Is there a role for consolidation therapy pre-transplantation?

There is much confusion and uncertainty regarding the need for consolidation therapy before bone marrow transplantation. There are no prospective studies that have established clear guidelines and much of the information has been based on retrospective analyses of data obtained from the international bone marrow transplant registries. These data suggest that there may not be a role for consolidation therapy before an allogeneic transplantation. However, this may not be applicable to transplants performed following reduced intensity conditioning or to transplants performed beyond first remission. The data for autologous transplantation are substantially more confused. Common practice includes the administration of consolidation therapy prior to transplantation, although there is enormous variability in the amount of cycles and in the doses that are given before transplantation.     

Mineralocorticoid receptor antagonists and hypertension: Is there a rationale?

Accumulating evidence indicates that aldosterone is involved in cardiovascular disease by inducing inflammation in the presence of moderate amounts of salt in the diet. Spironolactone and eplerenone are the mineralocorticoid receptor (MR) antagonists currently available for the treatment of hypertension. They have similar safety and antihypertensive efficacy. The advantage of eplerenone is the lower incidence of antiandrogenic and progestational side effects. The rationale for using MR blockade in the treatment of hypertension is threefold: the evidence of antihypertensive efficacy, the phenomenon of "aldosterone escape" occurring with angiotensin-converting enzyme inhibitor and angiotensin-receptor blockade therapy, and the compelling evidence that MR antagonism reduces target-organ damage in hypertensive patients and improves survival in patients with cardiovascular disease. Thus, blockade of the MR may be very useful in many patients with hypertension, particularly those at risk for or having evidence of target-organ damage.     

Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease?

One of the major causes of end-stage renal diseases is hypertensive renal disease, in which enhanced renal prostaglandin (PG) E2 production has been shown. PGE2, a major arachidonic acid metabolite produced in the kidney, acts on 4 receptor subtypes, EP1 through EP4, but the pathophysiological importance of the PGE2/EP subtypes in the development of hypertensive renal injury remains to be elucidated. In this study, we investigated whether an orally active EP1-selective antagonist (EP1A) prevents the progression of renal damage in stroke-prone spontaneously hypertensive rats (SHRSP), a model of human malignant hypertension. Ten-week-old SHRSP, with established hypertension but with minimal renal damage, were given EP1A or vehicle for 5 weeks. After the treatment period, vehicle-treated SHRSP showed prominent proliferative lesions in arterioles, characterized by decreased alpha-smooth muscle actin expression in multilayered vascular smooth muscle cells. Upregulation of transforming growth factor-beta expression and tubulointerstitial fibrosis were also observed in vehicle-treated SHRSP. All these changes were dramatically attenuated in EP1A-treated SHRSP. Moreover, EP1A treatment significantly inhibited both increase in urinary protein excretion and decrease in creatinine clearance but had little effect on systemic blood pressure. These findings indicate that the PGE2/EP1 signaling pathway plays a crucial role in the development of renal injury in SHRSP. This study opens a novel therapeutic potential of selective blockade of EP1 for the treatment of hypertensive renal disease.     

Obesity-related hypertension: Is there a role for selective leptin resistance?

Obesity is a risk factor for cardiovascular diseases, in particular for hypertension. Serum leptin levels and sympathetic nerve activity are both increased in obesity. Leptin has been demonstrated to increase sympathetic nerve activity. Thus, leptin-dependent sympathoactivation might contribute to obesity-related hypertension. However, leptin resistance occurs in obesity. One possibility is that leptin resistance is selective to the metabolic effects of leptin, sparing its sympathoexcitatory actions. In this article, we review experimental evidence supporting the novel concept of selective leptin resistance. We also discuss the sympathetic actions of leptin that are relevant to blood pressure modulation and potential mechanisms of leptin resistance. Disruption of leptin intracellular signaling pathways and resistance of specific leptin-responsive neural networks provide theoretic models of selective leptin resistance. However, most information about leptin-sympathetic actions and leptin-resistance mechanisms derive from in vitro and animal studies. Future research in humans is widely awaited.     

Is there a role for immune and anti-in-flammatory therapy in type 2 diabetes?

There is a growing body of evidence to suggest that type 2 diabetes is associated with a generalised activation of the innate immune system, in which there is a chronic low-grade inflammation. Further evidence for roles of inflammation in type 2 diabetes comes from clinical studies using either anti-inflammatory approaches or biological agents that target specific proinflammatory cytokine pathways to improve parameters of glucose control especially with IL-1β (Interleukin 1 β) antagonism and salsalate (non-acetylated prodrug of salicylate) treatment. In this review, recent evidence implicating the pathological involvement of the immune system in type 2 diabetes is examined, together with the role of potential treatment modalities targeting the immune system in the management of type 2 diabetes.     

Is there a role for thioguanine therapy in IBD in 2017 and beyond?

Introduction: Conventional thiopurines are effective for the maintenance of remission of Crohn’s disease and ulcerative colitis, however, up to half of patients are intolerant or unresponsive to these medications. Thioguanine is an alternative thiopurine that has shown efficacy in inflammatory bowel disease, and is particularly useful to circumvent certain side effects associated with conventional thiopurines, for example, pancreatitis. Its association with nodular regenerative hyperplasia of the liver has hindered its widespread use.

Areas covered: We aim to outline the rational use of thioguanine, including safety monitoring, with particular regard to hepatotoxicity. A literature search was performed: PubMed was searched for full papers and abstracts published in English since January 2000 using the following terms, alone and in combination: ‘azathioprine’, ‘thiopurine’, ‘Crohn’s disease’, ‘inflammatory bowel disease’, ‘nodular regenerative hyperplasia’, ‘mercaptopurine’, ‘thioguanine’, ‘ulcerative colitis’. Further relevant papers were identified from the reference lists of selected papers.

Expert commentary: Despite optimisation strategies such as metabolite measurements and the use of allopurinol, a significant proportion of patients will remain intolerant to thiopurines, especially those with allergic reactions, including pancreatitis. For this subgroup of patients we suggest that low dose thioguanine is an alternative to other therapies that are either parenteral or expensive.     

Is there still a role for neoadjuvant therapy in breast cancer?

The role of neoadjuvant chemotherapy in locally advanced breast cancer is firmly established. There is now also an emerging role for neoadjuvant systemic therapy in the treatment of operable breast cancer. There is good evidence that the chances of breast conserving surgery can be increased with this approach and results of randomised studies indicate that survival is at least as good with neoadjuvant as with adjuvant chemotherapy. Similar clinical data are emerging with neoadjuvant endocrine therapy. For the future, there are important potential advantages in having an in vivo measure of chemosensitivity rather than blindly treating micrometastatic disease in the adjuvant setting. Clinical response to neoadjuvant treatment, and in particular complete pathological response, are predictors of subsequent outcome. Pathological involvement of axillary nodes following neoadjuvant therapy portends a poor prognosis. The potential for biological surrogate markers of response to predict for long-term outcome may allow individualisation of systemic treatment and the rapid assessment of new drugs in early breast cancer.     

Target organ damage and changes in arterial compliance in white coat hypertension. Is white coat innocent?

The aim of this study was to perform an extensive evaluation of target organ status, metabolic abnormalities and hemodynamic alterations in white coat hypertension (WCH). Fifty normotensive (NT), 90 WCH (ambulatory daytime blood pressure < 135/85 mmHg) and 101 hypertensive (HT) subjects underwent extensive biochemical, echocardiographic, fundoscopic examination. In a subgroup study, arterial compliance and intima-media thickness (IMT) were measured by Doppler ultrasound in left common carotid artery. WCH subjects were found to have higher body mass index (BMI) than the NTs (p = 0.042). Left ventricle mass index (LVMI) was greater in the WCHs than the NTs (p < 0.001), but significantly less than the HTs (p < 0.001). Hypertensive retinopathy was observed in the WCHs, but was less severe and rare compared to the HTs (13% vs 27%). Both WCHs and HTs had high levels of urinary albumin excretion (UAE) (p = not significant). Total cholesterol was higher in WCHs than in the NTs (p = 0.04) The distensibility coefficient (DC) of the WCHs was significantly greater than the HTs (p < 0.01), while significantly smaller than the NTs (p < 0.01). The compliance coefficient (CC) of the WCHs was significantly higher than the HTs (p < 0.01), and significantly less than the NTs (p < 0.01). The IMT in the HTs was significantly higher than the WCHs (0.81 +/- 0.05 vs 0.70 +/- 0.04 mm; p < 0.001) and the NTs (p < 0.001). The difference between the NTs and the WCHs was not significant. Our data indicate that patients with WCH represent an intermediate group between NTs and sustained HTs where target organ damage and cardiovascular risk is concerned.