Antiproliferative and proapoptotic effects of Inula viscosa extract on Burkitt lymphoma cell line.

Burkitt lymphoma is a very aggressive B-cell non-Hodgkin lymphoma. Although remarkable progress has been made in the therapeutic scenario for patients with Burkitt lymphoma, search and development of new effective anticancer agents to improve patient outcome and minimize toxicity has become an urgent issue. In this study, the antitumoral activity of Inula viscosa, a traditional herb obtained from plants collected on the Asinara Island, Italy, was evaluated in order to explore potential antineoplastic effects of its metabolites on Burkitt lymphoma. Raji human cell line was treated with increasing Inula viscosa extract concentration for cytotoxicity screening and subsequent establishment of cell cycle arrest and apoptosis. Moreover, gene expression profiles were performed to identify molecular mechanisms involved in the anticancer activities of this medical plant. The Inula viscosa extract exhibited powerful antiproliferative and cytotoxic activities on Raji cell line, showing a dose- and time-dependent decrease in cell viability, obtained by cell cycle arrest in the G2/M phase and an increase in cell apoptosis. The treatment with Inula viscosa caused downregulation of genes involved in cell cycle and proliferation (c-MYC, CCND1) and inhibition of cell apoptosis (BCL2, BCL2L1, BCL11A). The Inula viscosa extract causes strong anticancer effects on Burkitt lymphoma cell line. The molecular mechanisms underlying such antineoplastic activity are based on targeting and downregulation of genes involved in cell cycle and apoptosis. Our data suggest that Inula viscosa natural metabolites should be further exploited as potential antineoplastic agents against Burkitt lymphoma.

Platelet Dynamics in Neurodegenerative Disorders: Investigating the Role of Platelets in Neurological Pathology.

Background: Neurological disorders, particularly those associated with aging, pose significant challenges in early diagnosis and treatment. The identification of specific biomarkers, such as platelets (PLTs), has emerged as a promising strategy for early detection and intervention in neurological health. This systematic review aims to explore the intricate relationship between PLT dynamics and neurological health, focusing on their potential role in cognitive functions and the pathogenesis of cognitive disorders. Methods: Adhering to PRISMA guidelines, a comprehensive search strategy was employed in the PubMed and Scholar databases to identify studies on the role of PLTs in neurological disorders published from 2013 to 2023. The search criteria included studies focusing on PLTs as biomarkers in neurological disorders, their dynamics, and their potential in monitoring disease progression and therapy effectiveness. Results: The systematic review included 104 studies, revealing PLTs as crucial biomarkers in neurocognitive disorders, acting as inflammatory mediators. The findings suggest that PLTs share common features with altered neurons, which could be utilised for monitoring disease progression and evaluating the effectiveness of treatments. PLTs are identified as significant biomarkers for detecting neurological disorders in their early stages and understanding the pathological events leading to neuronal death. Conclusions: The systematic review underscores the critical role of PLTs in neurological disorders, highlighting their potential as biomarkers for the early detection and monitoring of disease progression. However, it also emphasises the need for further research to solidify the use of PLTs in neurological disorders, aiming to enhance early diagnosis and intervention strategies.

Stiff substrates inhibit collagen accumulation via integrin α2ß1, FAK and Src kinases in human atrial fibroblast and myofibroblast cultures derived from patients with aortal stenosis.

The aim of the study was to confirm whether cell substrate stiffness may participate in the regulation of fibrosis. The involvement of integrin α2ß1, focal adhesion kinase (FAK) and Src kinase in signal transmission was investigated. Human atrial fibroblasts and myofibroblasts were cultured in both soft (2.23 ± 0.8 kPa) and stiff (8.28 ± 1.06 kPa) polyacrylamide gels. The cells were derived from the right atrium of patients with aortal stenosis undergoing surgery. The isolated cells, identified as fibroblasts or myofibroblasts, were stained positively with α smooth muscle actin, vimentin and desmin. The cultures settled on stiff gel demonstrated lower intracellular collagen and collagen type I telopeptide (PICP) levels; however, no changes in α1 chain of procollagen type I and III expression were noted. Inhibition of α2ß1 integrin by TC-I 15 (10-7 and 10-8 M) or α2 integrin subunit silencing augmented intracellular collagen level. Moreover, FAK or Src kinase inhibitors increased collagen content within the culture. Lower TIMP4 secretion was reported within the stiff gel cultures but neither MMP 2 nor TIMP-1, 2 or 3 release was altered. The stiff substrate cultures also demonstrated lower interleukin-6 release. Substrate stiffness modified collagen deposition within the atrial fibroblast and myofibroblast cultures. The elasticity of the cellular environment exerts a regulatory influence on both synthesis and breakdown of collagen. Integrin α2ß1, FAK and Src kinase activity participates in signal transmission, which may influence fibrosis in the atria of the human heart.

HERV-K Modulates the Immune Response in ALS Patients.

Human endogenous retrovirus (HERV)-K env-su glycoprotein has been documented in amyotrophic lateral sclerosis (ALS), where HERV-K env-su 19-37 antibody levels significantly correlated with clinical measures of disease severity. Herein, we investigated further the humoral and cell-mediated immune response against specific antigenic peptides derived from HERV-K in ALS. HERV-K env glycoprotein expression on peripheral blood mononuclear cells (PBMCs) membrane and cytokines and chemokines after stimulation with HERV-K env 19-37 and HERV-K env 109-126 were quantified in patients and healthy controls (HCs). HERV-K env glycoprotein was more expressed in B cells and NK cells of ALS patients compared to HCs, whereas HERV-K env transcripts were similar in ALS and HCs. In ALS patients, specific stimulation with HERV-K env 109-126 peptide showed a higher expression of IL-6 by CD19/B cells. Both peptides, however, were able to induce a great production of IFN-γ by stimulation CD19/B cells, and yielded a higher expression of MIP-1α and a lower expression of MCP-1. HERV-K env 19-37 peptide induced a great production of TNF-α in CD8/T cells. In conclusion, we observed the ability of HERV-K to modulate the immune system, generating mediators mainly involved in proinflammatory response.

VAPB ER-Aggregates, A Possible New Biomarker in ALS Pathology.

A point mutation (P56S) in the gene-encoding vesicle-associated membrane-protein-associated protein B (VAPB) leads to an autosomal-dominant form of amyotrophic lateral sclerosis (ALS), classified as ALS-8. The mutant VAPB is characterized by ER-associated aggregates that lead to a complete reorganization of ER structures. Growing evidences suggest VAPB involvement in ALS pathomechanisms. In fact, numerous studies demonstrated VAPB alteration also in sporadic ALS (sALS) and showed the presence of its aggregates when others ALS-related gene are mutant. Recently, the identification of new biomarkers in peripheral blood mononuclear cells (PBMCs) has been proposed as a good noninvasive option for studying ALS. Here, we evaluated VAPB as a possible ALS pathologic marker analyzing PBMCs of sALS patients. Immunofluorescence analysis (IFA) showed a peculiar pattern of VAPB aggregates in sALS, not evident in healthy control (HC) subjects and in Parkinson's disease (PD) PBMCs. This specific pattern led us to suppose that VAPB could be misfolded in sALS. The data indirectly confirmed by flow cytometry assay (FCA) showed a reduction of VAPB fluorescent signals in sALS. However, our observations were not associated with the presence of a genetic mutation or altered gene expression of VAPB. Our study brings further evidences of the VAPB role in ALS as a diagnostic biomarker.

Disruption of histamine/H3 receptor signal reduces collagen deposition in cultures scar myofibroblasts.

A suitable inflammatory signal influences extracellular matrix accumulation and determines the quality of the myocardial infarction scar. The aim of the present study was to determine the influence of mast cell sonicates or histamine on collagen accumulation in heart myofibroblast culture and on the deposition of collagen in the myocardial infarction scar. The histamine receptor involved in the process was investigated. Myocardial infarction was induced by ligation of the left coronary artery. Myofibroblasts were isolated from the scar of myocardial infarction. The effects of mast cell sonicates, histamine and its receptor antagonists, i.e. ketotifen (H1-receptor inhibitor), ranitidine (H2-receptor inhibitor), ciproxifan (H3-receptor inhibitor), JNJ7777120 (H4-receptor inhibitor), imetit (H3 receptor agonist), were investigated. The mast cell sonicates or histamine (10-10 - 10-5M) augmented collagen content in myofibroblast cultures; however, histamine-induced elevation was reduced by ciproxifan (10-5M, 10-6M). Imetit (10-9 - 10-5M) elevated collagen content in the culture. H3 receptor expression on myofibroblasts was confirmed. Our findings indicate that histamine increases the deposition of collagen in cultures of myofibroblasts isolated from the myocardial infarction scar. This effect is dependent on H3 receptor activation.

[DOPPS estimate of patient life years attributable to modifiable hemodialysis practices in Spain]. / Estimación, según el estudio DOPPS, de los años de vida de pacientes atribuibles a las prácticas de hemodiálisis modificables en España.

The increased mortality risk in hemodialysis (HD) patients unable to meet six targets in different areas of HD practice has been reported previously. Using a prevalent cross-sectional sample of Spanish HD patients (n = 613) from the second stage of the Dialysis Outcomes and Practice Patterns Study to determine the percentage with low dialysis dose, hyperphosphatemia, hypercalcemia, hypoalbuminemia, anemia, and catheter use and based on the mortality hazard ratios and the total HD population in Spain, according to the Spanish Society of Nephrology Report, we estimated the number of patient life years that could potentially be gained in our country. These characteristics of HD practice were selected because each is modifiable through changes in practice, each is associated with mortality, and each has a large number of patients outside the target guidelines. The targets that define "within guidelines" are as follows: dialysis dose (single pool Kt/V >1.2), anemia (hemoglobin >110 g/L), albumin after standardization (>40 g/L), serum phosphorus (1.1-1.5 mmol/L), serum calcium (2.1-2.4 mmol/L), and facility catheter use (<10%). Cox proportional hazards regression models were used to calculate the relative risk of mortality for all patients outside each guideline. In all models, calcium values were adjusted for low serum albumin. A separate Cox survival model adjusted for all six HD practices simultaneously to account for correlation that may exist between some facility practices. All models were adjusted for age, sex, race, time on ESRD, and 14 summary comorbid conditions. Patient years attributable to each of the six practice patterns were estimated and are reported here as the potential patient years gained. Comparison of the estimates by individual guideline shows that, in Spain, increasing patient albumin above 40 g/L in all patients would lead to an estimated gain of 9,269 patient years (a 7.9% increase). Additionally, if all facilities could decrease catheter use to less than 10%, 2,842 patient years could be gained (a 2.4% increase). Though it may be an unrealistic goal, if all Spanish patients currently outside the guidelines achieved all six target levels, an estimated 17,300 life years could be gained over the next five years (a 15% increase). A more achievable goal of bringing 50% of patients who are currently outside targets within targets would result in 9,266 life years gained. In conclusion, this analysis suggests large opportunities to improve HD patient care in Spain.

Outcome of hepatitis C virus-associated membranoproliferative glomerulonephritis after liver transplantation.

BACKGROUND: Hepatitis C virus was the most frequent cause of liver failure requiring liver transplantation in our series. Hepatitis C virus infection has been associated with glomerulonephritis and, more frequently, type I membranoproliferative glomerulonephritis. Renal disease in patients with liver failure is often clinically silent and difficult to diagnose; thus, biopsy is required to establish the diagnosis. Our aim was to study the evolution of six patients diagnosed with membranoproliferative glomerulonephritis some months before liver transplantation. METHODS: Liver transplantation alone was performed in four patients and combined liver-kidney transplantation in the remaining two, who were on hemodialysis for kidney failure. These patients were followed for a mean of 38.3+/-7.8 months. Evolution of proteinuria, renal function, hepatic function, and hepatitis C virus activity was studied. RESULTS: In the four patients who underwent liver transplantation alone, proteinuria became negative initially and renal function remained stable. Proteinuria reappeared and renal function was altered in two of these patients at 17 and 36 months of follow-up, respectively, coinciding with a recurrence of active chronic hepatitis. In the two patients who received a combined liver-kidney transplant, proteinuria became negative, and their renal grafts currently maintain normal renal function. CONCLUSIONS: Membranoproliferative glomerulonephritis does not constitute an absolute contraindication for liver transplantation alone; combined liver-kidney transplantations are reserved for patients with end-stage kidney failure. Proteinuria is reversed after liver transplantation, and recurrence seems to be associated with severe hepatitis C virus hepatic allograft disease relapse.

[Vascular access in Spain: analysis of its distribution, morbidity, and monitoring systems]. / El acceso vascular en España: análisis de su distribución, morbilidad y sistemas de monitorización.

Vascular access disfunction causes a therapeutic emergency with different implications in patients and care givers. The aim of this study was to know the distribution of different kinds of vascular access between prevalent hemodialysis patients, the proportion of incident patients that holds a permanent vascular access, the monthly hospital ratio for access repair and the use of surveillance systems of vascular access adequacy in the different Centers. This is a National survey that shows results of a questionnaire sent to all hemodialysis units in Spain on september 1999. Eighty-eight units answered the questionnaire (42%) providing information about 5,476 prevalent patients. Of these patients, 81% receives treatment through an arteriovenous fistula, 10% uses a central catheter and 9% a graft. Only 56% of incident patients have a permanent vascular access. Reasons for catheter use between prevalent patients were exhaustion of vascular sites in 42%, maduration of permanent access in 24%, thrombosis of the access in 14% and another reasons in 19%. Patients monthly hospitalization ratio for vascular repair was 3%, that might represent more than 5,600 hospital ingress by year. More than 80% of the Units releases different surveillance programs of access adequacy, 69% by fiscal detection problems, 47% by dynamic alterations and 18% by dilution and imaging procediments. The conclusions of this survey are that arteriovenous fistula is the most used vascular access in Spain. Almost half of the patients do not have vascular access in use for the beginning of hemodialysis. Exhausted vascular sites is the primary reason for central catheter using. A great proportion of Units are employing programs for access monitoring.

[Analysis of the survival of permanent vascular access ports]. / Análisis de supervivencia del acceso vascular permanente.

Complications arising from vascular access are major causes of morbidity in patients on renal replacement therapy. They contribute to frustration of health care providers and to high medical cost. To prevent failures in the future it will be helpful to identify the factors that are related to vascular access, malfunction. In a retrospective analysis we analysed the types, duration and primary patency rate of 1,033 permanent vascular access in 544 consecutive patients established during a 13-year period in a tertiary care hospital. Patient characteristics, incidence and risk factors related to vascular access failure were registered. In addition vascular access outcomes in patients who started haemodialysis with a catheter and in whom initial vascular access failure occurred were analysed separately. Forty-five per cent of patients required a central catheter at the start of HD, but 92% of them were being dialysed with an a-v fistula at the last observation. The total number of complications was 0.24 episodes per patient per year at risk, and the rate of thrombosis 0.1. A total of 52% of patients were dialysed throughout the observation period with their initial a-v fistula; 9.3% had more than three episodes of vascular access failure. The radiocephalic a-v fistula was the access with the best median duration, exceeding 7 years, but also the type that had the highest initial failure rate, i.e. 25% of patients and 13% of events. The brachiocephalic a-v fistula was the second most frequent type of vascular access, with a median duration of function of 3.6 years, in contrast the humerobasilar a-v fistula, lasted on average over 5 years. Average patency of the different types of grafts did not exceed 1 year, with the exception of the autologous saphenous graft with a median duration of function of 1.4 years. Patients with glomerulonephritis had the best function rates for their access, the median duration exceeding the duration of the study, whereas in half of diabetic patients it was less than 1 year. The duration of patency of the vascular access was twice as long in patients below age 65 years and in elderly males compared to elderly females. Patients who start HD with a catheter, as well as those with initial vascular access failure, have a higher rate of access failure in the subsequent course on renal replacement therapy. In conclusion, the radiocephalic and the brachiocephalic a-v fistula are the two types of vascular access with the longest duration of function, although a high rate of initial failure is seen with the radiocephalic a-v fistula. Age, female gender, presence of diabetic nephropathy, start of dialysis with a catheter, and failure to wait for initial maturation of vascular access are risk factors, and account for the majority of vascular access failure during renal replacement therapy.

[Results of the international hemodialysis study DOPPS in Spain and Europe]. / Resultados del estudio internacional de hemodiálisis DOPPS en Europa y España.

The Dialysis Outcomes and Practice Pattern Study (DOPPS) is an international observational study of treatment conditions and medical outcomes in hemodialysis patients. Prospective sampling has yielded long-term observational data from randomly selected groups of patients receiving treatment at representative, randomly selected hemodialysis units in each country. The data shown were collected at 20 hemodialysis units/centers in Spain. The data pertaining to Spain--Sp--refers to 575 patients and their comparison with those of the Euro-DOPPS countries--Eu--(Germany, France, United Kingdom, Italy and Spain), which encompass 3,038 patients, represent the formal goal of this paper. Diabetes mellitus, at 21.5% in Eu and 21.7% in Sp, was the most common cause of renal insufficiency in dialysis and coronariopathy, as a concomitant disease, was present in 67.8% in Eu as opposed to 75.8% in Sp. Differences were observed in the incident of hypertension (73.4% in Eu vs 77.4% in Sp), hepatitis C (11.6% vs 19.5%), depression (12.7 vs 16.2%) and left ventricular hypertrophy (54.9% vs 62.3%). The patterns of vascular access were similar (79% vs 81% AV fistulas in Eu and Sp, and 10% synthetic grafts for both) and the mean applied dose of dialysis--Kt/V--smaller (1.19) in Sp than in Eu (1.24); likewise the duration of the dialysis (in minutes) was shorter (234 in Eu vs 217 in Sp) and the % of synthetic membranes used was smaller (60% in Eu vs 52% in Sp). There were no differences between the groups in the figures for urea, creatinine, albumin, nPCR, calcium, phosphate or PTH. There were also no differences in the mean values of Hb (10.7 for Eu vs 10.8 for Sp), given that the values of ferritin were noticeably lower in Sp (288 vs 355) and the dose of EPO/kg/week was higher to in Sp (115 vs 102); s.c. route was used in similar proportions (69% in Eu vs 67% in Sp). The level of medical care, understood as contact with the physician at all or almost all treatments, was noticeably better in Sp (90%) that in Eu (66%), whereas the number of patients per hour of specialized personnel and % of specialized staff, were smaller. Mortality (death/100 patients-years) was one point lower in Sp than in Eu (15.4 vs 16.3). These data suggest that an increment in dialysis time and in the percentage of synthetic membranes used, as well as in the supply of intravenous iron, would be justified.

[Cutaneous trophic disorders secondary to arteriovenous fistula for hemodialysis]. / Trastornos tróficos cutáneos secundarios a fístula arteriovenosa para hemodiálisis.

The arteriovenous fistula is the vascular access of choice for hemodialysis treatment in patients with chronic renal failure. Clinical occurrence of local circulatory troubles caused by the fistula in addition to arterial robbery or venous hypertension are infrequent but may provoke serious consequences. Two patients with arteriovenous fistula with cutaneous trophic disorders secondary to the venous hypertension syndrome (case 1) and to the arterial robbery syndrome (case 2) are present. Prevalence, pathogenic factors, physiopathology, clinical aspects, and diagnosis and treatment of both syndromes are reviewed. Finally, the difficulty and morbidity of the creation of an efficient arteriovenous fistula in the diabetic patient is underlined.

[Isotopic renogram after captopril administration: clinical experience in the assessment of the hypertensive patient]. / Renograma isotópico después de la administración de captopril: experiencia clínica en la valoración del paciente hipertenso.

BACKGROUND: Isotopic renogram allows renal function to be estimated in both kidneys independently. The glomerular filtrate in ischemic kidneys is largely dependent on the tone of the efferent glomerular arteriolae and therefore on the concentration of circulating angiotensin II. METHODS: In 42 patients with severe high blood pressure in whom renal angiographic study was carried out for suspicion of vasculo-renal hypertension, an isotopic renogram using 99m Tc-DTPA as a tracer was performed in basal conditions and following the administration of 50 mg of oral captopril. RESULTS: In 21 patients both the angiographic examination and the post-captopril renogram were normal. In 16 patients in whom uni or bilateral stenosis higher than 50% of the lumen of renal artery was observed on angiographic examination, the post-captopril renogram showed changes. In 5 patients the angiography was normal while the renogram showed evaluable changes. No false negatives were observed in the post-captopril renogram, however the basal renogram was not demonstrative in 6 patients with stenosis of the renal artery. Sensitivity of the test was thus 100% and specificity 80%. The positive predictive value was 76% and the negative predictive value 100%. CONCLUSIONS: The post-captopril renogram may be a useful test in the functional study of renal behaviour in patients with vasculo-renal hypertension.

[A study of anemia in 86 patients on hemodialysis (author's transl)]. / Estudio de la anemia en 86 pacientes en hemodiálisis.

Anemia is one of the complications of terminal chronic renal failure that may worsen with periodical hemodialysis because of residual blood losses in the dialyzers that may be significant if clotting occurs within the circulation system. The potential iron deficiency component of the anemia has been studied in 86 patients submitted to periodic hemodialysis by measurement of hemoglobin, serum iron, transferrin saturation, total iron binding capacity, and ferritin. The following correlations were investigated: degree of anemia and type of renal disease, months on hemodialysis and hemoglobin, months on hemodialysis and serum ferritin, and liters of blood transfused and serum ferritin. Statistically significant correlations were found between months on hemodialysis and hemoglobin, and between liters of blood transfused and serum ferritin. From the correlation between serum iron and ferritin the patients could be classified in three groups: 1, with either normal or low serum iron and ferritin, candidates to iron therapy; 2, with elevated serum iron and ferritin, needing no iron treatment; and 3, with unequal changes of serum iron and ferritin, in whom iron kinetic studies are indicated in order to discover the patents that may benefit from iron therapy.

[Study of the causes of death in a hemodialysis unit (author's transl)]. / Estudio de las causas de fallecimiento en una unidad de hemodiálisis.

A review is made of the deaths which occurred in a hemodialysis unit between 1969 and 1977. Sixty-two patients were treated during this period, 18 of whom died. The actuarial percentages of survival are also established. The mortality rate was 15.5 percent during the initial period and 31.5 percent after the fourth year. Deaths in the first monts were caused by cardiac and infectious complications. Those occurring at a later period resulted from the lack of good vascular access which is necessary to maintain a good quality of dialysis.

Melatonin-induced glycosaminoglycans augmentation in myocardium remote to infarction.

Elevated levels of collagen as well as transient increases of glycosaminoglycans (GAG) have been shown in the myocardium remote to the infarction. The aim of the study is to observe the effect of melatonin on the accumulation of collagen and GAG in the left ventricle wall, remote to the infarction. A second aim is to determine whether the effect of the pineal indole is mediated by the membrane melatonin receptors of heart fibroblasts. Rats with myocardial infarction induced by ligation of the left coronary artery were treated with melatonin at a dose of 60 µg/100 g b.w. or vehicle (2% ethanol in 0.9% NaCl). The results were compared with an untreated control. In the second part of the study, the fibroblasts from the non-infarcted part of myocardium were isolated and cultured. Melatonin at a range of concentrations from 10(-8) M to 10(-6) M was applied to the fibroblast cultures. In the final part of the study, the influence of luzindole (10(-6) M), the melatonin membrane receptor inhibitor, on melatonin-induced GAG augmentation was investigated. Both collagen and GAG content were measured in the experiment. Melatonin elevated GAG content in the myocardium remote to the infarcted heart. Collagen level was not changed by pineal indoleamine. Fibroblasts isolated from the myocardium varied in shape from fusiform to spindle-shaped. Moreover, the pineal hormone (10(-7)M and 10(-6)M) increased GAG accumulation in the fibroblast culture. Luzindole inhibited melatonin-induced elevation of GAG content at 10(-6)M. Melatonin increased GAG content in the myocardium remote to infarction. This effect was dependent on the direct influence of the pineal indole on the heart fibroblasts. The melatonin-induced GAG elevation is blocked by luzindole, the melatonin membrane receptors inhibitor, indicating a direct effect of this indole.