Satisfaction and medication adherence in women with vulvovaginal atrophy: the CRETA.

OBJECTIVE: This study aimed to evaluate the self-reported satisfaction of Spanish postmenopausal women currently treated for vulvovaginal atrophy (VVA) symptoms. METHODS: The CRETA (CRoss sectional European sTudy on Adherence) is a multicenter cross-sectional study conducted in 29 public and private hospitals in Spain, which enrolled postmenopausal women receiving treatment with ospemifene, local hormone therapy (HT) or vaginal moisturizers for VVA. After the prior informed consent of the patients, sociodemographic and treatment perception data were collected using a structured questionnaire. RESULTS: Among 752 women who completed the survey, the satisfaction score was significantly higher for the group treated with ospemifene (mean 8.3 ± 1.4) compared with the local HT group (7.2 ± 1.7) and the vaginal moisturizer group (6.5 ± 2.1) according to a 10-point Likert scale (p < 0.0001). Compared to vaginal moisturizers and local HT, participants treated with ospemifene reported the highest adherence (96.7% vs. 70.2% and 78.6%, respectively) and the lowest number of missed doses in the last month (0.6 ± 1.3 standard deviation [SD] vs. 3.5 ± 4.3 SD and 2.0 ± 2.8 SD, respectively) (p < 0.0001). Ospemifene was significantly perceived as easy to use (83.9% vs. 44.9% and 58.6%, respectively; p < 0.0001), efficacious in reducing the time to relieve symptoms (17.1% vs. 7.0% and 6.7%, p = 0.0005 and p = 0.0006, respectively) and convenient for sexual life (53.1% vs. 25.6% and 42.3%, p < 0.0001 and p = 0.0234, respectively). CONCLUSIONS: Among postmenopausal women with VVA, treatment with ospemifene has the most positive perceptions and the highest overall satisfaction level and could be an optimal therapeutic approach, maximizing patient adherence.

The involvement of ADAM10 in acantholysis in mucocutaneous pemphigus vulgaris depends on the autoantibody profile of each patient.

BACKGROUND: Acantholysis in pemphigus vulgaris (PV) may be triggered by desmoglein (Dsg) and non-Dsg autoantibodies. The autoantibody profile of each patient results in distinct intracellular signalling patterns. OBJECTIVES: Based on our previous findings, we aimed to elucidate whether PV acantholysis in a mouse model may be mediated by activation of a disintegrin and metalloproteinase 10 (ADAM10). METHODS: We used three PV-IgG fractions from different patients containing high or low levels of anti-Dsg1 and anti-Dsg3 antibodies, and the presence or not of anti-desmocollin (Dsc) antibodies, using a passive transfer mouse model of PV. RESULTS: Although all of the PV-IgG fractions produced suprabasal acantholysis, only those containing anti-Dsg1/3, but not anti-Dsc2/3 antibodies, induced ADAM10 activation in a Src-dependent way, and an increase in the epidermal growth factor (EGF) receptor ligands EGF and betacellulin (BTC). In contrast, the presence of anti-Dsc2/3 antibodies, in addition to anti-Dsg1/3, triggered earlier and ADAM10-independent epidermal detachment, with no increase in EGF and BTC, which was associated with an earlier and more intense acantholysis. CONCLUSIONS: All PV-IgG fractions produced suprabasal acantholysis, but our results reveal that depending on the levels of anti-Dsg antibodies or the presence of non-Dsg antibodies, such as anti-Dsc, more severe cell-cell epidermal detachment will occur at different times, and in an ADAM10-dependent manner or not. Acantholysis in these different groups of patients with PV may be a consequence of the activation of specific intracellular mechanisms downstream of Autoantibodies binding to Dsg or non-Dsg proteins, and therefore more specific therapeutic approaches in PV should be used. What's already known about this topic? Suprabasal acantholysis in pemphigus vulgaris (PV) may be triggered by both desmoglein (Dsg) and non-Dsg autoantibodies. The autoantibody profile of each patient is associated with a distinct intracellular signalling pattern. What does this study add? In patients with PV with anti-Dsg3 and anti-Dsg1, but not anti-desmocollin (Dsc)3 antibodies, ADAM10 activation is induced in an Src-dependent way, together with an increase in the epidermal growth factor receptor (EGFR) ligands EGF and betacellulin. The presence of anti-Dsc3 antibodies triggers an earlier and ADAM10-independent acantholysis, without increasing EGFR ligands, and is associated with more severe epidermal detachment. Lower levels of anti-Dsc3 antibodies are associated with less severe acantholysis. What is the translational message? In some patients with PV, the severity and the timing for cell-cell detachment seem to depend on the level of anti-Dsg1/3 antibodies, although other as yet uncharacterized antibodies may also participate. These patients with PV would exhibit inhibition of acantholysis by Src, ADAM10, EGF and EGFR inhibitors. In other patients, the presence of non-Dsg antibodies, such as anti-Dsc2/3, would produce an earlier and more severe ADAM10-independent suprabasal acantholysis.

Time course of vascular prostanoid production in the fructose-hypertensive rat.

1 There is a relationship between hypertension, insulin resistance and an altered plasmatic lipid profile known as 'metabolic syndrome'. Fructose (F) overload induces in the rat a mild hypertension associated with metabolic alterations such as hyperglycemia, hypertriglyceridemia and insulin resistance, resembling such syndrome. 2 Prostanoids (PR), metabolites of arachidonic acid, include vasoactive substances synthesized and released by the vessel wall. An altered pattern of PR release has been previously found in mesenteric vessels of experimental diabetic rats. 3 This study analyzed the effects of F-overload during different periods (4, 9, 15 and 22 weeks) on PR release in aorta (A) and mesenteric vascular beds (MVB). Animals received tap water (control) or F solution (10% w/v) to drink. 4 Rats with F overload showed significantly higher systolic blood pressure, glycemia and triglyceridemia than controls; but no differences in this parameters were found among periods of treatment either in controls or experimental animals. 5 In A, prostacyclin was decreased at 9, 15 and 22 weeks of treatment when compared to 4 weeks and controls. In MVB, prostacyclin showed different patterns of release in the studied periods of F overload. Prostaglandin (PG) E(2) diminish in MVB at the same extent in all periods. No changes were observed in A. The vasoconstrictor thromboxane was elevated in the MVB at 9 weeks. PGF(2)alpha, also a vasoconstrictor, remains unchanged. 6 In conclusion, F overload provokes in the rat a decrease in the vascular production of vasodilator PR and, in one of the studied periods, an increase in the release of the vasoconstrictor thromboxane, leading to a negative imbalance in the prostacylin/thromboxane ratio. This could be involved in the blood pressure alterations found in this experimental model of metabolic syndrome.

The role of nitric oxide synthases in pemphigus vulgaris in a mouse model.

BACKGROUND: Pemphigus vulgaris (PV) is a blistering autoimmune disease characterized by IgG autoantibodies against desmoglein 3. Nitric oxide synthases (NOS) may contribute to the increase of inflammation in tissues by the generation of nitrotyrosine residues (NTR). OBJECTIVES: To investigate whether the production of NTR mediated by NOS may participate in the development of inflammation and acantholysis in PV. METHODS: Mice were pretreated or not with NOS, tyrosine-kinase (TK) or nuclear factor (NF)-kappaB inhibitors, and then injected with PV-IgG. PV manifestations were examined in all mice. The expression of NTR, constitutive NOS (cNOS) [endothelial NOS (eNOS) and neuronal NOS (nNOS)], inducible NOS (iNOS) and NF-kappaB factor were studied in epidermis of mice using immunohistochemical techniques. RESULTS: After PV-IgG injection, expressions of NTR, iNOS, eNOS and nNOS increased in acantholytic cells, as did nuclear translocation of NF-kappaB in the basal cells of the epidermis. Pretreatment of mice with inhibitors of TK, nNOS and nonselective NOS, completely prevented NTR expression and the clinical and histological findings of PV in mice. TK inhibitor genistein inhibited both nNOS and iNOS expression on the membrane of basal keratinocytes, and nuclear translocation of NF-kappaB. CONCLUSIONS: Upregulation of cNOS and iNOS, NTR generation and nuclear translocation of NF-kappaB may contribute to increased inflammation and tissue damage in PV lesions. The absence of the clinical and histological findings of PV and NTR expression in mice injected with PV-IgG, through pretreatment with TK and nNOS inhibitors, provides compelling evidence that these signalling molecules should be considered as potential therapeutic targets in PV.

Regulation of apoptosis by peptides of fibronectin in human monocytes.

Synthetic peptides with sequences present in extracellular matrix protein fibronectin have been described to stimulate human monocytes. We describe now that one of these peptides, FN6, induces apoptotic effects on monocytes and we investigate the molecular mechanisms involved in the regulation of this response. Incubation of monocytes with FN6 induces the activation of the small GTPase Rac. In turn, Rac mediates the increase of both JNK and p38 activities in a sustained fashion, as well as the phosphorylation levels of their respective substrates c-Jun and ATF-2. FN6 also stimulates caspases -9 and -3 and the delayed proteolysis of its substrates PARP and D4-GDI. In addition, initiator caspases-1 and -5 were activated by FN6 treatment of monocytes but, in contrast to that observed for caspases-9 and -3, this effect was not dependent on JNK or p38 activities. These kinases also mediated the increase of Bax levels, but only in some conditions Bcl-2 depletion caused by the peptide. Moreover, whereas initially only caspase-1 is involved in caspase-3 activation, later on caspase-9 seems also to participate. Therefore, we demonstrate that FN6 stimulation allows multiple, JNK and p38-dependent and -independent interacting signals to regulate the apoptotic response in human monocytes.

In vivo blockade of pemphigus vulgaris acantholysis by inhibition of intracellular signal transduction cascades.

BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune disease characterized by mucocutaneous intraepithelial blisters and pathogenic autoantibodies against desmoglein 3. The mechanism of blister formation in pemphigus has not been defined; however, in vitro data suggest a role for activation of intracellular signalling cascades. OBJECTIVES: To investigate the contribution of these signalling pathways to the mechanism of PV IgG-induced acantholysis in vivo. METHODS: We used the passive transfer mouse model. Mice were injected with IgG fractions of sera from a patient with PV, with or without pretreatment with inhibitors of proteins that mediate intracellular signalling cascades. RESULTS: Inhibitors of tyrosine kinases, phospholipase C, calmodulin and the serine/threonine kinase protein kinase C prevented PV IgG-induced acantholysis in vivo. CONCLUSIONS: These observations strongly support the role of intracellular signalling cascades in the molecular mechanism of PV IgG-induced acantholysis.

Pemphigus vulgaris autoantibodies induce apoptosis in HaCaT keratinocytes.

Pemphigus vulgaris (PV) is an autoimmune disease characterized by binding of IgG autoantibodies to epidermal keratinocyte desmosomes. IgG autoantibodies obtained from a patient with mucocutaneous PV reacted with plakoglobin (Plkg) in addition to desmoglein-3 (Dsg3) and Dsg1. Immunofluorescence analysis confirmed that IgG autoantibodies, unlike antibodies from a healthy volunteer, caused disruption of cell-cell contacts in HaCaT keratinocytes. Moreover, apoptosis was enhanced in cells treated with autoantibodies compared to those treated with normal antibodies. The apoptotic process induced by IgG autoantibodies was characterized by caspase-3 activation, Bcl-2 depletion and Bax expression. The present report demonstrates that PV IgG autoantibodies promote apoptosis in HaCaT keratinocytes.

Rhabdomyolysis as a result of Streptococcus pneumoniae: report of a case and review.

We report the case of a patient who presented with RM associated with bacteremic pneumococcal pneumonia and review the literature on this condition.

Seudotumor inflamatorio pulmonar en el niño: formas agresivas / Inflammatory pseudotumors of the lung in children: aggressive types

El seudotumor inflamatorio es una tumoración que puede presentar en el niño una naturaleza agresiva. Para resaltar este hecho, se presentan tres pacientes con seudotumor inflamatorio pulmonar, diagnosticados tras intervención quirúrgica y por biopsia pulmonar abierta, cada uno de ellos con presentación clínica, radiología y evolución muy variables entre sí. Se realizaron radiografía simple y tomografía computarizada (TC) en los tres casos y RM en dos, que proporcionaron resultados diagnósticos orientativos aunque inespecíficos, siendo el común denominador de todos ellos el comportamiento primariamente agresivo. Como conclusión, aunque el seudotumor inflamatorio pulmonar generalmente se presenta como una masa solitaria periférica de características benignas que evoluciona favorablemente tras cirugía, a veces se comporta primariamente de forma agresiva, dificultando el tratamiento quirúrgico que puede llegar a ser, incluso, hasta imposible. Las técnicas de imagen proporcionan hallazgos variables e inespecíficos, destacando las ventajas de la resonancia magnética (RM) sobre la TC para la relación de la masa con las estructuras adyacentes a ésta, así como para la detección y seguimiento de las recidivas (AU)

Mortalidad precoz hospitalaria de etiología infecciosa / Early hospital mortality due to infectious diseases

Introducción: Las enfermedades infecciosas suponen un grave problema de salud pública en nuestro medio debido a una mortalidad todavía nada desdeñable así como por el gran consumo de recursos sanitarios que originan. Dado que son escasas las publicaciones referentes a la mortalidad infecciosa en las primeras horas tras el ingreso hospitalario nos planteamos realizar este estudio. Material y métodos: Selección de la base de datos informatizada de nuestro Centro (1992-1999), de los pacientes fallecidos de causas infecciosas (ClE 9ª - Revisión, con su Modificación Clínica) en las primeras 48 horas después de su ingreso. Resultados: El 0,7 por ciento de los pacientes ingresados en nuestro Centro fallecieron en las primeras 48 horas del ingreso, en el 6,9 por ciento la causa de la muerte fue una infección. En este grupo la edad media fue de 73,2 años, y el 56.1 por ciento eran hombres. El 59,9 por ciento de los pacientes presentaba más de 1 un factor de riesgo extrínseco para el desarrollo de complicaciones infecciosas y el 70,7 por ciento nunca había ingresado previamente. Al ingreso, el 43,9 por ciento presentó fiebre, el 60,9 por ciento sepsis, el 24,4 por ciento sepsis severa, el 13,4 por ciento shock séptico y el 1,2 por ciento fracaso multiorgánico. El foco infeccioso más frecuente fue el respiratorio (76,8 por ciento), predominando la neumonía (58,5 por ciento), principalmente en 65 años (p = 0,03). En el 69,5 por ciento de los pacientes no se realizó ningún medio diagnóstico microbiológico, y su utilización disminuyó en los mayores de 65 años (p = 0,03), con independencia de la gravedad clínica o de la presencia de fiebre. En el 85,4 por ciento de los casos no se produjo identificación microbiológica Conclusiones: Entre las causas infecciosas de mortalidad intrahospitalaria en las 48 horas del ingreso las infecciones respiratorias, y más en concreto, las neumonías son las mas frecuentes. El 60,9 por ciento de los pacientes cumplia criterios de sepsis al ingreso. Las pruebas microbiológicas se realizaron en menos de un tercio de los pacientes y su utilización disminuye a medida que se incrementa la edad de los mismos (AU)

Background: Infectious diseases are an important health problem. Early hospital mortality (EHM) (first 48 hours after hospital admission) give us information about the etiology and the focus of infection. This study was designed because no articles have been found about this subject. Material and methods: We reviewed the medical records coded by the ICD-9-CM of all patients that suffered from EHM due to infectious diseases during the period 1992 to 1999. Results: Of all the patients analyzed, 0.7% died of EHM, and of theses, 6.9% were due to an infectious disease. Median age was 73.2 years; 56.1% were men. Index of comorbidity was higher than 1 in 59,9%, and 70,7% never has been admitted to the hospital before. At admission, fever was present in 43.9%. The illness severity was 60.9% sepsis, 24.4% severe sepsis, 13.4% septic shock and 1.2% multiorgan failure. Causes of death were respiratory (76.8%; pneumonia 58.5%). Pneumonia was more frequent among aged 65 years and older (p = 0.03). In 69.5% no microbiological techniques were performed with independence of the clinical severity or the presence or absence of fever. In 85.4% the casual agent was unidentified, but in the case of isolation, gram positive was the most frequent microorganism. Conclusions: Infections are an important cause of EHM, and community-acquired respiratory tract infection (mainly pneumonia) the most frequent cause of EHM. Patients were admitted to the hospital with sepsis in 60.9%, perhaps due to a diagnostic or therapeutic delay. Among aged 65 years and older, microbiological diagnostic procedures were rarely employed (AU)

p38 MAPK mediates the regulation of alpha1(I) procollagen mRNA levels by TNF-alpha and TGF-beta in a cell line of rat hepatic stellate cells(1).

The role of members of the mitogen-activated protein kinase (MAPK) family on tumor necrosis factor alpha (TNF-alpha)-mediated down-regulation of col1a1 gene was studied. TNF-alpha increased extracellular-regulated kinase and Jun-N-terminal kinase phosphorylation, but these effects were not related to its inhibitory effect on alpha1(I) procollagen (col1a1) mRNA levels. Phosphorylation of p38 MAPK was decreased in response to TNF-alpha, and the specific p38 MAPK inhibitor SB203580 mimicked the effect of TNF-alpha on col1a1 mRNA levels. Transforming growth factor beta (TGF-beta) increased p38 MAPK phosphorylation and SB203580 prevented the induction of col1a1 mRNA levels by TGF-beta. These results suggest that p38 MAPK plays an important role in regulating the expression of col1a1 in hepatic stellate cells in response to cytokines.

[Arterial oxygen desaturation during transport of the post-surgery patient from operation site to recovery ward]. / Desaturación de oxígeno arterial durante el traslado del paciente postquirúrgico de quirófano a la URPA.

BACKGROUND: One of the most frequent complications in the immediate post-operation period is the fall in arterial oxygen saturation due to different factors, outstanding of which is the time that the patient remains disconnected from the oxygen supply during transport from the operation site to the recovery ward. The aim of the present paper is to measure the proportion of arterial desaturation in patients who arrive in the recovery room proceeding from the operation site without oxygen provision during transport. MATERIAL AND METHOD: The study was made with a sample of 208 cases corresponding to the patients who underwent operations in the period from March 20th to April 19th 2000. Saturation was measured by pulse oximeter at the moment of arrival in the recovery unit prior to the provision of oxygen. Patients were classified in four groups according to average saturation and they were grouped by ASA and the anaesthetic technique employed. The statistical treatment was carried out with Student's t and variance analysis. RESULTS: The sixty three per cent of patients showed a saturation of > or =95%; 26.4% slight desaturation; 6.3% moderate desaturation and 1% severe desaturation. The average of saturation of the ASA III patients showed significant differences with the ASA II and ASA I patients (p=0.004). Patients with general anaesthetic showed a desaturation with significant differences with respect to the other anaesthetic techniques employed (p<0.05). CONCLUSIONS: ASA III patients and those subjected to general anaesthetic require oxygen provision during transport from the operation site to the recovery ward.

Correlation between profile of circulating mononuclear cells and clinical manifestations in patients with pemphigus vulgaris.

Phenotypes of 38 samples of mononuclear (PBMC) cells from 11 different patients with pemphigus vulgaris (PV) at different stages of the disease were explored looking for a possible relationship between cell immunity, mucocutaneous or mucosal lesion intensity and capacity of serum autoantibodies to elicit the disease in mice. PBMC from 5 patients with mucocutaneous lesions and sera with IgG capable of inducing the disease in neonatal mice had a high proportion of mature monocytes with CD14low DRhigh, and co-expressing CD16 and CD11b. In addition, a high proportion of CD19+CD5+ activated B cells and a very low proportion of naive CD4+CD45RA+ and CD8+CD11b+ T lymphocytes was observed. Monocytes from these patients expressed inducible nitric oxide synthase (iNOS). In contrast, PBMC from 6 patients, with lesions restricted to mucosal membranes and IgG lacking the capacity to induce the disease in mice, contained a high proportion of CD14high DRlow co-expressing CD16 circulating macrophages, CD8+CD11b+ T cells, and a low proportion of activated B lymphocytes. The results suggest a possible association between proportion of different antigen presenting cells (monocytes with high HLA-DR and low CD14 expression and activated B lymphocytes, or differentiated monocytes/macrophages), type of PV and capacity of serum autoantibodies to elicit the disease in mice.

Molecular mechanisms of apoptosis induced by an immunomodulating peptide on human monocytes.

A short immunomodulating peptide (Pa) containing a defined structural motif present in a number of extracellular matrix proteins and autoantigens was found to stimulate human monocytes. Pa-induced apoptosis of isolated monocytes, as indicated by internucleosomal DNA cleavage, increased annexin V binding capacity and cleavage of caspase substrates, such as poly(ADP)ribosylpolymerase. In addition, Bcl-2 protein levels were downregulated during Pa-induced cell death. Nuclear extracts of monocytes incubated with Pa showed higher neutral, Ca(2+)-dependent DNase activity than those obtained from nontreated monocytes. Caspase inhibitors prevented Pa-induced apoptosis, Bcl-2 depletion, and DNase activation. Treatment of monocytes with Pa activated c-Jun N-terminal kinases and p38 kinase, in an acidic sphingomyelinase- and caspase-dependent fashion. Pa-induced apoptosis was blocked by selective inhibitors of p38 kinase (SB203580) and acidic sphingomyelinase (SR33557). These results indicate that JNK and p38 kinase stimulation as well as monocyte apoptosis induced by Pa could depend, at least in part, on early activation of acidic sphingomyelinase.

Correlation of activated monocytes or B cells with T lymphocyte subsets in patients with Graves' disease.

We analyzed the phenotypic characteristics of PBMC from 34 patients with Graves' disease (GD) at different stages of the disease to explore the sequence of immunological events associated with it. In all cases their monocytes were in a state of activation and differentiation more advanced than those of a group of 23 healthy individuals. Strikingly, some patients had CD14++DR- immature monocytes, which were absent in healthy individuals. CD14+CD16+DRhigh monocytes were more abundant in patients. We found a positive correlation between the CD14++DR- monocyte and CD4+CD45RA- helper cells and a negative correlation between the same monocyte subset and CD4+CD45RA+ naive cells. CD14+/++DRlow monocytes directly correlated with this latter T4 subset and CD14+ CD16+DRhigh with CD4+CD45RO+ memory lymphocytes. There was also a positive correlation between memory T4 cells and the subset of activated B lymphocytes (CD19+CD5+) and suppressor T8 cells (CD8+CD11b+). T8 cytotoxic cells (CD8+CD11b-) positively correlated with T4 naive cells. The circulating levels of T3 and TSI (thyroid-stimulating immunoglobulin) directly correlated with a decrease in naive cells and an increase in T8 suppressors. The results suggest that the imbalance suppression/cytotoxicity in GD may be due to a reiterated presentation of autoantigens, or mimetic antigens, to T helpers by mature monocytes and activated B cells.

Nitric oxide activates granule-associated DNase in human monocytes.

Activated and differentiated human monocytes with a CD14+CD16+ phenotype were found to contain a DNase activity associated with secretion granules. Activated cells were obtained from patients with autoimmune diseases. Activation and differentiation of monocytes were also achieved after incubation of PBMC from healthy subjects with protein A (SpA) or immunopotentiating peptides. DNase activity corresponded to a 66-kDa protein, similar to that described in granules from T lymphocytes, active preferentially on double-strand DNA. DNA fragmentation activity increased when NO donors were present; the activity was higher in the presence of Ca2+, and at low pH values. The Ca2+-dependent activity was inhibited by Zn2+. NO-dependent activity was additive with that of Ca2+-dependent and it was not inhibited by Zn2+. Dithiothreitol did not modify the effect of NO on DNase activity. Incubation of PBMC in the presence of NMLA, an inhibitor of NO synthases, decreased this DNase activity. Data reported clearly suggest a regulatory role of NO in granule-associated DNase activity.

[Psoas abscess, a rare and forgotten entity. Report of 6 cases]. / Absceso de Psoas, una rara y olvidada entidad. Aportación de seis casos.

The psoas abscess is an entity, some times forgotten in our daily clinical practice. The gram-positive microorganisms are the most frequent, and S. aureus is the most important pathogen. We present a retrospective study of six cases. In our revision, five patients were women (83.3%), and one man (16.6%), with a median age of 65.83 years. The associated pathology were vertebral in four patients (66.6%), and urologic in two of them. The main symptoms were fever and lumbar pain. All the patients were diagnosed by CT. The correct identification of the microorganisms, and the prompt use of the antibiotherapy associated to surgery, helped to a total recuperation of this patients.