Postoperative mortality in infective endocarditis: determinant factors

OBJECTIVE: It has been shown recently that 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) is expressed as at least 2 isozymes. In the liver, 11 beta-HSD1 converts cortisone to cortisol; in the kidney, 11 beta-HSD2 converts cortisol to cortisone. Conventional assessment of 11 beta-HSD activity in vivo has relied on gas chromatographic measurement of the ratios of conjugated cortisol and cortisone metabolites. However, these do not permit distinction between the tissue-specific activities of the enzymes and do not reflect all forms of 11 beta-HSD deficiency. In this report, we have assessed the usefulness of measuring unconjugated cortisol metabolites and free cortisol and cortisone in urine as indices of renal 11 beta-HSD activity in man. DESIGN: Six healthy male subjects established in sodium balance were given either glycyrrhetinic acid (170 mg t.d.s., to inhibit 11 beta-HSD2), carbenoxolone (100 mg t.d.s., to inhibit both 11 beta-HSD1 and 11 beta- HSD2) or both inhibitors in combination. MEASUREMENTS: Urinary electrolytes were measured and the concentrations of total and unconjugated urinary cortisol and its metabolites were determined by gas chromatography mass spectrometry. RESULTS: Glycyrrhetinic acid and carbenoxolone inhibited renal 11 beta-HSD2 to a similar degree, as judged by similar sodium retention. As previously reported, conventional measurement of ratios of total cortisol to cortisone metabolites were influenced to a greater extent by glycyrrhetinic acid (100-200% increase in ratio from baseline) than by carbenoxolone (< 30% increase). However, the effect of carbenoxolone was readily detected by measurement of urinary unconjugated cortisol/cortisone (130-480% increase of ratio from baseline) and also by measurement of ratios of unconjugated cortisol metabolites (60-130% increase). CONCLUSIONS: Measurement of free cortisol and cortisone in urine provides the most sensitive index of renal 11 beta-HSD activity. Measurement of total and conjugated urinary steroids is insensitive in circumstances where 11 beta-HSD activity in liver or elsewhere may be abnormal.     

Discharge planning and community housing in Ontario

As hospital budgets in Ontario (and elsewhere) continue to shrink in the face of governmental fiscal pressure, bed closures lead to the discharge of increasingly vulnerable persons. Many of these persons have no family and no obvious place to go. Community supports to assist people outside the hospitals are not provided at a level commensurate with the need. The result is inadequate housing, social isolation, non-existent care and, in too many cases, reinstitutionalization and/or preventable deaths. This paper describes the process by which vulnerable adults wind up in unsuitable community settings, as a result of ill-conceived deinstitutionalization in the province of Ontario. It places a particular focus on the difficult role played by the discharge planner as conduit from hospital to community. The planner is often caught in the middle, facing hospital (and physician) directives to empty beds precipitously, alongside an acute shortage of suitable housing in the community. Departing patients are often sent to settings that lack any form of governmental inspection, regulation, licensure, or control: they are at the mercy of often indifferent and, at times, overtly rapacious landlords who may take the welfare cheque and give little in return. Selected case material, including one recent inquest, highlight the difficulties.     

Geranoyl-CoA carboxylase: a novel biotin-containing enzyme in plants

Geranoyl-CoA carboxylase (EC 6.4.1.4) is a biotin-containing enzyme previously described in two genera of bacteria. Here we report the presence of geranoyl-CoA carboxylase in kingdom Plantae. Geranoyl-CoA carboxylase was purified 180-fold from maize leaves. The enzyme has a biotin-containing subunit of 122 kDa. The pH optimum for activity is 8.3. The apparent Km values for the substrates geranoyl-CoA, bicarbonate, and ATP are 64 +/- 5 microM, 0. 58 +/- 0.04 mM, and 8.4 +/- 0.4 microM, respectively. Subcellular fractionations indicate that geranoyl-CoA carboxylase is located in plastids. Geranoyl-CoA carboxylase activity is ubiquitous in organs of monocots and dicots and varies with development. We postulate that geranoyl-CoA carboxylase plays an important role in isoprenoid catabolism in plants, in a pathway analogous to that shown in Psuedomonas sp. In plants, this catabolic pathway would require the interaction of at least three subcellular compartments (plastids, microbodies, and mitochondria) and two biotin-containing enzymes, geranoyl-CoA carboxylase and 3-methylcrotonyl-CoA carboxylase.     

Modulation of p27(Kip1) levels by the cyclin encoded by Kaposi's sarcoma-associated herpesvirus

DNA tumour viruses have evolved a number of mechanisms by which they deregulate normal cellular growth control. We have recently described the properties of a cyclin encoded by human herpesvirus 8 (also known as Kaposi's sarcoma-associated herpesvirus) which is able to resist the actions of p16(Ink4a), p21(Cip1) and p27(Kip1) cdk inhibitors. Here we investigate the mechanism involved in the subversion of a G1 blockade imposed by overexpression of p27(Kip1). We demonstrate that binding of K cyclin to cdk6 expands the substrate repertoire of this cdk to include a number of substrates phosphorylated by cyclin-cdk2 complexes but not cyclin D1-cdk6. Included amongst these substrates is p27(Kip1) which is phosphorylated on Thr187. Expression of K cyclin in mammalian cells leads to p27(Kip1) downregulation, this being consistent with previous studies indicating that phosphorylation of p27(Kip1) on Thr187 triggers its downregulation. K cyclin expression is not able to prevent a G1 arrest imposed by p27(Kip1) in which Thr187 is mutated to non-phosphorylatable Ala. These results imply that K cyclin is able to bypass a p27(Kip1)-imposed G1 arrest by facilitating phosphorylation and downregulation of p27(Kip1) to enable activation of endogenous cyclin-cdk2 complexes. The extension of the substrate repertoire of cdk6 by K cyclin is likely to contribute to the deregulation of cellular growth by this herpesvirus-encoded cyclin.     

Diltiazem and pentoxifylline determination in postmortem specimens

A 78-year-old woman was found dead in her basement. Qualitative screening of available postmortem specimens detected the presence of diltiazem and pentoxifylline. Quantitations were carried out by gas chromatography using nitrogen-phosphorus detection and confirmed by gas chromatography-mass spectrometry with the following results: blood, 0.59 mg/dL diltiazem and 0.63 mg/dL pentoxifylline; urine, 1.17 mg/dL diltiazem and 0.08 mg/dL pentoxifylline; bile, 0.40 mg/dL diltiazem and 0.22 mg/dL pentoxifylline; gastric contents, 0.28 mg/dL diltiazem and 0.02 mg/dL pentoxifylline. Both drugs were found qualitatively in formaline-fixed tissues.     

Sydenham Chorea: magnetic resonance imaging reveals permanent basal ganglia injury

We report the case of a 26-year-old man with diffuse esophageal leiomyomatosis involving the trachea. The tumor was resected by total esophagectomy and partial resection of the trachea and the left main bronchus. The tracheobronchial defect was repaired with a free forearm skin graft with satisfactory outcome. This approach offers good long-term prospects.     

Relationship between prothrombin activation fragment F1.2 and international normalized ratio in patients with atrial fibrillation. Stroke Prevention in Atrial Fibrillation Investigators

BACKGROUND AND PURPOSE: The prothrombin time (expressed as the international normalized ratio [INR]) is the standard method of monitoring warfarin therapy in patients with atrial fibrillation. Prothrombin activation fragment F1.2 provides an index of in vivo thrombin generation and might provide a better index of the effective intensity of anticoagulation. We examined the relationship between F1.2 and INR in patients with atrial fibrillation. METHODS: We measured INR and F1.2 levels in 846 patients with atrial fibrillation participating in the Stroke Prevention in Atrial Fibrillation III study. Two hundred nineteen (26%) were taking aspirin alone, 326 (39%) were taking adjusted-dose warfarin, and 301 (36%) were taking a low fixed dose of warfarin (1 to 3 mg) plus aspirin (combination therapy). F1.2 levels were measured with an enzyme-linked immunosorbent assay. RESULTS: Patients receiving adjusted-dose warfarin or combination therapy had significantly higher INR and significantly lower F1.2 values than those on aspirin alone (P < or = .0001 for each of the four comparisons). F1.2 values (nanomolar) were inversely correlated with INR (F1.2 = -0.1 + 2.3[1/INR]; R2 = .37; P < .0001; simple linear regression). However, significant variability remained. Among patients receiving warfarin, older patients had higher F1.2 values than younger patients after adjustment for INR intensity (P < .001) in the model. There was no difference in the relationship between F1.2 and INR between men and women. CONCLUSIONS: Increasing intensity of anticoagulation, as measured by the INR, is associated with decreasing thrombin generation as measured by the F1.2 level, but significant variability exists in this relationship. Older anticoagulated patients have higher F1.2 values than younger patients at equivalent INR values. The clinical significance of these differences is not clear. F1.2 measurement might provide information regarding anticoagulation intensity in addition to that reflected by the INR.