Simeprevir with peginterferon/ribavirin for treatment of chronic hepatitis C virus genotype 1 infection: pooled safety analysis from Phase IIb and III studies.

This pooled analysis of five Phase IIb and III studies evaluated the safety and tolerability of simeprevir, a once daily, oral hepatitis C virus (HCV) NS3/4A protease inhibitor. Data were summarised for patients who received simeprevir 150 mg once daily (n = 924) or placebo (n = 540) plus pegylated interferon-α/ribavirin for 12 weeks. During the first 12 weeks of treatment, few patients discontinued simeprevir or placebo due to adverse events (AEs) (both 2.2%). Pruritus (23.8% vs 17.4%), rash (any; 22.9% vs 16.7%) and photosensitivity (3.2% vs 0.6%) [Correction added on 16 January 2015, after first online publication: In the above sentence, the values in 'Photosensitivity' were previously incorrect and have now been changed to 3.2% vs 0.6%.] were more prevalent in the simeprevir vs the placebo groups. Most AEs were grade 1/2 (72.4% for simeprevir vs 71.3% for placebo). All grade 3/4 AEs occurred in <5.0% of patients, except neutropenia (9.8% vs 7.6%). Overall incidence of neutropenia was similar (17.3% vs 15.7%). Incidence of anaemia was 13.2% for simeprevir vs 10.9% for placebo, and incidence of increased bilirubin was 8.4% vs 2.8%. Bilirubin increases were mild-to-moderate and transient without concurrent transaminase increases or association with hepatic injury. Safety and tolerability did not vary with METAVIR score, although increased bilirubin and anaemia were more frequent in simeprevir-treated patients with METAVIR F4 (increased bilirubin, 13.0% vs 3.3%; anaemia, 19.0% vs 14.8%). Serious AEs were infrequent (2.1% for simeprevir vs 3.0% for placebo). No deaths were reported during the first 12 weeks of treatment. Patient-reported fatigue and other outcomes were comparable for both groups, but were of shorter duration for simeprevir due to the use of response-guided therapy. Simeprevir is well tolerated in HCV genotype 1-infected patients.

Outcome of HCV/HIV-coinfected liver transplant recipients: a prospective and multicenter cohort study.

Eighty-four HCV/HIV-coinfected and 252-matched HCV-monoinfected liver transplant recipients were included in a prospective multicenter study. Thirty-six (43%) HCV/HIV-coinfected and 75 (30%) HCV-monoinfected patients died, with a survival rate at 5 years of 54% (95% CI, 42-64) and 71% (95% CI, 66 to 77; p = 0.008), respectively. When both groups were considered together, HIV infection was an independent predictor of mortality (HR, 2.202; 95% CI, 1.420-3.413 [p < 0.001]). Multivariate analysis of only the HCV/HIV-coinfected recipients, revealed HCV genotype 1 (HR, 2.98; 95% CI, 1.32-6.76), donor risk index (HR, 9.48; 95% CI, 2.75-32.73) and negative plasma HCV RNA (HR, 0.14; 95% CI, 0.03-0.62) to be associated with mortality. When this analysis was restricted to pretransplant variables, we identified three independent factors (HCV genotype 1, pretransplant MELD score and centers with <1 liver transplantation/year in HIV-infected patients) that allowed us to identify a subset of 60 (71%) patients with a similar 5-year prognosis (69%[95% CI, 54-80]) to that of HCV-monoinfected recipients. In conclusion, 5-year survival in HCV/HIV-coinfected liver recipients was lower than in HCV-monoinfected recipients, although an important subset with a favorable prognosis was identified in the former.

Continuously evaluating performance in deceased donation: the Spanish quality assurance program.

The Spanish Quality Assurance Program applied to the process of donation after brain death entails an internal stage consisting of a continuous clinical chart review of deaths in critical care units (CCUs) performed by transplant coordinators and periodical external audits to selected centers. This paper describes the methodology and provides the most relevant results of this program, with information analyzed from 206,345 CCU deaths. According to the internal audit, 2.3% of hospital deaths and 12.4% of CCU deaths in Spain yield potential donors (clinical criteria consistent with brain death). Out of the potential donors, 54.6% become actual donors, 26% are lost due to medical unsuitability, 13.3% due to refusals to donation, 3.1% due to maintenance problems and 3% due to other reasons. Although the national pool of potential donors after brain death has progressively decreased from 65.2 per million population (pmp) in 2001 to 49 pmp in 2010, the number of actual donors after brain death has remained at about 30 pmp. External audits reveal that the number of actual donors could be 21.6% higher if all potential donors were identified and preventable losses avoided. We encourage other countries to develop similar comprehensive approaches to deceased donation performance.

Benchmarking in the process of donation after brain death: a methodology to identify best performer hospitals.

A benchmarking approach was developed in Spain to identify and spread critical success factors in the process of donation after brain death. This paper describes the methodology to identify the best performer hospitals in the period 2003-2007 with 106 hospitals throughout the country participating in the project. The process of donation after brain death was structured into three phases: referral of possible donors after brain death (DBD) to critical care units (CCUs) from outside units, management of possible DBDs within the CCUs and obtaining consent for organ donation. Indicators to assess performance in each phase were constructed and the factors influencing these indicators were studied to ensure that comparable groups of hospitals could be established. Availability of neurosurgery and CCU resources had a positive impact on the referral of possible DBDs to CCUs and those hospitals with fewer annual potential DBDs more frequently achieved 100% consent rates. Hospitals were grouped into each subprocess according to influencing factors. Hospitals with the best results were identified for each phase and hospital group. The subsequent study of their practices will lead to the identification of critical factors for success, which implemented in an adapted way should fortunately lead to increasing organ availability.

[Microbiological profile of infections in the Intensive Care Units of Colombia (EPISEPSIS Colombia]. / Perfil microbiológico de la Infecciones en Unidades de Cuidados Intensivos de Colombia (EPISEPSIS Colombia).

BACKGROUND AND OBJECTIVE: Valid and reliable data regarding sepsis is lacking in Colombia. Our aim was to determine the prevalence of the microorganisms in the main infections treated in Intensive Care Units (ICUs) in our country. METHODS: This is a sub-study of a prospective cohort with 10 general hospitals in Colombia during a 6-month period. The inclusion criteria were hospitalization in ICU and confirmation of infection according to the CDC definitions. Patients were classified into three groups, that is, community, hospital and intensive care, according to the site where the infection was acquired. RESULTS: A total of 826 patients were included in this analysis. Of these, 51% developed infections in the community, 5.33% in the hospital and 43.7% in intensive care unit. Overall, the most common diagnoses were pneumonia (29.54%), intra-abdominal infection (18.16%) and urinary tract infection (11.62%). The most frequent germ in community-acquired infections was E. coli -lung (16. 4%), peritoneum (57.7%), urine (55.5%), blood (22.4%)-. E. coli -peritoneum (29.3%), urine (52.9%)- also predominated in the ICU-acquired infections, except for lung and blood in which Staphylococcus aureus (32.4%) and Klebsiella pneumoniae (15.7%) were the most prevalent. Cultures were requested from 655 patients, 40% of them having received antibiotics before cultures were taken, although this did not affected the percentages of positive cultures (P=0.583). CONCLUSIONS: Pneumonia was the main cause of infection regardless of the site of acquisition. E. coli was the most prevalent germ, except in the pulmonary infections acquired in UCI in which S. aureus was the most prevalent.

SED-brachydactyly and distinctive speech: report of two new cases.

We describe two unrelated patients and the mother of one of them showing clinical and radiological features as those previously described in the spondyloepiphyseal dysplasia-brachydactyly and distinctive speech (SED-BDS, also named Fantasy Island syndrome or Tattoo dysplasia) clinically characterized by short stature with acral shortness, distinctive face, mild blepharophimosis, upslanted palpebral fissures, abundant eyebrows and eyelashes, thick and abundant hair and coarse voice; and radiologically by brachymetacarpalia, brachymetatarsalia and brachyphalangia of all fingers and toes, short and broad long bones with normal morphology and small pelvis. The clinical and radiological features present in mother and son suggest a probable autosomal dominant mode of inheritance and variable expressivity.

[Cervical cancer and DNA microarrays: tumour marker identification]. / Microarreglos de ADN y cáncer cervicouterino: identificación de marcadores tumorales.

Microarray technology has remarkably accelerated the understanding of the molecular events of neoplasias. By means of gene expression profiles, a molecular subclassification of cancer patients and the identification of thousand of genes involved in this pathology have been achieved. Herein, the general use of DNA microarrays in cervical cancer tumorigenesis is reviewed. Finally, putative molecular tumour markers as useful factors in diagnosis, prognosis, and tailor-made therapy for this disease are proposed.

[Liver and intestinal transplant in paediatric population]. / El trasplante hepático e intestinal en la población pediátrica.

Our organizational model allows an annual 1,000 liver transplants. Pediatric liver transplantation constitutes 5% of such activity and provides, in children with severe, progressive and irreversible liver disease, a 1 year-survival of 90% and more than 80% after 15 years of follow-up. The main indication is biliary atresia followed by metabolic liver disease and acute liver failure. Around half of the procedures are performed in children under two years and 25-30% in the first year of life. The waiting list remains at around 35 patients, with an average of 100 patients enrolled annually and 60 of them finally transplanted after an average of 136.3 days on the waiting list. The prioritization of the candidates uses the PELD as an objective tool for decision-making. However, the progressive aging of donors, with a profile increasingly different from the requirements of the pediatric patients included in the waiting list, requires strategies such as living donor liver transplantation and the split liver transplantation, to increase the probability of transplant while reducing both time and mortality on the waiting list at the same time. Pediatric intestinal transplantation registers a low indication but involves strict requirements that outline a very uncommon donor in our country which, together with the absence of alternatives that outweigh the impact of these difficulties, penalizes the chances of transplant for these patients.

The genetic structure of Mexican Mestizos of different locations: tracking back their origins through MHC genes, blood group systems, and microsatellites.

Mexican Mestizos, who are the result of the admixture of Spanish, Indian, and Black genes, were analyzed for different systems. Three populations from geographical distinct areas were studied: the north (State of Nuevo Leon ), the center (State of Guanajuato), and the highlands (mainly Mexico City). Ten blood group systems (N = 229), STRs (N = 107), HLA-A*, B*, C* (N = 116-167), and DRB1, DQA1, and DQB1 (N = 40, 101, 160, respectively) were analyzed in the samples of the highlands. The three groups cluster together in the same branch: Mestizos from Venezuela, Mediterranean and Jews close to the cluster of Orientals, followed by Amerindians. All markers demonstrate that Indian genes are strongly represented in the highlands: Di(a), O, D(-)(+), s, A*0201, *0206, B*1539 (*1541), *3902, *3905, *3512, *3517, *4002, *4005, Cw*0801, *0304, *0401 among others. Cw*0501, *1203, *1204, and *1601 are of White ancestry. The most frequent haplotypes *0407-*03011-*0302 and *0802-*0401-*0402 are of Indian descent as well. The center and mainly the north show a more Caucasian and Semitic profile. The results demonstrate the high variability resulting from interethnic admixture, suggesting that this mechanism is the main factor responsible for the large diversity found in urban populations.

Relevant residues of DRbeta1 third hypervariable region contributing to the expression and to severity of rheumatoid arthritis (RA) in Mexicans.

Rheumatoid arthritis (RA) is a chronic autoimmune disease leading to destruction of the joints. Residues at positions 67-74 of the DRB1 third hypervariable region are involved in susceptibility (S) and resistance (P) to RA. DNA from 83 patients and 175 controls, all of them Mexican Mestizos were oligotyped using PCR-SSOP and PCR-SSP. The (S) alleles are DRB*0404 (p = 0.000004), *0401 (p = 0.007) and *1001 (p = 0.008). Those associated with P are DRB1*0701 (p = 0.0001); *1101 (p = 0.01); *1503 (p = 0.02); *0801 (p = 0.04); *1401 (p = 0.04). Susceptibility/protection are recessive traits; SS genotypes are increased in the patients (p = 0.0003) while PP genotypes are decreased in them (p = 0.00004). The motif at 67-74 and the valine or glycine at position 86 are relevant in the development and severity of RA in Mexicans. The associations suggest that residues 67, 70, 71 are central for susceptibility. The P alleles have D-70 or carry V-86 in the absence of D-70. Thus, susceptibility/protection depends on the combination of basic residues at these positions and a non-polar aa at 86 contributes to resistance. Severity is also HLA influenced. DQA1*03011-DQB1*0302 are associated to severe lesions in the presence of any DR4 subtype. Analyzing different ethnic groups is essential to elucidate the etiopathogenesis of RA.

Mycobacterium tuberculosis at a comprehensive cancer centre: active disease in patients with underlying malignancy during 1990-2000.

Thirty HIV-seronegative cancer patients with active tuberculosis were evaluated. Eighteen (60%) were immigrants, 19 (63%) had haematological malignancy, and fever was the most common presentation (97%). Of 19 (63%) patients with pulmonary tuberculosis, 11 (58%) were misdiagnosed initially as suffering from cancer following radiography. Death was attributed to tuberculosis for six (21%) of 29 patients who received anti-mycobacterial therapy. All four patients who had received high-dose systemic corticosteroids within 4 weeks of diagnosis of infection died, whereas two (8%) deaths occurred in 25 individuals without corticosteroid exposure (p < 0.001; OR 8.67). At this institution, active tuberculosis was rare, and was seen mostly in immigrants. Recent high-dose corticosteroid therapy is a significant predictor of mortality in cancer patients with tuberculosis.

AIDS knowledge and sexual behavior among Mexican gay and bisexual men.

Little knowledge exists about AIDS and Human Immunodeficiency Virus (HIV) infection among Latin American gay males. In Latin America, sexual transmission from man to man is the leading cause of HIV infection. In Mexico, which ranks third in number of AIDS cases in the Americas, more than three-quarters of the cases are due to sexual transmission; among these cases, 35% and 23.7% are due to homosexual and bisexual male practices, respectively. A sample of 200 individuals from Juarez, Mexico, a city on the U.S. border, was interviewed. Information about their AIDS knowledge, sexual behavior, and condom use was obtained. Factory workers and individuals who meet sexual partners in the streets reported more sexual partners than workers in service or professional occupations and those who meet their partners in bars and discos. Number of sexual partners and respondents' age were inversely associated with condom use. Implications for HIV prevention are discussed.

PIP: Two hundred gay and bisexual men of mean age 26.4 years from Juarez, Mexico, were interviewed by the Mexican Federation of PRivate Associations for Community Development (FEMAP) about their AIDS knowledge, sexual behavior, and condom use. 88% were single and never married. 66% self-identified as being gay, 29% as bisexual, and 2% as transvestites; 10% reported having sex for money. 14% had had at least one sexually transmitted disease and 57% were negative about condom use. Having an average 4.46 sex partner/month, most respondents were knowledgeable about HIV transmission routes, AIDS symptoms, and HIV antibody tests. 75% and 77.5%, respectively, reported practicing receptive anal intercourse and insertive anal intercourse. They used condoms an average of 6.47 times in their most recent ten sexual encounters. By profession and social behavior, factory workers and individuals who recruit sex partners from the street reported having more sex partners than service and professional workers and those who meet their partners in bars and discos. Further, the number of sex partners and respondents' age were inversely associated with condom use. These findings clearly highlight the failure of knowledge about HIV to bring about change in sexual behavior among certain subpopulations in the study area. Since homosexuality remains unaccepted in Mexican society, the author suggests targeted peer education and small-group session prevention efforts which do not confront mainstream social structure and values.

An HIV/AIDS prevention project for Mexican homosexual men: an empowerment approach.

In this intervention, participants design and implement an HIV/AIDS prevention project for Mexican homosexual men. The intervention is consistent with, and contributes to, empowerment theory because it enhances collective action, provides opportunities to develop knowledge and skills, creates needed resources, and includes shared control with professional and among participants. The intervention described provides an illustration of an empowering process and distinguishes itself from empowerment outcomes. An evaluation of the project is also described, but the outcomes were HIV/AIDS-related behaviors rather than psychological empowerment of the participants. The results suggest that the participants' HIV/AIDS knowledge and preventive behavior improved when compared to individuals who did not participate in the intervention. In addition, the intervention generated community change initiated by participants. Implications for designing interventions using an empowerment approach are discussed.

Chemistry and nanoparticulate compositions of a 10,000 year-old ice core melt water.

Particulates extracted from a single section of a 10,000 year-old ice core melt sample exhibited characteristics of contemporary, airborne fine particulates: a majority were microcrystalline particulates and aggregated microcrystals, including some mixtures of microcrystals and carbonaceous matter. Particularly significant were the presence of carbon nanotubes and fullerene nanocrystals composing aggregated particulates reflecting global combustion products similar to contemporary, airborne carbon nanocrystal aggregates. ICP elemental analysis of the melt water showed significant concentrations of Ca, K and especially Na (corresponding to K, NaCl), S, Si, Se, and Zn. Overall, the elemental analysis of the melt water is similar to local tap water. However, lead was absent in the local tap water and only half the concentration of selenium was present in the tap water in contrast to the ice core water. While these observations cannot be generalized, the methodology illustrates the potential to characterize and compare airborne particulate regimes and water chemistries in antiquity.

Use of silica-immobilized humin for heavy metal removal from aqueous solution under flow conditions.

Humin extracted from Sphagnum peat moss was immobilized in a silica matrix and column experiments were performed in order to evaluate the removal and recovery of metal ions from aqueous solution under flow conditions. These experiments also allowed testing the recycling capacity of the column. Single-element solutions of Cu(II) and Pb(II), and a multi-metal solution containing Cd(II), Cu(II), Pb(II), Ni(II), and Cr(III) were passed through the columns at a flow rate of 2 ml/min. A 0.5 M sodium citrate solution was used as the stripping agent in the metal-ion recovery process. Humin immobilized in the silica matrix exhibited a similar, and in some cases, even a higher capacity than other biosorbents for the removal of metal ions from aqueous solutions under flow conditions. The sodium citrate was effective in removing Cu(II), Pb(II), Cd(II), and Ni(II) from the metal saturated column. The selectivity of the immobilized biomass was as follows: Cr(III)>Pb(II)>Cu(II)>Cd(II)>Ni(II). This investigation provides a new, environmentally friendly and cost-effective possibility to clean up heavy-metal contaminated wastewaters by using the new silica-immobilized humin material.

Bioaccumulation of cadmium, chromium and copper by Convolvulus arvensis L.: impact on plant growth and uptake of nutritional elements.

The remediation of heavy metal-contaminated sites using plants presents a promising alternative to current methodologies. In this study, the potential accumulation of Convolvulus arvensis L. for Cd(II), Cr(VI), and Cu(II) was determined using an agar-based medium. The shoots of C. arvensis plants exposed to 20 mgl(-1) of these heavy metals, demonstrated capability to accumulate more than 3800 mg of Cr, 1500 mg of Cd, and 560 mg of Cu per kg of dry tissue. The outcome of this study and the field data previously reported corroborate that C. arvensis is a suitable candidate for the phytoremediation of Cd(II), Cr(VI), and Cu(II) contaminated soils. Furthermore, the concentration of Cr determined in the dry leaf tissue (2100 mgkg(-1)) indicates that C. arvensis could be considered as a potential Cr-hyperaccumulator plant species.

Utilization of ICP/OES for the determination of trace metal binding to different humic fractions.

In this study, the use of inductively coupled plasma/optical emission spectrometry (ICP/OES) to determine multi-metal binding to three biomasses, Sphagnum peat moss, humin and humic acids is reported. All the investigations were performed under part per billion (ppb) concentrations. Batch pH profile experiments were performed using multi-metal solutions of Cd(II), Cu(II), Pb(II), Ni(II), Cr(III) and Cr(VI). The results showed that at pH 2 and 3, the metal affinity of the three biomasses exposed to the multi-metal solution that included Cr(III) presented the following order: Cu(II), Pb(II)>Ni(II)>Cr(III)>Cd(II). On the other hand, when Cr(VI) was in the heavy metal mixture, Sphagnum peat moss and humin showed the following affinity: Cu(II), Pb(II)>Ni(II)>Cr(VI)>Cd(II); however, the affinity of the humic acids was: Cu(II)>Pb(II), Cr(VI)>Ni(II)>Cd(II). The results demonstrated that pH values of 4 and 5 were the most favorable for the heavy metal binding process. At pH 5, all the metals, except for Cr(VI), were bound between 90 and 100% to the three biomasses. However, the binding capacity of humic acids decreased at pH 6 in the presence of Cr(VI). The results showed that the ICP/OES permits the determination of heavy metal binding to organic matter at ppb concentration. These results will be very useful in understanding the role of humic substances in the fate and transport of heavy metals, and thus could provide information to develop new methodologies for the removal of low concentrations of toxic heavy metals from contaminated waters.

How do the newer oral antimicrobials stack up against traditional agents?

As the antibiotic arsenal expands with the development of new oral agents, selecting appropriate therapy is becoming more difficult. What are the therapeutic indications for the newer antimicrobials, and what advantages do they have over traditional agents? Drs Gleckman and De La Rosa discuss current issues related to antibiotic treatment and offer specific recommendations for the best use of the newer agents.

[Congenital adrenal hyperplasia. Presentation of a case and review of the literature]. / Hiperplasia suprarrenal congénita. Presentación de un caso y revisión de la literatura.

Steroid 11 beta-hydroxylase deficiency is an autosomal recessive hereditary defect and one of the causes of congenital adrenal hyperplasia. Prenatal exposure to excess androgens results in virilization of the female fetus. Newborn males have normal genitalia. Postnatally, untreated females as well as males present with signs of androgen excess. Three forths of classic 21-hydroxylase deficiency cases do not effectively synthesize aldosterone and are salt-wasting, a condition that is potentially fatal. With carefully supervised medical treatment, congenital adrenal hyperplasia patients have the capacity for normal puberty and fertility.

[High- and low-risk molecular sequences in autoimmune diseases. An analysis of type I diabetes in Latin America]. / Secuencias moleculares de alto y bajo riesgo en enfermedades autoinmunes. Un análisis de la diabetes tipo I en Latinoamérica.

Type I diabetes is an autoimmune and a polygenic disease, in which MHC-class II genes contribute to 48% of the disease. The aim of the present study, is to provide a guideline to understanding the molecular association of these genes, through the immunogenetic analysis of 3 Latin american mestizo populations. We included 606 individuals, 349 patients with DMDI and 257 healthy controls coming from 3 geographical areas: Mexico City, Mexico; Caracas, Venezuela and Medellin, Colombia. The results clearly indicate that in mestizo groups, the diabetogenic haplotypes are from mediterranean ancestry, while protection is due to Amerindian genes. It was demonstrated that the relevant sequences for IDDM expression are located to DRB1 and DQB1 loci with a minimal contribution of DQA1 residues. The sequences determining peptide recognition and the induction of TH1 cells mediating the cellular autoimmune response are in positions DRB1-57 and 74 (an aspartic acid and a glutamic acid respectively, confer protection), modulated by D-57 in the DQ, 8 chain. These data show that DRB1-DQB1 haplotypes are central for IDDM expression and open new pathways for the disease management.