Characteristics and treatment of nonagenarian patients with vascular disease admitted to internal medicine services. NONAVASC-2 registry.

INTRODUCTION: Vascular disease (VD) is the most frequent cause of morbidity and mortality and its prevalence increases with age. Old patients are not included in studies on VD, their characteristics and treatments being unknown. OBJECTIVE: Know the clinical characteristics of nonagenarian patients hospitalized in Internal Medicine services with a diagnosis of established VD and the adequacy of their pharmacological management. MATERIAL AND METHODS: The NONAVASC-2 registry is an observational, prospective, multicentre study. Hospitalized patients for any cause were included. Data collection was carried out through an anonymous online database with sociodemographic, clinical, analytical, therapeutic and evolutionary parameters. RESULTS: One thousand forty-nine patients with a mean age of 93.14 years (57.8% women) were included. The prevalence of risk factors and VD was high: hypertension (84.9%), dyslipidemia (50.9%) and diabetes mellitus (29.4%). 33.4% presented severe-total dependency. 82.9% received antithrombotic treatment (53.7% antiplatelets, 25.4% anticoagulation and 3.8% double therapy). Only 38.2% received statins. The percentage of severe dependence (39.2% vs 24.1%; p = 0.00) and severe cognitive impairment (30.8% vs 13.8%; p = 0.00) was significantly higher among patients who did not receive them. 19% died during admission. CONCLUSIONS: Nonagenarian patients with VD present high comorbidity, dependence and mortality. Despite being in secondary prevention, 17% did not receive antithrombotics and only 38% received statins. The underprescription is conditioned, among other factors, by the functional status. More studies are necessary to determine the impact of this issue on their prognosis.

Nutritional Risk and Mortality at One Year for Elderly Patients Hospitalized with Nonvalvular Atrial Fibrillation. Nonavasc Registry.

OBJECTIVES: To determine whether nutritional risk is associated with the mortality of elderly patients hospitalized with nonvalvular atrial fibrillation (NVAF). DESIGN: Prospective, multicenter cohort study. SETTING: Internal medicine departments in Spain. PARTICIPANTS: Inpatients >75 years with NVAF. MEASUREMENTS: We measured the thrombotic and hemorrhagic risk at admission using the CHA2DS2-VASc and HAS-BLED scales, respectively, and the nutritional risk with the controlling nutritional status (CONUT) index. We established 4 degrees of nutritional risk: null (CONUT score 0-1 point), low (2-4 points), moderate (5-8 points) and high (9-12 points). We also conducted a 1-year follow-up. RESULTS: We included 449 patients, with a mean age of 85.2(5.2) years. The nutritional risk was null for 70(15.6%) patients, low for 206 45.9%), moderate for 152(33.8%) and high for 21(4.7%). At the end of one year, 177(39.4%) patients had died. The score on the CONUT index was higher for the deceased patients (4.6 vs. 3.6, p<0.001). The CONUT score (HR, 1.076; 95%CI 1.009-1.148; p=0.025), the Charlson index (HR, 1.080; 95%CI 1.017-1.148; p=0.013) and the presence of pressure ulcers (HR, 1.700; 95%CI 1.028-2.810; p=0.039) were independently associated with increased mortality at one year of follow-up. The prescription of oral anticoagulants at discharge was associated with lower mortality (HR, 0.440; 95%CI 0.304-0.638; p<0.001). CONCLUSIONS: More than a third of elderly patients hospitalized with NVAF have a moderate to high nutritional risk. These patients have greater mortality at the end of one year.

Sarcopenia, frailty, cognitive impairment and mortality in elderly patients with non-valvular atrial fibrillation. / Sarcopenia, fragilidad, deterioro cognitivo y mortalidad en pacientes ancianos con fibrilación auricular no valvular.

OBJECTIVES: To determine the prevalence of sarcopenia, frailty and cognitive impairment in elderly patients with nonvalvular atrial fibrillation (NVAF) and the factors' influence on survival. METHODS: Prospective, multicentre cohort study of patients older than 75 years with NVAF hospitalised in internal medicine departments in Spain. For each patient, we recorded the creatinine, haemoglobin and platelet levels, the scores on the CHA2DS2-VASc and HAS-BLED scales and Charlson index, as well as the use of oral anticoagulants. We measured sarcopenia with the SARC-F scale, frailty with the FRAIL scale and cognitive impairment with the Short Portable Mental State Questionnaire. We also conducted a 1-year follow-up. RESULTS: The study included 596 patients with NVAF, with a mean age of 84.9 (SD: 5.2) years. Of these, 295 (49.5%) presented sarcopenia, 305 (51.2%) presented frailty, and 251 (42.1%) presented cognitive impairment. At the end of 1year, 226 (37.9%) patients had died. Mortality was greater for the patients with sarcopenia, frailty and cognitive impairment. In the multivariate analysis, sarcopenia (HR: 1.775; 95%CI: 1.270-2.481), age, comorbidity and a history of peripheral embolism were associated with increased mortality, and the use of oral anticoagulants at discharge (HR: 0.415; 95%CI: 0.307-0.560) was associated with lower mortality. CONCLUSIONS: Sarcopenia, frailty and cognitive impairment are very common in elderly patients with NVAF and are frequently associated. Sarcopenia was associated with increased mortality.

Baseline functional status as the strongest predictor of in-hospital mortality in elderly patients with non-valvular atrial fibrillation: Results of the NONAVASC registry.

OBJECTIVES: Atrial fibrillation (AF) has been associated with higher mortality. We aimed to identify the baseline predictors of in-hospital mortality among elderly patients with non-valvular AF (NVAF) hospitalised for any reason. METHODS: Observational, prospective and multicentre study was carried out on patients with NVAF over the age of 75, who had been admitted for any acute medical condition to Internal Medicine departments in Spain. RESULTS: We evaluated 804 patients with a mean age of 85±5.1years, of which 53.9% were females. During the hospitalization 10.1% (n=81) of the patients died. The patients who died were older, had a greater percentage of institutionalization, worse previous basic functional status (Barthel Index), worse cognitive performance at admission and greater proportion of frailty and sarcopenia. Logistic regression multivariate analysis identified that the strongest determinants of in-hospital mortality were the baseline functional status (Barthel Index) (OR for total dependency 4.73, 95% CI 2.32-9.63), and admissions for stroke (OR 3.55, 95% CI 1.41-8.90) and acute renal failure (OR 1.93, 95% CI 1.12-3.32). CONCLUSION: The overall in-hospital mortality of elderly patients with NVFA is high. Among all factors evaluated in the global geriatric assessment the baseline functional status was the strongest predictor for in-hospital mortality on this population.

Degree and distribution of variability in the 5' untranslated, E1, E2/NS1 and NS5 regions of the hepatitis C virus (HCV).

Hepatitis C virus (HCV) shows a high degree of variability resulting in many different variants. In this work we described the variability of several subgenomic fragments from the 5' untranslated region (5'-UTR) and E1, E2/NS1 and NS5 regions comparing, for every position, all the sequences published in GenBank v. 88 (July 1995) as well as new sequences obtained in this work. Variability was determined in two ways. First, we analysed the degree and type of substitutions found in these regions. Second, we defined the most variable and conserved segments in each region and compared our prediction with previous studies. Our results confirm that HCV variability changes along the different regions. Although we found four variable domains in the 5'-UTR, this region was the only one to contain conserved domains. Envelope (E1, E2/NS1) and NS5 regions showed high variability throughout; however, we were able to define six and three hypervariable domains, respectively. The degree and distribution of variability established in this work is supported by the high number of sequences and the different types included in the study. Knowledge of how variability is distributed along the different regions of the HCV genome could be of use in the design of new diagnostic and therapeutic strategies against HCV infection.

Hypodiploidy and 22q11 rearrangements at diagnosis are associated with poor prognosis in patients with multiple myeloma.

Our aim was to evaluate the clinical use of cytogenetic analysis as a prognostic factor in the outcome of newly diagnosed multiple myeloma (MM) patients. The present series includes 111 newly diagnosed MM patients treated with one of three standard-dose regimens or autologous transplantation over an 8-year time interval. As expected, the presence of an abnormal karyotype (39% of patients) correlated with poor prognosis (progression rate 63% v 47%, P = 0.042), shorter event-free (EFS, P = 0.014) and overall (OS, P = 0.005) survival. Two distinct cytogenetic abnormalities were the most significant variables that influenced EFS and OS in the univariate analysis. The presence of hypodiploid karyotypes or rearrangements of band 22q11 were associated with higher progression rate (P = 0.001) and shorter EFS (P < 0.024) and OS (P < 0.004). The median EFS and OS for patients with hypodiploidy was 4 and 7 months respectively. Multivariate analysis showed that absence of hypodiploidy was the most favourable prognostic variable for OS (P = 0.022) followed by stage < or = IIA, serum calcium < or = 2875 micromol/l, and absence of abnormalities 22q. The data suggest that the presence of hypodiploid karyotypes and rearrangements on 22q11 band show a higher progression rate and shorter survival in MM patients.

Cytogenetic analysis of 280 patients with multiple myeloma and related disorders: primary breakpoints and clinical correlations.

Cytogenetic analysis of unstimulated short-term bone marrow cell cultures was performed on 280 patients with multiple myeloma and related disorders. In 65% of the cases, an additional short term B-cell stimulated culture was also examined. Chromosomally abnormal clones were found in 31% of the patients, 15% in Waldenström macroglobulinemia. 25% in monoclonal gammopathies, 33% in multiple myeloma, and 50% in plasma cell leukemia. Three primary chromosomal breakpoints were recurrently involved: 14q32, 16q22, and 22q11. Structural rearrangements of chromosome 1 were the most frequent (26% of the abnormal cases), but always as a secondary change. Rearrangements of band 14q32 were found in 22% of the abnormal cases. Among the multiple myeloma patients who showed an abnormal karyotype, 33 (46%) were hyperdiploid, most frequently, with 52-56 chromosomes, 29 patients (40%) were pseudodiploid, and the remaining 12 cases (14%) were hypodiploid. A highly significant relation was observed between the presence of an abnormal karyotype and the following clinical parameters: stage III (P = 0.0001), bone marrow plasma cell infiltration greater than 30% (P = 0.0001), presence of bone lesions (P = 0.0009), and beta 2-microglobulin levels greater than 4 mg/L (P = 0.0001).

Double-barreled wet colostomy: a safe and simple method after pelvic exenteration.

UNLABELLED: The clinical and functional outcome of ureteric division to the distal segment of a loop colostomy: the double-barrelled wet colostomy have been analysed. METHODS: 13 patients (8 female and 5 male, age 37 to 72 years) underwent pelvic exenteration with double-barrelled wet colostomy. The primary tumour included endometrial (n = 6), rectal (n = 1), anal (n = 1), cervical (n = 2), prostatic (n = 1) and bladder (n = 2). Indications for pelvic exenteration were locally advanced disease, recurrence and severe radiation or surgical damage. Six patients had pre-existing colostomy, and three had a Bricker ureteroileal diversion. The double-barrelled-wet colostomy technique consisted in anastomosing both ureters to a colon segment 25 cm distal to the loop colostomy. There was no operative mortality. Complications included one urinary leak which closed with conservative management and one case of recurrent episodes of pyelonephritis which finally required nephrectomy. Intravenous urography in the remaining patients showed good flow through the ureters to the conduit with no reflux. Postoperative plasma electrolytes, urea and creatinine were normal from day seven onwards. Urodynamic studies in four patients showed efficient contraction of the colon conduit with pressure levels similar to those in the colon proximal to the colostomy. In five cases biopsies of the conduit were taken at 3 and 16 months; no dysplasias were found. Four patients died due to disease progression. The overall mean survival was 41.2 months. The remainder are currently disease-free, maximum followup period being 19 months. Double-barrelled wet colostomy is a safe and simple technique with low morbidity. The patient needs to carry only one stoma and functional results are good.

Further insights on the inhibition of HIV type 1 infection in vitro by CD4-modified synthetic peptides containing phenylalanine.

Phenylalanine-containing peptides from CD4 were synthesized on the basis of chemical similarity with active CD4(81-92)-benzylated peptides. Systematic replacement of amino acids of these peptides bearing the benzyl group by phenylalanine, afforded several peptides that were able to block the binding of gp120 to CD4 and to inhibit HIV-induced syncytium formation. These experiments showed that substitution of residues 81 and 85 by phenylalanine was the most important for activity. Following optimization of the length of phenylalanine-substituted peptides it was found that FYICFVED and FYICFVEDE were the most active. Their IC50 for the inhibition of syncytium formation was around 1.2-1.6 microM. This activity is at least 30 times higher than that of the parent peptide FYIFFVEDQKEEDD previously reported (Lasarte et al., J Acquir Immune Defic Syndr 1994;7:129-134). Binding competition experiments with two different anti-peptide antisera recognizing the V3 region of gp120 and FYICFVEDE, show that the active peptides bind to V3 or to a sterically near region of V3. None of the active peptides was toxic to cells in vitro. The enhanced activity and simplicity of these new phenylalanine-substituted CD4 peptides might be a good starting point for the development of mimotopes of potential use for the treatment of AIDS.

A recurrent translocation, t(3;11)(q21;q13), found in two distinct cases of acute myeloid leukemia.

We report two cases of acute myeloid leukemia (M1 and M5B subtypes) with a similar translocation, t(3;11)(q21;q13). We discuss the involvement of these breakpoints in acute leukemia and their putative clinical implications.

A variant t(14;17) in acute promyelocytic leukemia. Positive response to retinoic acid treatment.

We present a case of acute promyelocytic leukemia (APL) carrying an atypical translocation involving chromosomes 14 and 17. This translocation could be considered a variant of the APL-specific t(15;17). Positive response to retinoic acid treatment suggests molecular rearrangement of retinoic acid receptor alpha.

The GCGGAA gene-regulatory motif of herpes simplex virus type-1 is also found in hepatitis C virus.

We have analyzed the sequence of the 5'-untranslated region of hepatitis C virus from 24 patients with chronic hepatitis C and we found a conserved six-nucleotide motif previously described as a modulator of gene expression.

Cytogenetic data in 41 patients with multiple myeloma. Karyotype and other clinical parameters.

Cytogenetic data of 41 patients diagnosed with multiple myeloma (MM) are reported. In all samples, cytogenetic studies were made of short-term and B-cell-stimulated culture: 20 cases (48.8%) showed chromosome abnormalities; 14 karyotypes were hypo- or pseudodiploid, and six were hyperdiploid. The most frequent numerical changes affected chromosomes 7, 11, 5 (gains), 14, 20, and Y (losses). Chromosome structural rearrangements of 22q were noted in six patients. Other and recurrent cytogenetic abnormalities were changes involving chromosomes 1, 14, and 17. A significant relation was observed between presence of chromosome abnormalities and the following hematologic parameters: clinical stage III (p = 0.0212), bone marrow (BM) plasma cell infiltration greater than 30% (p = 0.0379), presence of bone lesions (p = 0.0051), and beta 2-microglobulin levels greater than 4,000 md/dl (p = 0.0194).

Clastogenicity of triazinoindole derivatives in relation with the physicochemical properties of the substituents.

The clastogenicity of four compounds of the series 3-(4'-substituted-benzylidenamino)5H-1,2,3-triazin [5,4-b]indol-4-one, which showed an important activity as inhibitors of platelet aggregation, has been evaluated. The compounds studied differed in the physicochemical properties of the substituent occupying the 4' position of the benzilidenamino group. The 4' substituents were: -H, -NO2, -OCH3 and -C6H5. They were tested on V-79 cells, both with and without metabolic activation, and structural chromosome aberrations were scored. Compounds with -H, -NO2 and -OCH3 radicals were active both with and without metabolic activation. Compound with -C6H5 radical was clastogenic only at the highest dose tested and with metabolic activation. It appears that the compound with the biggest and most hydrophobic substituent is the least clastogenic of the series. These results are in agreement with some previous ones obtained in bacteria and show a good correlation between the results of the Ames test and the structural chromosome aberrations test.

Induction of neutralizing antibodies against human immunodeficiency virus type 1 using synthetic peptide constructs containing an immunodominant T-helper cell determinant from vpr.

Identification of immunodominant T-helper-cell determinants after natural infection is an important step in the design of immunogens for potential use in vaccination. Using cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals and a panel of peptides encompassing the sequence of the regulatory protein vpr from HIV-1, we identified the T-helper determinant QLLFIHFRIGCRHSR, which is active in 37.5% of these individuals. To gain insight on the efficacy of this peptide in helping induce neutralizing antibodies against a B-cell determinant (BD), we synthesized constructs containing B- and T-cell determinants and tested them in BALB/c mice, the highest responders to the T-cell determinant moiety among several strains tested. These immunogens induced antibodies against two chosen B-cell determinants from HIV-1IIIB gp160 (amino acids 310-322 from the V3 loop of gp120 and 736-751 from gp41) that were able to neutralize HIV-1 infection in vitro. The highest neutralization titer against HIV-1IIIB was obtained by immunization with the homopolymer of the construct containing the T-cell epitope from vpr and the B-cell epitope from the V3 loop. We believe that the immunodominant T-cell determinant from vpr is a promising epitope to consider in the design of future peptide vaccines.

Complex karyotype including 14q+ marker in a case of Waldenström's macroglobulinemia.

We describe a case of Waldenström's macroglobulinemia with a complex karyotype including a 14q+ marker. Secondary changes affected chromosomes 2, 4, 6, 7, 8, and 17. The cytogenetic significance of the changes and their prognostic value, as compared with those described in previous reports, are discussed.

Evaluation of the mutagenicity of 1-hydrazino-4-(3,5-dimethyl-1-pyrazolyl) pyridazino[4,5-b]indole.

The mutagenic potential of 1-hydrazino-4-(3,5-dimethyl-1-pyrazolyl) pyridazino [4,5-b]indole(A80a, CAS 135561-93-2), a new antihypertensive agent, was investigated in 3 test systems, according to the current EC Guidelines: Ames test with strains TA1535, TA1537, TA98 and TA100, SCE (sister chromatid exchange) test in V79 cells and micronucleus test in Swiss mice. No indications for a mutagenic potential were detected in bacteria and mice; positive results were obtained in eukaryotic cells. The potential for inducing chromosome aberrations in eukaryotic cells will be studied.

CD4-modified synthetic peptides containing phenylalanine inhibit HIV-1 infection in vitro.

Phenylalanine-containing peptides from CD4 were synthesized based on chemical similarity with active CD4(81-92)-benzylated peptides. The synthetic peptide FYIFFVEDQKEEDD blocked the binding of gp120 to CD4 and inhibited 50% human immunodeficiency virus (HIV)-induced syncytia formation at a concentration (IC50) of approximately 40-50 microM and HIV p17 expression with an IC50 of approximately 67 microM. The peptide is not toxic to cells in vitro. Moreover, acute toxicity studies carried out in Swiss mice showed the peptide to be nontoxic at a dose of 2,000 mg/kg. This phenylalanine-substituted CD4 peptide may prove to be useful in the treatment of AIDS.