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Feed: BRITISH MEDICAL BULLETIN - CURRENT ISSUE

British Medical Bulletin - RSS feed of current issue


Editor's choice
  By: Vetter, N.




The ethics of disclosing genetic diagnosis for Alzheimer's disease: do we need a new paradigm?
  By: Arribas-Ayllon, M.

Introduction or background

Genetic testing for rare Mendelian disorders represents the dominant ethical paradigm in clinical and professional practice. Predictive testing for Huntington's disease is the model against which other kinds of genetic testing are evaluated, including testing for Alzheimer's disease.

Sources of data

This paper retraces the historical development of ethical reasoning in relation to predictive genetic testing and reviews a range of ethical, sociological and psychological literature from the 1970s to the present.

Areas of agreement

In the past, ethical reasoning has embodied a distinct style whereby normative principles are developed from a dominant disease exemplar.

Areas of controversy

This reductionist approach to formulating ethical frameworks breaks down in the case of disease susceptibility.

Growing points

Recent developments in the genetics of Alzheimer's disease present a significant case for reconsidering the ethics of disclosing risk for common complex diseases. Disclosing the results of susceptibility testing for Alzheimer's disease has different social, psychological and behavioural consequences. Furthermore, what genetic susceptibility means to individuals and their families is diffuse and often mitigated by other factors and concerns.

Areas timely for developing research

The ethics of disclosing a genetic diagnosis of susceptibility is contingent on whether professionals accept that probabilistic risk information is in fact ‘diagnostic’ and it will rely substantially on empirical evidence of how people actually perceive, recall and communicate complex risk information.





Inflammatory markers in coronary heart disease
  By: Madjid, M., Willerson, J. T.

Introduction

Inflammation plays a key role in the development of atherosclerosis and coronary heart disease (CHD).

Sources of data

Peer-reviewed studies published in English-language journals were reviewed with a focus on C-reactive protein (CRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2).

Areas of agreement

Elevated levels of serum CRP and Lp-PLA2 are associated with an increased risk of incident CHD events in both primary and secondary prevention studies across a wide range of age, gender and ethnic groups.

Areas of controversy

The utility of inflammatory markers in predicting CHD risk when added to traditional risk factors is under debate. They are most useful in subjects in the intermediate-risk category.

Growing points

Treatment with a statin in subjects with elevated CRP but without hyperlipidemia can reduce the risk of CHD.

Areas timely for developing research

Extensive research is under way to identify additional novel serum markers with higher specificity for coronary artery plaque inflammation. Specific inhibitors against vascular inflammation in combination with medications to lower low-density lipoprotein cholesterol, i.e. statins, may help prevent cardiovascular events in the future.





The evidence of low-intensity pulsed ultrasound for in vitro, animal and human fracture healing
  By: Martinez de Albornoz, P., Khanna, A., Longo, U. G., Forriol, F., Maffulli, N.

Background

Physical stimulation therapies are currently available to enhance fracture healing.

Sources of data

A search of PubMed, Medline, CINAHL, DH data and Embase databases was performed using the keywords ‘ultrasound’ and ‘fracture healing’.

Areas of agreement

The evidence in vitro and animal studies suggests that low-intensity pulsed ultrasound (LIPUS) produces significant osteoinductive effects, accelerating the healing process and improving the bone-bending strength.

Areas of controversy

The evidence in human trials is controversial in fresh, stress fractures and in limb lengthening. LIPUS is effective in delayed unions, in smokers and in diabetic population.

Growing points

LIPUS is an alternative, less invasive form of treatment for complicated fractures, in patients with poor bone healing and may play a role in the management of large-scale bone defects producing substantial cost savings and decreasing associated disability.

Areas timely for developing research

There is heterogeneity among in vitro, animal studies and their application to human studies. Further randomized controlled trials of high methodological quality are needed.





Eosinophilic colitis: an update on pathophysiology and treatment
  By: Alfadda, A. A., Storr, M. A., Shaffer, E. A.

Background

Primary eosinophilic gastrointestinal disorders, a spectrum of inflammatory conditions, occurs when eosinophils selectively infiltrate the gut in the absence of known causes for such tissue eosinophilia. These may be classified into eosinophilic esophagitis, eosinophilic gastroenteritis and eosinophilic colitis (EC). This review focuses on EC: its pathogenesis, epidemiology, clinical presentation, diagnosis and current approach to treatment.

Sources of data

A literature review published in English was performed using Pubmed, Ovid, Google scholar search engines with the following keywords: eosinophilic gastrointestinal disorder, EC, eosinophils, colitis and gastrointestinal.

Areas of agreement

The basis for primary EC appears related to increased sensitivity to allergens, principally as a food allergy in infants and a T lymphocyte-mediated event in adults. Endoscopic changes are generally modest, featuring edema and patchy granularity.

Areas of controversy

Clear clinical and pathological diagnostic criteria of EC and its management strategy.

Growing points

Intestinal involvement of EC is primarily mucosal, presenting as a mild self-limited proctitis in infants and self-limited colitis in young adults. Therapeutic approaches based on case reports tend to use either elimination diets to avoid a presumed allergen; agents traditionally used in inflammatory disease or targeted drugs like anti-histamines or leukotriene receptor antagonists.

Areas timely for developing research

Prospective randomized controlled trials addressing the disease natural history, possible preventive methods and effective medical approach and long-term prognosis are required.





Non-surgical therapies for peripheral nerve injury
  By: Martinez de Albornoz, P., Delgado, P. J., Forriol, F., Maffulli, N.

Background

Non-surgical approaches have been developed to enhance nerve recovery, which are complementary to surgery and are an adjunct to the reinnervation process.

Sources of data

A search of PubMed, Medline, CINAHL, DH data and Embase databases was performed using the keywords ‘peripheral nerve injury’ and ‘treatment’.

Areas of controversy

Most of the conservative therapies are focused to control neuropathic pain after nerve tissue damage. Only physical therapy modalities have been studied in humans and their effectiveness is not proved.

Growing points

Many modalities have been experimented with to promote nerve healing and restore function in animal models and in vitro studies. Despite this, none have been actually translated into clinical practice.

Areas timely for developing research

The hypotheses proved in animals and in vitro should be translated to human clinical practice.





Suicide and mental illness: a clinical review of 15 years findings from the UK National Confidential Inquiry into Suicide
  By: Windfuhr, K., Kapur, N.

Introduction: Suicide risk is most commonly associated with mental illness. In particular, suicide in people under mental health care presents distinct patterns of risk and opportunities for prevention due to their close proximity to specialist care.

Sources of data: The National Confidential Inquiry into Suicide and Homicide by People with Mental Illness (Inquiry) is a unique UK-wide national database of all suicide cases in contact with mental health services in the 12 months preceding suicide. This review presents Inquiry findings from the beginning of the Inquiry in 1996 up to the present (2011) (15 years).

Areas of agreement: Suicide varies substantially by socio-demographic (age, gender) and clinical features (e.g. diagnosis; care variables). Effective suicide prevention initiatives should incorporate research findings to inform clinical practice and policy.

Areas of controversy: Risk assessment remains one of the most difficult areas of clinical practice and management although all areas of clinical practice, research and policy development would benefit from continued high-quality studies.

Growing points: The Inquiry work has positively influenced mental health practice and policy in the UK. These changes include: falling suicide rates in mental health patients, informing suicide prevention strategies and developing safety checklists for mental health services.

Areas timely for developing research: Investigating suicide in non-mental health settings, investigating suicide following different treatment services and investigating models of service delivery could usefully inform future directions for improving patient safety.





Stem cells and the endocrine pancreas
  By: Wu, Y., Persaud, S. J., Jones, P. M.

Background

Diabetes can be treated by β-cell replacement therapy but the supply of graft material from human donors is too limited to make a significant clinical impact. Substitute β-cells generated from stem cell populations offer a potential source for the large numbers of cells required.

Sources of data

Primary peer-reviewed reports of experimental studies.

Areas of agreement

Embryonic stem cells and/or induced pluripotent stem (iPS) cells are currently the most promising starting populations from which to generate large numbers of β-cells. Differentiation protocols that recapitulate in vivo development generate insulin-expressing cells in vitro.

Areas of controversy

Differentiation outcomes may depend on the source of the initial pluripotent cells. The insulin-expressing cells are not fully functional. In vivo maturation is inconsistent and not well understood.

Areas timely for developing research

Improvement of current protocols for complete in vitro differentiation to a functional β-cell phenotype. Systematic analysis to identify the most appropriate starting material. Improved purification methods to ensure safety of material for clinical transplantation.





Current understanding and challenges in bioprocessing of stem cell-based therapies for regenerative medicine
  By: Ratcliffe, E., Thomas, R. J., Williams, D. J.

Background

A novel manufacturing industry is emerging to translate unique cellular therapy bioprocesses to robust, scaled manufacturing production for successful clinical translation.

Source of data

This review summarizes key translational issues, and current and future perspectives to improve translation of cell-based therapy bioprocessing, based on literature search and author research.

Areas of agreement

It is widely recognized that cell-based therapies could revolutionize health care for a range of diseases, and that there are gaps in the overarching framework and technologies to generate clinical success.

Areas of controversy

There is limited understanding of how to fulfil requirements as regulatory and manufacturing guidelines are incomplete and few have achieved commercialization.

Growing points

Recent developments are encouraging adoption of automation and quality engineering approaches for bioprocessing of cell-based therapies.

Areas timely for developing research

Include technology development to improve the cost and purity of manufacture and final product quality.





Cell-based therapeutics for liver disorders
  By: Vosough, M., Moslem, M., Pournasr, B., Baharvand, H.

Introduction

Due to a lack of adequate liver donors and post-surgical complications, researchers propose that cell therapy should be an alternative treatment for patients with end-stage liver diseases.

Data sources

We performed a literature review on cell-based therapy for liver disorders.

Areas of agreement

Due to growing numbers of patients on waiting lists for liver transplantation, a substitute treatment strategy is needed for our patients. Cell therapy can save patients who are in life-threatening situations, enabling them to have more time and increase their chances of survival. Pluripotent stem cells can be a good resource for cell-based therapy after the establishment of efficient differentiation protocols in addition to the settlement of ethical and immunological issues. Cell-based therapy will be applicable after the approval of its efficiency via animal model studies.

Areas of controversy

Transplanted cells cannot integrate into the recipient liver and lose their functionality after a limited time. The rate of homing and transdifferentiation of transplanted cells into hepatocytes is scant.

Growing points

Application of autologous bone marrow mononuclear cells (MNCs), hematopoietic and mesenchymal stem cells (HSCs and MSCs) has improved the general conditions of certain patients. Although this improvement is temporary, new studies have focused on increasing their performance.

Timely areas for developing research

The safety, feasibility and efficacy of applying MNCs, HSCs and MSCs in liver disorders have been proven in clinical trials. Patient-specific cell therapy after the production of induced pluripotent stem cells and new discoveries in somatic cell conversion during transdifferentiation are promising insights.





Dopamine cell transplantation in Parkinson's disease: challenge and perspective
  By: Ma, Y., Peng, S., Dhawan, V., Eidelberg, D.

Background

Functional imaging provides a valuable adjunct to clinical evaluation for assessing the efficacy of cell-based restorative therapies in Parkinson's disease (PD).

Sources of data

In this article, we review the latest advances on the use of positron emission tomography (PET) imaging in evaluating the surgical outcome of embryonic dopamine (DA) cell transplantation in PD patients.

Areas of agreement

These studies suggest long-term cell survival and clinical benefit following striatal transplantation of fetal nigral tissue in PD patients and in models of experimental parkinsonism.

Areas of controversy

Adverse events subsequent to transplantation have also been noted and attributed to a variety of causes.

Growing points

Optimal outcomes of DA cell transplantation therapies are dependent on tissue composition and phenotype of DA neurons in the graft.

Areas timely for developing research

Given continued progress in DA neuron production from stem cells in recent years, transplantation of neural stem cells may be the next to enter clinical trials in patients.

Conclusion

The existing data from studies of embryonic DA transplantation for advanced PD have provided valuable insights for the design of new cell-based therapies for the treatment of this and related neurodegenerative disorders.





Stem cells of the human cornea
  By: Di Girolamo, N.

Introduction

Blindness affects 50 million individuals worldwide; a significant proportion of them require a cell or tissue-based repair or replacement strategy to mend their damaged or diseased cornea. This review will focus on the epithelial stem cell (ESC) population of the cornea, where they reside, how they are identified and what alternative cells can be used as functional substitutes.

Source of data

Data for this review were collated after performing literature searches by inserting key words (cornea, limbal, stem cells (SCs), epithelium, stroma, and endothelium) into the search engine PubMed.

Areas of agreement

The prevailing notion is that corneal ESCs reside in an exclusive niche and their activation is dictated by niche-specific signals.

Areas of controversy

Recent studies refute this hypothesis, as the central cornea of many animal species also possesses similar proliferative and clonogenic activity. The other area of controversy is in relation to the use of autologous and/or allogeneic cell therapies which are mostly contaminated with xenogeneic factors, potentially exposing the recipient to potentially harmful foreign infection.

Growing points

Due to the shortage of donor corneal biomaterial, alternative cellular sources are being sought, discovered and trialed.

Areas timely for developing research

With the exception of conjunctival and oral mucosal epithelium, no other cell type has been successfully used to treat patients with severe corneal epithelial defects. Embryonic and foetal SCs may have the greatest potential of all; however there are moral, legal, religious and scientific hurdles to overcome before they become routinely used in the clinic.





Corneal stem cells in the eye clinic
  By: Shortt, A. J., Tuft, S. J., Daniels, J. T.

Introduction or background: Corneal opacity is a common cause of blindness. The majority of cases result from ulceration and scarring following infection or trauma, but in a proportion corneal epithelial stem cell (SC) deficiency leads to an inability to maintain a healthy corneal surface.

Sources of data: This review includes systematic reviews and individual case series of treatments for corneal epithelial SC deficiency.

Areas of agreement: Two techniques such as transplantation of large segments of cornea from a healthy eye and ex vivo expansion of corneal SCs in the laboratory were compared. Both have merits and their clinical outcomes are similar. The smaller biopsy in the cell expansion approach has less risk for the donor eye, which is a significant advantage.

Areas of controversy: Treatment algorithms for different aetiologies of SC failure are evolving. The proportion of true corneal epithelial SCs in ex vivo culture is unclear and it is unknown whether these cells survive long term.

Growing points: In this study, the optimum method of cell culture and transplantation is being intensively investigated.

Areas timely for developing research: Development of tissues using multiple cell types, genetic modification to treat hereditary corneal disorders and development of cell therapy for other eye diseases are future possibilities.









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