Control of hyperphosphatemia in regular hemodialysis (HDx) patients by calcium acetate (CA) versus calcium carbonate (CC). A double blind crossover prospective study

This study included fourty chronic renal failure patients aged 37-83 years (mean 51.3±7) on thrice weekly HDx for 4-144 month (Kt/V >1.2). Acetate dialysate with calcium concentration of 3 mEq/L was used. All phosphate binders were discontinued for one month. Patients were divided in two groups. Group I (20 cases) received CA, while group II (20 cases) received CC in equimolar dose (10 mmol, of either t.i.d.) for one month. Crossover of treatment was done for another month while keeping patients on the same diet.Serum levels of total calcium (Ca), ionized Ca (iCa), phosphorus (P), alkaline phosphates (AP), urea (U), creatinine (Cr), ALT, AST, total proteins (TP) and albumin (Alb) were estimated before, and at the end of each month of CA and CC treatment. Serum Ca and iCa were significantly lower in group I after CA compared to values after CC (p<0.01). Similar results in Ca levels were observed in group II (P<0.05). In group II only serurn P was significantly lower after CA compared to its values after CC (P<0.05). There was no significant difference in AP, U, Cr, ALT, AST, TP and Alb before, and at the end of each month of CA and CC treatment (P>0.05 in all). We excluded 12.5% of cases due to CA intolerance while non of cases had similar intolerance to CC.Conclusion: 1) CA is not very superior to CC in control of hyperphosphataemia. 2) CA can be safely increased without the risk of hypercalcemia. 3) Active Vitamin D and high dialysate Ca can be used to suppress parathyroid activity more safely with CA than with CC. 4) Tolerability to CC is superior

Structure-based design, synthesis and preliminary evaluation of selective inhibitors of dihydrofolate reductase from Mycobacterium tuberculosis

Tuberculosis is an increasing threat, owing to the spread of AIDS and to the development of resistance of the causative organism, Mycobacterium tuberculosis, to the currently available drugs. Dihydrofolate reductase (DHFR) is an important enzyme of the folate cycle; inhibition of DHFR inhibits growth and causes cell death. The crystal structure of M. tuberculosis DHFR revealed a glycerol tightly bound close to the binding site for the substrate dihydrofolate; this glycerol-binding motif is absent from the human enzyme. A series of pyrimidine-2,4-diamines was designed with a two-carbon tether between a glycerol-mimicking triol and the 6-position of the heterocycle; these compounds also carried aryl substituents at the 5-position. These, their diastereoisomers, analogues lacking two hydroxy groups and analogues lacking the two-carbon spacing linker were synthesised by acylation of the anions derived from phenylacetonitriles with ethyl (4S,5R)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane-4-propanoate, ethyl (4S,5S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane-4-propanoate, tetrahydrooxepin-2-one and 2,3-O-isopropylidene-d-erythronolactone, respectively, to give the corresponding alpha-acylphenylacetonitriles. Formation of the methyl enol ethers, condensation with guanidine and deprotection gave the pyrimidine-2,4-diamines. Preliminary assay of the abilities of these compounds to inhibit the growth of TB5 Saccharomyces cerevisiae carrying the DHFR genes from M. tuberculosis, human and yeast indicated that 5-phenyl-6-((3R,4S)-3,4,5-trihydroxypentyl)pyrimidine-2,4-diamine selectively inhibited M. tuberculosis DHFR and had little effect on the human or yeast enzymes

Scanning ion conductance microscopy: a convergent high-resolution technology for multi-parametric analysis of living cardiovascular cells

Cardiovascular diseases are complex pathologies that include alterations of various cell functions at the levels of intact tissue, single cells and subcellular signalling compartments. Conventional techniques to study these processes are extremely divergent and rely on a combination of individual methods, which usually provide spatially and temporally limited information on single parameters of interest. This review describes scanning ion conductance microscopy (SICM) as a novel versatile technique capable of simultaneously reporting various structural and functional parameters at nanometre resolution in living cardiovascular cells at the level of the whole tissue, single cells and at the subcellular level, to investigate the mechanisms of cardiovascular disease. SICM is a multimodal imaging technology that allows concurrent and dynamic analysis of membrane morphology and various functional parameters (cell volume, membrane potentials, cellular contraction, single ion-channel currents and some parameters of intracellular signalling) in intact living cardiovascular cells and tissues with nanometre resolution at different levels of organization (tissue, cellular and subcellular levels). Using this technique, we showed that at the tissue level, cell orientation in the inner and outer aortic arch distinguishes atheroprone and atheroprotected regions. At the cellular level, heart failure leads to a pronounced loss of T-tubules in cardiac myocytes accompanied by a reduction in Z-groove ratio. We also demonstrated the capability of SICM to measure the entire cell volume as an index of cellular hypertrophy. This method can be further combined with fluorescence to simultaneously measure cardiomyocyte contraction and intracellular calcium transients or to map subcellular localization of membrane receptors coupled to cyclic adenosine monophosphate production. The SICM pipette can be used for patch-clamp recordings of membrane potential and single channel currents. In conclusion, SICM provides a highly informative multimodal imaging platform for functional analysis of the mechanisms of cardiovascular diseases, which should facilitate identification of novel therapeutic strategies

Modifiable risk factors remain significant causes of medium term mortality after first time Coronary artery bypass grafting

<p>Abstract</p> <p>Background</p> <p>Whilst there is much current data on early outcomes after Coronary artery bypass grafting(CABG), there is relatively little data on medium term outcomes in the current era. The purpose of this study is to present a single surgeon series comprising of all first time CABG patients operated on with the technique of cross clamp fibrillation from Feb-1996 to through to Jan-2003, and to seek risk factors for medium term mortality in these patients.</p> <p>Methods</p> <p>Data was collected from Hospital Episode Statistics and departmental patient administration and tracking systems and cross checked using database techniques. Patient outcomes were searched using the National Health Service strategic tracing service.</p> <p>Results</p> <p>Mean follow up was 5.3 years(0–9.4 years) and was complete for all patients. 30-day survival was 98.4%, 1-year survival 95% and 8-year survival 79%. Cox-regression analysis revealed that several modifiable pre-operative risk factors remain significant predictors of medium term mortality, including Diabetes(Hazard Ratio(HR) 1.73, 95%CI 1.21–2.45), Chromic obstructive pulmonary disease(HR 2.02, 95%CI 1.09–3.72), Peripheral vascular disease(HR 1.68, 95%CI 1.13–2.5), Body mass index>30(HR 1.54, 95%CI 1.08–2.20) and current smoker at operation(HR 1.67, 95%CI 1.03–2.72). However hypertension(HR 1.31, 95%CI 0.95–1.82) and Hypercholestrolaemia(HR 0.81, 95%CI 0.58–1.13) were not predictive which may reflect adequate post-operative control.</p> <p>Conclusion</p> <p>Coronary artery bypass surgery using cross clamp fibrillation is associated with a very low operative mortality. Medium term survival is also good but risk factors such as smoking at operation, Chronic obstructive pulmonary disease, obesity and diabetes negatively impact this survival and should be aggressively treated in the years post-surgery.</p

A standardized approach to treat complex aortic valve endocarditis: a case series

Background Surgical treatment of complicated aortic valve endocarditis often is challenging, even for experienced surgeons. We aim at demonstrating a standardized surgical approach by stentless bioprostheses for the treatment of aortic valve endocarditis complicated by paravalvular abscess formation. MethodsSixteen patients presenting with aortic valve endocarditis (4 native and 12 prosthetic valves) and paravalvular abscess formation at various localizations and to different extents were treated by a standardized approach using stentless bioprostheses. The procedure consisted of thorough debridement, root replacement with reimplantation of the coronary arteries and correction of accompanying pathologies (aortoventricular and aortomitral dehiscence, septum derangements, Gerbode defect, total atrioventricular conduction block, mitral and tricuspid valve involvement).ResultsAll highly complex patients included (14 males and 2 females; median age 63 years [range 31–77]) could be successfully treated with stentless bioprostheses as aortic root replacement. Radical surgical debridement of infected tissue with anatomical recontruction was feasible. Although predicted operative mortality was high (median logarithmic EuroSCORE I of 40.7 [range 12.8–68.3]), in-hospital and 30-day mortality rates were favorable (18.8 and 12.5% respectively). ConclusionsRepair of active aortic valve endocarditis complicated by paravalvular abscess formation and destruction of the left ventricular outflow tract with stentless bioprosthesis is a valuable option for both native and prosthetic valves. It presents a standardized approach with a high success rate for complete debridement, is readily available, and yields comparable clinical outcomes to the historical gold standard, repair by homografts. Additionally, use of one type of prosthesis reduces logistical issues and purchasing costs

Formal consensus study on surgery to replace the aortic valve in adults aged 18-60 years

Objective: There is uncertainty about surgical procedures for adult patients aged 18-60 years undergoing aortic valve replacement (AVR). Options include conventional AVR (mechanical, mAVR; tissue, tAVR), the pulmonary autograft (Ross) and aortic valve neocuspidisation (Ozaki). Transcatheter treatment may be an option for selected patients. We used formal consensus methodology to make recommendations about the suitability of each procedure. Methods: A working group, supported by a patient advisory group, developed a list of clinical scenarios across seven domains (anatomy, presentation, cardiac/non-cardiac comorbidities, concurrent treatments, lifestyle, preferences). A consensus group of 12 clinicians rated the appropriateness of each surgical procedure for each scenario on a 9-point Likert scale on two separate occasions (before and after a 1-day meeting). Results: There was a consensus that each procedure was appropriate (A) or inappropriate (I) for all clinical scenarios as follows: mAVR: total 76% (57% A, 19% I); tAVR: total 68% (68% A, 0% I); Ross: total 66% (39% A, 27% I); Ozaki: total 31% (3% A, 28% I). The remainder of percentages to 100% reflects the degree of uncertainty. There was a consensus that transcatheter aortic valve implantation is appropriate for 5 of 68 (7%) of all clinical scenarios (including frailty, prohibitive surgical risk and very limited life span). Conclusions: Evidence-based expert opinion emerging from a formal consensus process indicates that besides conventional AVR options, there is a high degree of certainty about the suitability of the Ross procedure in patients aged 18-60 years. Future clinical guidelines should include the option of the Ross procedure in aortic prosthetic valve selection

Impaired Vascular Contractility and Aortic Wall Degeneration in Fibulin-4 Deficient Mice: Effect of Angiotensin II Type 1 (AT1) Receptor Blockade

Medial degeneration is a key feature of aneurysm disease and aortic dissection. In a murine aneurysm model we investigated the structural and functional characteristics of aortic wall degeneration in adult fibulin-4 deficient mice and the potential therapeutic role of the angiotensin (Ang) II type 1 (AT1) receptor antagonist losartan in preventing aortic media degeneration. Adult mice with 2-fold (heterozygous Fibulin-4+/R) and 4-fold (homozygous Fibulin-4R/R) reduced expression of fibulin-4 displayed the histological features of cystic media degeneration as found in patients with aneurysm or dissection, including elastin fiber fragmentation, loss of smooth muscle cells, and deposition of ground substance in the extracellular matrix of the aortic media. The aortic contractile capacity, determined by isometric force measurements, was diminished, and was associated with dysregulation of contractile genes as shown by aortic transcriptome analysis. These structural and functional alterations were accompanied by upregulation of TGF-β signaling in aortas from fibulin-4 deficient mice, as identified by genome-scaled network analysis as well as by immunohistochemical staining for phosphorylated Smad2, an intracellular mediator of TGF-β. Tissue levels of Ang II, a regulator of TGF-β signaling, were increased. Prenatal treatment with the AT1 receptor antagonist losartan, which blunts TGF-β signaling, prevented elastic fiber fragmentation in the aortic media of newborn Fibulin-4R/R mice. Postnatal losartan treatment reduced haemodynamic stress and improved lifespan of homozygous knockdown fibulin-4 animals, but did not affect aortic vessel wall structure. In conclusion, the AT1 receptor blocker losartan can prevent aortic media degeneration in a non-Marfan syndrome aneurysm mouse model. In established aortic aneurysms, losartan does not affect aortic architecture, but does improve survival. These findings may extend the potential therapeutic application of inhibitors of the renin-angiotensin system to the preventive treatment of aneurysm disease