SiRNA technology, the gene therapy of the future?

A new era in genetics started 17 years ago, when co-suppression in petunia was discovered. Later, co-suppression was identified as RNA interference (RNAi) in many plant and lower eukaryote animals. Although an ancient antiviral host defense mechanism in plants, the physiologic role of RNAi in mammals is still not completely understood. RNAi is directed by short interfering RNAs (siRNAs), one subtype of short double stranded RNAs. In this review we summarize the history and mechanisms of RNAi. We also aim to highlight the correlation between structure and efficacy of siRNAs. Delivery is the most important obstacle for siRNA based gene therapy. Viral and nonviral deliveries are discussed. In vivo delivery is the next obstacle to clinical trials with siRNAs. Although hydrodynamic treatment is effective in animals, it cannot be used in human therapy. One possibility is organ selective catheterization. The known side effects of synthesized siRNAs are also discussed. Although there are many problems to face in this new field of gene therapy, successful in vitro and in vivo experiments raise hope for treating human disease with siRNA.     

Can statin therapy reduce the risk of melanoma? A meta-analysis of randomized controlled trials

A growing body of literature suggests that statins may have a chemopreventive potential against melanoma through pleiotropic anti-inflammatory, immunomodulatory, and antiangiogenesis mechanisms. Our aim was to examine this association through a detailed meta-analysis of randomized controlled trials (RCTs). A comprehensive search for trials published up to June 2009 was performed, reviews of each study were conducted and data were abstracted. Prior to meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk estimates (RR) and 95% confidence intervals (CIs) were calculated using the fixed- and the random-effects models. Subgroup and sensitivity analyses were also conducted. Sixteen RCTs of statins for cardiovascular outcomes, involving 62,568 individuals with a mean age of 60 years and an average follow-up of nearly 4.7 years, contributed to the analysis. We found no evidence of publication bias (P = 0.47) or heterogeneity among the studies (P = 0.25). Statin use did not significantly affect the risk of developing melanoma assuming either a fixed- (RR = 0.92, 95% CI: 0.67–1.26), or a random-effects model (RR = 0.92, 95% CI: 0.62–1.36). This neutral effect was further supported by the results of subgroup and sensitivity analyses. Our findings do not support a protective effect of statins against melanoma.     

Are doctors part of the problem?

Many doctors believe that the maternity services they provide are the key to achieving safe motherhood. With emergency facilities immediately available, they know that a complicated delivery is far less likely to result in maternal death. Most medical experts therefore tend to assume that more maternity beds means less maternal mortality. That assumption, however, may not be valid. Many women in Africa and elsewhere choose not to use available maternity facilities because they dislike the services provided by hospital physicians. Examples of women's aversion to hospital delivery are briefly presented from Guinea Bissau, the Philippines, and Ecuador. Women may not want to be attended by a male physician, have fear of being asked to give birth lying down rather than in a squatting position, and/or wish to avoid the rude and callous treatment received in hospital. Anthropology researchers working in Bolivia recommended regular discussion sessions between mothers-to-be and the hospital and health service staff to help make hospital services more acceptable to pregnant women without adversely affecting the quality of medical care.     

Can extracorporeal shock-wave therapy be used for the management of lateral elbow tendinopathy?

Lateral elbow tendinopathy (LET) is one of the two most common tendinopathies of the upper limb. The most effective treatment in the management of LET is the exercise program. Clinicians combine exercise program with other physiotherapy, electrotherapeutic and no, techniques. Extracorporeal shock wave therapy (ESWT) is one of the most common recommended electrotherapeutic modalities for the management of LET. Further research is needed to find out the optimal treatment protocol of ESWT in the management of LET     

Long-term contracts in the NHS: a solution in search of a problem?

Purchasers and providers in the National Health Service (NHS) are now required to move from annual contracting cycles to longer-term contracts. The benefits are expected to include more efficient investment and improved sharing of financial risk. This paper argues that the economic analysis of longer-term contracts has assumed implicitly that agents operate in the private sector. Once the constraints of the public sector are introduced, the apparent economic benefits of longer-term contracts become doubtful. The paper explores these issues using evidence collected from analysis of the contracts of a sample of Health Authorities and from semi-structured interviews with individuals involved in the contracting process. We conclude that with the property rights and financial structure of the public sector, the move from short- to long-term contracts is unlikely to produce the improvements in performance expected by the government.     

Use of medication technicians in US nursing homes: part of the problem or part of the solution?

OBJECTIVES: To determine the relation between organizational characteristics and medication technician (MT) use and quantify the impact of MTs on increasing the likelihood of using medications, employing the example of antiosteoporosis medications. DESIGN: Cross-sectional study. SETTING: The setting included 6344 Medicare/Medicaid certified nursing homes in 23 states. PARTICIPANTS: Residents older than 65 years of age. MEASUREMENTS: On-line Survey and Certification of Automated Records (OSCAR) provided facility characteristics information including structural, resource, and staffing levels. The Minimum Data Set (MDS) provided information regarding use of antiosteoporosis medications and resident factors. Adjusted estimates of MT use on antiosteoporosis medication use were derived using logistic regression with generalized estimating equations. RESULTS: MT use varied by state (6.7% in Alaska vs 85% in Kansas). Homes with greater nursing staffing levels per 100 beds (CNA, RN, LPN) were less likely to use MTs, while larger homes, homes using physician extenders, and contracting pharmacy services were more likely to use MTs. Homes with MTs were more likely to have medication error rates of at least 5% (10.1% vs 7.3%) than homes without MTs. After adjustment for resident and facility factors, residents in MT facilities were not more likely to receive antiosteoporosis treatment relative to those in homes without MTs. CONCLUSION: These data call into question the use of MTs in nursing homes. Use of MTs may lead to more errors, yet not increase use of medications that are labor intensive to administer.     

Can we reduce the number of fish in the OECD acute toxicity test?

OECD (Organisation for Economic Co-operation and Development) Guideline 203, Fish Acute Toxicity Test, states that the test should be performed using at least five concentrations in a geometric series with a separation factor not exceeding 2.2, with at least seven fish per concentration. However, the efficiency of this design can be questioned, because it often results in only one concentration that causes partial mortality (mortality >0% and <100%). We performed Monte Carlo computer simulations to assess whether more efficient designs could allow reductions in fish use. Simulations indicated that testing with six fish per concentration could yield 50% lethal concentration (LC50) estimates of quality similar to those obtained using seven fish. Experts attending a workshop organized to consider this finding and to identify the best methods for reducing fish use concluded that significant reductions could best be achieved by modifying the test paradigm. They suggested initiating testing using a 96-h fish embryo test instead of juvenile fish to cover the range from the upper threshold concentration (the lowest 50% effective concentration [EC50] in existing algae and daphnia studies) to the highest concentration with no mortality. This would be followed by a confirmatory limit test with juvenile fish at the highest concentration with no mortality or by a full test with juvenile fish, if a point estimate of the LC50 is required.     

Can the vulnerability concept support the construction of knowledge in collective health care?

The term vulnerability has been frequently used in scientific literature, especially after the 80's, in some epidemiologic studies, mainly focusing the risk perspective. The purpose of this article is to review the vulnerability concept through a systematic study of national and international circulation newspapers, to support knowledge and practices in the collective health care field. Furthermore, it indicates how this concept has been revisited in studies conducted in Brazil, mentioning issues which support the structural dimension of reality, linking them to the needs of a program for patients, health care users and their families. It is important to study the vulnerability concept due to the fact that an understanding of this concept will contribute to support the delivery of care, of collective health care including individual health care programs and health care policies.     

Can variability in the hormonal status of elderly women assist in the decision to administer estrogens?

Hormone replacement therapy (HRT) has been proposed for the prevention and treatment of many chronic conditions, ranging from osteoporosis, heart disease, urinary incontinence, and Alzheimer's disease. With the exception of osteoporosis, however, many of the suggested benefits remain controversial. Part of the controversy stems from the relative absence of randomized controlled trials, particularly those enrolling sufficient numbers of elderly women. We propose that another factor may also contribute, one that has been overlooked - failure to consider the variable endogenous estrogen status of elderly women. Highly variable levels of estrogens are present in nearly all postmenopausal women, even at advanced ages. Similar to other endocrine systems, estrogen deficiency and the need for its replacement are, therefore, likely to be relative rather than absolute. Recent studies indicate that elderly women who are less able to compensate for declining ovarian 17beta-estradiol production by adipose synthesis of estrone (E1) may be at greater risk for certain chronic conditions associated with relative estrogen deficiency. Because many markers of estrogen deficiency exhibit overlap between risk groups, their clinical usefulness as predictors of frailty, disability, and response to HRT has been limited. Future studies will need to focus not only on the use of highly variable circulating serum estrogen levels but also on markers of overall estrogenic effects at the level of individual target tissues (i.e., markers of bone turnover, karyopyknotic index on a vaginal wall smear). We propose that a clinical approach that takes into consideration the remarkable heterogeneity (physiological as well as psychological) of elderly women will enable us to approach the decision about HRT in a more individualized and possibly better targeted fashion.