Epidemiological and clinical characterization of community, healthcare-associated and nosocomial colonization and infection due to carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in Spain.

BACKGROUND: Community-acquired (CA) and healthcare-associated (HCA) infections caused by carbapenemase-producing Enterobacterales (CPE) are not well characterized. The objective was to provide detailed information about the clinical and molecular epidemiological features of nosocomial, HCA and CA infections caused by carbapenemase-producing Klebsiella pneumoniae (CP-Kp) and Escherichia coli (CP-Ec). METHODS: A prospective cohort study was performed in 59 Spanish hospitals from February to March 2019, including the first 10 consecutive patients from whom CP-Kp or CP-Ec were isolated. Patients were stratified according to acquisition type. A multivariate analysis was performed to identify the impact of acquisition type in 30-day mortality. RESULTS: Overall, 386 patients were included (363 [94%] with CP-Kp and 23 [6%] CP-Ec); in 296 patients (76.3%), the CPE was causing an infection. Acquisition was CA in 31 (8.0%) patients, HCA in 183 (47.4%) and nosocomial in 172 (48.3%). Among patients with a HCA acquisition, 100 (54.6%) had been previously admitted to hospital and 71 (38.8%) were nursing home residents. Urinary tract infections accounted for 19/23 (82.6%), 89/130 (68.5%) and 42/143 (29.4%) of CA, HCA and nosocomial infections, respectively. Overall, 68 infections (23%) were bacteremia (8.7%, 17.7% and 30.1% of CA, HCA and nosocomial, respectively). Mortality in infections was 28% (13%, 14.6% and 42.7% of CA, HCA and nosocomial, respectively). Nosocomial bloodstream infections were associated with increased odds for mortality (adjusted OR, 4.00; 95%CI 1.21-13.19). CONCLUSIONS: HCA and CA infections caused by CPE are frequent and clinically significant. This information may be useful for a better understanding of the epidemiology of CPE.

Effect of Remote Ischemic Preconditioning on the Incidence of Contrast-Induced Nephropathy in Patients Undergoing Endovascular Aneurysm Repair (Remote Ischemic Preconditioning-Endovascular Aneurysm Repair Study).

BACKGROUND: Contrast-induced nephropathy (CIN) is a major inconvenience in the use of iodinated contrast media (ICM) and it is associated with a significant increase in morbidity and mortality and cost of hospitalization. Remote ischemic preconditioning (RIPC) is a noninvasive and cost-effective tissue protection technique that has showed to be beneficial in decreasing renal insult in patients receiving intravascular contrast. AIM: The primary outcome of this study is to evaluate the impact of RIPC on the incidence of CIN in patients undergoing endovascular aneurysm repair. METHODS: Patients suffering from aortic aneurysm were recruited prior to the administration of ICM. Randomization was used to assign patients into the control/RIPC groups. Biochemical parameters determined renal function before and after surgery in immediate (24-72 hr) and at 30 days of follow-up. RESULTS: Of the 120 patients included in the study, 98,3% were male. Mean age was 73 years (range: 56-87 years). Diabetes and chronic renal failure (considering estimated glomerular filtration [eGFR] <60) was present prior to administration of ICM in 29.16% and 38.33%, respectively. RIPC was applied in 50% (n = 60) of the patients. A total of 24.17% developed CIN regardless of fluidotherapy, RIPC, and other protective strategies. RIPC did not influence outcomes in terms of incidence on CIN, serum creatinine, urea, eGFR, or microalbuminuria in immediate postoperative period. However, the group of RIPC patients showed a statistically significant benefit in renal function in terms of serum creatinine (1.46 ± 0.3 vs. 1.03 ± 0.5; P < 0.001), urea (61.06 ± 27.5 mg/dL vs. 43.78 ± 12.9 mg/dL; P = 0.003), and an increase in eGFR (56.37 ± 23.4 mL/min/1.73 m2 vs. 72.85 ± 17.7 mL/min/1.73 m2; P = 0.004) at 30 days of follow-up. CONCLUSIONS: RIPC seems to be a reasonable, effective, and low-cost technique to alleviate effects of ICM on the renal parenchyma in endovascular aneurysm repair procedures during short-term postoperative period.

Off-Label Use of a Flared Endograft Limb for Treatment of a Complicated Anastomotic Abdominal Aortic Pseudoaneurysm: Reverse Deployment Throught Axillary Artery.

A case of complicated abdominal aortic pseudoaneurysm not suitable for open repair is described. It was treated by means of endovascular methods with a flared endograft limb. The uniqueness of this case is the absence of a suitable femoral access, requiring the deployment of the graft in a reversed configuration through axillary artery. The technique is described and the need of imaginative off label use of endovascular devices in such emergent cases is discussed.

Doppler Ultrasound as a Unique Diagnosis Test in Peripheral Arterial Disease.

BACKGROUND: The aim of this study was to analyze duplex ultrasound (DUS) and intraoperative angiography concordance for diagnosis of lower limb peripheral artery disease and its value for surgical planning. MATERIALS AND METHODS: This was a prospective, observational study, including patients who underwent revascularization of the lower limbs during 2018, diagnosed by DUS only or combined with preoperative computed tomography (CT) angiography. The concordance between preoperative DUS or CT angiography and the intraoperative angiography was studied using the Cohen kappa coefficient (k). The degree of agreement between the DUS-based surgical plan and the final surgical technique was also evaluated. RESULTS: Fifty-one patients were included, with mean age of 71.8 ± 11.96 years (46-94); 23 had chronic kidney disease (45%). In 17 patients (34%), preoperative CT angiography was also performed. DUS showed a sensitivity of 100% (95% confidence interval (CI) [83.3-100%]), 80% (95% CI [50.21-100%,]), and 100% (95% CI [96.43-100%]) at the iliac, femoral, and popliteal sector, respectively, and a specificity of 93.55% (95% CI [83.29-100%]), 95.45% (95% CI [84.48-100%]), and 90.48% (95% CI [75.54-100%]) at the iliac, femoral, and popliteal sector, respectively. The positive predictive value for DUS was 60% (95% CI [7.06-100%]), 88.9% (95% CI [62.8-100%]), and 87.5% (95% CI [68.17-100%]) for the iliac, femoral, and popliteal sectors, respectively, whereas the negative predictive value was 100% (95% CI [98.28-100%]), 91.3% (95% CI [77.61-100%]), and 100% (95% CI, [97.37-100%]). The concordance between DUS and intraoperative angiography showed a k index of 0.587 (P = 0.000) in the iliac sector, 0.799 in the femoral sector (P = 0.000), and 0.699 in the popliteal sector (P = 0.000). The concordance between CT angiography/intraoperative angiography had a k index of 0.71 in the iliac sector (P = 0.0093), 0.566 in the femoral sector (P = 0.006), and 0.5 in the popliteal sector (P = 0.028). DUS-based surgical plan was accurate in 86% of cases (n = 44). CONCLUSIONS: Our experience suggests that DUS arterial mapping of the femoral and popliteal areas is better than CT angiography and can be considered as a unique preoperative imaging test during the surgical planning in patients undergoing a lower limb revascularization procedure.

Celiac trunk segmental arterial mediolysis: a rare cause of arteriopathy.

A 50-year-old male patient, without a previous medical history, presented sudden severe abdominal pain with no alterations in the blood analysis. A CT-Angiography (CTA) was performed that showed a wall thickening of the celiac trunk extended to the hepatic artery with a filiform lumen and no involvement of the splenic artery. There were no signs of intestinal or liver ischemia, therefore no further radiological tests were performed. The proteinogram and serology were normal, with no immunological and acute phase reactant markers, excluding vasculitis. It appeared as an isolated lesion with no signs of arterial dissection or pseudoaneurysms of the remaining abdominal vessels or the aorta. Therefore, it was considered as a Segmental Arterial Mediolisis (SAM).

Chile's role in global health diplomacy: a narrative literature review.

BACKGROUND: Global health diplomacy (GHD) has become an important field of investigation due to health concerns increasingly entering the foreign policy domain. Much of the existing academic writing focuses on North-South cooperation in global health, and emphasizes the role of security and economic interests by Northern countries as drivers of GHD. Chile presents a favourable environment for an expanded involvement in future GHD activities. However, there is little knowledge about what has been driving Chile's integration of health into foreign policy, and little effort to appropriate knowledge from international relations theories to better theoretically grasp the emergence of GHD. METHODS: To fill this knowledge gap, we conducted a narrative literature review of the driving forces behind Chile's integration of health into foreign policy. Drawing on a popular analytical framework used in international relations scholarship, we identified driving forces of the integration of health into Chile foreign policy at three levels of analysis. RESULTS: At the international/global level of analysis, the main driving forces were related to national security concerns and compliance with regulations of international organizations. At the regional level, GHD was driven by a commitment to regional solidarity through mutually beneficial cooperation in response to neoliberal reforms; health coordination in emergencies; and protection of indigenous peoples. Finally, at the domestic level, drivers identified include economic interests of various productive sectors and how health regulations might impact those; the high degree of social inequity which impacts on access to healthcare; and management of natural disasters. CONCLUSION: Health actions in the context of international relations in Chile are still mainly motivated by more traditional foreign policy interests rather than by a desire to satisfy health needs per se. This seems to conform with findings of existing GHD scholarship that emphasize the importance of security and economic interests as driving forces of GHD, and how health is often appropriated instrumentally within foreign policy settings to achieve other goals. But the review also reveals that in the context of South-South cooperation (and regional health diplomacy), solidarity and normative considerations can be important driving forces as well. Finally, the review demonstrates that there has been an evolution from chiefly domestically focused health policies (e.g. maternal and child nutrition treatment) towards internationally inspired integrated policies (e.g. maternal and child nutrition promotion aligned with international guidelines).

Conventional Hospitalization versus Sequential Outpatient Parenteral Antibiotic Therapy for Staphylococcus aureus Bacteremia: Post-Hoc Analysis of a Multicenter Observational Cohort.

It is not known whether sequential outpatient parenteral antimicrobial (OPAT) is as safe and effective as conventional hospitalization in patients with S. aureus bacteremia (SAB). A post-hoc analysis of the comparative effectiveness of conventional hospitalization versus sequential OPAT was performed in two prospective Spanish cohorts of patients with S. aureus bacteremia. The PROBAC cohort is a national, multicenter, prospective observational cohort of patients diagnosed in 22 Spanish hospitals between October 2016 and March 2017. The DOMUS OPAT cohort is a prospective observational cohort including patients from two university hospitals in Seville, Spain from 2012 to 2021. Multivariate regression was performed, including a propensity score (PS) for receiving OPAT, stratified analysis according to PS quartiles, and matched pair analyses based on PS. Four hundred and thirteen patients were included in the analysis: 150 in sequential OPAT and 263 in the full hospitalization therapy group. In multivariate analysis, including PS and center effect as covariates, 60-day treatment failure was lower in the OPAT group than in the full hospitalization group (p < 0.001; OR 0.275, 95%CI 0.129−0.584). In the PS-based matched analyses, sequential treatment under OPAT was not associated with higher 60-day treatment failure (p = 0.253; adjusted OR 0.660; % CI 0.324−1.345). OPAT is a safe and effective alternative to conventional in-patient therapy for completion of treatment in well-selected patients with SAB, mainly those associated with a low-risk source and without end-stage kidney disease.

PANC-1 cells proliferative response to ionizing radiation is related to GSK-3ß phosphorylation.

Radiotherapy may be used to treat pancreatic cancer and relieve pain. We have previously reported that histamine modulates pancreatic adenocarcinoma PANC-1 cell proliferation. This work was aimed to evaluate whether histamine improves radiosensitivity of PANC-1 cells in relation to phosphorylation/inhibition of glycogen synthase kinase-3ß (GSK-3ß). Immediately after γ irradiation, intracellular hydrogen peroxide was markedly decreased together with a rapid increase in catalase activity. Although histamine diminished catalase activity in nonirradiated cells, it only partially hindered the increase observed in irradiated cells and could not modify radiosensitivity. In control cells, a high expression of total and a very low expression of phosphorylated/inactive GSK-3ß were found. An increment in reactive oxygen species levels produced an augmentation in GSK-3ß phosphorylation and suppressed cell proliferation. In both control and histamine-treated irradiated cells, the rise in catalase activity lowered reactive oxygen species levels and only a small increase in phosphorylated GSK-3ß was detected. Alternatively, 3-aminotriazole, an irreversible inhibitor of catalase, reduced the survival fraction in irradiated control cells along with an increment in phosphorylated GSK-3ß. These results suggest that upon irradiation, early catalase activation may be responsible for keeping GSK-3ß active conceding cells a survival advantage toward cytotoxic effects of ionizing radiation.

Histamine modulates salivary secretion and diminishes the progression of periodontal disease in rat experimental periodontitis.

OBJECTIVE: We have recently reported that experimental periodontitis (EP) reduced methacholine-induced submandibular gland (SMG) salivary secretion. The aim of the present study was to determine whether histamine could prevent SMG impairment produced by EP. MATERIALS AND METHODS: Bilateral EP was induced for 2 weeks and histamine treatment (0.1 mg/kg subcutaneously) was started 5 days before the end of the experimental period in male rats. The histamine effects on periodontitis-altered functional and histological parameters of SMG and on periodontal bone loss were evaluated. RESULTS: Histamine treatment partially reversed the methacholine-induced salivation reduction produced by EP while preventing SMG histological damage. Histamine's effect on SMG was associated with an increased proliferation rate (2.2 ± 0.3 vs. 0.2 ± 0.2 proliferative cells per field, P < 0.001). Furthermore, histamine completely prevented enhanced EP-induced apoptosis (1.0 ± 0.4 vs. 60.9 ± 4.6 apoptotic cells per field, P < 0.001). The protective effect exerted by histamine on SMG functionality is associated with attenuation of lingual and vestibular bone loss (0.66 ± 0.04 vs. 0.97 ± 0.06 mm; P < 0.001). CONCLUSIONS: Histamine is able to reduce periodontitis-induced damage to SMG and bone structure.

Social, environmental, and COVID-19 pandemic-related effects on women's food security and health in Honduras.

The COVID-19 pandemic has disproportionally affected women in Honduras in terms of loss of employment and income opportunities, access to healthcare services, and increased poverty and food insecurity. The pre-pandemic gender inequalities in Honduras have resulted in harsher conditions for women since the onset of the pandemic. Early reports indicate that women have lost employment and incomes and have been burdened by other effects of the pandemic, such as more household work, childcare activities, and home schooling. Marginal groups such as indigenous women face greater challenges because of the structural and systemic inequalities which have existed for a long time. The impact of the COVID-19 pandemic has also differed across geographic areas and between rural and urban settings. In addition to the pandemic, the economic outlook for women in Honduras has worsened since the impact of Hurricanes Eta and Iota in November 2020, which displaced over a million people. The agricultural sector was devastated, and infrastructure was severely damaged. The recovery efforts have been slow because of the COVID-19 pandemic. This paper explores the root causes of gender inequalities and how it affects women's food security and health.

Readability of patient educational materials in venous thrombosis: analysis of the 2021 ESVS guidelines and comparison with other medical societies information.

BACKGROUND: In order for patients to comprehend health related information, it must be written at a level that can be readily understood by the intended population. During 2021 the European Society for Vascular Surgery (ESVS) published a sub-section about information for patients into its Guidelines on the Management of Venous Thrombosis. METHODS: Nine readability measures were used to evaluate the patient educational material regarding venous thrombosis published by seven medical societies: ESVS, Society for Vascular Medicine (SVM), Society for Vascular Surgery (SVS), Vascular Society for Great Britain and Ireland (VS), Australia and New Zealand Society for Vascular Surgery (ANZSVS), Canadian Society for Vascular Surgery (CSVS) and American Heart Association (AHA). RESULTS: The mean reading grade level (RGL) for all the 58 recommendations was 10.61 (range 6.4-14.5) and the mean Flesch Reading Ease (FRE) was 56.10 (51.3-62.9), corresponding to a "fairly difficult" reading level. The mean RGL of the ESVS recommendations (11.45, 95% CI, 9.90-13.00) was significantly higher than the others. Post-hoc analysis determined a significant difference between the ESVS and the SVS (10.86, 95% CI, 9.84-11.91) recommendations (P=0.005). All the patient's education information published by the medical societies presented a RGL higher than recommended. The fifteen sub-sections of the information for patients included into the ESVS clinical guidelines presented a mean RGL above 9.5 points, revealing that no one (0%) was written at or below the recommended GRL. The mean FRE was 47.63 (28.2-61.6), corresponding to a "difficult" reading level. CONCLUSIONS: Venous thrombosis patient educational materials produced by leading medical societies have readability scores that are above the recommended levels. The innovative patient's information included into the ESVS venous thrombosis guidelines represents an important advance in the amelioration of the medical information for patients, but their readability should be improved to adapt the understanding to the general population.

Prevalence, Incidence, and Risk Factors for Intestinal Colonization Due to Fluoroquinolone-Resistant ST131 Escherichia coli: a Longitudinal Study in Highly Dependent, Long-Term Care Facility Residents.

Escherichia coli ST131 clade C is an important driver for fluoroquinolone resistance (FQ-R). We conducted a prospective observational study in residents from two long-term care facilities (LTCFs) in Seville, Spain, in 2018. Fecal swabs and environmental samples were obtained. E. coli isolates were screened for clade C, FQ-R ST131 by PCR, and molecular typing by PFGE; representatives from pulsotypes were studied by whole-genome-sequencing (WGS) and assigned to lineages (cgSTs). Prevalence of colonization at each time point, incidence density, and risk factors for acquisition were studied. Seventy-six FQ-R ST131 E. coli isolates belonging to 34 cgSTs were obtained; 24 belonging to subclade C1 (116 isolates, 65.9%) and 10 to C2 (60, 34.1%). C1 lineages showed lower virulence scores than C2 (median [IQR], 19 [18 to 20] versus 21 [20 to 21.5], P = 0.001) and higher number of plasmids (4 [3 to 5] versus 2 [2 to 3], P = 0.01). aac(6')-Ib-cr and blaOXA-1 were less frequent in C1 than C2 (2 [8.3%] versus 6 [60%], P = 0.003 for both); ESBL genes were detected in eight (33.3%) C1 (5 blaCTX-M-27) and three (30%) C2 (all blaCTX-M-15). Of the 82 residents studied, 49 were colonized at some point (59.7%), with a pooled prevalence of 38.6%. Incidence density of new lineage acquisition was 2.22 per 100 resident weeks (1.28 and 0.93 C1 and C2 subclades, respectively). Independent risk factors for acquisitions were having a colonized roommate (HR = 4.21; 95% CI = 1.71 to 10.36; P = 0.002) and urinary or fecal incontinence (HR = 2.82; 95% CI = 1.21 to 6.56; P = 0.01). LTCFs are important reservoirs of clade C ST131 E. coli. The risk factors found suggest that cross-transmission is the most relevant transmission mechanisms. IMPORTANCE We aimed at investigating the microbiological and epidemiological features of clade C fluoroquinolone-resistant ST131 E. coli isolates colonizing highly dependent residents in long-term care facilities (LTCFs) during 40 weeks and the risk factors of acquisition. Isolates from C1 and C2 subclades were characterized in this environment. The clonality of the isolates was characterized and they were assigned to lineages (cgSTs), Resistance genes, virulence factors, and plasmids were also described. This study suggests that cross-transmission is the most relevant transmission mechanisms; however, environmental colonization might also play a role. We believe the data provide useful information to depict the epidemiology of these bacteria by merging detailed microbiological and epidemiological information.

Impact of nutritional and inflammatory status in patients with critical limb-threatening ischemia.

BACKGROUND: A pro-inflammatory state and a poor nutritional status have been associated with severity and prognosis of patients with peripheral arterial disease (PAD). The clinical applicability of the different pre-operative nutritional and inflammatory biomarkers in patients with critical limb-threatening ischemia (CLTI) was analyzed. METHODS: A retrospective observational study was performed, that included all patients with CLTI revascularized from January 2016 to July 2019. The inflammatory state was calculated using neutrophil/lymphocyte (NLR), lymphocyte/monocyte (LMR) and platelet/lymphocyte ratios (PLR). For nutritional status, the Prognostic Nutritional Index (PNI) was calculated. Mortality and number of major amputations at 6 months and hospital length-of stay were studied. RESULTS: 310 patients were included. Higher levels of NLR and lower levels of PNI were associated with mortality (6.61±5.6 vs. 3.98±3.27, P=0.034; 40.33±7.89 vs. 45.73±7.48, P=0.05, respectively). Lower levels of PNI and LMR (42.57±7.82 vs. 45.44±7.65, P=0.036; 2.77±1.61 vs. 3.22±1.75, P=0.013, respectively) and higher levels of NLR (6.91±7.85 vs. 3.94±2.57, P=0.023) were associated with major amputations. The mean hospital length-of-stay was higher in patients with lower levels of PNI and LMR (P=0.000 and P=0.003) and higher levels of NLR and PLR (P=0.001 and P=0.002). A PNI<42.87 predicted short-term mortality with a 66.7% of sensitivity and a 66.8% of specificity (P=0.000). CONCLUSIONS: Our experience suggests that these inflammatory and nutritional biomarkers are independent predictors of short-term mortality and major amputations. In addition, our results suggest that PNI could be used to predict the short-term mortality with high sensitivity and specificity.

Estudio coste-efectividad del diagnóstico de trombosis venosa profunda en el medio hospitalario / Cost-effectiveness study of deep venous thrombosis diagnosis at the hospital setting

Introducción y objetivos: la trombosis venosa profunda (tVP) supone una importante carga económica. nuestro objetivo primario es comparar dos estrategias diagnósticas en cuanto a costes y a efectividad: la prueba del dímero d a todos los pacientes con sospecha con condicionarla a la probabilidad clínica pretest. el secundario, analizar el coste del diagnóstico en nuestro centro y los factores asociados a su presentación. Material y métodos: estudio prospectivo de los pacientes atendidos con sospecha de tVP de extremidad inferior entre mayo y octubre de 2019. Se analizaron las variables de la escala de Wells, el teP asociado, el dímero d, el resultado del eco Doppler y los costes (atención en urgencias, el reactivo del dímero d y la realización de un eco Doppler, obtenidos del Boletín oficial de la comunidad y de la unidad de cobros del hospital). el análisis estadístico se realizó con SPSS, pruebas de χ2 y el test exacto de Fisher. Resultados: se estudiaron 249 pacientes. 116 (46,59 %) presentaron tVP. La edad media fue de 70 años (21-95). aquellos con tVP presentaron con más frecuencia: sexo masculino (52,6 % frente a 39,8 %, p = 0,04), cáncer (29,3 % frente a 16,5 %, p = 0,016), dolor (80,2 % frente a 45,1 %, p < 0,001), edema (93,1 % frente a 57,1 %, p < 0,001), empastamiento (72,4 % frente a 14,3 %, p < 0,001), teP (25,9 % frente a 13,5 %, p = 0,014), menor diagnóstico alternativo (0,9 % frente a 62,4 %, p < 0,001) y menor obesidad (7,8 % frente a 18,8 %, p = 0,011). el gasto generado fue de 192,49 euros por paciente. Para el objetivo primario se analizaron a 144 pacientes (aquellos con dímero d). La estrategia 1 generó un gasto de 190,41 euros por paciente, con una sensibilidad del 100 % y una especificidad del 7,1 %; la estrategia 2, 188,51 euros por paciente, con una sensibilidad del 88,3 % y una especificidad del 78,5 %. ambas estrategias son un 1 % y un 2 % más económicas que el gasto generado, respectivamente...(AU)

Introduction and objective: deep venous thrombosis (dVt) is a significant economic burden. the study primaryendpoint is to compare two diagnostic strategies in terms of cost and effectiveness: d-dimer to all patients withsuspected dVt vs conditioning it to the pre-test clinical probability; the secondary endpoint is to analyze the costof dVt diagnosis in our center and the factors associated with its presentation. Material and methods: this was a prospective study of patients with suspected dVt of lower extremities con-ducted between may and october 2019. the variables of the Wells scale, associated Pte, d-dimer levels, dopplerechocardiography and costs (emergency care, d-dimer and doppler echocardiography obtained from the regionofficial Bulletin and the hospital billing unit) were analyzed. the statistical analysis was performed with SPSS, thechi-square test, and Fisher's exact test. Results: a total of 249 patients were studied, 116 of whom (46.59 %) presented with dVt. the mean age was70 years (21-95). those with dVt were predominantly men (52.6 % vs 39.8 %; p = .04), had cancer (29.3 %vs 16.5 %, p = 0.016), pain (80.2 % vs 45.1 %; p < .001), edema (93.1 % vs 57.1 %, p < .001), slurring (72.4 % vs14.3 %; p < .001), Pte (25.9 % vs 13.5 %, p = .014), less alternative diagnosis (0.9 % vs 62.4 %; p = .001) and lessobesity (7.8 % vs 18.8 %; p = .011). the cost generated was € 192.49 per patient. Regarding the primary endpoint,144 patients (those with d-dimer) were analyzed. Strategy #1 resulted in a cost of €190.41 per patient with100 % sensitivity and 7.1 % specificity; strategy # 2, resulted in a cost of €188.51/patient, with 88.3 % and 78.5 %sensitivity and specificity rates, respectively. Both strategies are 1 % and 2 % cheaper than the cost generated.Conclusion: the application of diagnostic algorithms for suspected dVt is cost-effective, so its use should begeneralized.(AU)

Mechanisms underlying the radioprotective effect of histamine on small intestine.

PURPOSE: To examine the protective effects of histamine on intestinal damage produced by gamma-radiation. MATERIALS AND METHODS: 56 mice were divided into 4 groups. Histamine and Histamine-10 Gy groups received a daily subcutaneous histamine injection (0.1 mg/kg) starting 20 hours before irradiation and continued until the end of the experimental period; the untreated group received saline. Histamine-10 Gy and untreated-10 Gy groups were irradiated with a single dose on whole-body using Cesium-137 source (7 Gy/min) and were sacrificed 3 days after irradiation. Small intestine was removed, fixed and stained with hematoxylin and eosin. The number of intestinal crypts per circumference, and other histological characteristics of intestinal cells were evaluated. We further determined by immunohistochemistry the expression of proliferating cell nuclear antigen (PCNA), Bax, Bcl-2 (pro- and anti-apoptotic protein, respectively), antioxidant enzymes (Superoxide dismutase (SOD), Catalase and Glutathione peroxidase), histamine content and apoptosis by terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL) assay. Cells in the S phase of the cell cycle were identified by immunohistochemical detection of 5-bromo-2'-deoxyuridine (BrdU) incorporation. RESULTS: Histamine treatment reduced mucosal atrophy, edema and preserved villi, crypts and nuclear and cytoplasmic characteristics of small intestine after radiation exposure. Additionally, histamine treatment increased PCNA expression and the BrdU-positive cell number, histamine content, decreased the number of apoptotic cells and significantly increased Catalase and copper-zinc-containing SOD of irradiated mice. CONCLUSIONS: Histamine prevents radiation-induced toxicity by increasing proliferation of damaged intestinal mucosa and suppressing apoptosis that was associated with an increase in SOD and Catalase levels. This effect might be of clinical value in patients undergoing radiotherapy.

Histamine therapeutic efficacy in metastatic melanoma: Role of histamine H4 receptor agonists and opportunity for combination with radiation.

The aims of the work were to improve our knowledge of the role of H4R in melanoma proliferation and assess in vivo the therapeutic efficacy of histamine, clozapine and JNJ28610244, an H4R agonist, in a preclinical metastatic model of melanoma. Additionally, we aimed to investigate the combinatorial effect of histamine and gamma radiation on the radiobiological response of melanoma cells.Results indicate that 1205Lu metastatic melanoma cells express H4R and that histamine inhibits proliferation, in part through the stimulation of the H4R, and induces cell senescence and melanogenesis. Daily treatment with H4R agonists (1 mg/kg, sc) exhibited a significant in vivo antitumor effect and importantly, compounds reduced metastatic potential, particularly in the group treated with JNJ28610244, the H4R agonist with higher specificity. H4R is expressed in benign and malignant lesions of melanocytic lineage, highlighting the potential clinical use of histamine and H4R agonists. In addition, histamine increased radiosensitivity of melanoma cells in vitro and in vivo. We conclude that stimulation of H4R by specific ligands may represent a novel therapeutic strategy in those tumors that express this receptor. Furthermore, through increasing radiation-induced response, histamine could improve cancer radiotherapy for the treatment of melanoma.

Histamine-mediated signaling processes in human malignant mammary cells.

Histamine is a biogenic amine responsible for multiple biological actions including regulation of physiological functions of mammary gland. It has been postulated that histamine plays a critical role in proliferation of normal and cancer cells. To investigate the biological responses that histamine exerts in malignant cells derived from human mammary gland, we evaluated in MDA-MB-231 line the expression of histamine receptors, histamine intracellular content, the capacity of histamine to influence proliferation, cell cycle progression, differentiation and apoptosis. We also studied histamine involvement in cellular response to ionizing radiation. HBL-100 cells were used as control of non-tumorigenic breast cells. Proliferation and surviving fraction were assessed by clonogenic assay. Cell cycle progression and lipid accumulation were determined by flow cytometry while apoptosis was studied by Annexin V and DNA fragmentation assays. Both cell lines expressed the four histamine receptors subtypes as evaluated by western blot and RT-PCR analyses, and present endogenous histamine. Histamine regulated proliferation of cancer cells in a dose-dependent way and 10 microM histamine reduced significantly proliferation to 23% inducing cell cycle arrest in G(2)/M phase, differentiation by 26% and a significant increase in the number of apoptotic cells (p < 0.01). These responses were not observed in HBL-100 cells. Furthermore, 10 microM histamine exclusively enhanced the radiosensitivity of MDA-MB-231 cells. These results represent the first report about the expression of H3 and H4 receptors in human breast cells. In addition, we conclude that histamine exerts different effects on biological responses of normal and cancer breast cells representing a promising target for the development of more specific and less toxic cancer therapies.

Histamine inhibits cell proliferation and modulates the expression of Bcl-2 family proteins via the H2 receptor in human pancreatic cancer cells.

In this study, the mechanisms involved in the inhibitory effect of histamine (HA) on PANC-1 cell proliferation were investigated. The action of HA on cell growth was evaluated by determining the cell doubling time from experimental growth curves and analysing the cell cycle using a flow cytometer. The expression of proteins related to cell death and proliferation (PCNA, p53, c-Fos and Bcl-2 family proteins) was studied using Western blot, immunocytochemistry and flow cytometric analysis. The results indicated that HA produced an accumulation of PANC-1 cells in GO/Gl-phase and increased the doubling time via H2HA (H2R) stimulation. Expression of p53, c-Fos and Bcl-2 were not modulated by HA. However, HA decreased PCNA and Bax expression, while it increased the Bcl-x level. In summary, the antiproliferative effect exerted by HA was associated with a G0/G1-phase arrest and a modulation of the Bcl-2 family proteins.

Effect of rosiglitazone on N-nitroso-N-methylurea-induced mammary tumors in rat.

The objective of this study was to evaluate the in vivo antitumor action of rosiglitazone (Rosi) alone or in combination with tamoxifen (Tam) on experimental mammary tumors induced by N-nitroso-N-methylurea (NMU) in Sprague-Dawley rats. Animals bearing mammary tumors were treated with 0.06 mg/kg/day or 0.12 mg/kg/day of Rosi orally, 1 mg/kg/day of Tam s.c., or with the combined treatment (Rosi+Tam). After 25 days of treatment, the following responses were observed: 45% of tumors were responsive to 0.06 mg/kg/day of Rosi treatment, while 55% of tumors under Tam treatment responded. The results of the combined Rosi+Tam treatment indicated that 75% of tumors were responsive. Similar results were obtained with 0.12 mg/kg/day of Rosi. Apoptosis, necrosis and glandular hypersecretion were observed in Rosi-treated tumors. In all cases, the combined Rosi+Tam treatment potentiated the antitumor effect of Tam alone. No side-effects were observed after treatment at any assayed dose.

Effect of glibenclamide on N-nitroso-N-methylurea-induced mammary tumors in diabetic and nondiabetic rats.

The objective of this study was to evaluate the antitumor effect of glibenclamide (Gli) alone or in combination with tamoxifen (Tam) on experimental mammary tumors induced by N-nitroso-N-methylurea (NMU) in nondiabetic and diabetic rats. For experimental diabetes induction, Sprague-Dawley rats were injected with streptozotocin (STZ) on the second day of life. For experimental mammary tumor induction, nondiabetic and diabetic rats were injected IP with NMU at 50, 80, and 110 days of life. Nondiabetic and diabetic rats bearing mammary tumors were treated with 0.06 mg/day of Gli orally, Tam 1 mg/kg/day SC, or with the combined treatment (Gli + Tam). After 20 days of treatment, different responses were observed. In nondiabetic rats, 64% of tumors were responsive to Gli treatment (they regressed or remained stable), whereas 57% of tumors under treatment with Tam exhibited a response. Results of the combined Gli + Tam treatment indicated that all tumors were responsive: 58% regressed and 42% remained stable. Diabetic rats receiving Gli treatment did not show response to this treatment, while 65% of the tumors of Tam-treated diabetic rats showed regression. Histopathologic observation indicated an important intratumor secretion in all tumors of Gli-, Tam-, or Gli + Tam-treated rats. No secondary toxic effect was observed after treatment at any assayed doses. In conclusion, the present data demonstrate the in vivo antitumor action of Gli treatment on the experimental mammary tumors employed, indicating that Gli exerted a direct effect on tumor cells in nondiabetic rats. The combined Gli + Tam treatment potentiated the antitumor effect of each drug alone. Future research will examine the molecular aspects of these findings.