity. We report on a case of Dent's disease with a very unusual phenotype (dysmorphic features, ocular abnormalities, growth delay, rickets, mild mental retardation) in which a digenic inheritance was discovered. Two different, novel disease-causing mutations were detected, both inherited from the patient's healthy mother, that is a truncating mutation in the CLCN5 gene (A249fs*20) and a donor splice-site alteration in the OCRL gene (c.388+3A>G). The mRNA analysis of the patient's leukocytes revealed an aberrantly spliced OCRL mRNA caused by in-frame exon 6 skipping, leading to a shorter protein, but keeping intact the central inositol 5-phosphatase domain and the C-terminal side of the ASH-RhoGAP domain. Only wild-type mRNA was observed in the mother's leukocytes due to a completely skewed X inactivation. Our results are the first to reveal the effect of an epistatic second modifier in Dent's disease too, which can modulate its expressivity. We surmise that the severe Dent disease 2 phenotype of our patient might be due to an addictive interaction of the mutations at two different genes.
doi:10.1038/ejhg.2012.225
PMCID: PMC3658198  PMID: 23047739
Dent's disease; Lowe syndrome; CLCN5 gene; OCRL1 gene; digenic inheritance; epistatic interaction
16.  The odd fate of a chicken dinner 
BMJ Case Reports  2012;2012:bcr0120125588.
doi:10.1136/bcr.01.2012.5588
PMCID: PMC3369308  PMID: 22669211
17.  Hepatic arterial embolization in patients with neuroendocrine tumors 
Liver metastases occur in 46-93% of patients with neuroendocrine neoplasms (NENs). Presence and extension of liver metastases are considered important prognostic factors, as they may significantly impair the patient’s quality of life, because of either tumor bulk or hormonal hypersecretion. Therapies for NEN liver metastases include surgical resection, liver transplantation, chemotherapy and biotherapy. Surgery is the gold standard for curative therapy, but in most of NEN patients with liver metastases, when surgery can not be applied, minimally invasive therapeutic approaches are adopted. They include trans-arterial embolization (TAE), trans-arterial chemoembolization (TACE), radiofrequency thermal ablation and new emerging techniques.
TAE is based on selective infusion of particles in the branch of the hepatic artery supplying the tumor lesions. The goal of TAE is to occlude tumor blood vessels resulting in ischemia and necrosis. Many reports have shown that TAE can reduce tumor size and hormone output, resulting in palliation of symptoms without the use of cytotoxic drugs, resulting in better tolerability. This review will focus on TAE performance and safety in NEN patients with liver metastases.
doi:10.1186/1756-9966-33-43
PMCID: PMC4038067  PMID: 24887262
Embolization; Chemoembolization; Liver metastases; Neuroendocrine tumor
18.  Restoration of anterior teeth using an indirect composite technique. Case report 
Oral & Implantology  2014;6(4):99-102.
SUMMARY
Objective.
This article presents a case report of restoration of anterior teeth using an indirect technique with composite veneers in order to restore the dental anatomy and to provide aesthetic and function of anterior teeth.
Materials and methods.
A treatment of upper anterior teeth with indirect micro-hybrid composite restoration was proposed to a 40-year-old woman with old discolored and fractured ceramic veneers. Upper six anterior teeth were prepared and, after impressions with VPS of maxillary arche, the composite veneers were placed.
Discussion and results.
There are several advantages offered by indirect techniques compared to direct techniques. The increased practice of veneering technique with indirect composites is due to improvement in the properties of composite materials in the last years. The results are very favourable and the patient is satisfied.
Conclusions.
The restorations with composite veneers have proved durable and aesthetic, protect tooth structure and aesthetic and function is predictably re-established.
PMCID: PMC4051270  PMID: 24971164
veneers; composite; restoration; indirect technique; aesthetic
19.  Fertility drugs, reproductive strategies and ovarian cancer risk 
Several adverse effects have been related to infertility treatments, such as cancer development. In particular, the relationship between infertility, reproductive strategies, and risk of gynecological cancers has aroused much interest in recent years. The evaluation of cancer risk among women treated for infertility is very complex, mainly because of many factors that can contribute to occurrence of cancer in these patients (including parity status). This article addresses the possible association between the use of fertility treatments and the risk of ovarian cancer, through a scrupulous search of the literature published thus far in this field. Our principal objective was to give more conclusive answers on the question whether the use of fertility drug significantly increases ovarian cancer risk. Our analysis focused on the different types of drugs and different treatment schedules used. This study provides additional insights regarding the long-term relationships between fertility drugs and risk of ovarian cancer.
doi:10.1186/1757-2215-7-51
PMCID: PMC4020377  PMID: 24829615
Fertility drugs; Ovarian cancer; Ovarian stimulation; in vitro fertilization; Clomiphene citrate
20.  Adipokines as Potential Biomarkers in Rheumatoid Arthritis 
Mediators of Inflammation  2014;2014:425068.
Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease characterized by severe joint injury. Recently, research has been focusing on the possible identification of predictor markers of disease onset and/or progression, of joint damage, and of therapeutic response. Recent findings have uncovered the role of white adipose tissue as a pleiotropic organ not only specialized in endocrine functions but also able to control multiple physiopathological processes, including inflammation. Adipokines are a family of soluble mediators secreted by white adipose tissue endowed with a wide spectrum of actions. This review will focus on the recent advances on the role of the adipokine network in the pathogenesis of RA. A particular attention will be devoted to the action of these proteins on RA effector cells, and on the possibility to use circulating levels of adipokines as potential biomarkers of disease activity and therapeutic response.
doi:10.1155/2014/425068
PMCID: PMC3985296  PMID: 24799765
21.  Tracking the Luminal Exposure and Lymphatic Drainage Pathways of Intravaginal and Intrarectal Inocula Used in Nonhuman Primate Models of HIV Transmission 
PLoS ONE  2014;9(3):e92830.
Over 80% of sexual HIV-1 transmissions originate from a single viral variant, but the underlying basis for this transmission bottleneck remains to be elucidated. Nonhuman primate models of mucosal virus transmission allow opportunities to gain insight into the basis of this mucosal bottleneck. We used simulated inocula consisting of either non-infectious vital dye or contrast dye with non-invasive magnetic resonance imaging (MRI) to visualize mucosal exposure and passive lymphatic drainage patterns following vaginal and rectal exposures in Indian origin rhesus macaques. Results revealed a limited overall distance of dye coverage from the anal verge following 1 ml (n  = 8) intrarectally administered, which greatly increased with a 3 ml (n = 8) volume. Intravaginal dye exposure using 2 ml revealed complete coverage of the mucosa of the vagina and ectocervix, however dye was not detectable in the endocervix, uterus, fallopian tubes or ovaries in nuliparous sexually mature rhesus macaques (n = 9). In addition, following submucosal and intranodal injections of vital dye or MRI contrast dye in the rectum (n = 9), or distal and proximal vagina (n = 4), the lymphatic drainage pathways were identified as first the internal then common iliac chain followed by para-aortic lymph nodes. Drainage from the distal descending colon (n = 8) was via the para-colonic lymph nodes followed by the inferior mesenteric and para-aortic lymph nodes. Analysis after vaginal challenge with infectious SIVmac239 followed by euthanasia at day 3 revealed a pattern of viral dissemination consistent with the imaging results. These results provide insights into potential patterns of viral dissemination that can help guide efforts to better elucidate the earliest events of virus transmission and potential intervention strategies.
doi:10.1371/journal.pone.0092830
PMCID: PMC3965472  PMID: 24667371
22.  VEGF and VEGFR polymorphisms affect clinical outcome in advanced renal cell carcinoma patients receiving first-line sunitinib 
British Journal of Cancer  2012;108(5):1126-1132.
Background:
Currently, sunitinib represents one of the therapeutic strongholds for renal cell carcinoma, but the criteria for treatment selection are lacking. We assessed the role of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) polymorphisms in the prediction of the clinical outcome in metastatic renal cell carcinoma (mRCC) patients.
Methods:
A total of 84 tumour samples from mRCC patients receiving first-line sunitinib were tested for VEGF and VEGFR single-nucleotide polymorphisms (SNPs). The SNP results were correlated with progression-free survival (PFS) and overall survival (OS).
Results:
Median PFS was 8.22 months, although whereas median OS was 32.13 months. The VEGF A rs833061 resulted significant in PFS (17 vs 4 months; P<0.0001) and OS (38 vs 10 months; P<0.0001). The VEGF A rs699947 was significant for PFS (18 vs 4 months; P=0.0001) and OS (37 vs 16 months; P<0.0001). The VEGF A rs2010963 was significant in PFS (18 vs 8 vs 2 months; P=0.0001) and OS (31 vs 36 vs 9 months; P=0.0045). The VEGR3 rs6877011 was significant in PFS (12 vs 4 months; P=0.0075) and OS (36 vs 17 months; P=0.0001). At multivariate analysis, rs833061, rs2010963 and rs68877011 were significant in PFS, and rs833061 and rs68877011 were independent factors in OS.
Conclusions:
In our analysis, patients with TT polymorphism of rs833061, CC polymorphism of rs699947, CC polymorphism of rs2010963 and CG polymorphism of rs6877011 seem to have a worse PFS and OS when receiving first-line sunitinib.
doi:10.1038/bjc.2012.501
PMCID: PMC3619056  PMID: 23511629
angiogenesis; polymorphism; renal cell carcinoma; sunitinib; VEGF
23.  Perceptual asymmetries and handedness: a neglected link? 
Healthy individuals tend to weigh in more the left than the right side of visual space in a variety of contexts, ranging from pseudoneglect to perceptual asymmetries for faces. Among the common explanations proposed for the attentional and perceptual advantages of the left visual field, a link with the prevalence of right-handedness in humans has never been suggested, although some evidence seems to converge in favor of a bias of spatial attention toward the region most likely coincident with another person’s right hand during a face-to-face interaction. Such a bias might imply an increased efficiency in monitoring both communicative and aggressive acts, the right limb being more used than the left in both types of behavior. Although attentional and perceptual asymmetries could be linked to right-handedness at the level of phylogeny because of the evolutionarily advantage of directing attention toward the region where others’ dominant hand usually operates, it is also legitimate to question whether, at the ontogenetic level, frequent exposure to right-handed individuals may foster leftward biases. These views are discussed in the light of extant literature, and a number of tests are proposed in order to assess our hypotheses.
doi:10.3389/fpsyg.2014.00163
PMCID: PMC3938099  PMID: 24592250
perceptual and attentional asymmetries; handedness; left face bias; face; body
24.  The role of LDH serum levels in predicting global outcome in HCC patients treated with sorafenib: implications for clinical management 
BMC Cancer  2014;14:110.
Background
In many tumour types serumlactate dehydrogenase (LDH) levels proved to represent an indirect marker of tumour hypoxia, neo-angiogenesis and worse prognosis. As we previously reported LDH is an important predictive factor in hepatocellular carcinoma (HCC) patients undergoing transarterial chemoembolization (TACE). Sorafenib represents the therapeutic stronghold in advanced HCC patients. As a tyrosine kinase inhibitor (TKI) mainly directed against the angiogenetic pathway, the correlation of sorafenib administration with markers of hypoxia could be an important tool in patients management. Aim of our analysis was to evaluate the role of LDH pre-treatment levels and its variation during treatment in HCC patients receiving sorafenib.
Methods
78 patients were available for our analysis. For all patients LDH values were collected within one month before the start of treatment and after the end of therapy. For study purposes we divided our patients into two groups, according to LDH pre-treatment levels, cut-off levels was determined with ROC curve analysis. Patients were, also, classified according to the variation in LDH serum levels pre- and post-treatment (increased vs decreased).
Results
Patients proved homogeneous for all clinical characteristics analyzed. In patients with LDH values under the cut-off median progression free survival (PFS) was 6.7 months, whereas it was 1.9 months in patients above the cut-off (p = 0.0002). Accordingly median overall survival (OS) was 13.2 months and 4.9 months (p = 0.0006). In patients with decreased LDH values after treatment median PFS was 6.8 months, and median OS was 21.0 months, whereas PFS was 2.9 months and OS 8.6 months in patients with increased LDH levels (PFS: p = 0.0087; OS: p = 0.0035).
Conclusions
In our experience, LDH seemed able to predict clinical outcome in terms of PFS and OS for HCC patients treated with sorafenib. Given the correlation between LDH levels and tumour angiogenesis we can speculate that patients with high LDH pretreatment levels may be optimal candidates for other emerging therapeutic agents or strategies targeting different molecular pathways.
doi:10.1186/1471-2407-14-110
PMCID: PMC3930857  PMID: 24552144
Hepatocellular carcinoma; Lactate dehydrogenase; Sorafenib; Angiogenesis
25.  Autoimmune uveitis: a retrospective analysis of 104 patients from a tertiary reference center 
Background
The aim of this study was to identify the main features of a cohort of Caucasian patients with idiopathic (I) and systemic disease-associated (SDA) autoimmune uveitis (AU) who were followed up at a single tertiary reference center. The study consisted of a retrospective analysis of the demographic, clinical, and laboratory features and the response to treatment of 104 patients with AU evaluated between 2004 and 2013, with a median follow-up of 4.8 years. The primary outcome measure was the response to systemic treatment after 24 months of therapy. The data are expressed as the range, percentage, or mean ± standard error. Categorical variables were assessed by Fisher's exact test.
Results
The mean age at diagnosis was 40.1 ± 17.8 years for men and 44.1 ± 15.3 years for women. There was a slight female predominance. Of the 104 patients, 72.1% had I-AU and 27.9% SDA-AU. The most frequent associations were with ankylosing spondyloarthritis, autoimmune thyroiditis, inflammatory bowel diseases, and Behcet's disease. Symptoms at presentation consisted of eye redness and pain (28.8%), decreased visual acuity (25.9%), and floaters (18.3%). Complications included cataracts (24%), retinal neovascularization (16.3%), chorio-retinal scars (10.6%), cystoid macular edema (8.6%), glaucoma/ocular hypertension (7.7%), epiretinal membranes (4.8%), and retinal detachment (3.8%). The prevalence of autoantibodies, mostly antinuclear antibodies, was comparable between the I-AU and SDA-AU groups. Fisher's exact test showed a direct correlation between patients with class I HLA B27, Cw8, B5 (51, 52), B51, or Cw2 and the presence of AU, whereas among patients with class II HLA, only DQ1 was a predisposing factor for AU. The therapeutic spectrum included corticosteroids and immunosuppressive agents, given either alone or in various combinations according to the severity of AU and the extent of the clinical response. Among the immunosuppressive drugs, azathioprine was preferentially used for anterior uveitis, and cyclosporine-A for intermediate and posterior uveitis. An assessment of the patients after 24 months of therapy showed a complete remission in 43.3% and a significant clinical improvement in 26.9%.
Conclusions
At our tertiary reference center, the prevalence in Caucasian patients of I-AU was approximately 2.5-fold higher than that of SDA-AU. Our findings point to the need for a patient-tailored therapeutic approach according to the anatomic site and the severity of AU. Therapy should be prolonged, over a period of months and even up to 1–2 years, in order to achieve stable control of the disease and to prevent severe complications. The outcome of SDA-AU is also influenced by treatment of the underlying systemic disease. Additional controlled trials are needed to assess the efficacy and the long-term safety of both the prescribed therapeutic agents and their combinations.
doi:10.1186/s12348-014-0017-9
PMCID: PMC4108222  PMID: 25097673
Autoimmune uveitis; Ankylosing spondyloarthritis; Behcet's disease; Class I and II HLA; Corticosteroids; Immunosuppressive drugs

Results 1-25 (132)