Effect of age and breast density on screening mammograms with false-positive findings

OBJECTIVE: The objective of this study was to examine the effect of breast density and age on screening mammograms with false-positive findings. MATERIALS AND METHODS: The study sample was taken from the Washington State Mammography Tumor Registry, which links data from participating radiologists with the Puget Sound Cancer Surveillance System and the Washington State Cancer Registry. Participants (n = 73,247) were women 35 years old and older who underwent screening mammography for which an assessment and a four-category density rating were coded. A total of 46,340 mammograms were sampled to avoid interpreter bias. In this study of false-positive mammograms, only women with no diagnosis of breast cancer within 12 months of the index mammogram were included. Logistic regression was used to estimate the odds ratios of a false-positive mammogram being associated with each category of breast density or age, adjusting for the other factor as a covariate. RESULTS: After controlling for breast density, we found that the risk of a false-positive mammogram was not affected by age (p = 27). However, the trend of increasing risk of a false-positive mammogram with increasing breast density was highly significant (p < .001). Women with extremely dense breast tissue were almost two times more likely to have a false-positive mammogram than were women with fatty breast tissue. This effect persisted after controlling for age. CONCLUSION: Breast density, not age, is an important factor when predicting risk of a false-positive mammogram. Breast density should be considered when educating individual women on the risks and benefits of screening mammography.     

Interaction of intravenous anesthetics with human neuronal potassium currents in relation to clinical concentrations

BACKGROUND: Neuronal voltage-dependent potassium (K) currents are crucial for various cellular functions, such as the integration of temporal information in the central nervous system. Data for the effects of intravenous anesthetics on human neuronal K currents are limited. It was the authors' aim to evaluate the concentration-related effects of three opioids (fentanyl, alfentanil, sufentanil) and seven nonopioids (thiopental, pentobarbital, methohexital, propofol, ketamine, midazolam, droperidol) used in clinical anesthesia on neuronal voltage-dependent K currents of human origin. METHOD: K currents were measured in SH-SY5Y cells using the whole cell patch-clamp technique. Currents were elicited by step depolarization from a holding potential of -80 to -50 mV through +90 mV, and their steady state amplitudes were determined. RESULTS: All drugs inhibited the K currents in a concentration-dependent and reversible manner. Because time dependence of inhibition differed among the drugs, effects were measured after 54-64 ms of the test pulse. The IC50 values (concentration of half-maximal inhibition) for current suppression ranged from 7 microM for sufentanil to 2 mM for pentobarbital. Suppression of the K currents by the opioids occurred at 10-fold lower IC50 values (concentration of half-maximal inhibition) than that by the barbiturates. As estimated from the concentration-response curves, K-current suppression at clinical concentrations would be less than 0.1% for the opioids and approximately 3% for the other drugs. CONCLUSIONS: Effects of intravenous anesthetics on voltage-dependent K currents occur at clinical concentrations. The IC50 values for current inhibition of the nonopioid anesthetics correlated with these concentrations (r = 0.95). The results suggest that anesthetic drug action on voltage-dependent K currents may contribute to clinical effects or side effects of intravenous anesthetics.     

Altered bladder function in transgenic mice expressing rat elastin

The elasticity of tissues subjected to repeated deformation is provided by the presence of elastic fibers in the extracellular matrix (ECM). The most abundant component of elastic fibers is elastin, whose soluble precursor is tropoelastin. To establish the role elastin plays in the bladder, this study describes the biosynthetic, histologic, and physiologic consequences of expression of an isoform of rat tropoelastin in transgenic mouse bladder. The polymerase chain reaction (PCR) was used to determine expression of a rat tropoelastin minigene in transgenic mice. Histochemical methods were used to demonstrate changes in elastic fibers in frozen sections of bladder. Cystometric analysis was carried out in transgenic and non-transgenic mice, prior to and after 3 weeks of partial outlet obstruction. The PCR assay demonstrated that bladder tissue of transgenic mice expressed rat tropoelastin mRNA, whereas non-transgenes did not. Increased deposition of elastic fibers was demonstrated with the Verhoeff-van Gieson stain. Bladders of transgenic animals were more compliant than bladders of their non-transgenic littermates. Partial outlet obstruction resulted in increased bladder volume and more compliant bladders in non-transgenic mice. In contrast, the bladder volume and compliance in transgenes was almost unchanged by obstruction. This study demonstrates that normal elastic fiber assembly is prerequisite for the compliant properties of the bladder wall. Moreover, the response of the bladder to obstruction is critically influenced by elastin synthesis.     

The evaluation of contrast sensitivity in children and adolescents with insulin-dependent diabetes mellitus]

PURPOSE: The evaluation of contrast sensitivity in children and adolescents with type I diabetes mellitus with and without retinopathy, taking into account metabolic control. MATERIAL AND METHODS: We examined 100 young patients (71 without retinopathy and 29 with background retinopathy on fluorescein angiography) and 60 control non-diabetic subjects matched for age and sex, without visual or systemic symptoms. Contrast sensitivity was measured in spatial frequency of 3, 6, 12 and 18 cycles/degree (c/d). RESULTS: Contrast sensitivity was significantly lower (p < 0.001) in four spatial frequencies in all diabetic patients and in IDDM patients without retinopathy than in control group. Patients with IDDM and retinopathy had abnormal contrast sensitivity at spatial frequency 18 c/d when compared with patients without retinopathy. There was no correlation between contrast sensitivity and HbA1c values. CONCLUSIONS: Contrast sensitivity measurement in children and adolescents with type I diabetes is useful in the evaluation of the nature of early abnormalities in retinal function of diabetics.     

Serotonin (5-HT) release in the dorsal raphé and ventral hippocampus: Raphé control of somatodendritic and terminal 5-HT release

Summary Somatodendritic and terminal release of serotonin (5-HT) was investigated by simultaneously measuring extracellular concentrations of 5-HT, 5-hydroxyindole-3-acetic acid (5-HIAA) and homovanillic acid (HVA) in the dorsal raphé and ventral hippocampus in freely moving rats. Perfusion of tetrodotoxin (TTX, 1M and 10M) into the dorsal raphé simultaneously decreased dorsal raphé and hippocampal 5-HT release. However, following TTX perfusion into the hippocampus (10M), hippocampal 5-HT release was profoundly reduced but dorsal raphé 5-HT remained unchanged.Systemic injections with the 5-HT_1a agonist, buspirone (1.0–5.0mg/kg, i.p.) decreased 5-HT and 5-HIAA and increased HVA concentrations in the dorsal raphé and in the hippocampus. The decreases in raphé and hippocampal 5-HT induced by systemic buspirone were antagonized in rats pretreated with 1.OmM (–) pindolol, locally perfused into the dorsal raphé. Local dorsal raphé perfusion of (–) pindolol alone (0.01–1.0mM) increased dorsal raphé 5-HT and concomitantly induced a small increase in hippocampal 5-HT. Buspirone perfusion into the dorsal raphé did not change (10 nM, 100nM), or produced a small increase (1.0mM) in raphé 5-HT, without changing hippocampal 5-HT.These data provide evidence that 5-HT release in the dorsal raphé is dependent on the opening of fast activated sodium channels and that dorsal raphé 5-HT_1a receptors control somatodendritic and hippocampal 5-HT release.     

GABAB receptor protein and mRNA distribution in rat spinal cord and dorsal root ganglia

The presence of metabotropic receptors for GABA, GABAB, on primary afferent terminals in mammalian spinal cord has been previously reported. In this study we provide further evidence to support this in the rat and show that the GABAB receptor subunits GABAB1 and GABAB2 mRNA and the corresponding subunit proteins are present in the spinal cord and dorsal root ganglion. We also show that the predominant GABAB1 receptor subunit mRNA present in the afferent fibre cell body appears to be the 1a form. In frozen sections of lumbar spinal cord and dorsal root ganglia (DRG) GABAB receptors were labelled with [3H]CGP 62349 or the sections postfixed with paraformaldehyde and subjected to in situ hybridization using oligonucleotides designed to selectively hybridize with the mRNA for GABAB(1a), GABAB(1b) or GABAB2. For immunocytochemistry (ICC), sections were obtained from rats anaesthetized and perfused-fixed with paraformaldehyde. The distribution of binding sites for [3H]CGP 62349 mirrored that previously observed with [3H]GABA at GABAB sites. The density of binding sites was high in the dorsal horn but much lower in the ventral regions. By contrast, the density of mRNA (pan) was more evenly distributed across the laminae of the spinal cord. The density of mRNA detected with the pan probe was high in the DRG and distributed over the neuron cell bodies. This would accord with GABAB receptor protein being formed in the sensory neurons and transported to the primary afferent terminals. Of the GABAB1 mRNA in the DRG, approximately 90% was of the GABAB(1a) form and approximately 10% in the GABAB(1b) form. This would suggest that GABAB(1a) mRNA may be responsible for encoding presynaptic GABAB receptors on primary afferent terminals in a manner similar to that we have previously observed in the cerebellar cortex. GABAB2 mRNA was also evenly distributed across the spinal cord laminae at densities equivalent to those of GABAB1 in the dorsal horn. GABAB2 mRNA was also detected to the same degree within the DRG. Immunocytochemical analysis revealed that GABAB(1a), GABAB(1b) and GABAB2 were all present in the spinal cord. GABAB(1a) labelling appeared to be more dense than GABAB(1b) and within the superficial dorsal horn GABAB(1a) was present in the neuropil whereas GABAB(1b) was associated with cell bodies in this region. Both 1a and 1b immunoreactivity was expressed in motor neurons in lamina IX. GABAB2 immunoreactivity was expressed throughout the spinal cord and was evident within the neuropil of the superficial laminae.     

The CINOD, AZD3582, exhibits an improved gastrointestinal safety profile compared with naproxen in healthy volunteers

COX-inhibiting nitric oxide donators (CINODs) are a new class of drugs in development for the treatment of acute and chronic pain. They comprise a COX-inhibiting moiety linked to a nitric-oxide-donating component and are designed to provide an innovative mechanism of action of balanced COX inhibition and controlled nitric oxide donation. Through these pathways, CINODs should provide analgesic and anti-inflammatory efficacy, while offering gastrointestinal safety through the tissue-protective effects of nitric oxide donation. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is the first agent in the CINOD class to enter extensive clinical development. Pre-clinical studies demonstrate that AZD3582 has a superior gastrointestinal safety profile to naproxen, while demonstrating analgesic and anti-inflammatory efficacy. In healthy human volunteers, AZD3582 caused little gastrointestinal damage compared with equimolar doses of naproxen. Studies to evaluate the longer-term gastrointestinal safety of AZD3582, alongside its efficacy in alleviating chronic and acute pain, are ongoing.     

Genetic analysis of the RNASEL gene in hereditary, familial, and sporadic prostate cancer.

PURPOSE: The RNASEL gene has been proposed as a candidate gene for the HPC1 locus through a positional cloning and candidate gene approach. Cosegregation between the truncating mutation E265X and disease in a hereditary prostate cancer (HPC) family and association between prostate cancer risk and the common missense variant R462Q has been reported. To additionally evaluate the possible role of RNASEL in susceptibility to prostate cancer risk, we performed a comprehensive genetic analysis of sequence variants in RNASEL in the Swedish population. EXPERIMENTAL DESIGN: Using 1624 prostate cancer cases and 801 unaffected controls, the truncating mutation E265X and five common sequence variants, including the two missense mutations R462Q and D541E, were evaluated for association between genotypes/haplotypes and prostate cancer risk. RESULTS: The prevalence of E265X carriers among unaffected controls and prostate cancer patients was almost identical (1.9 and 1.8% in controls and cases, respectively), and evidence for segregation of E265X with disease was not observed within any HPC family. Overall, the analyses of common sequence variants provided limited evidence for association with prostate cancer risk. We found a marginally significant inverse association between the missense mutation D541E and sporadic prostate cancer risk (odds ratio, 0.77; 95% confidence interval, 0.59-1.00) and reduced risk of prostate cancer in carriers of two different haplotypes being completely discordant. CONCLUSIONS: Considering the high quality in genotyping and the size of this study, these results provide solid evidence against a major role of RNASEL in prostate cancer etiology in Sweden.