Falls at the interface between geriatric and psychiatric patients: a critical review from a psychopharmacological perspective.

Falls in the elderly represent one of the major clinical problems as they are serious events that often result in high residual disability and mortality rates. Knowledge on the subject derives mainly from geriatric and gerontopsychiatric research. However, gerontopsychiatric patients differ from geriatric patients not only for the psychiatric and neurological comorbidities, which are often not sufficiently taken into account in the scientific context, but also for the intake of psychotropic drugs, notoriously described as one of the main risk factors for falls. Such drugs are widely prescribed in this group of patients, often even off-label. Clinicians therefore should pay particular attention to falls, since various comorbidities and polypharmacy as a prescribing issue can have important consequences for clinical management. Falls have not been sufficiently investigated yet in a purely psychiatric context.

High Blood Concentration of Leukocyte-Derived Extracellular Vesicles Is Predictive of Favorable Clinical Outcomes in Patients with Pancreatic Cancer: Results from a Multicenter Prospective Study.

Pancreatic cancer (PC) is one of the leading causes of cancer-related death worldwide. Identification of novel tumor biomarkers is highly advocated in PC to optimize personalized treatment algorithms. Blood-circulating extracellular vesicles hold promise for liquid biopsy application in cancer. We used an optimized flow cytometry protocol to study leukocyte-derived EVs (CD45+) and PD-L1+ EVs in blood from 56 pancreatic cancer patients and 48 healthy controls (HCs). Our results show that PC patients presented higher blood levels of total EVs (p = 0.0003), leukocyte-derived EVs (LEVs) (p = 0.001) and PD-L1+ EVs (p = 0.01), as compared with HCs. Interestingly, a blood concentration of LEVs at baseline was independently associated with improved overall survival in patients with borderline resectable or primary unresectable PC (HR = 0.17; 95% CI 0.04-0.79; p = 0.02). Additionally, increased blood-based LEVs were independently correlated with prolonged progression-free survival (HR = 0.10; 95% CI 0.01-0.82; p = 0.03) and significantly associated with higher disease control rate (p = 0.02) in patients with advanced PC receiving standard chemotherapy. Notably, a strong correlation between a decrease in blood LEVs concentration during chemotherapy and disease control was observed (p = 0.005). These intriguing findings point to the potential of LEVs as novel blood-based EV biomarkers for improved personalized medicine in patients affected by PC.

The specific deletion of cyclooxygenase-1 in megakaryocytes/platelets reduces intestinal polyposis in ApcMin/+ mice.

Clinical and experimental evidence sustain the role of cyclooxygenase (COX)-1 in intestinal tumorigenesis. However, the cell type expressing the enzyme involved and molecular mechanism(s) have not been clarified yet. We aimed to elucidate the role of platelet COX-1 (the target of low-dose aspirin in humans) in intestinal tumorigenesis of ApcMin/+ mice, considered a clinically relevant model. To realize this objective, we generated an ApcMin/+ mouse with a specific deletion of Ptgs1(COX-1 gene name) in megakaryocytes/platelets (ApcMin/+;pPtgs1-/-mice) characterized by profound inhibition of thromboxane(TX)A2 biosynthesis ex vivo (serum TXB2; by 99%) and in vivo [urinary 2,3-dinor-TXB2(TXM), by 79%]. ApcMin/+ mice with the deletion of platelet COX-1 showed a significantly reduced number (67%) and size (32%) of tumors in the small intestine. The intestinal adenomas of these mice had decreased proliferative index associated with reduced COX-2 expression and systemic prostaglandin(PG)E2 biosynthesis (urinary PGEM) vs. ApcMin/+mice. Extravasated platelets were detected in the intestine of ApcMin/+mice. Thus, we explored their contribution to COX-2 induction in fibroblasts, considered the primary polyp cell type expressing the protein. In the coculture of human platelets and myofibroblasts, platelet-derived TXA2 was involved in the induction of COX-2-dependent PGE2 in myofibroblasts since it was prevented by the selective inhibition of platelet COX-1 by aspirin or by a specific antagonist of TXA2 receptors. In conclusion, our results support the platelet hypothesis of intestinal tumorigenesis and provide experimental evidence that selective inhibition of platelet COX-1 can mitigate early events of intestinal tumorigenesis by restraining COX-2 induction.

Efficacy and safety of intravesical fibrin glue instillation for management of patients with refractory hemorrhagic cystitis: 12-months results. A promising therapy for hemorrhagic cystitis.

OBJECTIVES: Fibrin glue (FG) endo-vesical application seems to be a promising therapy for hemorrhagic cystitis (HC). We aimed to evaluate efficacy and safety of FG instillation in patients with HC. METHODS: Patients with HC not responsive to conventional treatments (bladder irrigation, catheterization, blood transfusions, hyperhydration and endoscopic coagulation) were treated with FG endo-vesical instillation (April 2017- December 2018). FG was prepared from 120 mL of patient blood with the Vivostat® system. After standard cystoscopy, bladder was insufflated with carbon dioxide (CO2) according to bladder compliance and autologous FG was applied to bladder wall and bleeding sites. RESULTS: Ten patients included with grade 2 or higher HC secondary to bone marrow graft for hematological diseases (30%) or to actinic cystitis caused by prostate cancer radiotherapy (RT) (70%). The median HC onset time after RT was 4.8 (IQR 3.9- 6.3) years and 35 (IQR 27.5-62.5) days after hematopoietic stem cell transplantation (HSCT). Five patients had a complete response after one treatment, three patients had clinical response (grade < 2 hematuria, amelioration of symptoms), one of them required catheterization and bladder irrigation. One patient required a second instillation of FG achieving a clinical response. No adverse events related to the procedure were recorded, however one patient died for causes not related to the procedure. Median Interstitial Cystitis Symptoms Index was 13.0 (IQR 11.0-15.0) pre-operatively and 4.0 (IQR 2.0-5.0) post-operatively. CONCLUSIONS: Our study showed that, even in hematological patients, autologous FG instillation maybe a safe, repeatable and effective treatment modality in patients with refractory HC.

Enhanced Expression of miR-181b in B Cells of CLL Improves the Anti-Tumor Cytotoxic T Cell Response.

The clinical progression of B cell chronic lymphocytic leukemia (CLL) is associated with immune cell dysfunction and a strong decrease of miR-181b-5p (miR-181b), promoting the death of CLL cells. Here we investigated whether the reduction of miR-181b impairs the immune response in CLL. We demonstrate that activated CD4+ T cells increase miR-181b expression in CLL through CD40-CD40L signaling, which enhances the maturation and activity of cytotoxic T cells and, consequently, the apoptotic response of CLL cells. The cytotoxic response is facilitated by a depletion of the anti-inflammatory cytokine interleukin 10, targeted by miR-181b. In vivo experiments in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice confirmed that miR-181b promotes the apoptotic death of CLL cells only when functional T cells are restored. Overall, our findings suggest that the reinstatement of miR-181b in CLL cells could be an exploitable adjuvant therapeutic option for the treatment of CLL.

Relationship between MUTYH, OGG1 and BRCA1 mutations and mRNA expression in breast and ovarian cancer predisposition.

The aetiology of breast and ovarian cancer (BC/OC) is multi-factorial. At present, the involvement of base excision repair (BER) glycosylases (MUTYH and OGG1) in BC/OC predisposition is controversial. The present study investigated whether germline mutation status and mRNA expression of two BER genes, MUTHY and OGG1, were correlated with BRCA1 in 59 patients with BC/OC and 50 matched population controls. In addition, to evaluate the relationship between MUTYH, OGG1 and BRCA1, their possible mutual modulation and correlation among mutational spectrum, gene expression and demographic characteristics were evaluated. The results identified 18 MUTYH and OGG1 variants, of which 4 were novel (2 MUTYH and 2 OGG1) in 44 of the 59 patients. In addition, two pathogenic mutations were identified: OGG1 p.Arg46Gln, detected in a patient with BC and a family history of cancer, and MUTYH p.Val234Gly in a patient with OC, also with a family history of cancer. A significant reduced transcript expression in MUTYH was observed (P=0.033) in cases, and in association with the presence of rare variants in the same gene (P=0.030). A significant correlation in the expression of the two BER genes was observed in cases (P=0.004), whereas OGG1 and BRCA1 was significantly correlated in cases (P=0.001) compared with controls (P=0.010). The results of the present study indicated that the relationship among mutational spectrum, gene expression and demographic characteristics may improve the genetic diagnosis and primary prevention of at-risk individuals belonging to families with reduced mRNA expression, regardless of mutation presence.

Decision tree for ward admissions of older patients at the emergency department after a fall.

AIM: Falls are a prevalent issue for the older population, and for the healthcare system in terms of emergency department (ED) access and hospitalizations. There is still a lack of knowledge and guidelines, however, regarding the need to hospitalize older patients accessing the ED after a fall. In the present study, we aimed to analyze the factors and the decisional process that led to older patients accessing the ED after a fall being admitted to hospital or discharged. METHODS: The study sample included 2144 older people who accessed the ED after a fall. For each patient, we obtained information on the nature of the fall and the related injuries, previous falls, dementia and ongoing medical therapies. As the outcome variable, we considered the indication for ward admission after the ED visit. RESULTS: Of the 2144 individuals who accessed the ED after a fall, 38% had at least one fracture, and 40.1% were admitted to a ward. The decision tree obtained using the chi-squared automatic interaction detection algorithm showed that the indication for ward admission could be accurately predicted (risk estimate 0.205) by just five factors, namely: presence and severity of fall-related injuries, reportedly suspicious fall dynamics, use of anticoagulants, polypharmacy, and dementia. CONCLUSIONS: The need for ward admission in older patients who access the ED after a fall seems to be determined not only by the severity of fall-related injuries, but also by the fall dynamics and the individual's clinical complexity. Geriatr Gerontol Int 2018; 18: 1388-1392.

Synergistic activity of platelet rich plasma and high volume image guided injection for patellar tendinopathy.

PURPOSE: Platelet rich plasma and high volume image guided injections of saline have been used in the treatment of patellar tendinopathy with positive results. As the different mechanisms of action do not interfere each other, it can be hypothesized that they can be used in combination. Aim of this study was twofold: first, to evaluate the efficacy of these two treatments in the management of patellar tendinopathy; second, to verify whether the combination of these therapies could provide further advantages. METHODS: Fifty-four patients suffering from patellar tendinopathy were enrolled. After clinical (VAS and VISA-P) and sonographic evaluation, two ultrasound guided injections (2 weeks apart) of platelet rich plasma, high-volume image-guided injections of saline, or both in association were performed. The VAS and VISA-P scores obtained from the three treatments groups (18 patients in each group) were compared across the different follow-up times (3 and 6 months). RESULTS: In the short term both treatments showed comparable efficacy, whereas in the medium term the positive effects of high-volume image-guided injections gradually diminished and platelet rich plasma showed greater efficacy. Better results (reduced pain, improved function and increased number of subjects who exhibited optimal recovery [> 20 points in VISA-P score]) were observed when both procedures were associated. CONCLUSIONS: The contemporaneous administration of platelet rich plasma and high volume image guided injections of saline treatments, which influence tendon repair by means of different mechanisms, grants a greater improvement for patellar tendinopathy. This finding has clinical relevance, given that this condition has a substantial impact on sports and work performance. LEVEL OF EVIDENCE: III.

Factors influencing short-term outcomes for older patients accessing emergency departments after a fall: The role of fall dynamics.

BACKGROUND: While the relevance of falls in raising the risk of fractures, hospitalization and disability in older age is well recognized, the factors influencing the onset of fractures and the need for ward admission after a fall have yet to be fully elucidated. We investigated which factors and fall dynamics were mainly associated with fall-related injuries and hospitalization among elderly persons accessing the Emergency Department (ED) following a fall. METHODS: The study involved 2144 older subjects who accessed the ED after a fall. Data on the fall´s nature and related injuries, ward admissions, history of falls, dementia, and medical therapies were examined for all patients. Considering dynamics, we distinguished accidental falls (due to interaction with environmental hazards while in motion) and falls from standing (secondary to syncope, lipothymia, drop attack, or vertigo). RESULTS: The overall prevalence of fractures in our population did not differ significantly with advancing age, though hip fractures were more common in the oldest, and upper limb fractures in the youngest patients. Falls from standing were associated with polypharmacy and with higher ward admission rate despite a lower fractures´ prevalence than accidental falls. The chances of fall-related fractures were more than fourfold as high for accidental dynamics (OR=4.05, 95%CI:3.10-5.29, p<0.0001). Ward admission was associated with polypharmacy, dementia, anticoagulants´ use and fall-related fractures (OR=6.84, 95%CI:5.45-8.58, p<0.0001), while it correlated inversely with accidental fall dynamics. CONCLUSIONS: Outcomes of falls in older age depend not only on any fall-related injuries, but also on factors such as polypharmacy, cognitive status and fall dynamics.

Correlation between mutations and mRNA expression of APC and MUTYH genes: new insight into hereditary colorectal polyposis predisposition.

BACKGROUND: Transcript dosage imbalance may influence the transcriptome. To gain insight into the role of altered gene expression in hereditary colorectal polyposis predisposition, in the present study we analyzed absolute and allele-specific expression (ASE) of adenomatous polyposis coli (APC) and mutY Homolog (MUTYH) genes. METHODS: We analyzed DNA and RNA extracted from peripheral blood mononuclear cells (PBMC) of 49 familial polyposis patients and 42 healthy blood donors selected according similar gender and age. Patients were studied for germline alterations in both genes using dHPLC, MLPA and automated sequencing. APC and MUTYH mRNA expression levels were investigated by quantitative Real-Time PCR (qRT-PCR) analysis using TaqMan assay and by ASE assays using dHPLC-based primer extension. RESULTS: Twenty out of 49 patients showed germline mutations: 14 in APC gene and six in MUTYH gene. Twenty-nine patients did not show mutations in both genes. Results from qRT-PCR indicated that gene expression of both APC and MUTYH was reduced in patients analyzed. In particular, a significant reduction in APC expression was observed in patients without APC germline mutation vs control group (P < 0.05) while APC expression in the mutation carrier patients, although lower compared to control individuals, did not show statistical significance. On the other hand a significant reduced MUTYH expression was detected in patients with MUTYH mutations vs control group (P < 0.05). Altered ASE of APC was detected in four out of eight APC mutation carriers. In particular one case showed a complete loss of one allele. Among APC mutation negative cases, 4 out of 13 showed a moderate ASE. ASE of MUTYH did not show any altered expression in the cases analyzed. Spearman's Rho Test analysis showed a positive and significant correlation between APC and MUTYH genes both in cases and in controls (P = 0.020 and P < 0.001). CONCLUSIONS: APC and MUTYH showed a reduced germline expression, not always corresponding to gene mutation. Expression of APC is decreased in mutation negative cases and this appears to be a promising indicator of FAP predisposition, while for MUTYH gene, mutation is associated to reduced mRNA expression. This study could improve the predictive genetic diagnosis of at-risk individuals belonging to families with reduced mRNA expression regardless of presence of mutation.

Efficacy and safety profile of a compound composed of platelet-rich plasma and hyaluronic acid in the treatment for knee osteoarthritis (preliminary results).

BACKGROUND: The combined use of hyaluronic acid and platelet-rich plasma has never been reported in the treatment for osteoarthritis. Aim of this paper was to evaluate the efficacy of this association and to compare retrospectively these results with those of a cohort of patients treated with platelet-rich plasma only. MATERIALS AND METHODS: Subjects with mild-to-moderate knee osteoarthritis were enrolled. After clinical and ultrasound evaluation, patients received a weekly intra-articular injection of 2 ml of hyaluronic acid added with 2 ml of platelet-rich plasma for 3 weeks. Follow-up was performed at 1, 3, and 6 months. The same clinical parameters were retrospectively collected from a cohort of patients treated with 4-5 ml of platelet-rich plasma only. RESULTS: Forty knees were treated in both groups. The intra-group comparison showed a significant improvement in clinical and functional outcomes at 1, 3, and 6 months, while the infra-group comparison did not show any significant difference. CONCLUSIONS: The association of platelet-rich plasma + hyaluronic acid has the same efficacy of platelet-rich plasma only, administered in higher volume. We may infer that hyaluronic acid works synergically and improves the activity of several molecules contained in platelet-rich plasma.

Increased variance in germline allele-specific expression of APC associates with colorectal cancer.

BACKGROUND & AIMS: Germline variations in allele-specific expression (ASE) are associated with highly penetrant familial cancers, but their role in common sporadic cancers is unclear. ASE of adenomatous polyposis coli (APC) is associated with pathogenesis of familial adenomatous polyposis. We investigated whether moderate variations in ASE of APC contribute to common forms of colorectal cancer (CRC). METHODS: Denaturing high-performance liquid chromatography was used to analyze germline ASE of APC in blood samples from patients with CRC (cases, n = 53) and controls (n = 68). Means, medians, and variances of ASE were compared. Variants in the APC gene region also were analyzed. RESULTS: The distribution of ASE differed significantly between groups; cases had significantly larger amounts of variance than controls (P = .0004). Risk for CRC increased proportionally with the degree of deviation from the mean. The odds ratio for individuals with levels of ASE that deviated more than 1 standard deviation from the mean was 3.97 (95% confidence interval, 1.71-9.24; P = .001); for those with levels greater than 1.645 standard deviations, the odds ratio was 13.46 (95% confidence interval, 1.76-609.40; P = .005). Sequence analysis revealed that a patient with a high level of ASE who did not have a family history of CRC carried a nonsense mutation in APC (p.Arg216X). Genotype analysis of APC associated multiple single-nucleotide polymorphisms with ASE values and/or variance among cases, but not controls. Cis variants, therefore, might account for some of the variance in ASE of APC. CONCLUSIONS: Patients with CRC have a larger variance in germline levels of ASE in APC than controls; large distances from the mean ASE were associated with risk for common forms of CRC.

Fucans, but not fucomannoglucuronans, determine the biological activities of sulfated polysaccharides from Laminaria saccharina brown seaweed.

Sulfated polysaccharides from Laminaria saccharina (new name: Saccharina latissima) brown seaweed show promising activity for the treatment of inflammation, thrombosis, and cancer; yet the molecular mechanisms underlying these properties remain poorly understood. The aim of this work was to characterize, using in vitro and in vivo strategies, the anti-inflammatory, anti-coagulant, anti-angiogenic, and anti-tumor activities of two main sulfated polysaccharide fractions obtained from L. saccharina: a) L.s.-1.0 fraction mainly consisting of O-sulfated mannoglucuronofucans and b) L.s.-1.25 fraction mainly composed of sulfated fucans. Both fractions inhibited leukocyte recruitment in a model of inflammation in rats, although L.s.-1.25 appeared to be more active than L.s.-1.0. Also, these fractions inhibited neutrophil adhesion to platelets under flow. Only fraction L.s.-1.25, but not L.s.-1.0, displayed anticoagulant activity as measured by the activated partial thromboplastin time. Investigation of these fractions in angiogenesis settings revealed that only L.s.-1.25 strongly inhibited fetal bovine serum (FBS) induced in vitro tubulogenesis. This effect correlated with a reduction in plasminogen activator inhibitor-1 (PAI-1) levels in L.s.-1.25-treated endothelial cells. Furthermore, only parent sulfated polysaccharides from L. saccharina (L.s.-P) and its fraction L.s.-1.25 were powerful inhibitors of basic fibroblast growth factor (bFGF) induced pathways. Consistently, the L.s.-1.25 fraction as well as L.s.-P successfully interfered with fibroblast binding to human bFGF. The incorporation of L.s.-P or L.s.-1.25, but not L.s.-1.0 into Matrigel plugs containing melanoma cells induced a significant reduction in hemoglobin content as well in the frequency of tumor-associated blood vessels. Moreover, i.p. administrations of L.s.-1.25, as well as L.s.-P, but not L.s.-1.0, resulted in a significant reduction of tumor growth when inoculated into syngeneic mice. Finally, L.s.-1.25 markedly inhibited breast cancer cell adhesion to human platelet-coated surfaces. Thus, sulfated fucans are mainly responsible for the anti-inflammatory, anticoagulant, antiangiogenic, and antitumor activities of sulfated polysaccharides from L. saccharina brown seaweed.

Platelet activation markers in patients with nephrotic syndrome. A comparative study of different platelet function tests.

BACKGROUND/AIM: Enhanced platelet reactivity may play a significant role in the genesis of the hypercoagulable state of nephrotic syndrome. However, the role of platelet function testing in nephrosis is controversial, partly because the methods used to assess platelet function (platelet aggregation and immunoassays of plasma beta-thromboglobulin and platelet factor 4) have such marked methodological problems. In the present study, we evaluated several tests assessing platelet function in 18 adult patients with idiopathic nephrotic syndrome and normal renal function. METHODS: Platelet function was assessed by measurement of plasma beta-thromboglobulin (enzyme-linked immunosorbent assay, ELISA), plasma P-selectin (ELISA), circulating platelets exposing the activation-dependent antigens P-selectin (CD62P) and lysosomal GP53 (CD63) (flow cytometry), and by aggregation response to agonists such as ADP and collagen. Results were compared to those obtained in a group of 16 age- and gender-matched healthy subjects. RESULTS: Levels of plasma beta-thromboglobulin (p = 0.001), plasma P-selectin (p < 0.001), and CD62P/CD63-positive platelets (p < 0.001 for both) were increased in nephrotic patients as compared to healthy controls. Platelet hyperaggregability in vitro was found in 13/18 patients. The reproducibility of platelet activation markers, as assessed by blood sample collection a week later from all patients, was found to be higher for plasma P-selectin (Spearman correlation coefficient, R = 0.99) and circulating activated platelets (CD62P: R = 0.97; CD63: R = 0.96) than for plasma beta-thromboglobulin (R = 0.78). CONCLUSIONS: Pronounced platelet activation takes place in nephrotic syndrome and may contribute to the hypercoagulability of nephrosis. Whole blood flow cytometry assay of platelet activation and plasma P-selectin assay may represent useful tests to assess the hypercoagulable state in nephrotic patients.