Prognostic impact of cytogenetic and interphase fluorescence in situ hybridization-defined chromosome 13 deletion in multiple myeloma: early results of total therapy II

Cytogenetic abnormalities of chromosome 13 (CA 13) and those detected by fluorescence in situ hybridization (FISH 13) have both been associated with poor prognosis in multiple myeloma (MM) patients. The prognostic implications of CA, FISH 13 and other standard laboratory parameters were examined in the first 231 patients enrolled in Total Therapy II, an intensive cytotoxic chemotherapy programme with tandem autotransplants. Three-year projections of event-free survival (EFS) and overall survival (OS) were 71% and 77% respectively. CA 13 was detected in 14% and significantly correlated with FISH 13 (present in 51%), tumour burden, proliferative activity and lactic dehydrogenase (LDH). Both EFS and OS were significantly shorter in patients with CA 13, FISH 13, LDH >or= 190 U/l, beta2 microglobulin >or= 4 mg/l and C reactive protein >or= 4.0 mg/l; other CA was an additional risk factor for OS. Two-thirds of CA 13 patients were identified by FISH 13 and plasma-cell-labelling index (PCLI) >or= 0.4%; however, PCLI failed to identify additional risk groups in FISH subsets. Although present in considerably fewer patients, CA 13 imparted more rapid relapse (61% at 3 years) and death (43% at 3 years) than FISH 13 (38% and 35%; P = 0.02 and 0.1 respectively) and should be part of the initial work-up of patients with MM.     

Lower visceral and subcutaneous but higher intermuscular adipose tissue depots in patients with growth hormone and insulin-like growth factor I excess due to acromegaly

CONTEXT: GH and IGF-I are important regulators of metabolism and body composition. In acromegaly, a state of GH and IGF-I excess, the lipolytic and insulin antagonistic effects of GH may alter adipose tissue (AT) distribution. OBJECTIVES: Our objective was to test the hypothesis that in acromegaly whole-body AT mass is less and to examine for the first time the relationship between GH/IGF-I excess and intermuscular AT (IMAT), an AT depot associated with insulin resistance in other populations. DESIGN, SETTING, AND PATIENTS: We conducted a cross-sectional study in 24 adults with active acromegaly compared with predicted models developed in 315 healthy non-acromegaly subjects. OUTCOME MEASURES: Mass of AT in the visceral AT (VAT), sc AT (SAT), and IMAT compartments from whole-body magnetic resonance imaging and serum levels of GH, IGF-I, insulin, and glucose were measured. RESULTS: VAT and SAT were less in active acromegaly (P < 0.0001); these were 68.2 +/- 27% and 79.5 +/- 15% of predicted values, respectively. By contrast, IMAT was greater (P = 0.0052) by 185.6 +/- 84% of predicted. VAT/trunk AT ratios were inversely related to IGF-I levels (r = 0.544; P = 0.0054). Acromegaly subjects were insulin resistant. CONCLUSIONS: VAT and SAT, most markedly VAT, are less in acromegaly. The proportion of trunk AT that is VAT is less with greater disease activity. IMAT is greater in acromegaly, a novel finding, which suggests that increased AT in muscle could be associated with GH-induced insulin resistance. These findings have implications for understanding the role of GH in body composition and metabolic risk in acromegaly and other clinical settings of GH use.     

Effect of colestipol and clofibrate on plasma lipid and lipoproteins in Type IIa hyperlipoproteinemia

The effects of 2.0 g of clofibrate and 15, 20 and 30 g of colestipol on plasma lipid and lipoprotein levels were evaluated in adult patients with Type IIa hyperlipoproteinemia. Clofibrate treatment was associated with decreases of 11.0% in plasma cholesterol, 15.2% in LDL cholesterol, 26.1% in triglycerides, and an 11.3% increase in HDL cholesterol. The reductions in total cholesterol with the various doses of colestipol ranged from 11.9 to 17.8% and reductions in LDL cholesterol ranged from 16.1 to 27.3%. Colestipol treatment was not associated with any significant change in HDL cholesterol levels and minor increases in triglycerides. The addition of clofibrate to patients receiving colestipol resulted in a significant increase in HDL cholesterol and a decrease in triglycerides, but no additional reduction in total or LDL cholesterol.     

Filiform Polyposis of the Colon Presenting as Massive Hemorrhage: An Uncommon Complication of Crohn''s Disease

A case of localized filiform polyposis of the colon is presented. This lesion was part of a more generalized inflammatory bowel disease with clinicopathological features indicative of Crohn's disease. An unusual feature of this case was profuse rectal bleeding, initially from a solitary sigmoid ulcer and later from the area of filiform polyposis. A step by step clinicopathological follow-up emphasizing the development of filiform polyps is provided.     

Up-regulation of connexin45 in heart failure

INTRODUCTION: Heart failure is associated with reduced expression of the major gap junction protein connexin43 (Cx43), which may contribute to arrhythmias and sudden cardiac death in this patient population. Other cardiac connexins may be altered as well. Because connexin45 (Cx45) has been shown to colocalize with Cx43, we determined whether the number, size, or distribution of Cx45 gap junctions is altered in the failing heart. METHODS AND RESULTS: Cx45 expression levels were measured by immunoblotting and quantitative immunostaining in failing and control human left ventricles. Total Cx45 protein was significantly (P = 0.021) up-regulated 1.8-fold in failing hearts. Cx45 immunohistochemical signal was increased by 80% (P = 0.005) due to a 3.5-fold increase in the number of gap junctions containing Cx45. Cx45 mRNA was not altered in failing hearts, suggesting reduced degradation of Cx45 protein in the failing heart. Cx43 signal, on the other hand, was reduced by 49% in failing hearts. Double-label experiments demonstrated colocalization of Cx45 and Cx43 in the same gap junctions. CONCLUSION: Cx45 is markedly enhanced in the failing heart. Up-regulation of Cx45 in conjunction with down-regulation of Cx43 could result in abnormal impulse propagation and generation of ventricular arrhythmias, thereby predisposing patients in heart failure to sudden cardiac death.     

Development and evaluation of a microdevice for amino acid biomarker detection and analysis on Mars

The Mars Organic Analyzer (MOA), a microfabricated capillary electrophoresis (CE) instrument for sensitive amino acid biomarker analysis, has been developed and evaluated. The microdevice consists of a four-wafer sandwich combining glass CE separation channels, microfabricated pneumatic membrane valves and pumps, and a nanoliter fluidic network. The portable MOA instrument integrates high voltage CE power supplies, pneumatic controls, and fluorescence detection optics necessary for field operation. The amino acid concentration sensitivities range from micromolar to 0.1 nM, corresponding to part-per-trillion sensitivity. The MOA was first used in the lab to analyze soil extracts from the Atacama Desert, Chile, detecting amino acids ranging from 10-600 parts per billion. Field tests of the MOA in the Panoche Valley, CA, successfully detected amino acids at 70 parts per trillion to 100 parts per billion in jarosite, a sulfate-rich mineral associated with liquid water that was recently detected on Mars. These results demonstrate the feasibility of using the MOA to perform sensitive in situ amino acid biomarker analysis on soil samples representative of a Mars-like environment.     

Old age security and the defense of social norms

This paper identifies various kinds of risk and uncertainty observable in rural areas of developing countries and explains the relative importance of those pertaining to disability and old age. It compares the modern system (based on old age pensions and social security) for mitigating or coping with these risks with the traditional intrafamilial support mechanisms. The paper concludes that, when the traditional system is functioning smoothly, it can address these needs at far lower cost than the modern system. The efficiency and viability of the traditional system can be considerably enhanced by the presence of social norms, on the one hand, and of strategic instruments in the hands of household heads, on the other. Since both of these defenses are often undermined prematurely by modernizing influences, the paper identifies possible actions for avoiding or postponing the effects of such influences.The author expresses his appreciation to Richard Anker, Mussadegh Chowdhury, Richard Easterlin, Jeremy Evans and one of the editors for useful comments and suggestions and to the US Agency for International Development for financial support for some earlier research upon which this paper is partially based.     

Electrocardiographic changes associated with β-blocker toxicity

Study objective: We sought to characterize the ECG changes associated with symptomatic β-blocker overdose. Methods: The study population consisted of a prospective cohort of patients reporting to 2 regional poison centers with β-blocker overdose. Each patient received an ECG on presentation and a structured follow-up. The inclusion criteria for symptomatic overdose included heart rate of less than 60 beats/min or systolic blood pressure of less than 90 mm Hg; symptoms consistent with decreased end-organ perfusion; therapeutic intervention with cardioactive medication; and corroboration by 2 of the authors that this was a clear-cut case of symptomatic β-blocker overdose with cardiovascular toxicity. Exclusion criteria included cardioactive coingestants, age younger than 6 years, and no available ECG. Results: Of 167 patients, 13 were determined to have symptomatic exposures. First-degree heart block (>200 ms) was the most common ECG finding (10/12) and also had the greatest likelihood ratio (5.31) when comparing those with symptomatic exposures with those with asymptomatic exposures. Comparing the asymptomatic with the symptomatic groups, the mean PR interval was 167 ms (95% confidence interval [CI] 162 to 171 ms) versus 216 ms (95% CI 193 to 238 ms), the mean QRS interval was 89 ms (95% CI 87 to 91 ms) versus 112 ms (95% CI 92 to 132 ms), the mean QTc interval was 422 ms (95% CI 417 to 428) versus 462 ms (95% CI 434 to 490 ms), and the mean heart rate was 72 beats/min (95% CI 69 to 74 beats/min) versus 66 beats/min (95% CI 59 to 73 beats/min). Two cases of symptomatic acebutolol exposure appeared unique by demonstrating disproportionate prolongation of the QTc interval, an RaVR height of 3 mm or greater, and associated ventricular tachydysrhythmia. Conclusion: The majority of clinically significant β-blocker intoxications demonstrate negative dromotropic effects on ECG. Several ECG differences in acebutolol intoxication might reflect unique pathophysiologic processes relative to other β-blockers. [Ann Emerg Med. 2002;40:603-610.]     

Confinement of caspase-12 proteolytic activity to autoprocessing

Caspase-12 is a dominant-negative regulator of caspase-1 (IL-1beta-converting enzyme) and an attenuator of cytokine responsiveness to septic infections. This molecular role for caspase-12 appears to be akin to the role of cFLIP in regulating caspase-8 in the extrinsic cell death pathway; however, unlike cFLIP/Usurpin, we demonstrate here that caspase-12 is catalytically competent. To examine these catalytic properties, rat caspase-12 was cloned, and the recombinant enzyme was used to examine the cleavage of macromolecular and synthetic fluorogenic substrates. Although caspase-12 could mediate autoproteolytic maturation of its own proenzyme, in both cis and trans, it was not able to cleave any other polypeptide substrate, including other caspase proenzymes, apoptotic substrates, cytokine precursors, or proteins in the endoplasmic reticulum that normally undergo caspase-mediated proteolysis. The dearth of potential substrates for caspase-12 also was confirmed by whole-cell diagonal-gel analysis. Autolytic cleavage within the caspase-12 proenzyme was mapped to a single site at the large-small subunit junction, ATAD(319), and this motif was recognized by caspase-12 when incorporated into synthetic fluorogenic substrates. The specific activity of caspase-12 with these substates was several orders of magnitude lower than caspases-1 and -3, highlighting its relative catalytic paucity. In intact cells, caspase-12 autoproteolysis occurred in the inhibitory complex containing caspase-1. We propose that the proteolytic activity of caspase-12 is confined to its own proenzyme and that autocleavage within the caspase-1 complex may be a means for temporal limitation of the inhibitory effects of caspase-12 on proinflammatory cytokine maturation.