2224 research outputs found
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Late Cytomegalovirus Infection in Kidney Transplant Recipients after a Six-Month Prevention Protocol
Get PDFBACKGROUND:
Despite a reduction in the incidence of cytomegalovirus (CMV) infections after kidney transplantation, less is known about late CMV infection in kidney transplant recipients.
OBJECTIVE:
To assess incidence of CMV infection in a cohort of patients under a high surveillance CMV prevention protocol and identify factors associated with late CMV infection.
METHODS:
Analysis of a consecutive cohort of 181 kidney allograft recipients between January 2012 and Aug 2015. CMV prevention-protocol consisted of 6-month universal prophylaxis and pre-emptive therapy for high-risk group (D+/R- or patients submitted to lymphocyte-depleting agent for induction or rejection treatment) and pre-emptive therapy for standard-risk group (D±/R+). Stopping valganciclovir was followed by CMV screening in the next two appointments.
RESULTS:
CMV infection was identified in 73 of 181 patients; the rate in high-risk group and standard-risk group was similar (p=0.443). However, in the latter group, the infection occurred mostly in the first 6 months. Late CMV infection occurred in 25 of 181 patients (5 of standard-risk group and 20 of high-risk group), after a median (IQR) of 253 (230.3-312.3) days after transplantation and 55 (41-89.5) days after the protocol period. Screening for CMV after valganciclovir discontinuation revealed 56% of late CMV infections. In high-risk group, D+/R- was associated with late CMV infection (HR 2.7, p=0.039) and in standard-risk group; lower age was associated with late CMV infection (HR 0.89, p=0.02).
CONCLUSION:
The incidence of CMV infection was similar to that reported in the literature. In high-risk patients, antigenemia surveillance during prophylaxis did not appear to reduce late CMV infections. Antigenemia screening after valganciclovir had limited results in the diagnosis of late CMV infection. D+/R- was associated to late CMV infection in high-risk group. Lower age appeared to influence late CMV infection in standard-risk group.info:eu-repo/semantics/publishedVersio
Mutational mechanism for DAB1 (ATTTC)n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution.
No full textDynamic mutations by microsatellite instability are the molecular basis of a growing number of neuromuscular and neurodegenerative diseases. Repetitive stretches in the human genome may drive pathogenicity, either by expansion above a given threshold, or by insertion of abnormal tracts in nonpathogenic polymorphic repetitive regions, as is the case in spinocerebellar ataxia type 37 (SCA37). We have recently established that this neurodegenerative disease is caused by an (ATTTC)n insertion within an (ATTTT)n in a noncoding region of DAB1. We now investigated the mutational mechanism that originated the (ATTTC)n insertion within an ancestral (ATTTT)n . Approximately 3% of nonpathogenic (ATTTT)n alleles are interspersed by AT-rich motifs, contrarily to mutant alleles that are composed of pure (ATTTT)n and (ATTTC)n stretches. Haplotype studies in unaffected chromosomes suggested that the primary mutational mechanism, leading to the (ATTTC)n insertion, was likely one or more T>C substitutions in an (ATTTT)n pure allele of approximately 200 repeats. Then, the (ATTTC)n expanded in size, originating a deleterious allele in DAB1 that leads to SCA37. This is likely the mutational mechanism in three similar (TTTCA)n insertions responsible for familial myoclonic epilepsy. Because (ATTTT)n tracts are frequent in the human genome, many loci could be at risk for this mutational process.info:eu-repo/semantics/publishedVersio
L-cysteine/hydrogen Sulfide Pathway Induces cGMP-dependent Relaxation of Corpus Cavernosum and Penile Arteries From Patients With Erectile Dysfunction and Improves Arterial Vasodilation Induced by PDE5 Inhibition
No full textThe aim was to evaluate and characterize H2S-induced relaxation of human corpus cavernosum (HCC) and penile resistance arteries (HPRA) from patients with erectile dysfunction (ED). HCC and HPRA were obtained from men with ED at the time of penile prosthesis insertion. H2S-mediated relaxations were evaluated by exposing these tissues to the stable analogue, NaHS, and to the precursor of H2S, L-cysteine (CYS). The effects of NaHS and CYS were also evaluated on cGMP accumulation in HCC and on acetylcholine- and sildenafil-mediated relaxations in HCC and HPRA. NaHS consistently relaxed HPRA and HCC and more potently than human prostate and bladder. NaHS-induced relaxations in HCC and HPRA were unaffected by the ATP-sensitive K+-channel blocker, glibenclamide or the NO synthase inhibitor, L-NAME, slightly reduced by the Ca2+-activated K+-channel blocker, tetraethylammonium, and markedly inhibited by the soluble guanylyl cyclase inhibitor, ODQ. NaHS caused a cGMP increase in HCC that was inhibited by ODQ. CYS produced relaxations of HCC and HPRA that were sensitive to ODQ and to inhibition of the H2S synthesizing enzymes, cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS). CYS also increased cGMP in HCC. In contrast to NaHS, CYS-induced relaxations were prevented by endothelium removal in HPRA. Only in HPRA, treatment with CYS (30 μM) potentiated acetylcholine- and sildenafil-induced relaxations. This effect was prevented by CSE/CBS inhibition and by removing the endothelium. Exogenous and endogenous H2S relaxes HCC and HPRA from ED patients through cGMP accumulation and potentiates vasodilatory capacity of PDE5 inhibition, supporting the therapeutic potential of modulating H2S pathway.info:eu-repo/semantics/publishedVersio
The Doctor, the Smoking Patient and the Challenge of Electronic Cigarettes
Get PDFApesar dos esforços e das medidas de prevenção e
controlo que vêm sendo adotadas desde a década de 80 do
século passado, o tabagismo continua a ser, em Portugal
e no mundo, um dos mais importantes fatores evitáveis de
doença crónica e de mortalidade prematura. 1
A carga da doença atribuível ao tabaco em Portugal foi
estimada por Borges et al 2 há mais de uma década. Nesse
estudo 11,7% das mortes em Portugal foram atribuídas
ao consumo de tabaco. Medida a carga da doença atra-
vés dos anos de vida ajustados por incapacidade (disabi-
lity adjusted life years — DALY) gerados pela mortalidade,
a proporção da carga da doença atribuível ao tabaco foi
de 11,2%. Baseados em dados disponíveis para Portugal,
em 2005, os autores evidenciaram grande disparidade na
análise de género, sendo o tabaco no homem responsável
por 15,4% da carga da doença e 17,7% das mortes, e na
mulher responsável por 4,9% da carga da doença e 5,2%
das mortes. O estudo apresentava ainda estimativas sobre
a carga da doença redutível, ou seja, a redução de mortali-
dade e DALY que ocorreriam se os fumadores abandonas-
sem o tabagismo e passassem a apresentar o risco médio
das populações de ex-fumadores, caso em que a carga da
doença se reduziria em 5,8% (7,8% dos homens e 2,8%
das mulheres) e as mortes em 5,8% (8,5% dos homens e
2,9% das mulheres). Nos anos seguintes, muito foi feito em
Portugal para melhorar o controlo do tabagismo. No entan-
to, e apesar destes esforços, o consumo de tabaco é ainda
crescente na mulher portuguesa 1 .
Em 2007, a Direção-Geral de Saúde emitiu o Progra-
ma-Tipo de Actuação em Cessação Tabágica 3 e em 2008,
a Convenção-Quadro para o Controlo do Tabagismo da
Organização Mundial de Saúde (OMS) propôs um conjunto
de estratégias concertadas para ajudar os países a contro-
lar a epidemia do tabaco e a reduzir o seu rasto mortífero. 4
O acrónimo MPOWER resume as seis políticas com mais
impacto: M — Monitorizar a epidemia e as políticas de con-
trolo; P — Proteger do fumo ambiental; O — Oferecer ajuda
na cessação tabágica; W — (Warn) avisar sobre os male-
fícios do tabaco; E — (Enforce bans) Impor a proibição da
publicidade, promoção e patrocínio do tabaco; R — (Raise
taxes) Aumentar os impostos sobre os produtos do taba-
co. Estes pilares viriam a servir de referência para o Plano
Nacional para a Prevenção e Controlo do Tabagismo
(PNPCT) em Portugal, lançado em 2012. 5 Oferecer ajuda
na cessação tabágica é uma das principais estratégias no
controlo do tabagismo, mas as restantes medidas preconi-
zadas pela OMS necessitam de implementação e desen-
volvimento, para que o seu efeito sinérgico se faça sentir.
Um enorme desafio surgiu, nos últimos anos, com o
aparecimento de novos produtos de tabaco, entre os quais
os cigarros electrónicos (CE), que podem colocar em cau-
sa os esforços desenvolvidos nas últimas duas décadas.
Em Portugal, este fenómeno é ainda menos expressivo do
que o observado em muitos países, mas obriga o médico a
estar bem informado sobre estes novos produtos e os seus
riscos (já conhecidos ou potenciais).
Apesar da população portuguesa ter aumentado a per-
cepção de risco relacionado com estes produtos, 6 cerca de
um terço da população europeia (29,1%) não sabe se são
ou não prejudiciais. 6 Consequentemente, tem-se verificado
um aumento crescente da sua experimentação e consumo
diário, não só em Portugal 6 como na Europa em geral. 7
Habitualmente o médico não aborda o consumo de CE
com o seu doente. Uma investigação recente 8 conclui que
apenas uma minoria dos médicos o faz de acordo com as
recomendações para a melhor prática da cessação tabági-
ca. Um dos maiores problemas da ‘discussão sobre cigar-
ros eletrónicos’ é o da ambivalência gerada pela incerteza e
contradição da informação científica disponível.info:eu-repo/semantics/publishedVersio
Breathe, breathe in the air, don't be afraid to care
No full textinfo:eu-repo/semantics/publishedVersio
CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort
No full textBACKGROUND:
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder characterized by 3 overlapping phenotypes: salt-wasting (SW), simple virilizing (SV), and non-classic (NC). We aimed at conducting a nationwide genotype description of the CAH pediatric patients and to establish their genotype-phenotype correlation.
METHODS:
CAH patients were recruited from Portuguese pediatric endocrinology centers and classified as SW, SV, or NC. Genetic analysis was performed by polymerase chain reaction (sequence specific primer, restriction fragment length polymorphism) or direct Sanger sequencing. Genotypes were categorized into 4 groups (0, A, B, and C), according to their predicted enzymatic activity. In each group, the expected phenotype was compared to the observed phenotype to assess the genotype-phenotype correlation.
RESULTS:
Our cohort comprises 212 unrelated pediatric CAH patients (29% SW, 11% SV, 60% NC). The most common pathogenic variant was p.(Val282Leu; 41.3% of the 424 alleles analyzed). The p.(Val282Leu) variant, together with c.293-13A/C>G, p.(Ile173Asn), p.(Leu308Thr), p.(Gln319*), and large deletions/conversions were responsible for 86.4% of the mutated alleles. Patients' stratification by disease subtype revealed that the most frequent pathogenic variants were c.293-13A/C>G in SW (31.1%), p.(Ile173Asn) in SV (46.9%), and p.(Val282Leu) in NC (69.5%). The most common genotype was homozygosity for p.(Val282Leu; 33.0%). Moreover, we found 2 novel variants: p.(Ile161Thr) and p.(Trp202Arg), in exons 4 and 5, respectively. The global genotype-phenotype correlation was 92.4%. Group B (associated with the SV form) showed the lowest genotype-phenotype correlation (80%).
CONCLUSION:
Our cohort has one of the largest NC CAH pediatric populations described. We emphasize the high frequency of the p.(Val282Leu) variant and the very high genotype-phenotype correlation observed.info:eu-repo/semantics/publishedVersio