Overall mortality in diabetes mellitus: where do we stand today?

Life expectancy for a patient with type 2 diabetes remains substantially shorter than an equivalent individual without diabetes, largely because of a greater risk of cardiovascular disease. Diabetes is also associated with an increased incidence of many types of cancer, suggesting that malignancy may also contribute to higher rates of mortality. Hyperglycemia is one of the key risk factors for diabetes-associated macro- and microvascular disease, and as such, intensive glycemic control is associated with improved outcomes for patients, including a reduction in this risk of death from any cause, when initiated early in the disease course. Recent trials in patients with more advanced disease have failed to demonstrate a mortality benefit with intensive glycemic control, although this may reflect their short observation period. Intensive multifactorial therapy, including lifestyle intervention and control of hyperglycemia, hypertension, lipids, thrombosis, and microalbuminuria, is likely to be the best strategy against diabetes-associated macrovascular mortality. However, analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial indicates that there may be a subpopulation of patients who are unable to achieve glycemic targets with intensive therapy and that aggressive intensification of treatment in this group may increase mortality risk. It remains to be determined whether the relationship between diabetes and malignancy is causal or whether they share common risk factors. Current recommendations for a healthy lifestyle based on good diet, physical exercise, and weight management in order to control diabetes-related complications are likely to apply in reducing the risk of many forms of cancer and should be advocated for all patients.     

Atrial fibrillation – where do we stand today?

The basic underlying mechanisms behind atrial fibrillation (AF), the most abundant therapy demanding cardiac dysrhythmia, have until recently being largely unknown. Once established, AF is not only self-perpetuating but also self-destructive, prompting rapid treatment against possible initiating mechanisms. Recent observations reveal that the ectopic beats, initiating AF, often originate in the walls of the pulmonary veins and that the deterioration of the ectopic impulse to AF may be linked to an impaired inferoposterior interatrial conduction. The underlying mechanisms behind these functional defects are still obscure. The observations has however, permitted evaluation of new types of treatment, directly interfering with the newly verified findings.     

Medical management of critical limb ischaemia: where do we stand today?

Critical limb ischaemia (CLI) is a severe form of peripheral arterial disease (PAD). CLI often causes disabling symptoms of pain and can lead to loss of the affected limb. It is also associated with increased risk of myocardial infarction, stroke and death from cardiovascular disease. The aims of management in patients with CLI are to relieve ischaemic pain, heal ulcers, prevent limb loss, improve function and quality of life and prolong survival. Here, current evidence regarding the medical management of CLI is reviewed. Cardiovascular risk factors should be assessed in all patients with CLI; smoking cessation and treatment of hypertension, hyperlipidaemia and diabetes all reduce the mortality rate in those with PAD. Antiplatelet agents (either aspirin or clopidogrel) are recommended to reduce both the incidence of cardiovascular events and risk of arterial occlusion. By contrast, routine use of anticoagulation (either warfarin or heparin) is not recommended. Treatment of the limbs themselves is often more challenging. Prostanoids may have some efficacy for treating rest pain and for ulcer healing, and iloprost shows favourable results in reducing the risk of major amputations, but long-term follow-up data regarding disease progression are lacking. There is insufficient evidence to support the use of naftidrofuryl or cilostazol, and pentoxifylline is not beneficial. Furthermore, there is no evidence of proven benefit of hyperbaric oxygen. A number of angiogenic growth factors have been studied in Phase I studies and randomized controlled trials (RCTs). They appear to be safe, but efficacy results have been mixed. Treatment with stem cells also shows some potential from early trials, but further larger RCTs are needed to demonstrate clear benefit. Thrombolysis may be an alternative for patients who develop acute limb ischaemia and are unsuitable for surgical intervention. However, newer endovascular techniques are likely to have a greater role in the future.     

4 years after withdrawal of rofecoxib: where do we stand today?

On the 24th of October 2006, the European Medicines Agency (EMEA) stated that "it cannot be excluded that non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) may be associated with a small increase in the absolute risk for thrombotic events". Reviewing the most recent literature including meta-analyses of randomized clinical studies and pharmacoepidemiological studies show that this statement contrasts with the 2005 EMEA evaluation of cyclooxygenase-2 inhibitors, which contained a number of regulations including several contraindications for coxibs. Recent clinical data indicate that the entire substance group of NSAIDs may have cardiovascular side effects but to different degrees. Results of basic research support these observations showing that the increase for cardiovascular risk not only depends on the ratio of inhibition of thromboxan and prostacyclin but also on other mechanisms including blood pressure elevation and cyclooxygenase independent actions. In clinical practice, many patients require anti-inflammatory therapy with NSAIDs but are at high cardiovascular and gastrointestinal risk. The combination of nsNSAIDs with proton pump inhibitors shows comparable safety to coxibs in averting upper gastrointestinal events, but evidence is increasing coxibs have advantages regarding lower gastrointestinal side effects. Concomitant therapy with aspirin is another issue. There is a negative effect on gastrointestinal safety, as well as the influence of nsNSAIDs on the cardioprotective effect of aspirin. As the contraindications for coxibs announced by the EMEA may prevent some patients from receiving optimal treatment, a warning for the entire substance group, as issued by the American Food and Drug Administration, with no contraindictions, would certainly be more reasonable.     

Immunomodulation of asthma: where do we stand?

Conclusions Better treatment options should reduce symptoms, enhance quality of life, improve the course of disease, reverse pathogenetic and physiologic changes, have few side effects, and be cost effective. Because of the heterogeneous nature of asthma, specific agents will probably work best for selected types of patients. However, regardless of the obstacles, ongoing research into the wide range of therapeutic possibilities will provide new insights into the pathogenesis of allergic respiratory diseases.     

Islet transplantation: where do we stand now?

After many years of limited success in islet transplantation, researchers developing this procedure have made great strides, and several centers have now reported that islet transplantation can result in long‐term insulin independence for patients with type 1 diabetes mellitus. The improved quality of life achieved in some islet allograft recipients suggests that this important line of investigation should proceed. Yet, several factors limit the technique and these hurdles must be overcome before it can be considered a practical treatment for the millions of individuals with diabetes, be it type 1 or type 2. Most obvious is the gross disparity between the number of islets available for clinical transplantation and the number of patients with diabetes who might benefit. Other important limitations, too often lost in the discussion, include complications associated with the technique itself, the toxicity of currently available immunosuppressive drugs, and the imperfect glycemia control achieved in most patients. In fact, our ongoing analysis as to whether transplantation‐based therapy improves survival for patients with type 1 diabetes suggests that, for many at least, the opposite may be true. Two variables, as yet undefined, also need to be considered: (1) can the procedure, when done well, prevent or reverse diabetes‐associated complications and (2) what are the long‐term consequences of intrahepatic islets? Published in 2003 by John Wiley & Sons, Ltd.     

Normothermic ex-vivo liver perfusion: where do we stand and where to reach?

ABSTRACT

Introduction: Nowadays liver transplantation is considered as the treatment of choice, however, the scarcity of suitable donor organs limits the delivery of care to the end-stage liver disease patients leading to the death while on the waiting list. The advent of ex-situ normothermic machine perfusion (NMP) has emerged as an alternative to the standard organ preservation technique, static cold storage (SCS). The newer technique promises to not only restore the normal metabolic activity but also attempt to recondition the marginal livers back to the pristine state, which are otherwise more susceptible to ischemic injury and foster the poor post-transplant outcomes.

Areas covered: An extensive search of all the published literature describing the role of NMP based device in liver transplantation as an alternative to SCS was made on MEDLINE, EMBASE, Cochrane, BIOSIS, Crossref, Scopus databases and clinical trial registry on 10 May 2018.

Expert commentary: The main tenet of NMP is the establishment of the physiological milieu, which permits aerobic metabolism to continue through out the period of preservation and limits the effects of ischemia-reperfusion (I/R) injury. In addition, by assessing the various metabolic and synthetic parameters the viability and suitability of donor livers for transplantation can be determined. This important technological advancement has scored satisfactorily on the safety and efficacy parameters in preliminary clinical studies. The present review suggests that NMP can offer the opportunity to assess and safely utilize the marginal donor livers if deemed appropriate for the transplantation. However, ongoing trials will determine its full potential and further adoption.