Subcellular remodeling as a viable target for the treatment of congestive heart failure

It is now well known that congestive heart failure (CHF) is invariably associated with cardiac hypertrophy, and changes in the shape and size of cardiomyocytes (cardiac remodeling) are considered to explain cardiac dysfunction in CHF. However, the mechanisms responsible for the transition of cardiac hypertrophy to heart failure are poorly understood. Several lines of evidence both from various experimental models of CHF and from patients with different types of CHF have indicated that the functions of different subcellular organelles such as extracellular matrix, sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, and nucleus are defective. Subcellular abnormalities for protein contents, gene expression, and enzyme activities in the failing heart become evident as a consequence of prolonged hormonal imbalance, metabolic derangements, and cation maldistribution. In particular, the occurrence of oxidative stress, development of intracellular Ca2+ overload, activation of proteases and phospholipases, and alterations in cardiac gene expression result in changes in the biochemical composition, molecular structure, and function of different subcellular organelles (subcellular remodeling). Not only does subcellular remodeling appear to be intimately involved in the transition of cardiac hypertrophy to heart failure, the mismatching of the function of different subcellular organelles leads to the development of cardiac dysfunction. Although blockade of the renin-angiotensin system, sympathetic nervous system, and various other hormonal actions have been reported to produce beneficial effects on cardiac remodeling and heart dysfunction in CHF, the actions of various cardiac drugs on subcellular remodeling have not been examined extensively. Some recent studies have indicated that both the angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists attenuate changes in sarcolemma, sarcoplasmic reticulum, and myofibril enzyme activities, protein contents, and gene expression, and partly improve cardiac function in the failing hearts. It is suggested that subcellular remodeling is an excellent target for the development of improved drug therapy for CHF. Furthermore, extensive studies should investigate the effects of different agents individually or in combination on reverse subcellular remodeling, cardiac remodeling, and cardiac dysfunction in various experimental models of CHF.     

Macular photostress testing: sensitivity and recovery with an automated perimeter

PURPOSE: To describe a novel method for the evaluation of macular function with photostress testing and outline normative foveal threshold and recovery data for the adult population. METHODS: In this prospective study, 50 adult subjects (25 men and 25 women aged 30-49 years) with no ocular disease underwent foveal threshold testing using the Humphrey Visual Field Perimeter Model 750. Baseline values and recovery time after photostress were measured. Baseline measurements were compared with threshold sensitivity after photostress at 1, 2, 4, 6, and 10 minutes. RESULTS: Mean foveal sensitivities were reduced from 38.53 db to 32.36 db after photostress, representing an average sensitivity reduction of 16%. The mean recovery time to baseline sensitivity was 6.58 minutes. There was no significant difference between sexes, races, or smokers and nonsmokers. CONCLUSIONS: This standardized protocol for testing the foveal threshold response to photostress is an inexpensive and noninvasive adjunct for following macular disease and also distinguishing optic neuropathy from macular disease.     

Potentially inappropriate prescribing in Canada relative to the US

OBJECTIVE: To explore the prescribing of potentially inappropriate drug therapy in Ontario, Canada where there is a restrictive drug formulary relative to the US where there is no single drug formulary. METHODS: A retrospective, cohort study using an administrative database (Ontario, Canada) compared with published survey results (US). All 1,088,680 community-dwelling adults >or=66 years of age in Ontario, Canada compared with published survey results from 2455 community-dwelling older adults in the US in 1996.Patterns of potentially inappropriate drug prescribing were compared between countries using a list of 33 potentially inappropriate drug therapies. These therapies were classified by an expert panel into three categories: (i) those to always avoid; (ii) those which are rarely appropriate; and (iii) those with only some indications to prescribe. RESULTS: Among the 33 potentially inappropriate drug therapies, 15 (45%) prescribed in the US were not available through Ontario's drug formulary. Potentially inappropriate drug therapies available through the Ontario Drug Benefit Plan (ODB) and also in the US were frequently prescribed in both Ontario and the US. Differences in prescribing patterns of individual drug therapies were noted between the two countries. Specifically, in the rarely appropriate category, diazepam, a long half-life benzodiazepine, was much more frequently dispensed in Ontario than in the US (3.18% vs 1.37%). In contrast, dextropropoxyphene, an opioid with a poor adverse event profile was more frequently prescribed in the US than in Ontario (6.21% vs 0.74%). CONCLUSION: Almost half of the potentially inappropriate drug therapies that are available in the US are unavailable from Ontario's drug formulary. Potentially inappropriate drug therapies that were available through the ODB were frequently prescribed in both countries. Alternative approaches that make information immediately accessible to physicians at the time they make prescribing decisions should be considered to improve prescribing practices.     

An integrated computational and laboratory approach for selective amplification of mRNAs containing the adenylate uridylate-rich element consensus sequence

Messenger RNAs that have the stability determinants, adenylate uridylate-rich elements (AREs), in their 3' untranslated region (UTR) code for key products that regulate early and transient biological responses. We used a computational laboratory approach for amplification of large, including full-length, protein-coding regions for ARE genes. Statistical analysis of the initiation regions in the 5' UTR of ARE-mRNAs was performed. Accordingly, several 5' primers and a single universal 3' primer that targeted the initiation consensuses and ARE regions, respectively, were designed. Using optimized conditions, the primers were able to enrich and amplify large protein-coding regions for the ARE gene family. The selective amplification of ARE cDNAs was verified using specific polymerase chain reactions (PCRs) to known ARE mRNA molecules and monitoring the abundance of the non-ARE beta-actin signal. A mini-library from the amplified ARE products was constructed for further confirmation of ARE selection. Distinct ARE amplified cDNA pools were selectively generated by distinct 5' primers. The biological utility of the method was shown with differential display. The up-regulation of several ARE-mRNAs, including the full-length coding region of the small inducible cytokine A4 (SCYA4) gene, was shown in endotoxin-stimulated monocytic cells. The integrated computational and laboratory approach should lead to enhanced capability for discovery and expression analysis of early and transient response genes.     

The diagnosis and management of MSUD in Saudi Arabia by using two different methods

Plasma amino acid concentrations were measured in Maple Syrup Urine Disease (MSUD) infants using reversed phase high performance liquid chromatography (HPLC). The technique involved an automated data acquisition system and phenylisothiocyanate (PITC) pre-column derivatization. During a period of three years more than 14 cases of MSUD have been confirmed in our hospital suggesting an alarmingly high rate of incidence of this disease in the Kingdom as compared to the West. We present here a simple and reliable method of quantitating the branched chain and other amino acid concentrations in plasma samples of children with metabolic disorders. In addition, we also present a fluorimetric COBAS based enzymatic method for the rapid semiquantitative measurement of branched chain amino acids for a disease in which a prompt initial diagnosis is essential.