Occlusive disease confined to the right coronary artery: Clinical features, surgical treatment and long-term follow-up in 124 patients

The clinical presentation and surgical results in 124 consecutive patients who underwent aorta to right coronary arterial bypass surgery from January 1970 through June 1977 were reviewed. Preoperatively, 75 percent of the patients were in New York Heart Association functional class III or IV, 9 percent presented with unstable angina and 5 percent had life-threatening ventricular arrhythmias. All patients had high grade occlusive disease confined to the right coronary artery; 34 percent of the patients had associated nonsignificant disease (less than 50 percent intraluminal narrowing) of the left anterior descending or circumflex artery. Left ventricular function was normal in 63 percent and minimally impaired in 37 percent. The operative mortality rate was 1.6 percent. The course of the 122 survivors was followed up for 3.7 years. There were four late deaths, and the 5 year mortality rate was 4.0 percent. Eight patients were reoperated on because of recurrence of symptoms and occlusion of the graft or progression of occlusive disease of the other major coronary arteries, or both. Of the remaining 110 patients, 98 are either in functional class I or II, 60 are taking no cardiovascular medications, 52 are working full time without angina and 73 are asymptomatic. In summary, bypass surgery for isolated right coronary artery disease has a low mortality rate and results in excellent long-term symptomatic improvement.     

Spontaneous vesiculation of phospholipids: a simple and quick method of forming unilamellar vesicles.

Phosphatidic acid dispersions in H2O vesiculate when the pH is increased transiently (less than 2 min) from approximately 3 to 10.5-11. The same phenomenon is observed in mixed dispersions of phosphatidylcholine and phosphatidic acid in H2O when the pH is increased from approximately 3 to 7 to 8. With phosphatidic acid, this treatment produces small closed unilamellar vesicles (200-600 A) from 50-60% of the total phospholipid, with the remainder present as large unilamellar vesicles and multilamellar structures. The extent of vesiculation depends on the pH that the dispersion is exposed to. With mixed phospholipid dispersions, similar vesicles are obtained; in addition to pH, the extent of vesiculation depends on the phosphatidylcholine/phosphatidic acid (wt/wt) ratio; as this ratio increases, the percentage of small unilamellar vesicles formed decreases. The short exposure of the phospholipids to high pH does not cause lipid degradation, as assessed by thin-layer chromatography; hence, the formation of degradation products can be ruled out as being responsible for the spontaneous vesiculation. Ionization of the phosphate group, resulting in a high surface charge density, may be an important factor in the spontaneous vesiculation. The proportion of phospholipid present as small unilamellar vesicles was determined by gel filtration on Sepharose 4B and by 1H NMR. The small vesicles gave rise to a reasonably well resolved high-resolution NMR spectrum. A good correlation was found between the proportion of phospholipid giving rise to the high resolution spectrum, as derived from spectral intensity measurements, and the proportion present as small unilamellar vesicles, as derived from gel filtration.     

A substance P (neurokinin-1) receptor mutant carboxyl-terminally truncated to resemble a naturally occurring receptor isoform displays enhanced responsiveness and resistance to desensitization

Two isoforms of the substance P (SP) receptor, differing in the length of the cytoplasmic carboxyl-terminus by ≈8 kDa, have been detected previously in rat salivary glands and other tissues. The binding and functional properties of these two isoforms have been investigated using full-length (407 amino acids) and carboxyl-terminally truncated (324 amino acids) rat SP receptors transfected stably into Chinese hamster ovary cells. Both the full-length and the truncated receptor bound radiolabeled SP with a similar K_d (≈0.1 nM). The average number of high affinity SP binding sites per cell was 1.0 × 10⁵ and 0.3 × 10⁵ for the full-length and the truncated SP receptor, respectively. In both cell lines, SP induced a rapid but transient increase in cytosolic calcium concentration ([Ca²⁺]_i), which consisted of the release of Ca²⁺ from intracellular stores and the influx of extracellular Ca²⁺. Both components are dependent on phospholipase C activation. Although the full-length and the truncated receptor utilize the same calcium pathways, they differ in their EC₅₀ values (0.28 nM for the full-length; 0.07 nM for the truncated). These differences in responsiveness may be related to the observed differences in receptor desensitization. The truncated receptor, in contrast to the full-length receptor, does not undergo rapid and long-lasting desensitization. Cells possessing the short isoform of the SP receptor would thus be expected to exhibit a prolonged responsiveness.     

Direct acute tubular damage contributes to Shigatoxin‐mediated kidney failure

The pathogenesis and therapy of Shigatoxin 2 (Stx2)‐mediated kidney failure remain controversial. Our aim was to test whether, during an infection with Stx2‐producing E. coli (STEC), Stx2 exerts direct effects on renal tubular epithelium and thereby possibly contributes to acute renal failure. Mice represent a suitable model because they, like humans, express the Stx2‐receptor Gb3 in the tubular epithelium but, in contrast to humans, not in glomerular endothelia, and are thus free of glomerular thrombotic microangiopathy (TMA). In wild‐type mice, Stx2 caused acute tubular dysfunction with consequent electrolyte disturbance, which was most likely the cause of death. Tubule‐specific depletion of Gb3 protected the mice from acute renal failure. In vitro, Stx2 induced secretion of proinflammatory cytokines and apoptosis in human tubular epithelial cells, thus implicating a direct effect of Stx2 on the tubular epithelium. To correlate these results to human disease, kidney biopsies and outcome were analysed in patients with Stx2‐associated kidney failure (n = 11, aged 22–44 years). The majority of kidney biopsies showed different stages of an ongoing TMA; however, no glomerular complement activation could be demonstrated. All biopsies, including those without TMA, showed severe acute tubular damage. Due to these findings, patients were treated with supportive therapy without complement‐inhibiting antibodies (eculizumab) or immunoadsorption. Despite the severity of the initial disease [creatinine 6.34 (1.31–17.60) mg/dl, lactate dehydrogenase 1944 (753–2792) U/l, platelets 33 (19–124)/nl and haemoglobin 6.2 (5.2–7.8) g/dl; median (range)], all patients were discharged after 33 (range 19–43) days with no neurological symptoms and no dialysis requirement [creatinine 1.39 (range 0.84–2.86) mg/dl]. The creatinine decreased further to 0.90 (range 0.66–1.27) mg/dl after 24 months. Based on these data, one may surmise that acute tubular damage represents a separate pathophysiological mechanism, importantly contributing to Stx2‐mediated acute kidney failure. Specifically in young adults, an excellent outcome can be achieved by supportive therapy only. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Patient‐reported convenience of once‐daily versus three‐times‐daily dosing during long‐term studies of pramipexole in early and advanced Parkinson’s disease

Background and purpose: In chronic diseases including Parkinson’s disease (PD), complex pharmacotherapy dosing schedules are reported to reduce adherence, perhaps leading to less‐effective symptom control and, in PD, more erratic stimulation of dopamine receptors. However, blinded clinical‐trial designs preclude direct comparisons of adherence to various schedules. Methods: In two double‐blind (DB) studies of early PD and one of advanced PD, subjects received three‐times‐daily (t.i.d.) pramipexole or placebo. In open‐label (OL) extensions, subjects took extended‐release, once‐daily (q.d.) pramipexole. At 24 or 32 OL weeks, q.d. versus t.i.d. dosing preference was surveyed by questionnaire. Results: Of 590 DB‐trial completers with early PD, 511 entered the OL extension. Of 374 survey respondents, 94.4% preferred q.d. dosing (72.2% of them found it ‘very much more convenient’ and 27.8%‘more convenient’), 2.7% preferred t.i.d., and 2.9% chose ‘no difference’. Of 465 DB‐trial completers with advanced PD, 391 entered its OL extension. Of 334 survey respondents, 88.9% preferred q.d. dosing (59.9% of them found it ‘very much more convenient’ and 40.1%‘more convenient’), 5.7% preferred t.i.d., and 5.4% chose ‘no difference’. Results excluding DB‐placebo recipients were highly similar. Conclusions: In this first direct comparison of patient preference for q.d. versus t.i.d. dopamine‐agonist dosing, patients with early or advanced PD had a strong preference for q.d. rather than t.i.d. pramipexole. The high proportion of advanced‐PD patients declaring this preference indicates that it does not depend on whether a patient is taking concomitant PD medications dosed more frequently than q.d.