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•Hydroxamic acid inhibitor D13 developed for protocatechuate 3,4-dioxygenase.•Treatment of Rhodococcus jostii with D13 leads to formation of protocatechuic acid.•Treatment of R. ...jostii RHA1 with disulfiram leads to formation of 4-carboxymuconolactone.•Treatment of P. fluorescens with disulfiram generates glycine betaine aldehyde.
Bacterial lignin degradation could be used to generate aromatic chemicals from the renewable resource lignin, provided that the breakdown pathways can be manipulated. In this study, selective inhibitors of enzymatic steps in bacterial degradation pathways were developed and tested for their effects upon lignin degradation. Screening of a collection of hydroxamic acid metallo-oxygenase inhibitors against two catechol dioxygenase enzymes, protocatechuate 3,4-dioxygenase (3,4-PCD) and 2,3-dihydroxyphenylpropionate 1,2-dioxygenase (MhpB), resulted in the identification of selective inhibitors D13 for 3,4-PCD (IC50 15μM) and D3 for MhpB (IC50 110μM). Application of D13 to Rhodococcus jostii RHA1 in minimal media containing ferulic acid led to the appearance of metabolic precursor protocatechuic acid at low concentration. Application of 1mM disulfiram, an inhibitor of mammalian aldehyde dehydrogenase, to R. jostii RHA1, gave rise to 4-carboxymuconolactone on the β-ketoadipate pathway, whereas in Pseudomonas fluorescens Pf-5 disulfiram treatment gave rise to a metabolite found to be glycine betaine aldehyde.
A 23 year old pregnant lady at 35 weeks gestation presented to accident and emergency with worsening dyspnoea, palpitations and dizziness. Twelve lead electrocardiogram, routine bloods and ...echocardiography were normal. Ambulatory monitoring previously had shown an episode of monomorphic broad complex tachycardia (BCT) and a short episode of ventricular standstill. She was admitted for cardiac monitoring until delivery. Several episodes of ventricular standstill and self-terminating BCT were recorded, which were not associated with symptoms. The patient's symptoms either corresponded with sinus rhythm or supraventricular tachycardia. She underwent elective caesarean section at 37 weeks with no complications. The patient's symptoms reduced considerably post delivery, and she was discharged three days later. Unfortunately she then had a presyncopal episode whilst holding her baby. Due to concern regarding the safety of her baby she had a permanent pacemaker implanted to allow safe beta-blockade. She remains asymptomatic six months later.
Implantation of a device to narrow the coronary sinus and increase myocardial venous pressure was compared with a sham procedure in patients with refractory angina. The proportion of patients with ...improvement at 6 months was significantly greater with the device.
A growing number of patients with severe and diffuse obstructive coronary artery disease who are not candidates for revascularization have debilitating angina despite medical therapy.
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The worldwide prevalence of refractory angina is increasing, and new therapeutic options are needed.
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An endoluminal, balloon-expandable, stainless steel, hourglass-shaped device designed for percutaneous implantation in the coronary sinus (Reducer, Neovasc) creates a focal narrowing that leads to increased pressure in the coronary sinus, which may relieve angina (Figure 1). A nonrandomized first-in-human study involving 15 patients with refractory angina who were treated with the device showed significant improvement with respect to angina class. . . .
Objective
Rheumatoid arthritis (RA) is associated with increased cardiovascular event (CVE) risk. The impact of statins in RA is not established. We assessed whether atorvastatin is superior to ...placebo for the primary prevention of CVEs in RA patients.
Methods
A randomized, double‐blind, placebo‐controlled trial was designed to detect a 32% CVE risk reduction based on an estimated 1.6% per annum event rate with 80% power at P < 0.05. RA patients age >50 years or with a disease duration of >10 years who did not have clinical atherosclerosis, diabetes, or myopathy received atorvastatin 40 mg daily or matching placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, or any arterial revascularization. Secondary and tertiary end points included plasma lipids and safety.
Results
A total of 3,002 patients (mean age 61 years; 74% female) were followed up for a median of 2.51 years (interquartile range IQR 1.90, 3.49 years) (7,827 patient‐years). The study was terminated early due to a lower than expected event rate (0.70% per annum). Of the 1,504 patients receiving atorvastatin, 24 (1.6%) experienced a primary end point, compared with 36 (2.4%) of the 1,498 receiving placebo (hazard ratio HR 0.66 95% confidence interval (95% CI) 0.39, 1.11; P = 0.115 and adjusted HR 0.60 95% CI 0.32, 1.15; P = 0.127). At trial end, patients receiving atorvastatin had a mean ± SD low‐density lipoprotein (LDL) cholesterol level 0.77 ± 0.04 mmoles/liter lower than those receiving placebo (P < 0.0001). C‐reactive protein level was also significantly lower in the atorvastatin group than the placebo group (median 2.59 mg/liter IQR 0.94, 6.08 versus 3.60 mg/liter IQR 1.47, 7.49; P < 0.0001). CVE risk reduction per mmole/liter reduction in LDL cholesterol was 42% (95% CI −14%, 70%). The rates of adverse events in the atorvastatin group (n = 298 19.8%) and placebo group (n = 292 19.5%) were similar.
Conclusion
Atorvastatin 40 mg daily is safe and results in a significantly greater reduction of LDL cholesterol level than placebo in patients with RA. The 34% CVE risk reduction is consistent with the Cholesterol Treatment Trialists’ Collaboration meta‐analysis of statin effects in other populations.
Management of Refractory Angina Pectoris Cheng, Kevin; Sainsbury, Paul; Fisher, Michael ...
European Cardiology Review,
12/2016, Letnik:
11, Številka:
2
Journal Article
Odprti dostop
With improvements in survival from coronary artery disease (CAD) and an ageing population, refractory angina (RA) is becoming an increasingly common clinical problem facing clinicians in routine ...clinical practice. These patients experience chronic symptoms in the context of CAD, characterised by angina-type pain, which is uncontrolled despite optimal pharmacological, interventional and surgical therapy. Although mortality rates are no worse in this cohort, patients experience a significantly impaired quality of life with disproportionately high utilisation of healthcare services. It has been increasingly recognised that the needs of RA patients are multifactorial and best provided by specialist multi-disciplinary units. In this review, we consider the variety of therapies available to clinicians in the management of RA and discuss the promise of novel treatments.
Objective: to establish whether an echocardiogram is always necessary when investigating heart failure (HF) in elderly patients. Method: a clinical assessment was compared with echocardiography in 51 ...elderly patients aged ≥75 years complaining of breathlessness of more than 1 month's duration. Results: the greater the number of clinical features of HF present, the more likely was echocardiography to reveal a potential cause. It revealed a potential cause of HF in all 16 patients with strong clinical evidence (four or more features present). Of the 20 patients in whom clinical evidence of HF was equivocal (two or three features present), the echocardiogram revealed a potential cause of HF in nine and so was valuable in directing the diagnosis towards or away from HF. In only two of the 15 patients with minimal clinical evidence of HF (one feature or less) did the echocardiogram reveal a potential cause of HF. Severe valvular lesions were common, occurring in 20 (39%) patients. These were difficult to identify clinically as clinical features were non-specific and murmurs were not always present. Conclusions: echocardiography is most useful in those elderly patients in whom the clinical diagnosis of HF is uncertain or for whom valvular surgery might be considered.
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