Expression of alpha-methylacyl-CoA racemase (P504s) in various malignant neoplasms and normal tissues: astudy of 761 cases

Alpha-methylacyl CoA racemase (AMACR), also known as P504S, plays an important role in peroxisomal beta-oxidation of branched-chain fatty acids. It has recently been shown that AMACR is highly expressed in prostate cancer and that it may be an important diagnostic marker for prostate carcinoma. However, little is known about expression of AMACR in normal tissues and other malignant tumors. In this study, we investigated expression of AMACR in 539 malignant tumors and 222 normal human tissues of various types by immunohistochemical analysis. mRNA levels of AMACR in normal organs and in selected tumors were assessed by real time PCR. In normal tissue, high expression of AMACR mRNA was identified in liver, kidney and salivary gland, while AMACR protein was detected in liver (hepatocytes), kidney (tubular epithelial cells), lung (only bronchial epithelial cells), and gallbladder (only mucosal epithelial cells). High expression of AMACR mRNA was found in prostate, liver, and kidney cancers but rarely in stomach and bladder cancers. A high percent of adenocarcinomas arising from these organs express AMACR, including 17 of 21 (81%) of hepatocellular carcinomas and 18 of 24 (75%) of renal cell carcinomas. In addition, carcinomas arising from tissues normally not expressing AMACR were also positive for the antigen, including 17 of 18 (94%) prostate carcinomas, 9 of 29 (31%) of urothelial carcinomas, and 4 of 15 (27%) of gastric adenocarcinomas. Two hundred and fifty cases of adenocarcinomas from lung, breast, pancreas, bile duct, adrenal gland, salivary gland, ovary, thyroid and endometrium were negative or rarely positive for AMACR. Neuroendocrine carcinomas rarely expressed AMACR. Melanomas, squamous cell carcinomas, basal cell carcinomas, soft tissue tumors (including epithelioid sarcomas and synovial sarcoma), thymomas, and germ cell tumors were negative for AMACR. Our data provide important baseline information for using AMACR in clinical practice and also are valuable in furthering understanding of the pathogenic role of AMACR in malignant neoplasms.     

Origin of multiple "primary" colon carcinomas. A retrospective flow cytometric study

Multiple, synchronous, apparently primary carcinomas of the colon are a relatively common occurrence. The DNA ploidy in 23 colon carcinomas from 10 patients was determined to see if this parameter supported common or independent origins for such synchronous lesions. Paraffin blocks of each tumor were prepared for flow cytometry, then analyzed for nuclear DNA content. In 3 of the 10 cases, the tumors within each colon differed with respect to DNA ploidy; in four cases all tumors were diploid; and in three cases both (all) tumors within each colon had identical aneuploid DNA indices. Tumors from the same colon with identical DNA histograms often had dissimilar histology. The replicate aneuploid DNA indices strongly suggest a common origin for the multiple tumors within these colons; tumors in the other groups are compatible with either single or multiple origins. These findings suggest that multiple "primary" colon carcinomas may, in some cases, arise as translumenal metastases from an initial single lesion.     

The use and effects of vital fluorescent dyes: observation of motor nerve terminals and satellite cells in living frog muscles

Summary Several different fluorescent mitochondrial dyes were tested as vital stains for motor nerve terminals and other cells in frog skeletal muscles. It was found that 3,3diethyloxadicarbocyanine iodide and 4-(4-diethylaminostyryl)-N-methylpyridinium iodide were most useful. Both dyes labelled motor nerve terminals with high reliability. Electrophysiological and morphological control experiments showed that these dyes could be used to repeatedly observe neuromuscular junctions in living animals without affecting synaptic growth or remodelling. The importance of appropriate controls was emphasized by the finding that illumination, if excessively intense or prolonged, can cause physiological and structural damage to nerve terminals. Additional observations indicated that these dyes may be useful for determining the mitochondrial content, and therefore oxidative capacity, of living muscle fibres. It was also found that the fluorescent dyes labelled cells identified as muscle satellite cells, and that these myoblast precursors could be visualized in fixed whole mounts with a nitroblue tetrazolium stain. Both methods were used to study reactive cells that were closely associated with muscle fibres in lesioned muscles. Mitochondrial dyes also labelled the microvasculature, associated axons and other cells.     

Adverse events associated with pediatric exposures to dextromethorphan

Study objective: Dextromethorphan is the most common over-the-counter (OTC) antitussive medication. We sought to characterize adverse events associated with dextromethorphan in children <12 years old from a surveillance program of OTC cough/cold medication exposures.

Methods: This is a retrospective case series of oral exposures to dextromethorphan with ≥1 adverse event from multiple U.S. sources (National Poison Data System, FDA Adverse Event Reporting System, manufacturer safety reports, news/media, medical literature) reported between 2008 and 2014. An expert panel determined the relationship between exposure and adverse events, estimated dose ingested, intent of exposure, and identified contributing factors to exposure.

Results: 1716 cases contained ≥1 adverse event deemed at least potentially related to dextromethorphan; 1417 were single product exposures. 773/1417 (55%) involved only one single-ingredient dextromethorphan product (dextromethorphan-only). Among dextromethorphan-only cases, 3% followed ingestion of a therapeutic dose; 78% followed an overdose. 69% involved unsupervised self-administration and 60% occurred in children <4 years old. No deaths or pathologic dysrhythmias occurred. Central nervous system [e.g., ataxia (N?=?420)] and autonomic symptoms [e.g., tachycardia (N?=?224)] were the most common adverse events. Flushing and/or urticarial rash occurred in 18.1% of patients. Dystonia occurred in 5.4%.

Conclusions: No fatalities were identified in this multifaceted surveillance program following a dextromethorphan-only ingestion. Adverse events were predominantly associated with overdose, most commonly affecting the central nervous and autonomic systems.     

Efficacy and safety of fluvastatin therapy for hypercholesterolemia after heart transplantation: results of a randomised double blind placebo controlled study

BACKGROUND: Hypercholesterolemia is frequent after heart transplantation. Statins can reduce cholesterol levels but their use in heart transplant patients is complicated by pharmacokinetic interactions with cyclosporin and the risk of serious adverse effects including rhabdomyolysis. Fluvastatin has been used safely to treat hypercholesterolemia in renal transplant patients but there are few data relating to its use after heart transplantation. Therefore, we conducted a randomised blinded placebo controlled trial. METHODS AND RESULTS: Seventy-nine patients, 3 months to 12 years after heart transplantation with a low density lipoprotein (LDL) cholesterol between 3.5 and 8.0 mmol/l were randomly assigned, in a 2:1 ratio, to receive either fluvastatin 40 mg od (n=52) or matching placebo (n=27). Changes in total cholesterol (TC) in the fluvastatin and placebo groups were -17.0% and +4.5%, respectively, (p<0.001); the corresponding changes in LDL were -20.5% and +4.8% (P<0.001) and in triglycerides -14.5% and +7.1% (p=0.012) at the end of the 1-year study period. Withdrawals were more frequent in the fluvastatin group (23% vs. 11% p=0.24). Two deaths occurred during the study (the rate expected from International Society of Heart Lung Transplantation registry) and appeared to be unrelated to the study medication. There were no episodes of rhabdomyolysis or other serious drug-related side effects. CONCLUSIONS: Fluvastatin (40 mg/day) was both an effective and a safe treatment for hypercholesterolemia in patients who had undergone heart transplantation more than 3 months previously.     

Diagnosis of inferior wall myocardial infarction during right ventricular apical pacing.

The diagnosis of inferior wall myocardial infarction is often masked during ventricular pacing. We observed paced ventricular beats with a qR pattern in leads 2,3, and aVF in a patient with acute inferior wall myocardial infarction and a temporary pacemaker at the apex of the right ventricle. Such a pattern might be specific for the diagnosis of inferior wall myocardial infarction, because it is never seen during uncomplicated pacing from anywhere within the right ventricular cavity.     

A UK Single Centre Retrospective Analysis of the Relationship between Haemodynamic Changes and Outcome in Patients Undergoing Prolonged Left Ventricular Assist Device Support

Purpose: Despite their efficacy, LVADs remain associated with serious complications. The relationship between haemodynamic changes during support and outcome remains inadequately characterised. This association was investigated in LVAD recipients undergoing prolonged support.Methods: Forty patients receiving LVAD therapy for >2 years were reviewed retrospectively (mean support duration was 38.62 ± 15.28). Pre- and on-LVAD haemodynamic data were assessed in three groups: (1) those receiving ongoing support (n = 24); (2) those who underwent cardiac transplantation (n = 4); (3) those who died during support (n = 12).Results: For group 1 and 2, LVAD support achieved a decrease in mean PAP, mean PCWP, TPG, and PVR and an increase in thermodilution blood flow (TBF) with significance at ≤5% level. For group 3, there were non-significant changes in TPG and PVR at the 5% level but for mean PAP, mean PCWP, and TBF the changes were similar to Groups 1 and 2 with significance at ≤5% level. Aggregated data from all three groups showed a 58% increase in TBF on LVAD support.Conclusion: Highly significant and favourable haemodynamic changes were found. However, group 3 did not undergo decrease in TPG and PVR possibly because of suboptimal LVAD flow, right heart dysfunction and unavoidable prolongation of support.     

Neural response to emotional stimuli during experimental human endotoxemia

Increases in peripheral cytokines during acute inflammation may affect various neuropsychological functions. The aim of this functional magnetic resonance imaging (fMRI) study was to investigate the effects of acute endotoxemia on mood and the neural response to emotionally aversive visual stimuli in healthy human subjects. In a double‐blind, randomized crossover study, 18 healthy males received a bolus injection of bacterial lipopolysaccharide (LPS; 0.4 ng/kg) or saline. Plasma levels of pro‐ and anti‐inflammatory cytokines and cortisol as well as mood ratings were analyzed together with the blood‐oxygen‐level dependent (BOLD) response during the presentation of aversive versus neutral pictures. Endotoxin administration induced pronounced transient increases in plasma levels of TNF‐α, IL‐1ra, IL‐6, IL‐10, and cortisol. Positive mood was decreased and state anxiety increased. In addition, activation of right inferior orbitofrontal cortex (OFC) in response to emotional visual stimuli was significantly increased in the LPS condition. Increased prefrontal activation during the presentation of emotional material may reflect enhanced cognitive regulation of emotions as an adaptive response during an acute inflammation. These findings may have implications for the putative role of inflammatory processes in the pathophysiology of depression. Hum Brain Mapp 34:2217–2227, 2013. © 2012 Wiley Periodicals, Inc.     

Forensic postmortem computed tomography: volumetric measurement of the heart and liver

Purpose

The purpose of this study was to investigate the utility of postmortem computed tomography (PMCT) images in estimating organ sizes and to examine the use of the cardiothoracic ratio (CTR).

Methods

We included 45 individuals (19 females), who underwent a medico-legal autopsy. Using the computer software program Mimics^®, we determined in situ heart and liver volumes derived from linear measurements (width, height and depth) on a whole body PMCT-scan, and compared the volumes with ex vivo volumes derived by CT-scan of the eviscerated heart and liver. The ex vivo volumes were also compared with the organ weights. Further, we compared the CTR with the ex vivo heart volume and a heart weight-ratio (HWR). Intra- and inter-observer analyses were performed.

Results

We found no correlation between the in situ and ex vivo volumes of the heart and liver. However, a highly significant correlation was found between the ex vivo volumes and weights of the heart and liver. No correlations between CTR and the ex vivo heart volume nor with HWR was found. Concerning cardiomegaly, we found no agreement between the CTR and HWR. The intra- and inter-observer analyses showed no significant differences.

Conclusions

Noninvasive in situ PMCT methods for organ measuring, as performed in this study, are not useful tools in forensic pathology. The best method to estimate organ volume is a CT-scan of the eviscerated organ. PMCT-determined CTR seems to be useless for ascertaining cardiomegaly, as it neither correlated with the ex vivo heart volume nor with the HWR.

     

Refractory Heart Failure Dependent on Short‐Term Mechanical Circulatory Support: What Next? Heart Transplant or Long‐Term Ventricular Assist Device

Chronic heart failure is a progressive and eventually fatal illness. Although the disease cannot be cured and treatment is symptom oriented, most of the patients benefit from optimum medical treatment. Patients with rapid deterioration in chronic advanced heart failure refractory to medical treatment need inotropic support and may need intra‐aortic balloon pump to maintain circulatory support, which of course cannot be prolonged beyond a certain limit. The outcome of heart transplant and long‐term ventricular assist device (VAD) in such patients is poor. The short‐term mechanical circulatory support (MCS) offered to such patients not only provides effective circulatory support and stabilizes them hemodynamically, but also halts the ensuing or reverts the established end‐organ failure. As the name suggests, the short‐term MCS offers support for the short term, usually less than a month. Although some patients with acute heart failure experience recovery of myocardial function with short‐term MCS support, others become dependent. These patients, stabilized and “stuck” with short‐term MCS, can be “rescued” with long‐term VAD or heart transplantation. Both the procedures, when done in this special situation, have their inherent advantages, disadvantages, and complications and hence need the careful consideration about the choice of the procedure. We have tried to elucidate this situation by considering the advantages and disadvantages of both options.