A locus on mouse chromosome 13 inversely regulates CD1d expression and the development of invariant natural killer T-cells.

Invariant natural killer T (iNKT)-cell development is controlled by many polymorphic genes present in commonly used mouse inbred strains. Development of type 1 diabetes (T1D) in NOD mice partly results from their production of fewer iNKT-cells compared with non-autoimmune-prone control strains, including ICR. We previously identified several iNKT-cell quantitative trait genetic loci co-localized with known mouse and human T1D regions in a (NOD × ICR)F2 cross. To further dissect the mechanisms underlying the impaired iNKT-cell compartment in NOD mice, we carried out a series of bone marrow transplantation as well as additional genetic mapping studies. We found that impaired iNKT-cell development in NOD mice was mainly due to the inability of their double-positive (DP) thymocytes to efficiently select this T-cell population. Interestingly, we observed higher levels of CD1d expression by NOD than by ICR DP thymocytes. The genetic control of the inverse relationship between the CD1d expression level on DP thymocytes and the frequency of thymic iNKT-cells was further mapped to a region on chromosome 13 between 60.12 and 70.59 Mb. The NOD allele was found to promote CD1d expression and suppress iNKT-cell development. Our results indicate that genetically controlled physiological variation of CD1d expression levels modulates iNKT-cell development.

Systematic review of the implantation of penile prosthesis in major ambulatory surgery.

INTRODUCTION AND OBJECTIVE: Penile prosthesis (PP) implantation is an effective option for erectile dysfunction. Although initially PP surgery was carried out in an inpatient setting, there is a growing trend to implant PP as a major ambulatory surgery (MAS). This study aimed to perform a systematic review of the literature to identify available evidence of the implantation of PP under MAS setting and go carry out a comparison between MAS and inpatient procedures. MATERIAL AND METHODS: PubMed, EMBASE, Cochrane Library and MEDES electronic databases and non-indexed supplements for scientific congresses were searched to identify articles related to the surgical implantation of PP in MAS up to February 2021. Key search terms included penile prosthesis, erectile dysfunction, ambulatory surgery, ambulatory care, and surgery. RESULTS: Among 171 publications retrieved (51 PubMed, 73 EMBASE, 3 Cochrane, 2 using MEDES and 42 manual searching), 5 studies were finally selected. There were no significant differences between MAS or inpatient setting in terms of the type of device, surgical approach, or location of reservoir. Complication rates observed in both groups were similar. Implantation of PP in MAS was less expensive than inpatient surgery and was associated with acceptable patient satisfaction rates and adequate pain control. CONCLUSIONS: Studies demonstrated that outpatient PP surgery can achieve similar outcomes in terms of safety and satisfaction to implantation of PP in the inpatient setting, while it could reduce costs and improve the efficiency. This research could support decision makers to extend PP surgery into the ambulatory setting.

Estimating diffusion coefficients of probe molecules into polyelectrolyte brushes by electrochemical impedance spectroscopy.

Molecular transport through thin polymer films has become a subject with a variety of challenges and opportunities for chemists, physicists, and material scientists in recent years. The diffusion of probe molecules in and out of macromolecular environments plays a major role in the response of polymer-based sensor materials or the design of time-released drug delivery systems. Obtaining an improved understanding of the relevant dynamic phenomena, like transport of molecular probes, in boundary layers represents a crucial step to develop a clearer picture of the molecular transport processes taking place at interfaces modified with macromolecular assemblies. In this work, we present a new approach based on the derivation of the theoretical impedance transfer function to unambiguously describe the impedance response of gold electrodes modified with poly(methacryloyloxy)-ethyl-trimethyl-ammonium chloride (PMETAC) brushes. We demonstrate that this methodology not only enables the description of the experimental data but also provides insightful information about the dynamics of the diffusion of probe molecules inside the brush. More important, we show the capabilities of electrochemical impedance spectroscopy to gather information on a molecular transport process inside the brush under experimental conditions in which other electrochemical techniques are no longer applicable. As such, we consider that this experimental approach constitutes a new and powerful tool to estimate diffusion coefficients of probe molecules into interfacial macromolecular assemblies.

Red wine intake prevents nuclear factor-kappaB activation in peripheral blood mononuclear cells of healthy volunteers during postprandial lipemia.

BACKGROUND: Several epidemiological studies have demonstrated the beneficial effect of red wine intake in reducing total and cardiovascular mortality. This effect has been attributed in part to its antioxidant properties. Because the monocytes/macrophages and the nuclear transcription factor kappaB (NF-kappaB) are implicated in the pathogenesis of atherosclerotic lesions, we examined the effect of red wine intake on the activation of NF-kappaB in peripheral blood mononuclear cells. METHODS AND RESULTS: Sixteen healthy volunteers were studied 3 times each: after a moderate dose, a low dose, and no wine with a fat-enriched breakfast. Lipid profile and NF-kappaB activation (electrophoretic mobility shift assay) were examined in blood samples taken before and 3, 6, and 9 hours after wine intake. In addition, mononuclear cells were incubated with VLDL in the presence of some antioxidants (quercetin and alpha-tocopherol succinate) contained in red wine to study their effects on NF-kappaB activation. Subjects receiving a fat-enriched breakfast had increased NF-kappaB activation in peripheral blood mononuclear cells coinciding with the augmentation in total triglycerides and chylomicrons. Red wine intake prevented NF-kappaB activity even though it induced a certain increase in serum lipids, particularly VLDL, that did not increase after the fat ingestion alone. However, another form of alcohol intake (vodka) did not modify the NF-kappaB activation provided by postprandial lipemia. In cultured mononuclear cells, isolated human VLDL caused NF-kappaB activation in a time-dependent manner that did not occur in the presence of the red wine antioxidants quercetin and alpha-tocopherol. CONCLUSIONS: Our results provide a new potential mechanism to explain the beneficial effects of red wine intake in the reduction of cardiovascular mortality.

HMG-CoA reductase inhibition by atorvastatin reduces neointimal inflammation in a rabbit model of atherosclerosis.

OBJECTIVES: To study the effect of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-reductase inhibitor atorvastatin on the potential mechanisms involved in the recruitment of monocytic cells into the vessel wall. BACKGROUND: Inhibitors of HMG-CoA-reductase reduce cardiovascular mortality though the mechanisms yet elucidated. Most ischemic events are secondary to disruption of atherosclerotic plaques highly infiltrated by macrophages. METHODS: Atherosclerosis was induced in the femoral arteries of rabbits by endothelial damage and atherogenic diet for 4 weeks. Then, animals were switched to standard chow and randomized to receive either no treatment or atorvastatin (5 mg/kg/d) and killed after 4 weeks. RESULTS: Atorvastatin induced a significant reduction in serum lipids and in lesion size. Arterial macrophage infiltration was abolished by the treatment, and monocyte chemoattractant protein-1 (MCP-1) was significantly diminished in the neointima and in the media. Nuclear factor kappa-B (NF-kappaB) was activated in the 60% of the lesions, both in macrophages and vascular smooth muscle cells (VSMC), of the untreated group while only in 30% of the atorvastatin group. NF-kappaB activity was also lower in the uninjured aorta and liver of treated compared with untreated rabbits. In cultured VSMC, MCP-1 expression and NF-kappaB activity induced by tumor necrosis factor alpha were downregulated by atorvastatin. CONCLUSIONS: In a rabbit atherosclerosis model, atorvastatin diminishes the neointimal inflammation, and this could contribute to the stabilization of the atherosclerotic plaque. This may be an additional explanation for the reduction of acute ischemic events in patients treated with statins.

Atorvastatin reduces NF-kappaB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells.

Cardiovascular mortality, mainly due to the rupture of unstable atherosclerotic plaques, is reduced by 3-hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Inflammatory cells, attracted to the vascular lesion by chemokines, have been implicated in the process of the plaque rupture. In cultured vascular smooth muscle cells (VSMC) and U937 mononuclear cells we have studied the effect of Atorvastatin (Atv) on nuclear factor kappaB (NF-kappaB) activity, an inducer of the mRNA expression of chemokines such as interferon-inducible protein 10 (IP-10) and monocyte chemoattractant protein 1 (MCP-1). Angiotensin II (Ang II) and tumor necrosis factor alpha (TNF-alpha) increased NF-kappaB activity in VSMC (2 and 5-fold, respectively). Preincubation of cells with 10(-7) mol/l Atv diminished this activation (44 and 53%). The inhibition was reversed by mevalonate, farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), but not by other isoprenoids. Coinciding with the NF-kappaB activation in VSMC, there was a diminution of cytoplasmic IkappaB levels that was recovered by pretreatment with Atv. Ang II and TNF-alpha induced the expression of IP-10 (1.5 and 3.4-fold) and MCP-1 (2.4 and 4-fold) in VSMC. Atv reduced this overexpression around 38 and 35% (IP-10), and 54 and 39% (MCP-1), respectively. Our results strongly suggest that Atv, through the inhibition of NF-kappaB activity and chemokine gene expression, could reduce the inflammation within the atherosclerotic lesion and play a role in the stabilization of the lesion.

Trace metals in suspended particles, sediments and Asiatic clams (Corbicula fluminea) of the Río de la Plata Estuary, Argentina.

Suspended particulate matter (SPM), sandy sediments and Asiatic clams were collected at seven sites along 150 km of the Río de la Plata coast to assess the magnitude of trace metal pollution in the area. Metal concentrations in SPM (Cu: 7.4-109; Cr: 75-408; Mn: 525-1341 microg(-1)), sediments (Cr: 16-27; Zn: 26-99; Mn: 221-489 microg(-1)) and bivalves (Cd: 0.5-1.9; Ni: 1.3-6.4; Cr: 1.3-11; Mn: 15-81; Cu: 28-89; Zn: 118-316 microg g(-1)) are comparable to those reported for other moderately polluted world rivers. Cu levels in Asiatic clams are among the highest, similar to those reported for heavily polluted sites. SPM Cu and Cr concentrations displayed a clear geographical trend with values increasing with proximity to major urban centers. Sediments showed a less clear pattern possibly due to their coarse nature (>98% sand) and higher proportion of mineral-associated residual metals. The clams showed a complex pattern due to the variability introduced by size-related factors and the natural dynamics of SPM in the estuary. Cr and Mn showed an apparent reverse industrial trend with higher concentrations in clams collected at distant stations near the turbidity maximum zone, possibly reflecting enhanced particle retention. Cu, Cd and Ni showed no clear geographical pattern, whereas Zn increased in the clams collected in the most industrialized area. A significant relationship with clam size was observed for Cu (positive) and Zn (negative) suggesting different physiological requirements for both metals with age. A principal component analysis confirmed these geographical and size-related trends.

Sources, distribution and variability of airborne trace metals in La Plata City area, Argentina.

Airborne particulate trace metals have been measured bimonthly during day and night hours in four permanent stations located in residential, industrial and commercial sectors of La Plata City region, to characterize the sources and variability of atmospheric inputs. Airborne trace metal regional averages (Pb 64 +/- 62, Cu 30 +/- 27, Mn 26 +/- 20, Zn 273 +/- 227, Fe 1183 +/- 838, Ca 5343 +/- 3614, Mg 1472 +/- 967, Cr 4.3 +/- 2.4, Ni 3.2 +/- 3.5 and Cd 0.41 +/- 0.42 ng/m3) are comparable to the values reported for not grossly polluted cities and below the general trend described for urban particulates. Two- and three-way analysis of variance and variance components tests (P < 0.05) were performed to assess the contribution of the diurnal (day vs. night), spatial (inter-station) and temporal (inter-month) components of variability. Trace metal concentrations followed the behavior of total suspended particles with higher concentrations during the day and at the Downtown station and lower at the Residential site. In general, spatial and temporal variations prevailed over diurnal differences. Spatial differences were clearly most significant for Pb, which presented higher values at the Downtown site reflecting the importance of motor exhaust inputs. In contrast, diurnal differences were more important for Mn due to increased dust resuspension during day hours. A seasonal trend with concentrations usually increasing during winter months and decreasing in spring-summer was also detected. Enrichment factors (EF) were calculated to evaluate anthropogenic versus natural element sources. High EF (21-376) were obtained for Pb, Zn, Cd and Cu reflecting the importance of anthropic inputs. The comparison with EF calculated for high-emitting vehicle particle emissions indicated that motor exhausts are the most important source of these elements in La Plata region. In contrast, the EF calculated for Mn, Cr, Ni, Ca and Mg were low (1.3-7.5) suggesting chiefly natural sources, i.e. soil-derived dusts.

[Combination of cisplatin and vinorelbin in the neoadjuvant treatment of locally advanced cervical carcinoma. Phase II study]. / Associazione di cisplatino e vinorelbina nel trattamento neoadiuvante del cancro cervicale localmente avanzato. Studio di fase II.

BACKGROUND: Aim of this phase II study is to evaluate the cytoreductive efficacy and the toxicity of a regimen consisting of cisplatin and vinorelbine as neoadjuvant chemotherapy for three cycles every 21 days in patients with locally-advanced cervical carcinoma. METHODS: Between April 1996 and December 1998, 33 untreated patients with locally-advanced cervical carcinoma received neoadjuvant chemotherapy with cisplantino 80 mg/m2 (day 1) plus vinorelbine 25 mg/m2 (day 1 and 8). Within 28 days from completion of chemotherapy patients in complete or partial response were submitted to radical hysterectomy plus pelvic lymphadenectomy. RESULTS: Twenty-six patients (79%) were submitted to radical surgery; four patients were not submitted to surgery because of poor response to treatment, two for anesthesiological contraindications and one refused surgery. The combination of cisplatin plus vinorelbine in this phase II study induced a clinical overall response rate of 90%, with 8 pathologic complete response (24%). CONCLUSIONS: The association of cisplatin and vinorelbine as neoadjuvant chemotherapy in locally-advanced cervical carcinoma showed to be safe and effective with a low cost and poor toxicity.

Splenic involvement in ovarian cancer. Description of three cases.

Metastatic involvement of the spleen in patients with ovarian cancer is unusual. Solitary splenic metastasis in the absence of disseminated disease are rare. Three cases of advanced ovarian cancer with splenic involvement are reported. The splenectomy was adopted in two patients.

[Cytomegalovirus colitis in a patient carrying the human immunodeficiency virus: the endoscopic image similar to pseudomembranous colitis]. / Colitis por citomegalovirus en un paciente portador del virus de la inmunodeficiencia humana: imagen endoscópica similar a una colitis pseudomembranosa.

Endoscopically detected ulcers and submucous haemorrhage are common findings related to cytomegalovirus infection. We report a case of cytomegalovirus colitis in a patient seropositive for human immunodeficiency virus. Endoscopic findings showed elevated, white-yellowish, small size plaques with an erythematous central depression, resembling those found in pseudomembranous colitis.

[Abdominal echography in patients with human immunodeficiency virus (HIV) infection. Diagnostic usefulness in the evaluation of associated medico-surgical pathology]. / Ecografía abdominal en el paciente con infeción por el virus de la inmunodeficiencia humana (VIH). Utilidad diagnóstica en la valoración de la patología médico-quirúrgica asociada.

BASIS: The abdominal manifestations in the patient with HIV infection are increasingly frequent. We have conducted the present study in order to determine the diagnostic usefulness of the abdominal echography in the clinical assessment of the patient. MATERIALS AND METHODS: We review the echographic findings of 112 patients carrying the HIV with or without the Acquired Immunodeficiency Syndrome (AIDS). Seventy eight patients were men and 34, women, with an average age of 30 years. The main risk group was parenterally drug addiction (72%). The stage of the HIV infection was IVC1 in 41% of the cases, II in 23%, III in 13% and IVC2 in 13%. The echographic exploration was performed using a real-time echography, with a probe of 3.5 Mhz, assessing according to conventional criteria the abdominal organs and their pathology, masses and free intraabdominal fluid. The echographic characteristics were first broadly assessed in the patients from the series and later on, according to the patient's pathology. (Infectious, acute abdominal, hepatic biochemical disorders, HIV carrier-associated pathology). RESULTS: In 33% of the cases, the echography was normal. Hepatomegaly was the most frequent echographic sign: 56 patients (50%), followed by splenomegaly in 43 patients (38.3%), standing out the affection of the biliary and/or vesicular ductus in 7 patients (6.2%). The echographic findings were not related to the HIV infection stage, nor with the presence of hepatic biochemical disorders. However, the presence of organomegaly (hepatosplenomegaly associated or not to retroperitoneal adenopathies) were more frequent in the group with infectious complication, 33.3% vs 19.6% (p < 0.01), that in the patients without associated infectious processes. In patients with medical or surgical acute abdominal pathology, the echography was diagnostic in 9 out of 10 patients. CONCLUSION: In the HIV patient, the echography allows an specific initial diagnostic assessment, being able in most of the patients with abdominal manifestations to diagnose the causal pathology.

Revisión sistemática de la implantación de prótesis de pene en cirugía mayor ambulatoria / Systematic review of the implantation of penile prosthesis in major ambulatory surgery

Introducción y objetivo La implantación de prótesis deZ pene (PP) es una alternativa eficaz para la disfunción eréctil. Aunque inicialmente la cirugía de PP se realizaba en régimen hospitalario, existe una tendencia creciente a realizar el implante de PP en un modelo de cirugía mayor ambulatoria (CMA). El objetivo de este estudio es realizar una revisión sistemática de la literatura para identificar la evidencia disponible sobre la implantación de PP en el marco de la CMA en comparación con el procedimiento realizado en régimen hospitalario. Material y métodos Se realizó una búsqueda en las bases de datos electrónicas PubMed, EMBASE, Cochrane Library y MEDES y en los suplementos no indexados de los congresos científicos para identificar artículos relacionados con la implantación quirúrgica de PP en CMA hasta febrero de 2021. Los términos de búsqueda incluyeron prótesis de pene, disfunción eréctil, cirugía ambulatoria, atención ambulatoria y cirugía. Resultados Entre las 171 publicaciones obtenidas (51 en PubMed, 73 en EMBASE, 3 en Cochrane, 2 mediante MEDES y 42 mediante búsqueda manual), se seleccionaron finalmente 5 estudios. No hubo diferencias significativas entre la CMA y el régimen hospitalario en términos del tipo de dispositivo, el abordaje quirúrgico o la ubicación del reservorio. Las tasas de complicaciones observadas en ambos grupos fueron similares. La implantación de PP en régimen de CMA supuso un menor coste que la cirugía en régimen hospitalario y se asoció con tasas aceptables de satisfacción de los pacientes y un adecuado control del dolor. Conclusiones Los estudios demostraron que la implantación de PP en régimen de CMA puede lograr resultados similares en términos de seguridad y satisfacción a la implantación de PP en el régimen hospitalario, pudiendo también reducir los costes y mejorar la eficiencia. Esta investigación podría ayudar a los responsables de la toma de decisiones a extender la cirugía de PP al régimen ambulatorio (AU)

Introduction and objective Penile prosthesis (PP) implantation is an effective option for erectile dysfunction. Although initially PP surgery was carried out in an inpatient setting, there is a growing trend to implant PP in a major ambulatory surgery (MAS). This study aimed to perform a systematic review of the literature to identify available evidence of the implantation of PP under MAS setting and go carry out a comparison between MAS and inpatient procedures. Material and methods PubMed, EMBASE, Cochrane Library and MEDES electronic databases and non-indexed supplements for scientific congresses were searched to identify articles related to the surgical implantation of PP in MAS up to February 2021. Key search terms included penile prosthesis, erectile dysfunction, ambulatory surgery, ambulatory care, and surgery. Results Among 171 publications retrieved (51 PubMed, 73 EMBASE, 3 Cochrane, 2 using MEDES and 42 manual searching), 5 studies were finally selected. There were no significant differences between MAS or inpatient setting in terms of the type of device, surgical approach, or location of reservoir. Complication rates observed in both groups were similar. Implantation of PP in MAS was less expensive than inpatient surgery and was associated with acceptable patient satisfaction rates and adequate pain control. Conclusions Studies demonstrated that outpatient PP surgery can achieve similar outcomes in terms of safety and satisfaction to implantation of PP in the inpatient setting, while it could reduce costs and improve the efficiency. This research could provide support decision makers to extend PP surgery into the ambulatory setting (AU)

[Transitional cell carcinoma in a young heavy marihuana smoker]. / Carcinoma de células transicionales en un joven fumador severo de marihuana.

OBJECTIVE: To report a case of low grade papillary transitional cell carcinoma of the left renal pelvis in a young, heavy smoker of marihuana who denied cocaine use, alcohol intake and other habits. METHODS/RESULTS: Intravenous pyelogram demonstrated a filling defect in the left renal pelvis and calyces. Biopsy revealed a urothelial carcinoma. The pathological analysis demonstrated diffuse low-grade non-invasive (Ta) papillary transitional cell carcinoma of the renal pelvis and calyces. Nephroureterectomy was performed. CONCLUSIONS: This case indicates a cause-effect relationship between heavy and long-term marihuna smoking and transitional cell cancer. However, further cases from the literature or observations in larger populations are warranted.

In situ non-radioactive detection of nuclear factors in paraffin sections by Southwestern histochemistry.

BACKGROUND: Transcriptional activities of genes require intermediary regulators (nuclear factors) that bind to specific segments of nuclear DNA. A method to localize in situ the distribution of these factors using nonradioactive oligonucleotides in paraffin wax-embedded tissues is described. The distribution of two nuclear factors, activated protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB), was studied in two experimental models of immune complex glomerulonephritis in rats and atherosclerosis in rabbits. METHODS: Sections were fixed with 0.2% paraformaldehyde and were digested with pepsin A. Oligonucleotides containing the consensus sequence of NF-kappaB and AP-1 were 3'-labeled with digoxigenin. The preparations were incubated with the labeled probes (4 degreesC, overnight). After washing, the sections were incubated with an antidigoxigenin antibody conjugated with alkaline phosphatase, and the color reaction was developed. In addition, this method was combined with standard immunohistochemistry to identify the cell-type-specific localization of these DNA-binding factors. RESULTS: Kidney sections from rats with immune complex nephritis showed positive nuclear staining for AP-1 in the nuclei of several glomerular and tubulointerstitial cells. Arteries from rabbits with focal atherosclerosis presented nuclear staining for NF-kappaB in the neointima and media. The nuclear staining was highly specific, as assessed by several negative controls. In addition, Southwestern histochemistry in rabbits, followed by immunohistochemistry, demonstrated that the NF-kappaB activity was present in the area occupied by macrophages and smooth muscle cells. CONCLUSION: These results show a novel method of in situ transcription factors detection using nonradioactive probes in paraffin wax-embedded tissues, which allows a simultaneous visualization of the cell-type-specific localization of these nuclear factors.

Serum levels of tumour necrosis factor-alpha predict response to recombinant human erythropoietin in patients with myelodysplastic syndrome.

We measured pretreatment serum levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) in 25 patients with myelodysplastic syndrome receiving recombinant human erythropoietin (rhEPO) at dosages up to 300 U/kg thrice weekly for 12 weeks. Both TNF-alpha and IL-1 beta levels were measured using commercially available enzyme-linked immunoassays. A complete response (CR) was defined as a rise in untransfused haemoglobin concentrations of at least 2 g/dl or a 100% decrease in RBC transfusion requirements over the treatment period; a partial response (PR) was an increase in untransfused haemoglobin values of 1-2 g/dl or a decrease in RBC transfusion requirements equal to or greater than 50%; no response (NR) was defined as a response less than a PR. After 12 weeks of rhEPO treatment, four patients showed a CR, five patients a PR, and 16 patients NR. Serum levels of both TNF-alpha (80.5 %/- 64.8 vs 8.1 +/- 4.2 ng/l, P < 0.001) and IL-1 beta (60.4 +/- 49.9 vs 8.9 +/- 4.7 ng/l, P < 0.001) were higher in MDS patients than in a group of 28 normal controls. Responders (CR + PR) showed significantly lower serum levels of TNF-alpha than non-responders (21.6 +/- 26.2 vs 106.3 +/- 60.8 ng/l, P < 0.001), whereas IL-1 beta concentrations between those who benefited from therapy and unresponsive cases were not significantly different (39.8 +/- 48.9 vs 73.4 +/- 48.2 ng/l, P = 0.120). It is noteworthy that TNF-alpha levels were within the normal range in all responsive patients but one, whereas all non-responders presented elevated cytokine concentrations. No relationship was found between TNF-alpha or IL-1 beta values and haemoglobin levels, transfusion requirement, serum EPO or ferritin concentrations. We conclude that pre-treatment TNF-alpha levels might help to select those MDS patients who are most likely to benefit from rhEPO treatment.

ACE inhibitor quinapril reduces the arterial expression of NF-kappaB-dependent proinflammatory factors but not of collagen I in a rabbit model of atherosclerosis.

Increasing evidence supports an association between inflammation and plaque rupture. Macrophages and vascular smooth muscle cells are a source of cytokines and growth factors, which contribute to ongoing inflammation during atherogenesis. In a rabbit model of atherosclerosis, we evaluated the effect of the ACE inhibitor quinapril on different parameters implicated in the pathogenesis of the plaque, such as the presence of chemokines (interleukin-8, monocyte chemoattractant protein-1), collagen I, and vascular smooth muscle cell proliferation (PDGF-B). Since nuclear factor kappaB (NF-kappaB) has been implicated in the control of chemokine transcription and cell proliferation, we also investigated its activation and localization in the lesion. Quinapril administration for 28 days caused a down-regulation in arterial expression of interleukin-8 and monocyte chemoattractant protein-1 (mRNA and protein). However, collagen I expression (mRNA and protein) was not modified. PDGF-B expression was reduced in both the intima and the media. Active NF-kappaB, found in both macrophages and vascular smooth muscle cells, was also reduced by quinapril. Nevertheless, no significant changes were noted in the mild neointima formation, although a certain trend toward normalization was found in the quinapril-treated group. In conclusion, our results show that quinapril treatment attenuates several parameters associated with inflammation within the atherosclerotic lesions that are controlled by NF-kappaB, although it has no effect on collagen I expression. Both effects could contribute to the stabilization of the atherosclerotic plaque.

Early predictors of peripheral neurotoxicity in cisplatin and paclitaxel combination chemotherapy.

BACKGROUND: We investigated the possible use of clinical signs of chemotherapy-induced peripheral neurotoxicity (CIPN) or of nerve growth factor (NGF) circulating levels to predict the final outcome of CIPN. PATIENTS AND METHODS: Sixty-two women affected by locally advanced squamous cervical carcinoma treated with TP (paclitaxel 175 mg/m2 over a 3 h infusion plus cisplatin 75 mg/m2) or TIP (TP plus ifosphamide 5 mg/m2) were examined and scored according to the Total Neuropathy Score (TNS), before and during chemotherapy. RESULTS: A correlation with the final severity of CIPN was observed with vibration perception and deep tendon reflex evaluation, while pin sensibility, strength, and autonomic symptoms and signs were not informative. A highly significant correlation existed between the decrease in circulating levels of NGF and the severity of CIPN (r = -0.579; P < 0.001; 95% confidence limits -0.702 to -0.423). However, circulating levels of NGF were not effective as predictors of the final neurological outcome of each patient. CONCLUSION: Our study indicates that a precise clinical evaluation of the peripheral nervous system of patients treated with platinum and taxane combination polychemotherapy not only gives reliable information regarding the course of CIPN, but also can be used to predict the final neurological outcome of the treatment.

Antibodies to bovine beta-casein in diabetes and other autoimmune diseases.

Cow's milk is thought to be an environmental trigger for autoimmune response in Type 1 diabetes. In the present study, our aim was to investigate the antibody response to bovine beta-casein in different immune- and non-immune-mediated diseases and to establish whether such an antibody response is specific to Type 1 diabetes. We measured antibodies to bovine beta-casein using an enzyme-linked immunosorbent assay in a total of 519 sera from subjects as follows: 71 patients with Type 1 diabetes, 33 patients with coeliac disease, 100 patients with latent autoimmune diabetes in adults (LADA), 50 patients with autoimmune thyroid disease (ATD), 50 patients with Type 2 diabetes, 24 patients with multiple sclerosis (MS), and 3 different groups of controls (n = 191). Significantly increased levels of antibodies to beta-casein were found in patients with Type 1 diabetes, coeliac disease and in LADA compared to age-matched controls (p = 0.01, p = 0.02 and p = 0.01, respectively). No differences were observed in beta-casein antibody titres between patients with other disease conditions (MS, and ATD) and age-matched controls. The highest antibody response to beta-casein in Type 1 diabetic patients and in patients with coeliac disease could reflect the gut mucosal immune disorders common to Type 1 diabetes and coeliac disease. Furthermore, the elevated beta-casein antibody levels found in LADA patients suggest that the antibody response to this protein may be relevant in autoimmune diabetes.

Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-kappa B activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis.

BACKGROUND: The migration of monocytes into the vessel wall is a critical event leading to the development of atherosclerosis. Monocyte chemoattractant protein-1 (MCP-1) is the main chemotactic factor involved in this phenomenon, and nuclear factor-kappa B (NF-kappa B) is one of the nuclear factors controlling its expression. ACE inhibitors have been useful in some experimental models of atherosclerosis. In this work, we addressed the hypothesis that angiotensin II (Ang II) may be implicated in the recruitment of monocytes into the vessel wall through the activation of NF-kappa B and the induction of MCP-1 expression. METHODS AND RESULTS: Accelerated atherosclerosis was induced in the femoral arteries of rabbits by endothelial desiccation and atherogenic diet for 7 days. Atherosclerotic vessels exhibited an increase in NF-kappa B-like activity, and p50 and p65 NF-kappa B subunits were identified as components of this activity. MCP-1 (mRNA and protein) was also expressed in the injured vessels coincidently with the neointimal macrophage infiltration. ACE inhibition with quinapril reduced these three parameters. In cultured monocytic and vascular smooth muscle cells. Ang II elicited an increase in NF-kappa B activation and MCP-1 expression that was prevented by preincubation of cells with pyrrolidinedithiocarbamate, an inhibitor of NF-kappa B activation. CONCLUSIONS: The present data support a role for Ang II in neointimal monocyte infiltration through NF-kappa B activation and MCP-1 expression in a model of accelerated atherosclerosis in rabbits. Our results suggest that ACE inhibitors may have a beneficial effect in early atherosclerosis.