Miopericitoma mitóticamente activo / Mitotically Active Myopericytoma

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Crystalglobulinemia manifested as acute renal failure and thrombotic vasculopathy.

Crystalglobulinemia is an extremely rare pathology that is associated in most cases with plasma cell dyscrasia, mainly multiple myeloma. In most cases, it may be the manifestation of incipient gammopathy or it manifests shortly after diagnosis. We report a patient with ischemic lesions of thrombotic origin in lower limbs. Subsequently, renal involvement occurs, in view of this involvement, it is suspected that the patient may have an associated vasculitis. After performing the biopsy and with the subsequent diagnosis of monoclonal gammopathy of uncertain significance, the diagnosis is made. We review the most recent bibliography of patients who have been diagnosed with crystalglobulinemia associated with plasma dyscrasia focusing in those with thrombotic vasculopathy or acute renal failure. In our case, in addition to being associated with monoclonal gammopathy of undetermined significance that is less frequent, the debut of the symptoms is years before the detection of the monoclonal peak. This could speak of patients with a low peak of monoclonal component (not detected by immunoelectrophoresis) who could have kidney and vascular damage.

Lesiones ampollosas en las palmas / Blistering Lesions Involving the Palms

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Very low level viraemia and risk of virological failure in treated HIV-1-infected patients.

OBJECTIVES: The aim of the study was to investigate whether very low level viraemia (VLLV) (20-50 HIV-1 RNA copies/mL) was associated with increased risk of virological failure (VF) as compared with persistent full suppression (< 20 copies/mL). METHODS: From the VACH Cohort database, we selected those patients who started antiretroviral therapy (ART) after January 1997 and who achieved effective viral suppression [two consecutive viral loads (VLs) < 50 copies/mL] followed by full suppression (at least one VL <20 copies/mL). We carried out survival analyses to investigate whether the occurrence of VLLV rather than maintaining full suppression at < 20 copies/mL was associated with virological failure (two consecutive VLs > 200 copies/mL or one VL > 200 copies/mL followed by a change of ART regimen, administrative censoring or loss to follow-up), adjusted for nadir CD4 cell count, sex, age, ethnicity, transmission group, type of ART and time on effective suppression at < 50 copies/mL. RESULTS: Of 21 480 patients who started ART, 13 674 (63.7%) achieved effective suppression at < 50 copies/mL, of whom 4289 (31.4%) further achieved full suppression at < 20 copies/mL after May 2009. A total of 2623 patients (61.1%) remained fully suppressed thereafter, while 1666 had one or more episodes of VL detection > 20 copies/mL (excluding virological failure). A total of 824 patients had VLLV after suppression at < 20 copies/mL. VLLV was not associated with virological failure as compared with persistent full suppression [hazard ratio (HR) 0.67; 95% confidence interval (CI) 0.44-1.00], independently of the number of blips recorded (from one to 18). CONCLUSIONS: In our population of HIV-infected patients on ART who achieved viral suppression at < 20 copies/mL, the risk of virological failure was no different for patients who remained fully suppressed compared with those who experienced subsequent episodes of VLLV.

Two novel recessive mutations in KRT14 identified in a cohort of 21 Spanish families with epidermolysis bullosa simplex.

BACKGROUND: Basal epidermolysis bullosa simplex (EBS) is a group of blistering genodermatoses mostly caused by mutations in the keratin genes, KRT5 and KRT14. Recessive mutations represent about 5% of all EBS mutations, being common and specific in populations with high consanguinity, where affected patients show severe phenotypes. OBJECTIVES: To accomplish the first mutational analysis in patients of Spanish origin with EBS and to delineate a comprehensive genotype-phenotype correlation. METHODS: Twenty-one EBS families were analysed. Immunofluorescence mapping at the dermoepidermal junction level was performed on skin biopsies from patients. Mutation screening of the entire coding sequences of KRT5 and KRT14 in genomic DNA was assessed by polymerase chain reaction and direct sequencing. RESULTS: KRT5 or KRT14 causative mutations were identified in 18 of the 21 EBS families. A total of 14 different mutations were disclosed, of which 12 were dominant missense mutations and two truncating recessive mutations. Five of the 14 mutations were novel including three dominant in KRT5 (p.V186E, p.T321P and p.A428T) and two recessive in KRT14 (p.K116X and p.K250RfsX8). The two patients with EBS carrying homozygous recessive mutations were affected by severe phenotypes and belonged to consanguineous families. All five families with the EBS Dowling-Meara subtype carried recurrent mutations affecting the highly conserved ends of the α-helical rod domain of K5 and K14. The seven mutations associated with the localized EBS subtype were widely distributed along the KRT5 and KRT14 genes. Two families with mottled pigmentation carried the P25L mutation in KRT5, commonly associated with this subtype. CONCLUSIONS: This study further confirms the genotype-phenotype correlation established for EBS in other ethnic groups, and is the first in a Mediterranean country (excluding Israel). This study adds two novel recessive mutations to the worldwide record to date, which includes a total of 14 mutations. As in previous reports, the recessive mutations resulted in a lack of keratin K14, giving rise to a generalized and severe presentation.

Role of pegylated interferon-alpha-2a and ribavirin concentrations in sustained viral response in HCV/HIV-coinfected patients.

The effect of simultaneous plasma concentrations of pegylated interferon-alpha-2a (pegIFN-alpha-2a) and ribavirin (Rbv) on viral response has not been addressed to date. Hepatitis C virus (HCV)/human immunodeficiency virus (HIV)-coinfected patients received pegIFN-alpha-2a and Rbv under routine clinical care conditions. Plasma concentrations of the two drugs were measured using enzyme-linked immunosorbent assay and high-performance liquid chromatography after 2, 4, 8, and 12 weeks and at the end of the treatment period (24-48 weeks, according to HCV genotype and treatment duration). Large interindividual variability was observed in the plasma levels of both drugs. After multivariate analysis, only HCV genotype 3, low HCV-RNA levels, and pegIFN-alpha-2a exposure remained as independent factors associated with sustained viral response (SVR). The probability of attaining an SVR in HCV genotypes 1 and 4 was more than three to four times higher in patients with pegIFN-alpha-2a levels above the selected cutoff point. Early therapeutic drug monitoring of pegIFN-alpha-2a levels could be beneficial in improving current treatment outcomes.

Inhibitory quotient as a prognostic factor of response to a salvage antiretroviral therapy containing ritonavir-boosted saquinavir. The CIVSA Study.

BACKGROUND: The addition of a low dose of ritonavir to protease inhibitors (PIs) has become a widespread strategy to improve PI pharmacokinetics. As resistance is a major barrier to long-term suppression, in salvage therapy genotype and/or phenotype scoring is currently used to predict the response. We evaluated the relationship between the saquinavir (SQV) inhibitory quotient (IQ) (virtual and genotypic) and virological response. METHODS: Eligible patients were on a PI-containing highly active antiretroviral therapy (HAART) regimen excluding SQV and had a viral load >5000 HIV-1 RNA copies/mL. The PI was switched to SQV/ritonavir (RTV) 1000/100 mg twice a day (bid) and the same two backbone nucleoside reverse transcriptase inhibitors (NRTIs) were maintained at least until week 4, when the resistance test results became available. Genotype and virtual phenotype were determined at baseline, while the SQV trough plasma concentration was determined at week 4. RESULTS: Fifty-three patients were included in the study. Mean baseline viral load and CD4 count were 137,693 copies/mL and 263 cells/microL, respectively, the mean number of previous PIs was 2.3 and the mean number of protease gene mutations (PGMs) was 4.1. Using an on-treatment analysis, at week 16 the mean increase in CD4 count was 70.9 cells/microL, viral load was <200 copies/mL in 17 out of 37 patients (45.9%), and 30 out of 45 patients (66.7%) were considered virological responders (VRs) (viral load <200 copies/mL or viral load declined > or =1 log(10) at week 16). Median virtual phenotype was 1.3 (0.6-6.9). Baseline differences were detected between VR and non-VR populations: the mean numbers of PGMs were 3.2 and 5.8 (P<0.05), the mean numbers of SQV-associated mutations were 2 and 3.8 (P<0.05), and the mean CD4 counts were 365.9 and 184.3 cells/microL (P<0.05), respectively. Mean SQV trough concentrations at week 4 were 1.1 and 1.0 microg/mL (not significant), and mean virtual IQs were 0.7 and 0.1 (P<0.01), respectively. Multivariate analysis showed that baseline PGMs >5 or SQV-associated mutations>5, virtual phenotype, baseline viral load >50,000 copies/mL, and virtual IQ <0.5, but not genotypic IQ, were the variables independently associated with non-VR. CONCLUSION: In heavily pretreated patients, the use of SQV virtual IQ or alternatively virtual phenotype, as well as PGMs, is a useful tool for the prediction of virological response.

Synthesis and mass spectroscopy kinetics of a novel ternary copper(II) complex with cytotoxic activity against cancer cells.

The X-ray structure of the [Cu(I-hip)(phen)2](+).(I-hip-).(H2O)7 complex (1) (where I-hipH is referred to o-iodohippuric acid and phen is 1,10-phenanthroline) and its binary synthetic intermediate [Cu(I-hip)2(H2O)3].(H2O)2 (2) have been solved and characterized by different techniques. This ternary [Cu(I-hip)(phen)2]+.(I-hip-).7H2O complex generates the copper(I) complex [Cu(phen)2]+ in aqueous solution without the addition of any external reductant, possibly by an intramolecular red-ox process in the presence of oxygen; the ESI-HRMS spectra (electrospray ionization-high resolution mass spectroscopy) detect these species and 24h after the solution, [Cu(phen)2]+ is the main product. The complex 1 is capable of cleaving DNA. To evaluate the biological properties, we carried out: cell culture, cell proliferation assays, cell cycle analysis, and electrophoresis (SDS-PAGE) and immunoblotting. Complex 1 induced apoptosis of A549 cells at low nanomolar and induced marked decreases of cancer cells at concentrations that did not change adipocyte survival. These data indicate that the parent complex is a potential anticancer drug.

Ovarian epithelioid trophoblastic tumor in a cynomolgus monkey.

Epithelioid trophoblastic tumor (ETT) is an unusual type of trophoblastic tumor, with features resembling carcinoma. In this study, we describe a 4-year-old cynomolgus monkey (Macaca fascicularis) showing, at necropsy, a lobulated mass replacing the left ovary and several nodular lesions within the lungs. Histologically, the mass in the ovary and lung metastases were characterized by nests of epithelioid cells, with intermingled, occasional, multinucleate tumor cells consistent with syncytiotrophoblasts and moderate amount of eosinophilic, hyaline-like material. Immunohistochemically, the tumor cells were diffusely positive for cytokeratins (AE1/AE3) and inhibin-alpha, but only focal immunoreactivity was observed for human chorionic gonadotropin, whereas placental alkaline phosphatase was always negative. On the basis of morphology and immunohistochemical reactivity, tumor cells were identified as intermediate trophoblast.

Effect of metal complexes of acyclovir and its acetylated derivative on Herpes simplex virus 1 and Herpes simplex virus 2 replication.

The effect of zinc, nickel, cobalt and cadmium complexes of acyclovir (ACV) and its omicron-acetylated derivative (Ac-ACV) on the replication of wild type (wt) and ACV-resistant (ACV(R)) strains of Herpes simplex virus 1 (HSV-1) and Herpes simplex virus 2 (HSV-2) was examined. According to cytotoxicity, these compounds followed the order Ni-ACV chloride > Cd-ACV 3 Ni-ACV nitrate > ACV = Zn-ACV nitrate = Ac-ACV = Zn-Ac-ACV > Zn-ACV chloride > Co-ACV. Besides Ac-ACV, the only active complexes in inhibiting virus replication were Zn-ACV nitrate and Zn-Ac-ACV, which effectively suppressed the growth of both wt and ACVR strains of HSV-1 and HSV-2. The most active and most selective inhibitor of the growth of ACVR strains of HSV-1 and HSV-2 was Ac-ACV; its EC50 and SI were 100 and 10 times higher than those of ACV, respectively. Zn-Ac-ACV was less active than Ac-ACV, obviously due to the stability of the complex. Zn-ACV nitrate was active against both wt and ACVR strains of HSV-1; its activity and selectivity were 100 and 75 times higher than those of ACV, respectively. Ac-ACV and Zn-Ac-ACV suppressed the pre-mitotic arrest caused by HSV-1 infection during the first 2 hrs of infection and later on restored the cell division.

Ternary complexes metal [Co(II), Ni(II), Cu(II) and Zn(II)]--ortho-iodohippurate (I-hip)--acyclovir. X-ray characterization of isostructural [(Co, Ni or Zn)(I-hip)(2)(ACV)(H(2)O)(3)] with stacking as a recognition factor.

Four ternary metal--ortho-iodohippurate (I-hip)--acyclovir (ACV) complexes, [M(I-hip)(2)(ACV)(H(2)O)(3)] where M is Co(II) (1), Ni(II) (2), Cu (3) and Zn(II) have been obtained by reaction between the corresponding binary complexes M(II)(I-hip)(2)xnH(2)O and ACV. Three ternary complexes (M=Co, Ni and Zn) and the corresponding Zn(II)--ortho-iodohippurate binary derivative have been structurally characterized by X-ray diffraction: The studies show these three ternary complexes are isostructural and present, in solid state, an interesting stacking between the nucleobase and the aryl ring of the hippurate moiety, which probably promotes the formation of ternary complexes. Moreover, the two different ligands interact between them by means of ancillary hydrogen bonds with water molecules coordinated to the metal ion. It must be mentioned that these two recognition factors, hydrogen bonds plus stacking, could explain the reason for the isostructurality of these ternary derivatives with so different three metal ions, with diverses trends in coordination numbers and geometries. In solid state, there are two enantiomeric molecules that are related by an inversion center as the crystal-building unit (as a translational motif) for the ternary complexes.

Uracilato and 5-halouracilato complexes of Cu(II), Zn(II) and Ni(II). X-ray structures of [Cu(uracilato-N(1))(2)(NH(3))(2)].2(H(2)O), [Cu(5-chlorouracilato-N(1))(2)(NH(3))(2)](H(2)O)(2), [Ni(5-chlorouracilato-N(1))(2)(en)(2)].2H(2)O and [Zn(5-chlorouracilato-N(1))(NH(3))(3)].(5-chlorouracilato-N(1)).(H(2)O).

Four new complexes of uracilato and 5-halouracilato with the divalent metal ions Cu(II), Zn(II) and Ni(II) were obtained and structurally characterized. [Cu(uracilato- N(1))(2)(NH(3))(2)].2(H(2)O) (1) and [Cu(5-chlorouracilato-N(1))(2)(NH(3))(2)](H(2)O)(2) (2) complexes present distorted square planar co-ordination geometry around the metal ion. Although an additional axial water molecule is present [Cu(II)-OH(2)=2.89 A (for 1) and 2.52 A (for 2)] in both cases, only in the complex 2 would be considered in the limit of a bond distance. The Zn(II) in [Zn(5-chlorouracilato-N(1))(NH(3))(3)].(5-chlorouracilato-N(1)).(H(2)O) presents a tetrahedral co-ordination with three ammonia molecules and the N(1) of the corresponding uracilato moiety. A non-coordinated uracilato molecule is present as a counterion and a recognition between co-ordinated and free ligands, by means a tandem of H-bonds, should be mentioned. Finally, the complex [Ni(5-chlorouracilato-N(1))(2)(en)(2)] (H(2)O)(2) (where en is ethylenediamine) presents a typical octahedral trans co-ordination with additional hydrogen bonds between 5-chlorouracilato and the NH(2) groups of ethylenediamine units.