Therapeutic review: antibiotic prophylaxis for bacterial endocarditis

A recent survey of antibiotic prophylaxis found that local practice often differed from that recommended by authoritative bodies such as the British Society for Antimicrobial Chemotherapy (BSAC) and the American Heart Association (AHA). Practitioners found the subject confusing and requested guidance. For these reasons we present current recommendations. Unfortunately all recommendations are based on animal studies and an understanding of the pathogenesis of bacterial endocarditis in humans. There are no controlled trials in humans on which to base guidelines, so rigidity is inappropriate. It is also important to realise that optimal prophylaxis will not eliminate bacterial endocarditis. In developed countries it has been estimated that only 10% of cases of endocarditis are theoretically preventable.     

C-terminal modifications of nonpeptide renin inhibitors: improved oral bioavailability via modification of physicochemical properties.

We describe the development of a series of soluble, potent, and bioavailable nonpeptide renin inhibitors. These inhibitors derived from a series of novel nonpeptide renin inhibitors which were recently identified in our laboratories, by alteration of the nature of the C-terminus (P2') of the molecules. Introduction of basic substituents into modified hydroxyethylene dipeptide isosteres gave inhibitors with improved solubility as well as improved potency against human plasma renin. In addition, these modifications produced inhibitors which displayed markedly improved intraduodenal bioavailability in both the ferret and cynomolgus monkey. We also present data which demonstrate excellent efficacy in the monkey for A-74273 (65), with an intraduodenal bioavailability of 16 +/- 4% in the monkey, compared to 1.7 +/- 0.5% for the dipeptide renin inhibitor enalkiren (A-64662, 75). A-74273 is an example of a nonpeptide inhibitor which possesses a good balance of the desirable properties of potency, solubility, and lipophilicity and which is well absorbed into the intestine.     

Coronary atherosclerosis of the donor heart--impact on early graft failure.

OBJECTIVE: Due to the shortage of donor hearts, the criteria for organ acceptability have been considerably extended and donor grafts with coronary atherosclerosis are among those offered. This study evaluated whether and to what degree pre-existing coronary atherosclerosis may be acceptable. METHODS: A total of 1253 consecutive HTx recipients were investigated retrospectively for donor-transmitted coronary atherosclerosis (DCAS). Donor-transmitted coronary atherosclerosis was defined as focal atherosclerosis with stenosis of at least 50%. Inclusion criteria were absence of pre-HTx angiogram but performance of angiogram or autopsy within 6 months after heart transplantation. Kaplan-Meier analysis and log-rank test were used. RESULTS: Eighty-five out of 1253 (6.8%) cases were excluded, since coronary evaluation was not performed within 6 months (n=45) or hearts had undergone pre-transplant angiography (n=40). In 1086 patients no donor-transmitted coronary atherosclerosis was found (NDCAS group) and in 82 patients (7%) donor-transmitted coronary atherosclerosis was diagnosed by angiography (n=49) or autopsy (n=33). Single-vessel donor-transmitted coronary atherosclerosis was found in 53/82 patients (DCAS1 group) and double- or triple-vessel donor-transmitted coronary atherosclerosis in 26/82 patients (DCAS2/3 group). Three of the 82 patients with donor-transmitted coronary atherosclerosis were excluded since the autopsy report was unclear regarding degree of atherosclerosis. Early after heart transplantation the 30-day mortality in the NDCAS and DCAS1 groups was 12.2% versus 13.2% whereas in the DCAS2/3 group it was 61.5%. Beyond the first year the annual decrease with and without donor-transmitted coronary atherosclerosis (single-vessel disease) is comparable. CONCLUSIONS: Donor screening without coronary angiogram overlooks significant atherosclerotic lesions in a considerable number of cases (7.0%). Therefore, angiographic donor screening should be performed. Donor grafts with single-vessel coronary atherosclerosis may be accepted as marginal hearts; however, in our opinion, revascularisation (CABG, PTCA) should be considered. Grafts with two- or even three-vessel coronary atherosclerosis seem to have a serious risk for early graft failure. Beyond the first year the outcome of healthy grafts and grafts with donor-transmitted coronary atherosclerosis seems to be comparable.     

Quantifying the blood oxygenation level dependent effect in cerebral blood volume-weighted functional MRI at 9.4T.

In cerebral blood volume (CBV)-weighted functional MRI (fMRI) employing superparamagnetic contrast agent, iron dose and blood oxygenation level dependent (BOLD) contamination are two important issues for experimental design and CBV quantification. Both BOLD and CBV-weighted fMRI are based upon the susceptibility effect, to which spin-echo and gradient-echo sequences have different sensitivities. In the present study, CBV-weighted fMRI was conducted using spin-echo and gradient-echo sequences at 9.4T by systematically changing the doses of contrast agent. Results suggest that BOLD contamination is a significant component in CBV-weighted fMRI at high field, particularly when relatively low dose of contrast agent is administered. A mathematical model was developed to quantify the extravascular (EV) BOLD effect. With a TE of 35 ms, the EV BOLD effect was estimated to account for 76+/-12% of the observed spin-echo fMRI signal at 9.4T. These data suggest that correcting BOLD effect may be necessary for accurately quantifying activation-induced CBV changes at high field.     

Entacapone improves complex movement performance in patients with Parkinson's disease.

BACKGROUND: A possible strategy to prolong plasma metabolism of Levodopa/Carbidopa (LD/CD) is Entacapone addition (EN), which improves impaired motor behaviour in patients with Parkinson's disease (PD). AIMS OF THE STUDY: Objectives were to evaluate the clinical response to an increased dopaminergic substitution with EN by clinical rating and assessment of complex motions and to investigate the change of movement in PD patients during repeat drug administration during an eight hour interval. METHODS: We used peg insertion with a computer based device and clinical rating for assessment of motor function in 20 treated PD patients. They received LD/CD and then the same LD/CD dosage plus EN in a standardised, open label fashion. RESULTS: Motor scores and performance of the instrumental task were significantly better and the fluctuation of movement was less intense during the LD/CD/EN condition according to the motor test outcomes. CONCLUSION: EN supplementation improves motor symptoms and provides a more continuous movement behaviour in PD patients.     

Sentinel Bleeding After Pancreaticoduodenectomy: A Disregarded Sign

Introduction Delayed massive hemorrhage induced by pancreatic fistula after pancreaticoduodenectomy is a rare but life-threatening complication. The purpose of this study was to analyze the clinical course of patients with late hemorrhage, with or without sentinel bleeding, to better define treatment options in the future. Material and Methods From April 1998 to December 2006, 189 pancreaticoduodenectomies were performed. Eleven patients, including two patients referred from other hospitals, were treated with delayed massive hemorrhage occurring 5 days or more after pancreaticoduodenectomy. Sentinel bleeding was defined as minor blood loss via surgical drains or the gastrointestinal tract with an asymptomatic interval until development of hemorrhagic shock. The clinical data of patients with bleeding episodes were analyzed retrospectively. Results Eight of the 11 patients had sentinel bleeding, and seven of them had it at least 6 h before acute deterioration. Seven out of 11 patients died, five out of eight with sentinel bleeding. No differences could be detected between patients with or without sentinel bleeding before delayed massive hemorrhage. The only difference found was that non-surviving patients were significantly older than surviving patients. Delayed massive hemorrhage is a common cause of death after pancreaticoduodenostomy complicated by pancreatic fistula formation. The observation of sentinel bleeding should lead to emergency angiography and dependent from the result to emergency relaparotomy to increase the likelihood of survival.