Usefulness of muscle denervation as an MRI sign of peripheral nerve pathology

Peripheral nerve disorders may be classified into compressive or entrapment neuropathies and non‐compressive neuropathies. Muscle denervation recognized on MRI may be a useful sign in the diagnosis of peripheral nerve disorders. Acute or subacute denervation results in prolonged T2 relaxation time, producing increased signal in skeletal muscle on short tau inversion‐recovery and fat‐suppressed T2‐weighted images. Chronic denervation produces fatty atrophy of skeletal muscles, resulting in increased muscle signal on T1‐weighted images. This review will outline and illustrate the various ways that muscle denervation as seen on MRI may assist in the diagnosis and localization of peripheral nerve disorders.     

Association of COMT Val108/158Met genotype with smoking cessation in a nicotine replacement therapy randomized trial.

We investigated the association of catechol O-methyltransferase (COMT) genotype with abstinence following a smoking cessation attempt among a large cohort of smokers who attempted to quit using either the nicotine transdermal patch or placebo and were followed up over an 8-year period following their initial cessation attempt. In addition, we examined the possible moderating influence of sex on any association. The genotype x treatment interaction effect at 12-week follow-up indicated a greater benefit of active nicotine replacement treatment compared with placebo on likelihood of abstinence in the COMT Met/Met genotype group (33% versus 12%), in comparison to the Met/Val + Val/Val group (22% versus 16%). Our results indicate that COMT genotype may moderate the effect of active transdermal nicotine patch compared with placebo, with reduced relative benefit of nicotine replacement therapy in individuals with Met/Val or Val/Val genotype. Our data follow an emerging pattern of results suggesting that genetic variation in the dopamine pathway may provide a future basis for tailored smoking cessation therapies, but indicate that different genes influencing various components of this pathway may have different effects on response to smoking cessation pharmacotherapy.     

Thyrocyte release of asymmetric dimethylarginine does not account for human thyrocyte inhibition of endothelial cell cyclic GMP

BACKGROUND: The thyroid gland produces and responds to the signalling molecule nitric oxide (NO). The activity of NO synthase (NOS) may be regulated by endogenous NOS inhibitors such as asymmetric dimethylarginine (ADMA). OBJECTIVE: To investigate whether human thyrocytes are capable of regulating NOS activity via the production of ADMA. DESIGN: Human thyrocytes were incubated with human umbilical vein endothelial cells (HUVEC) in order to determine the effect on HUVEC NOS activity. HUVEC cGMP production over a 3-h period was measured as an indicator of NOS activity in the absence and presence of thyrocytes. To determine thyrocyte production of ADMA, samples of conditioned media were analysed by HPLC. RESULTS: The presence of primary human thyrocytes or immortalized human thyrocyte SGHTL-189 cells caused a significant inhibition of both basal (approximately 57% inhibition) and thrombin-stimulated (approximately 42% inhibition) HUVEC cGMP production. Both primary human thyrocytes and SGHTL-189 cells released ADMA (approximately 0. 28 microg per 10(6) thyrocytes over a 3-day period). However, excess L-arginine, the natural substrate for NOS, was unable to overcome thyrocyte inhibition of HUVEC cGMP production. CONCLUSION: These data indicate that human thyrocytes potently reduce endothelial cell cGMP concentrations, and that thyrocytes produce the endogenous NOS inhibitor, ADMA. However, the inhibition of endothelial cGMP is not mediated via thyrocyte production of a competitive NOS inhibitor.     

A comparison of fetal abdominal circumference measurements and Doppler ultrasound in the prediction of small-for-dates babies and fetal compromise

A total of 145 pregnancies clinically suspected of being small-for-dates was studied at presentation with a single measurement of the fetal abdominal circumference and Doppler studies of the umbilical and arcuate arteries. The abdominal circumference measurement gave the best prediction of the small-for-gestational-age (SGA) baby (sensitivity 73%, umbilical artery sensitivity 47%, arcuate artery sensitivity 29%). The umbilical artery measurement gave the best prediction of antenatal fetal compromise; the performance of the tests was compared for a fixed sensitivity of 100% (i.e. all cases of antenatal compromise would be detected), the specificity of the umbilical artery measurement was 77%, abdominal circumference measurement 12% and arcuate artery measurement 2%. In our data, umbilical artery studies were not a sensitive predictor of the SGA baby but they did give an accurate prediction of the potentially compromised SGA fetus.     

Maternal HIV infection, drug use, and growth of uninfected children in their first 3 years

OBJECTIVE: To determine the separate effects of maternal HIV infection and drug use during pregnancy on growth of uninfected children in their first 3 years. DESIGN: Retrospective analysis of measurements from health visitor records made during routine child health surveillance at 6 weeks, 10 months, and 3 years of age. Multilevel analysis allowed for between-infant variation in fitted growth lines, and adjustment for other factors. Growth was described in terms of an intercept (z score at term) and growth slopes (change in z score per year) up to, and from, 4 months. SUBJECTS: 290 case babies delivered in Edinburgh hospitals to women who reported injection drug use by either themselves or their HIV infected partner, and 186 community controls. A total of 131 (45%) of the case babies were born to women who used drugs, predominantly opiates, during pregnancy and 93 (32%) to HIV infected women. The eight infected children were excluded from analysis. MAIN OUTCOME MEASURES: Age and sex standardised z scores for height, weight, and body mass index. RESULTS: 459 (96%) of the 476 records for cases and controls were traced, yielding 1432 weight and 939 height measurements. Maternal HIV infection was not found to affect growth; at 3 years the estimated effect on weight z score was 0.16 with 95% confidence interval (-0.25 to 0.57) and for height 0.18 (-0.19 to 0.55). Drug use during pregnancy was associated with lighter babies at 40 weeks followed by depressed growth in the first four months, these infants remaining just slightly smaller at 3 years with an estimated effect on z scores of -0.5 for weight with 95% confidence interval (-0.89 to -0.11) and -0.37 (-0.72 to -0.02) for height. CONCLUSIONS: Maternal HIV infection does not adversely affect growth in uninfected infants, and the effect of drug use during pregnancy is limited to small decrease in size at 3 years.     

Identifying molecular targets mediating the anticancer activity of histone deacetylase inhibitors: a work in progress

The anticancer properties of histone deacetylase inhibitors have been known for some time. However, it is only recently that the functional identities of the intracellular targets mediating the anticancer properties have started to be revealed. These targets appear to play significant roles in cell cycle control, apoptosis and differentiation. Importantly, the modulation of these activities is likely to be mediated by alterations in the acetylation status of both histone and non-histone targets. Identification of these targets, and the specific histone deacetylase enzymes that modulate them, is an important step in designing rational-based therapies for the treatment of cancer. In this review we discuss the state of progress in identifying the molecular pathways/events mediating the anticancer activity of histone deacetylase inhibitors.     

Stromal inhibition of megakaryocytic differentiation is associated with blockade of sustained Rap1 activation

Coculture with stromal cells tends to maintain normal hematopoietic progenitors and their leukemic counterparts in an undifferentiated, proliferative state. An example of this effect is seen with megakaryocytic differentiation, wherein stromal contact renders many cell types refractory to potent induction stimuli. This inhibitory effect of stroma on megakaryocytic differentiation correlates with a blockade within hematopoietic cells of protein kinase C-epsilon (PKC-epsilon) up-regulation and of extracellular signal-regulated kinase/mitogen-activated protein (ERK/MAP) kinase activation, both of which have been implicated in promoting megakaryocytic differentiation. In this study K562DeltaRafER.5 cells, expressing an estradiol-responsive mutant of the protein kinase Raf-1, were used to determine the relevance and stage of ERK/MAPK pathway blockade by stromal contact. Activation of DeltaRafER by estradiol overrode stromal blockade of megakaryocytic differentiation, implicating the proximal stage of the ERK/MAPK pathway as a relevant control point. Because stromal contact blocked delayed but not early ERK activation, the small guanosine triphosphatase (GTPase) Rap1 was considered as a candidate inhibitory target. Activation assays confirmed that Rap1 underwent sustained activation as a result of megakaryocytic induction, as previously described. As with ERK activation, stromal contact selectively blocked delayed but not early Rap1 activation, having no effect on Ras activation. Enforced expression of either wild-type Rap1 or the GTPase (GAP) resistant mutant Rap1 V12 failed to override stromal inhibition, suggesting that the inhibitory mechanism does not involve GAP up-regulation but rather may target upstream guanine nucleotide exchange factor (GEF) complexes. Accordingly, coimmunoprecipitation demonstrated stromally induced alterations in a protein complex associated with c-Cbl, a scaffolding factor for Rap1-GEF complexes.     

Fibroblast growth factor receptor-1 and neonatal compensatory lung growth after exposure to 95% oxygen

Neonatal rats exposed to 95% oxygen (O2) for 7 days from birth had inhibited lung growth, DNA synthesis, and secondary septation. These parameters were rapidly restored by a period of recovery in air. Northern and Western blot analysis and immunohistochemistry were used to screen for the fibroblast growth factor receptor-1 (FGF-R1) and its high affinity ligand, basic fibroblast growth factor (bFGF), which could have a role in this recovery process. Expression of bFGF in the lung was significantly reduced at the end of the 7-day exposure to 95% O2 and was increased after 3 days of recovery in air. Expression of FGF-R1 was not affected by exposure to 95% O2 or recovery in air. We hypothesized that the increase in bFGF after removal from 95% O2, acting through the FGF-R1, would be critical for compensatory growth. Intraperitoneal injection of soluble truncated FGF-R1 at the onset of the recovery phase arrested compensatory lung DNA synthesis and secondary septation seen in control animals after 3 days of recovery, confirming a role for FGF-R1 in this model of compensatory neonatal lung growth.