Gene transfer for ischemic cardiovascular disease: is this the end of the beginning or the beginning of the end?

The past decade has represented a period of high expectations for cardiovascular gene transfer on the basis of the findings from preclinical experiments and promising early clinical results. Yet, randomized studies have not demonstrated similar results. Do these poor results mean that gene transfer for ischemic cardiovascular disease has failed in its promise, or do they merely signify the inherent challenges of a pioneering field? In this paper we briefly review the clinical experience of gene transfer for ischemic cardiovascular disease and propose future directions for research.     

Genetics of ACPA-positive rheumatoid arthritis: the beginning of the end?

Heritability is a measure for the contribution of genetic variation to the variation in liability to disease and for rheumatoid arthritis (RA) had previously been estimated to be about 60%. This has been recently confirmed and could show that the heritability of anti-citrullinated protein autoantibody (ACPA)-positive and ACPA-negative RA is similar. Apart from gender, the main known genetic factor is HLA, and its contribution to genetic variation has previously been estimated as 37% but recent studies indicate that this figure may be too high. HLA-linked genes, and in particular the HLA-DRB1 SE alleles, predispose much more strongly to ACPA-positive than to ACPA-negative RA. The same is true for the protective effect of DERAA-positive DRB1 alleles. It has been calculated that the contribution of the protective and predisposing HLA alleles to genetic variance is about 40% for ACPA-positive and 2% for ACPA-negative RA. A meta-analysis indicated that the protective effect may be confined to the HLA-DRB1*1301 allele. The search for non-HLA genes contributing to the genetic variation in RA susceptibility has implicated about 30 other loci/genes. The OR of the associations with these non-HLA polymorphisms is considerably lower than the ORs of sex and HLA as is their contribution to the genetic variation-namely, altogether only about 5%. This means that known genetic factors do not explain much more than 50% of the genetic variance of ACPA-positive RA. Until recently, the only established non-genetic factor contributing to RA susceptibility was smoking. It has recently been shown that non-inherited maternal HLA-DRB1 DERAA-positive antigens (NIMA) should be added to the environmental factors affecting RA susceptibility.     

The era of direct-acting antivirals has begun: the beginning of the end for HCV?

The year 2011 marks the dawn of the new era of direct-acting antivirals for hepatitis C. For the first time since 1998, the U.S. Food and Drug Administration approved two new antiviral drugs for the treatment of chronic hepatitis C virus genotype 1. Dual therapy with pegylated interferon and ribavirin is no longer the standard of care for genotype 1. The new treatment paradigm includes one direct-acting antiviral, a protease inhibitor, in combination with pegylated interferon and ribavirin. This combination nearly doubles the chances of response to treatment, but at the cost of increased toxicity. Many agents with different mechanisms of action and improved safety profiles are in clinical development. The holy grail of HCV treatment is an all oral, interferon-free treatment. The ideal regimen will be potent, well tolerated, with minimal drug-drug interactions and once daily. This article covers new concepts of treatment of hepatitis C with DAAs and gives an overview of the recent highlights in direct-acting antiviral development.     

Changing spectrum of HIV infection and its associated conditions in Spain: the end of the beginning?

To evaluate the natural history and the impact that different strategies have had on HIV infection and its associated conditions, a cohort of 970 patients (432 had AIDS) who had been seen over a period of 13 years were studied. The incidence of new HIV-infected patients had increased steadily since 1985, peaking in 1993 (52.9 cases/100,000 population), to significantly decrease in the subsequent years. The most common AIDS-defining illnesses (ADIs) were tuberculosis (52.3% of the patients), Pneumocystis carinii pneumonia (30%), and candidal esophagitis (28.6%). The frequency of new cases of tuberculosis per patient with ADI clearly decreased over this period (p < 0.0001), whereas that of P. carinii pneumonia decreased slowly until 1994, to fall thereafter to about half the previous levels (p = 0.005). Candidal esophagitis showed a biphasic pattern, the second peak probably due to the emergence of fluconazole resistance. The number of ADIs per patient increased from the beginning of the observation period, peaking in 1995 (1.67 ADI/patient), followed by a statistically significant decrease that, in 1997, reached the 1987 levels (1.22 ADI/patient). We conclude that the clinical spectrum of HIV infection is improving in the last years. Except for tuberculosis, prophylaxis for other ADIs, although effective, does not seem to have had a dramatic impact on occurrence. The most impressive reductions have been observed only after the introduction of antiretroviral combination therapy.     

Treatment of sexually transmitted infections for HIV prevention: end of the road or new beginning?

Observational and biological data provide compelling evidence of the importance of sexually transmitted infections (STIs) in HIV transmission, but only one of nine intervention trials has shown an effect. This article reviews the observational studies, critically examines the nine randomized controlled trials evaluating the impact of STI treatment interventions on HIV incidence, and discusses implications for HIV prevention policy, programs and future research. The role of other vaginal infections is also briefly considered. In aggregate, the evidence strongly supports the concept that STI treatment prevents HIV infection. However, issues in trial design and conduct, including HIV epidemic phase, STI prevalence, intervention in comparison groups, and power have affected five of the six trials of treatment of curable STIs. In the three herpes intervention trials, antivirals for HSV suppression were insufficiently potent to alleviate persistent genital inflammation in HIV-negative HSV2-positive persons, and the reduction in HIV levels in HIV-positive persons was insufficient to reduce HIV transmission. It is time for a new phase of exploration of how, when, and in whom to include STI control as a key component of HIV prevention, driven by basic research to elucidate the mechanisms by which STIs and vaginal infections facilitate HIV transmission. From a policy perspective, treatment of curable STIs is an essential part of primary healthcare and is a cheap, simple, and effective intervention when appropriately targeted and delivered. It should be promoted as an essential component of HIV control programs in communities in which the burden of STIs is substantial.     

Is this the end of clinical research?

SIR, Research by NHS consultants and their juniors has beena tradition of the Health Service since its inception. It hasamused the participants and added to the data available. Ithas been regarded as meritorious both by appointments committeesand the merit award system. I now feel that our ability to performthis research is under serious threat from all angles such thatit may become impractical. I write as a full-time NHS consultantwho has averaged three original papers a year in refereed journalssince my first publication in 1985. The ethics committee Once upon a time you only applied for ethical approval if youwere intervening in a patient's care, or you had ethical issuesthat you perceived and     

Acute pancreatitis at the beginning of the 21st century： The state of the art

Acute pancreatitis is an acute inflammatory disease of the pancreas which can lead to a systemic inflammatory response syndrome with significant morbidity and mortality in 20% of patients. Gallstones and alcohol consumption are the most frequent causes of pancreatitis in adults. The treatment of mild acute pancreatitis is conservative and supportive; however severe episodes characterized by necrosis of the pancreatic tissue may require surgical intervention. Advanced understanding of the pathology, and increased interest in assessment of disease severity are the cornerstones of future management strategies of this complex and heterogeneous disease in the 21st century.