From the Cover: Oral advanced glycation endproducts (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1

The epidemics of insulin resistance (IR) and type 2 diabetes (T2D) affect the first world as well as less-developed countries, and now affect children as well. Persistently elevated oxidative stress and inflammation (OS/Infl) precede these polygenic conditions. A hallmark of contemporary lifestyle is a preference for thermally processed nutrients, replete with pro-OS/Infl advanced glycation endproducts (AGEs), which enhance appetite and cause overnutrition. We propose that chronic ingestion of oral AGEs promotes IR and T2D. The mechanism(s) involved in these findings were assessed in four generations of C57BL6 mice fed isocaloric diets with or without AGEs [synthetic methyl-glyoxal-derivatives (MG⁺)]. F3/MG⁺ mice manifested increased adiposity and premature IR, marked by severe deficiency of anti-AGE advanced glycation receptor 1 (AGER1) and of survival factor sirtuin 1 (SIRT1) in white adipose tissue (WAT), skeletal muscle, and liver. Impaired 2-deoxy-glucose uptake was associated with marked changes in insulin receptor (InsR), IRS-1, IRS-2, Akt activation, and a macrophage and adipocyte shift to a pro-OS/inflammatory (M1) phenotype. These features were absent in F3/MG⁻ mice. MG stimulation of 3T3-L1 adipocytes led to suppressed AGER1 and SIRT1, and altered InsR, IRS-1, IRS-2 phosphorylation, and nuclear factor kappa-light chain enhancer of activated B cells (Nf-κB) p65 acetylation. Gene modulation revealed these effects to be coregulated by AGER1 and SIRT1. Thus, prolonged oral exposure to MG-AGEs can deplete host-defenses AGER1 and SIRT1, raise basal OS/Infl, and increase susceptibility to dysmetabolic IR. Because exposure to AGEs can be decreased, these insights provide an important framework for alleviating a major lifestyle-linked disease epidemic.     

After treat-to-target: can a targeted ultrasound initiative improve RA outcomes?

For patients with rheumatoid arthritis (RA), remission can be achieved with tight control of inflammation and early use of disease modifying agents. The importance of remission as an outcome has been recently highlighted by European League Against Rheumatism recommendations. However, remission when defined by clinical remission criteria (disease activity score, simplified disease activity index, etc) does not always equate to the complete absence of inflammation as measured by new sensitive imaging techniques such as ultrasound (US) . There is evidence that imaging synovitis is frequently found in these patients and associated with adverse clinical and functional outcomes. This article reviews the data regarding remission, ultrasound imaging and outcomes in patients with RA to provide the background to a consensus statement from an international collaboration of ultrasonographers and rheumatologists who have recently formed a research network--the Targeted Ultrasound Initiative (TUI) group. The statement proposes that targeting therapy to PD activity provides superior outcomes compared with treating to clinical targets alone and introduces the rationale for a new randomised trial using targeted ultrasound in RA.     

Access to the next wave of biologic therapies (Abatacept and Tocilizumab) for the treatment of rheumatoid arthritis in England and Wales

Patients in England and Wales with rheumatoid arthritis (RA) receive treatment from the National Health Service (NHS) with therapies approved by the European Medicines Agency (EMA), under guidance from the National Institute for Health and Clinical Excellence (NICE). This document overviews the current NICE guidelines for the treatment of RA and identifies scenarios when such guidance may not represent the optimum management strategy for individual patients. Specifically, we consider the use of tocilizumab or abatacept as the most appropriate treatments for some patients. In such scenarios, it may be possible for the clinician to secure access to the required therapy through an application procedure known as an 'individual funding request', the process of which is described in detail here. At present, it is unclear the extent to which the proposed reform of the NHS will affect the role of NICE in providing guidance and setting standards of care. Until the full impact of the proposed changes are realized, individual funding requests will remain a valuable way of securing the optimal treatment for all patients suffering from RA.     

Surgical repair of atrial septal defect with severe pulmonary hypertension during pregnancy: a case report with literature review

We are reporting a case of a 37-year-old pregnant woman with a large secundum atrial septal defect with left-to-right shunt and severe pulmonary hypertension. Her atrial septal defect was undiagnosed before this pregnancy. After carefully considering all the options, we repaired her atrial septal defect with an open heart surgical closure at 20 weeks of gestation. A substantial and consistent reduction in pulmonary arterial pressure after the surgery and subsequent uneventful delivery indicate that surgical repair of atrial septal defects is a viable option that should be considered for such patients.     

Myocardial Recovery With Left Ventricular Assist Devices

OPINION STATEMENT: Advanced heart failure (HF) is a condition that is rarely thought of in terms of cure. Left ventricular assist devices (LVADs), like no therapy before them, provide complete decongestion of the left ventricle, with resulting favorable changes at all levels, from reversal of hypertrophy of cardiomyocytes to recovery of normal geometry and function of the ventricles. Although not a frequent phenomenon at most institutions, LV recovery is achieved in 20-25?% of LVAD recipients in some programs. Patients with good chances for recovery are usually young, with nonischemic cardiomyopathy and short duration of HF symptoms. After LVAD removal, patients with recovered function remain asymptomatic for years. To reach this level of sustainable restoration of cardiac function, several steps need to be taken: 1) myocardial recovery has to be recognized as a therapeutic goal, especially in patients with nonischemic cardiomyopathy; 2) HF medications have to be restarted and aggressively uptitrated after LVAD implantation; 3) regular monitoring for signs of myocardial recovery (eg, echocardiography or hemodynamics) should become a standard practice in LVAD centers; and 4) weaning protocols should be discussed and accepted at each LVAD program. While some protocols involve extensive several-day testing both at rest and with exercise, others are mostly guided by echocardiographic evaluation.     

Electrical devices for left ventricular dysfunction and heart failure: do we need revised guidelines?

Three recent trials have demonstrated the benefit of cardiac resynchronization therapy (CRT) in the New York Heart Association (NYHA) class II patients with heart failure (HF) with ischemic or nonischemic cardiomyopathy as well as in NYHA class I (asymptomatic) patients mostly with ischemic cardiomyopathy. Earlier intervention with CRT in asymptomatic or minimally symptomatic patients improves survival and reduces HF hospitalizations. The reduction or the prevention of HF hospitalizations is of paramount importance because the HF episodes seem to alter the natural history of disease and are associated with deterioration of left ventricular (LV) function and a marked increase in mortality. The CRT benefit is greatest in patients with a QRS ≥ 150 ms. At this time, it would seem prudent to consider CRT-D (D = ICD) therapy for class I NYHA patients with a QRS ≥ 150 ms and an LV ejection fraction ≤ 30% regardless of etiology. Although the data for NYHA class I patients with nonischemic cardiomyopathy are scanty, the recommendation for class I patients is justified because CRT achieves a much greater degree of LV reverse remodeling in nonischemic compared to ischemic patients. With regard to lone ICDs, there is no evidence that they prevent sudden cardiac death more efficiently in symptomatic than in asymptomatic patients. Cardiomyopathy should be the primary target for device therapy regardless of symptoms for both CRT and lone ICD therapy. New guidelines are needed to address the role of CRT in hospitalized NYHA class IV HF patients or those who depend on inotropic therapy or an LV assist device because randomized CRT trials have not included these patients. CRT in these patients remains controversial. The mortality of such patients even with CRT is very high despite the occasional positive response. The role of CRT in patients waiting for cardiac transplantation also needs guidelines. With the expansion of CRT indications to minimally symptomatic or asymptomatic patients, the benefit of device therapy must be carefully weighed against the potential risk of lifelong device complications.     

Subjective and objective results of arthroscopic debridement of ulnar-sided TFCC (Palmer type 1B) lesions with stable distal radio-ulnar joint

Purpose

The purpose of this study was to determine functional and subjective results of patients who received arthroscopic debridement for their TFCC Palmer 1B lesions and to compare their results with those of arthroscopic suture repair.

Methods

Between March 2007 and August 2011, 36 patients were diagnosed with Palmer type 1B tears and underwent arthroscopic debridement. 31 patients (15 males and 16 females) were followed up for an average of 26.7 months (±17.4 months) postoperatively. Their average age was 36.7 years (±12.7 years). Follow-up included the determination of range of motion (ROM), grip strength, pain, and wrist scores (modified Mayo wrist score (MMWS), Disabilities of the Arm, Shoulder and Hand questionnaire (DASH score)).

Results

Postoperative ROM averaged 99.2 % for the extension/flexion arc, 95.5 % for the radial/ulnar deviation arc, and 99.4 % for the pronation/supination arc of motion when compared with the contralateral wrist. The MMWS was rated excellent in 48 % of patients, good in 39 %, fair in 13 %, and poor in 0 %. The average DASH score was 17.02 (±14.92). There was a significant reduction in pain. The grip strength was 96.7 % (±15.8), pulp-to-pulp pinch 101.9 % (±17.4), and the ulnar variance ?0.12 ± 1.69 mm.

Conclusions

Arthroscopic debridement of Palmer type 1B lesions in stable DRUJ yields satisfactory to excellent results. Our study showed similar results compared with the studies of arthroscopic suture repair with shorter postoperative care and fewer complications.