Prostate cancer and its mimics at multiparametric prostate MRI.

One in six males will develop prostate cancer during their lifetime. Prostate cancer is the second leading cause of cancer death in American males, behind only lung cancer. Unfortunately, even though this disease is so common, clinical screening methods such as prostate-specific antigen test and transrectal ultrasound-guided prostate biopsy lack sensitivity and specificity in diagnosing prostate cancer. In recent years, multiparametric prostate MRI has emerged as a very important tool in the diagnosis of prostate carcinoma with a high accuracy. However, diagnostic difficulty is often encountered even with an experienced abdominal radiologist. That is mainly because many normal and abnormal entities can mimic prostate carcinoma at multiparametric MRI. Therefore, the purpose of this pictorial review is to discuss the usefulness of multiparametric prostate MRI in the diagnosis of prostate carcinoma, emphasizing the key MRI features that help to make a distinction of prostate carcinoma from its mimics.

Current approaches, challenges and future directions for monitoring treatment response in prostate cancer.

Prostate cancer is the most commonly diagnosed non-cutaneous neoplasm in men in the United States and the second leading cause of cancer mortality. One in 7 men will be diagnosed with prostate cancer during their lifetime. As a result, monitoring treatment response is of vital importance. The cornerstone of current approaches in monitoring treatment response remains the prostate-specific antigen (PSA). However, with the limitations of PSA come challenges in our ability to monitor treatment success. Defining PSA response is different depending on the individual treatment rendered potentially making it difficult for those not trained in urologic oncology to understand. Furthermore, standard treatment response criteria do not apply to prostate cancer further complicating the issue of treatment response. Historically, prostate cancer has been difficult to image and no single modality has been consistently relied upon to measure treatment response. However, with newer imaging modalities and advances in our understanding and utilization of specific biomarkers, the future for monitoring treatment response in prostate cancer looks bright.

Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications.

Second-generation antipsychotics (SGAs), such as risperidone, clozapine and olanzapine, are the most common drug treatments for schizophrenia. SGAs presented an advantage over first-generation antipsychotics (FGAs), particularly regarding avoidance of extrapyramidal symptoms. However, most SGAs, and to a lesser degree FGAs, are linked to substantial weight gain. This substantial weight gain is a leading factor in patient non-compliance and poses significant risk of diabetes, lipid abnormalities (that is, metabolic syndrome) and cardiovascular events including sudden death. The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic-induced weight gain (AIWG). We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases. There has been considerable progress reaffirming previous findings and discovery of novel genetic factors. The HTR2C and leptin genes are among the most promising, and new evidence suggests that the DRD2, TNF, SNAP-25 and MC4R genes are also prominent risk factors. Further promising findings have been reported in novel susceptibility genes, such as CNR1, MDR1, ADRA1A and INSIG2. More research is required before genetically informed, personalized medicine can be applied to antipsychotic treatment; nevertheless, inroads have been made towards assessing genetic liability and plausible clinical application.

Mutation of residues 423 (Met/Ile), 444 (Thr/Met), and 506 (Asn/Ser) confer cholesteryl esterase activity on rat lung carboxylesterase. Ser-506 is required for activation by cAMP-dependent protein kinase.

Site-directed mutagenesis is used to identify amino acid residues that dictate reported differences in substrate specificity between rat hepatic neutral cytosolic cholesteryl ester hydrolase (hncCEH) and rat lung carboxylesterase (LCE), proteins differing by only 4 residues in their primary sequences. Beginning with LCE, the substitution Met(423) --> Ile(423) alone or in combination with other mutations increased activity with p-nitrophenylcaprylate (PNPC) relative to more hydrophilic p-nitrophenylacetate (PNPA), typical of hncCEH. The substitution Thr(444) --> Met(444) was necessary but not sufficient for expression of cholesteryl esterase activity in COS-7 cells. The substitution Asn(506) --> Ser(506), creating a potential phosphorylation site, uniformly increased activity with both PNPA and PNPC, was necessary but not sufficient for expression of cholesteryl esterase activity and conferred susceptibility to activation by cAMP-dependent protein kinase, a property of hncCEH. The 3 mutations in combination were necessary and sufficient for expression of cholesteryl esterase activity by the mutated LCE. The substitution Gln(186) --> Arg(186) selectively reduced esterase activity with PNPA and PNPC but was not required for cholesteryl esterase activity. Homology modeling from x-ray structures of acetylcholinesterases is used to propose three-dimensional models for hncCEH and LCE that provide insight into the effects of these mutations on substrate specificity.

Nitric oxide regulates interleukin-8 gene expression in activated endothelium by inhibiting NF-kappaB binding to DNA: effects on endothelial function.

Nuclear factor-kappaB (NF-kappaB) binds to nucleotide sequences between -80 and -70 bp upstream of the transcriptional start site in the interleukin-8 (IL-8) promoter and is crucial for transcription of the IL-8 gene. We showed that exogenous nitric oxide in the form of a nitric oxide donor significantly reduced IL-8 mRNA in cytokine-activated ECV304. Similarly, nitric oxide significantly reduced migration of polymorphonuclear neutrophils through cytokine-activated ECV304 monolayers, an IL-8-dependent process. Using a luciferase reporter construct containing the NF-kappaB site of the IL-8 gene, we showed that exposing cytokine-activated ECV304 to exogenous nitric oxide resulted in significant reduction of NF-kappaB binding. Follow-up studies using a luciferase reporter construct possessing a mutated NF-kappaB site confirmed that the luciferase activity observed in the NF-kappaB reporter resulted from NF-kappaB binding. These studies demonstrate that nitric oxide, supplied exogenously into reactions containing activated endothelium, down-regulates pro-inflammatory activity, such as the secretion of chemokines, and functional activity, such as transendothelial migration of neutrophils.

Molecular cloning and expression of rat lung carboxylesterase and its potential role in the detoxification of organophosphorus compounds.

The 1,839-base pair complementary DNA (cDNA) for rat lung carboxylesterase was cloned by reverse transcriptase polymerase chain reaction from total rat lung RNA using specific primers derived from the 5' and 3' untranslated regions of rat hepatic cholesteryl ester hydrolase (CEH). The unique cDNA was sequenced and found to be similar to hepatic CEH, pI 6.1 esterase, and hydrolase A. In Northern blot analysis, the cDNA hybridized with a single band from lung messenger RNA (mRNA). The 1.7-kb coding sequence, predicting a 62-kD protein, was transfected into COS-7 cells and Chinese hamster ovary (CHO) cells. Expression in COS-7 and CHO cells was accompanied by 4- and 3.2-fold increases in carboxylesterase activity (hydrolysis of p-nitrophenyl acetate), respectively. Unlike the hepatic CEH, the expressed lung carboxylesterase described here did not hydrolyze cholesterol esters. In situ hybridization experiments localized the lung carboxylesterase mRNA to the airway epithelium. The organophosphorus compound phosphoric acid diethyl 4-nitrophenyl ester, paraoxon, completely inhibited this lung carboxylesterase, placing it in the family of B esterases by this criterion.

Acute myocardial infarction: home and hospital treatment.

This is a preliminary report of a co-operative study of 1,203 episodes of acute myocardial infarction in men under 70 years in four centres in the south west of England. The mortality at 28 days was 15%. A comparison is made between home care by the family doctor and hospital treatment initially in an intensive care unit: 343 cases were allocated at random. The randomized groups do not differ significantly in composition with respect to age; past history of angina, infarction, or hypertension; or hypotension when first examined. The mortality rates of the random groups are similar for home and hospital treatment. The group sent electively to hospital contained a higher proportion of initially hypotensive patients whose prognosis was bad wherever treated; those who were not hypotensive fared rather worse in hospital.For some patients with acute myocardial infarction seen by their general practitioner home care is ethically justified, and the need for general admission to hospital should be reconsidered.