Imaging of atherosclerosis. Elastography

Intravascular ultrasound elastography is a method for measuring the local elastic properties of coronary atherosclerotic plaques using intravascular ultrasound (IVUS). Mechanical properties of the different tissues within a plaque are measured through strain. In the last decade, several groups have applied elastography intravascularly with various levels of success. In this paper, the approaches of the different research groups will be discussed and the focus will be on our approach to the application of intravascular elastography.     

In vitro evaluation of the quality of essential drugs on the Tanzanian market

We evaluated the in vitro availability and its stability under simulated tropical conditions of various formulations of four essential drugs marketed in Tanzania. We obtained 22 formulations (containing paracetamol, acetylsalicylic acid, chloroquine or sulphadoxine/pyrimethamine) from wholesale pharmacies in Dar es Salaam and the Medical Stores Department (Tanzania). The drug content, in vitro availability (dissolution) and its stability under simulated tropical conditions were determined using methods specified in the United States Pharmacopoeia (USP) 24 monograph of the respective drugs. All formulations passed the pharmacopoeia requirements for the drug content. However, seven formulations (three acetylsalicylic acid, two sulphadoxine/pyrimethamine and two paracetamol) failed to meet the USP 24 tolerance limits for dissolution. Another five formulations (three paracetamol and two chloroquine) failed to meet the dissolution tolerance limits after being subjected to an accelerated stability test under simulated tropical conditions (75% RH/40 degrees C) for 6 months. The study has demonstrated the presence on the Tanzanian market of essential drug formulations that met potency requirements and yet had unsatisfactory in vitro availability as they were not robust enough to withstand storage under simulated tropical conditions.     

Abnormal stimulus-response intensity functions in posttraumatic stress disorder: an electrophysiological investigation

OBJECTIVE: The purpose of this study was to explore the relationship between combat-related posttraumatic stress disorder (PTSD) and specific augmentation versus reduction patterns for the N100 and P200 components of auditory event-related potentials evoked by tones of increasing intensity. METHOD: Event-related potentials of subjects with PTSD (N=36), subjects with no psychopathology (N=20), subjects with major depression but no PTSD (N=10), and subjects with a history of chronic alcohol abuse but no PTSD (N=8) were recorded. Brain responses were evoked by a 2000-Hz tone presented in intensity blocks of 65, 72.5, 80, 87.5, and 95 dB (SPL). RESULTS: Evoked data from five PTSD subjects were of poor quality and excluded from further analyses. For all but one subject with no psychopathology and for all subjects with a history of alcohol abuse or major depression (but no PTSD), the Cz amplitude of the P200 response component showed augmentation as a nearly linear function of tone intensity. As a group, subjects with PTSD showed no such increase in P200 response magnitude. Examination of the data from individual subjects with PTSD showed that 42% exhibited augmentation patterns similar to those seen for subjects in the comparison groups. However, 58% showed evidence of P200 reduction, with the response to the loudest tone being smaller than responses to tones of intermediate intensity. CONCLUSIONS: The data suggest that there is a significant subgroup of patients with combat-related PTSD who enter into a state of protective inhibition at relatively low stimulus intensities. It is hypothesized that this is an appropriate adaptive mechanism for these subjects rather than an indication of a core neurobiological abnormality.     

Use of diffusion weighted MRI to predict the occurrence and severity of hemorrhagic transformation in a rabbit model of embolic stroke

Alpha-synuclein is a brain presynaptic protein that is linked to familiar early onset Parkinson's disease and it is also a major component of Lewy bodies in sporadic Parkinson's disease and other neurodegenerative disorders. Alpha-synuclein expression increases in substantia nigra of both MPTP-treated rodents and non-human primates, used as animal models of parkinsonism. Here we describe an increase in alpha-synuclein expression in a human neuroblastoma cell line, SH-SY5Y, caused by 5-100 microM MPP+, the active metabolite of MPTP, which induces apoptosis in SH-SY5Y cells after a 4-day treatment. We also analysed the activation of the MAPK family, which is involved in several cellular responses to toxins and stressing conditions. Parallel to the increase in alpha-synuclein expression we observed activation of MEK1,2 and ERK/MAPK but not of SAPK/JNK or p38 kinase. The inhibition of the ERK/MAPK pathway with U0126, however, did not affect the increase in alpha-synuclein. The highest increase in alpha-synuclein (more than threefold) in 4-day cultures was found in adherent cells treated with low concentrations of MPP+ (5 microM). Inhibition of ERK/MAPK reduced the damage caused by MPP+. We suggest that alpha-synuclein increase and ERK/MAPK activation have a prominent role in the cell mechanisms of rescue and damage, respectively, after MPP+ -treatment.     

Amino acids regulate the intracellular trafficking of the general amino acid permease of Saccharomycescerevisiae

The delivery to the plasma membrane of the general amino acid permease, Gap1p, of Saccharomyces cerevisiae is regulated by the quality of the nitrogen source in the growth medium. In an effort to define how different nitrogen sources control Gap1p sorting, we find that mutations in GDH1 and GLN1 that decrease the flux through the glutamate and glutamine synthesis pathways result in increased Gap1p sorting to the plasma membrane. Conversely, deletion of MKS1, which increases glutamate and glutamine synthesis, decreases Gap1p sorting to the plasma membrane. Glutamate and glutamine are not unusual in their ability to regulate Gap1p sorting, because the addition of all natural amino acids and many amino acid analogs to the growth medium results in increased Gap1p sorting to the vacuole. Importantly, amino acids have the capacity to signal Gap1p sorting to the vacuole regardless of whether they can be used as a source of nitrogen. Finally, we show that rapamycin does not affect Gap1p sorting, indicating that Gap1p sorting is not directly influenced by the TOR pathway. Together, these data show that amino acids are a signal for sorting Gap1p to the vacuole and imply that the nitrogen-regulated Gap1p sorting machinery responds to amino acid-like compounds rather than to the overall nutritional status associated with growth on a particular nitrogen source.     

Molecular evolution of the HoxA cluster in the three major gnathostome lineages

The duplication of Hox clusters and their maintenance in a lineage has a prominent but little understood role in chordate evolution. Here we examined how Hox cluster duplication may influence changes in cluster architecture and patterns of noncoding sequence evolution. We sequenced the entire duplicated HoxAa and HoxAb clusters of zebrafish (Danio rerio) and extended the 5' (posterior) part of the HoxM (HoxA-like) cluster of horn shark (Heterodontus francisci) containing the hoxa11 and hoxa13 orthologs as well as intergenic and flanking noncoding sequences. The duplicated HoxA clusters in zebrafish each house considerably fewer genes and are dramatically shorter than the single HoxA clusters of human and horn shark. We compared the intergenic sequences of the HoxA clusters of human, horn shark, zebrafish (Aa, Ab), and striped bass and found extensive conservation of noncoding sequence motifs, i.e., phylogenetic footprints, between the human and horn shark, representing two of the three gnathostome lineages. These are putative cis-regulatory elements that may play a role in the regulation of the ancestral HoxA cluster. In contrast, homologous regions of the duplicated HoxAa and HoxAb clusters of zebrafish and the HoxA cluster of striped bass revealed a striking loss of conservation of these putative cis-regulatory sequences in the 3' (anterior) segment of the cluster, where zebrafish only retains single representatives of group 1, 3, 4, and 5 (HoxAa) and group 2 (HoxAb) genes and in the 5' part of the clusters, where zebrafish retains two copies of the group 13, 11, and 9 genes, i.e., AbdB-like genes. In analyzing patterns of cis-sequence evolution in the 5' part of the clusters, we explicitly looked for evidence of complementary loss of conserved noncoding sequences, as predicted by the duplication-degeneration-complementation model in which genetic redundancy after gene duplication is resolved because of the fixation of complementary degenerative mutations. Our data did not yield evidence supporting this prediction. We conclude that changes in the pattern of cis-sequence conservation after Hox cluster duplication are more consistent with being the outcome of adaptive modification rather than passive mechanisms that erode redundancy created by the duplication event. These results support the view that genome duplications may provide a mechanism whereby master control genes undergo radical modifications conducive to major alterations in body plan. Such genomic revolutions may contribute significantly to the evolutionary process.     

Chronic pancreatitis and maldigestion

Patients with chronic pancreatitis may suffer from maldigestion and malnutrition. Longstanding inflammation and fibrosis in the gland can destroy exocrine tissue, leading to inadequate delivery of digestive enzymes to the duodenum in the prandial and postprandial period and subsequent maldigestion. Maldigestion is augmented by inadequate bicarbonate delivery to the duodenum, with secondary inactivation of enzymes and bile acids by gastric acid. Abdominal pain, sitophobia, nausea, vomiting, postprandial satiety, and on-going alcohol abuse may contribute to poor oral intake. Gastric dysmotility and mechanical gastric outlet obstruction from fibrosis in the pancreatic head may contribute to malnutrition and clinical decline. Patients with chronic pancreatitis may at times experience profound steatorrhea and weight loss. In this article, we examine the natural history of exocrine insufficiency in chronic pancreatitis, outline the important nutritional issues in these patients, review the methods of diagnosis of maldigestion, and discuss the approach to therapy.     

A comparison of once-daily tramadol with normal release tramadol in the treatment of pain in osteoarthritis

OBJECTIVE: To compare the efficacy and tolerability of once daily (OD) tramadol tablets with normal release tramadol capsules (50 mg) taken 3 or 4 times daily in a multicenter, double blind, double dummy parallel study. METHODS: Patients with moderate to severe pain due to osteoarthritis (OA) were recruited from general practice. Following a titration period of a week, patients were assessed over one month for the analgesic efficacy and tolerability of the test medications. RESULTS: Both treatments were shown to be effective. There was no difference between treatments and both produced good pain control as shown by clinically relevant decreases from baseline pain scores, low escape medication use, and sleep disturbance. The efficacy of the OD tramadol over the 24 h dosing interval was confirmed by the low sleep disturbance, absence of "end of dose" effects in morning pain scores, and low escape medication use. Of the 279 patients recruited, 140 withdrew, mostly because of adverse events. The adverse event profiles were typical of opioids and were similar for both treatments. CONCLUSION: Tramadol OD was at least as effective and well tolerated as normal release tramadol in the management of OA pain. However, OD tramadol offers the advantage of a reduced dosing regimen, which is especially valuable in the elderly population.