OBJECTIVE

To investigate the quantitative impact of frequency drift on Gamma-Aminobutyric acid (GABA+)-edited MRS of the human brain at 3 Tesla (T).

METHODS

Three sequential GABA+-edited MEGA-PRESS acquisitions were acquired in fifteen sessions; in ten of these, MRS was preceded by functional MRI (fMRI) to induce frequency drift, which was estimated from the creatine resonance at 3.0 ppm. Simulations were performed to examine the effects of frequency drift on the editing efficiency of GABA and co-edited macromolecules (MM) and of subtraction artifacts on GABA+ quantification. The efficacy of postprocessing frequency correction was also investigated.

RESULTS

Gradient-induced frequency drifts affect GABA+ quantification for at least 30 min after imaging. Average frequency drift was low in control sessions and as high as -2 Hz/min after fMRI. Uncorrected frequency drift has an approximately linear effect on GABA+ measurements with a -10 Hz drift resulting in a 16% decrease in GABA+, primarily due to subtraction artifacts.

CONCLUSIONS

Imaging acquisitions with high gradient duty cycles can impact subsequent GABA+ measurements. Postprocessing can address subtraction artifacts, but not changes in editing efficiency or GABA:MM signal ratios; therefore, protocol design should avoid intensive gradient sequences before edited MRS Magn Reson Med 72:941-948, 2014. © 2013 Wiley Periodicals, Inc.

The paracrine linkage of endothelins (ET) between keratinocytes and melanocytes suggested that ETs are intrinsic mediators for human melanocytes in UVB-induced pigmentation. In this study, the role of ET-1 in the epidermal hyperpigmentation was investigated in vivo and in vitro. The addition of 10 nM ET-1 induced a H-7 (10 microM) suppressible-increase in tyrosinase activity in cultured human melanocytes and was accompanied by elevated levels of tyrosinase and tyrosinase-related protein-1 mRNA expression as shown by Northern blotting. Analysis of signaling mechanisms leading to tyrosinase activation demonstrated the involvements of quick translocation of PKC, the H-7 (10 microM) suppressible-phosphorylation of the threonine residue of several proteins, and highly elevated level of cyclic AMP (4-fold over control). Reverse transcription polymerase chain reaction (RT-PCR) of RNA isolated from the epidermis of human skin exposed to UVB revealed that UVB irradiation with a dose of 2 MED caused a significant increase in the expressions of ET-1, IL-1 alpha, and tyrosinase mRNA signals 5 days after irradiation. The involvement of ET-1 in UVB-pigmentation was also corroborated by the experiments that the extracts of M. Chamomilla, which can act as an antagonist for ET-receptor binding-mediated signaling but has no inhibitory effect on tyrosinase activity in culture, had a significant inhibitory effect on UVB-induced pigmentation in vivo when daily applied immediately after UVB exposure to human skin. These findings suggest that ET-1 is an important mediator in the epidermis for UVB-induced pigmentation in vivo.

Lipopolysaccharide (LPS) can induce mouse macrophages to produce a number of cytokines and other inflammatory mediators. Our laboratory previously reported that LPS-dependent macrophage-derived tumor necrosis factor alpha (TNF-alpha) production could be significantly potentiated by pretreatment with LPS at substimulatory LPS priming doses. The observed potentiation was shown to be coincident with a down-regulation of LPS-dependent nitric oxide (NO) production (X. Zhang and D. C. Morrison, J. Exp. Med. 177: 511-516, 1993). In order to determine whether these LPS reprogramming effects in mouse macrophages were selective for these two macrophage-derived mediators, we have examined the effects of LPS pretreatment on LPS-dependent interleukin 6 (IL-6) production. Thioglycolate-elicited mouse peritoneal macrophages were pretreated with various subthreshold stimulatory concentrations of LPS for 6 h, washed three times, and then stimulated with an effective stimulatory concentration of smooth LPS for 18 h. In confirmation of earlier studies, pretreatment of mouse macrophages with substimulatory doses of LPS inhibited the subsequent LPS-dependent NO production. This down-regulation was accompanied by a coordinate up-regulation of LPS-dependent IL-6 production, similar to what was shown earlier for TNF-alpha production. These priming effects with the substimulatory dose of smooth LPS are shown to be independent of doses of LPS used for subsequent activation and are not restricted to specific LPS stimulation. Moreover, the enhancement of the IL-6 response by LPS pretreatment is still observed in the presence of neutralizing antibody to TNF-alpha. These findings, therefore, provide further support for the conclusion that LPS-dependent macrophage reprogramming is likely to involve common regulatory pathways that control the secretion of both IL-6 and TNF-alpha.

Sjögren's syndrome (SS) is an autoimmune disease that specifically targets exocrine glands, including salivary glands, and results in an impairment of secretory function. P2Y(2) nucleotide receptors for extracellular ATP and UTP are up-regulated in response to stress or injury in a variety of tissues including submandibular glands (SMGs) [Ahn JS, Camden JM, Schrader AM, Redman RS, Turner JT. Reversible regulation of P2Y(2) nucleotide receptor expression in the duct-ligated rat submandibular gland. Am J Physiol Cell Physiol 2000;279:C286-94; Hou M, Malmsjö M, Möller S, Pantev E, Bergdahl A, Zhai X-H, et al. Increase in cardiac P2X(1)- and P2Y(2)-receptor mRNA levels in congestive heart failure. Life Sci 1999;65:1195-206; Kishore BK, Wang Z, Rab H, Haq M, Soleimani M. Upregulation of P2Y(2) purinoceptor during ischemic reperfusion injury (IRI): possible relevance to diuresis of IRI. J Am Soc Nephrol 1998;9:581 (abstract); Koshiba M, Apasov S, Sverdlov V, Chen P, Erb L, Turner JT, et al. Transient up-regulation of P2Y(2) nucleotide receptor mRNA expression is an immediate early gene response in activated thymocytes. Proc Natl Acad Sci U S A 1997;94:831-6; Turner JT, Landon LA, Gibbons SJ, Talamo BR. Salivary gland P2 nucleotide receptors. Crit Rev Oral Biol Med 1999;10:210-24; Seye CI, Gadeau AP, Daret D, Dupuch F, Alzieu P, Capron L, et al. Overexpression of the P2Y(2) purinoceptor in intimal lesions of the rat aorta. Arterioscler Thromb Vasc Biol 1997;17:3602-10; Seye C, Kong Q, Erb L, Garrad RC, Krugh B, Wang M, et al. Functional P2Y(2) nucleotide receptors mediate uridine 5'-triphosphate-induced intimal hyperplasia in collared rabbit carotid arteries. Circulation 2002;106:2720-6].

OBJECTIVE

To assess whether P2Y(2) receptor expression is up-regulated in SMGs of the NOD.B10 mouse model of primary SS as compared to SMGs of normal C57BL/6 mice.

METHODS

SMG cells were isolated from normal C57BL/6 and diseased NOD.B10 mice. P2Y(2) receptor mRNA expression was determined by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization, whereas functional P2Y(2) receptor activity was analyzed by measuring UTP-induced increases in [Ca(2+)](i).

RESULTS

In contrast to SMG cells from C57BL/6 mice, SMG cells from 4- to 19-week-old NOD.B10 mice exhibited increased P2Y(2) receptor mRNA localized to both ductal and acinar cell types. The levels of mRNA for other uridine nucleotide receptors, i.e., P2Y(4) and P2Y(6) receptors, showed no significant differences between SMG cells of C57BL/6 and NOD.B10 mice, suggesting that only the P2Y(2) receptor was up-regulated in NOD.B10 mice. Moreover, P2Y(2) receptor activity in SMG cells from NOD.B10 mice increased with age (i.e., disease progression).

CONCLUSIONS

P2Y(2) receptor up-regulation in SMGs is associated with the SS phenotype in NOD.B10 mice, which encourages further attempts to determine the role of this pathway in the development of SS.

Cerebral blood flow (CBF) can be measured noninvasively with nuclear magnetic resonance (NMR) by using arterial water as an endogenous perfusion tracer. However, the arterial spin labeling (ASL) techniques suffer from poor temporal resolution due to the need to wait for the exchange of labeled arterial spins with tissue spins to produce contrast. In this work, a new ASL technique is introduced, which allows the measurement of CBF dynamics with high temporal and spatial resolution. This novel method was used in rats to determine the dynamics of CBF changes elicited by somatosensory stimulation with a temporal resolution of 108 ms. The onset time of the CBF response was 0.6 +/- 0.4 sec (mean +/- SD) after onset of stimulation (n = 10). The peak response was observed 4.4 +/- 3.7 sec (mean +/- SD) after stimulation began. These results are in excellent agreement with previous data obtained with invasive techniques, such as laser-Doppler flowmetry and hydrogen clearance, and suggest the appropriateness of this novel technique to probe CBF dynamics in functional and pathological studies with high temporal and spatial resolution. Magn Reson Med 42:425-429, 1999.

Small non-coding microRNAs (miRNAs) are epigenetic regulators that target specific cellular mRNA to modulate gene expression patterns and cellular signaling pathways. miRNAs are involved in a wide range of biological processes and are frequently deregulated in human cancers. Numerous miRNAs promote tumorigenesis and cancer progression by enhancing tumor growth, angiogenesis, invasion and immune evasion, while others have tumor suppressive effects (Hayes, et al., Trends Mol Med 20(8): 460-9, 2014; Stahlhut and Slack, Genome Med 5 (12): 111, 2013). The expression profile of cancer miRNAs can be used to predict patient prognosis and clinical response to treatment (Bouchie, Nat Biotechnol 31(7): 577, 2013). The majority of miRNAs are intracellular localized, however circulating miRNAs have been detected in various body fluids and represent new biomarkers of solid and hematologic cancers (Fabris and Calin, Mol Oncol 10(3):503-8, 2016; Allegra, et al., Int J Oncol 41(6): 1897-912, 2012). This review describes the clinical relevance of miRNAs, lncRNAs and snoRNAs in the diagnosis, prognosis and treatment response in patients with chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML) and acute adult T-cell leukemia (ATL).

Fatty acid amide hydrolase (FAAH) is a serine hydrolase responsible for the degradation of anandamide, an endogenous cannabinoid agonist, and oleamide, a sleep-inducing lipid. Recently, Boger and co-workers reported a potent, selective, and efficacious class of reversible alpha-ketoheterocycle inhibitors of FAAH that produce analgesia in animal models (J. Med. Chem. 2005, 48, 1849-1856; Bioorg. Med. Chem. Lett. 2005, 15, 1423-1428). Key aspects of the structure-activity data are addressed here through computational analysis of FAAH inhibition using Monte Carlo (MC) simulations in conjunction with free energy perturbation (FEP) calculations. The MC/FEP simulations demonstrate that incorporation of pyridine at the C5 position of the 2-keto-oxazole and 2-keto-1,3,4-oxadiazole derivatives significantly enhances binding affinity by formation of a hydrogen-bonded array between the pyridyl nitrogen and Lys142 and Thr236. The results also attribute the activity boost upon substitution of oxazole by oxadiazole to reduced steric interactions in the active site and a lower torsional energy penalty upon binding.

Two Atlantic (SARG and NATL1) strains and one Mediterranean (MED) strain of Prochlorococcus sp., a recently discovered marine, free-living prochlorophyte, were grown over a range of "white" irradiances (lg) and under low blue light to examine their photoacclimation capacity. All three strains contained divinyl (DV) chlorophylls (Chl) a and b, both distinguishable from "normal" Chls by their red-shifted blue absorption maximum, a Chl c-like pigment at low concentration, zeaxanthin, and [alpha]-carotene. The presence of two phaeophytin b peaks in acidified extracts from both Atlantic strains grown at high lg suggests that these strains also had a normal Chl b-like pigment. In these strains, the total Chl b to DV-Chl a molar ratio decreased from about 1 at 7.5 [mu]mol quanta m-2 s-1 to 0.4 to 0.5 at 133 [mu]mol quanta m-2 s-1. In contrast, the MED strain always had a low DV-Chl b to DV-Chl a molar ratio, ranging between 0.13 at low lg and 0.08 at high lg. The discrepancies between the Atlantic and MED strains could result from differences either in the number of light-harvesting complexes (LHC) II per photosystem II or in the Chl b-binding capacity of the apoproteins constituting LHC II. Photosynthesis was saturated at approximately 5 fg C(fg Chl)-1 h-1 or 6 fg C cell-1 h-1, and growth was saturated at approximately 0.45 d-1 for both MED and SARG strains at 18[deg]C, but saturating irradiances differed between strains. Atlantic strains exhibited increased light-saturated rates and quantum yield for carbon fixation under blue light.

BACKGROUND

Evidence on the short-term effects of fine and coarse particles on morbidity in Europe is scarce and inconsistent.

OBJECTIVE

We aimed to estimate the association between daily concentrations of fine and coarse particles with hospitalizations for cardiovascular and respiratory conditions in eight Southern European cities, within the MED-PARTICLES project.

METHODS

City-specific Poisson models were fitted to estimate associations of daily concentrations of particulate matter with aerodynamic diameter ≤ 2.5 μm (PM2.5), ≤ 10 μm (PM10), and their difference (PM2.5-10) with daily counts of emergency hospitalizations for cardiovascular and respiratory diseases. We derived pooled estimates from random-effects meta-analysis and evaluated the robustness of results to co-pollutant exposure adjustment and model specification. Pooled concentration-response curves were estimated using a meta-smoothing approach.

RESULTS

We found significant associations between all PM fractions and cardiovascular admissions. Increases of 10 μg/m3 in PM2.5, 6.3 μg/m3 in PM2.5-10, and 14.4 μg/m3 in PM10 (lag 0-1 days) were associated with increases in cardiovascular admissions of 0.51% (95% CI: 0.12, 0.90%), 0.46% (95% CI: 0.10, 0.82%), and 0.53% (95% CI: 0.06, 1.00%), respectively. Stronger associations were estimated for respiratory hospitalizations, ranging from 1.15% (95% CI: 0.21, 2.11%) for PM10 to 1.36% (95% CI: 0.23, 2.49) for PM2.5 (lag 0-5 days).

CONCLUSIONS

PM2.5 and PM2.5-10 were positively associated with cardiovascular and respiratory admissions in eight Mediterranean cities. Information on the short-term effects of different PM fractions on morbidity in Southern Europe will be useful to inform European policies on air quality standards.

Hepatocellular carcinoma (HCC) is one of the most critical global health issues. With frequent association of viral liver disease, HCC is highly complex, harboring both cancer and chronic liver disease. The tumor stage and underlying liver function are both major determinants of the treatment selection as well as prognosis in HCC patients, thus allowing no more than a 20% chance for potentially curative therapies. Radiotherapy technology has been evolved remarkably during the past decade, and radiation can be precisely delivered, thereby permitting higher doses to the tumour and reduced doses to surrounding normal tissues. There has been increasing interest in the merits of radiotherapy in HCC over the past few years, as indicated by a Pub Med search. Radiotherapy has been used as the definitive therapy with curative intent in early stage tumours. It has been used also in combination with TACE for intermediate stage tumours. In locally advanced tumours, radiotherapy has been combined with systemic agents. Despite its efficacy, radiotherapy has not yet been incorporated into the standard management guidelines of HCC. The lack of high evidence level data, especially randomized controlled trials, has posed an obstacle in including radiotherapy into the routine treatment schema of HCC. Therefore, well-designed prospective studies are strongly recommended using developing technology for radiotherapy alone or combination therapies. Also, many issues such as the optimal dose-fractionation, intra- or extrahepatic metastasis after radiotherapy, and radiation-induced hepatic dysfunction remain to be solved. In this review, current status of radiotherapy for HCC will be discussed with regard to technical consideration and combination strategy. The limitation and future perspectives will also be discussed.

OBJECTIVE

To study prospectively the relation of coffee drinking with fatal and nonfatal coronary heart disease (CHD) and all-cause mortality and to perform a cross-sectional analysis at baseline on the association between coffee drinking and CHD risk factors, diagnosed diseases, self-reported symptoms, and use of medicines.

METHODS

The study cohort consisted of 20 179 randomly selected eastern Finnish men and women aged 30 to 59 years who participated in a cross-sectional risk factor survey in 1972, 1977, or 1982. Habitual coffee drinking, health behavior, major known CHD risk factors, and medical history were assessed at the baseline examination. Each subject was followed up for 10 years after the survey using the national hospital discharge and death registers. Multivariate analyses were performed by using the Cox proportional hazards model.

RESULTS

In men, the risk of nonfatal myocardial infarction was not associated with coffee drinking. The age-adjusted association of coffee drinking was J shaped with CHD mortality and U shaped with all-cause mortality. The highest CHD mortality was found among those who did not drink coffee at all (multivariate adjusted). Also, in women, all-cause mortality decreased by increasing coffee drinking. The prevalence of smoking and the mean level of serum cholesterol increased with increasing coffee drinking. Non-coffee drinkers more often reported a history of various diseases and symptoms, and they also more frequently used several drugs compared with coffee drinkers.

CONCLUSIONS

Coffee drinking does not increase the risk of CHD or death. In men, slightly increased mortality from CHD and all causes in heavy coffee drinkers is largely explained by the effects of smoking and a high serum cholesterol level. Arch Intern Med. 2000;160:3393-3400.

The purpose of this study was to determine the feasibility of performing far-lateral lumbar discectomy by using the microendoscopic discectomy (MED) technique. The authors studied 11 consecutive patients with unilateral, single-level radiculopathy secondary to far-lateral disc herniation. There were eight men and three women, with an average age of 43 years. In all patients magnetic resonance imaging and/or computerized tomography scanning documented far-lateral disc herniations. Six patients experienced motor deficits, nine patients sensory abnormalities, and five depressed reflexes. All patients complained of radicular pain, which failed to improve with conservative care. After induction of epidural anesthesia, single-level, unilateral percutaneous discectomies were performed using the MED technique. Five discectomies were performed at L3-4 and six at L4-5. There were four contained and seven sequestered disc herniations. All surgeries were performed on an outpatient basis. Follow up ranged from for 12 to 27 months. Improvement was shown in all patients postoperatively. Using modified Macnab criteria to assess results of surgery, there were 10 excellent results and one good result. None of the patients experienced residual motor deficits, four had residual decreased sensation, and one still had some degree of nonradicular pain. There were no complications. Although various open techniques exist for the treatment of far-lateral disc herniation, MED is unique in that far-lateral pathological entities can be directly visualized and removed via a 15-mm paramedian incision. The percutaneous approach avoids larger, potentially denervating and destabilizing procedures. The need for general anesthesia can be avoided, and surgery is performed on an outpatient basis, thereby reducing hospital cost and length of stay.

Transverse myelitis is a neurological disorder causing acute spinal cord injury as a result of acute inflammation, often associated with para infectious processes and autoimmune disease. The purpose of this article is to review the literature on the geoepidemiology of transverse myelitis and assess its environmental associations. Articles from 1981 to 2009 were reviewed in Pub Med along with potential causes such as autoimmune disease (focusing on systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome (APS), and Sjogren's), infection, vaccination, and intoxication.

OBJECTIVE

Good general lay knowledge of tuberculosis (TB), its cause and treatment is considered important for both prompt healthcare seeking and adherence to treatment. The main aim of this study was to describe the knowledge of TB among med and women with a cough for more than three weeks and to see how their health seeking related to TB knowledge.

METHODS

A population-based survey was carried out within a demographic surveillance site in Vietnam. The study population included 35,832 adults aged 15 years or over. Cough cases were identified at household level and structures interviews were carried out with all cases of cough in person.

RESULTS

A total of 559 people (1.6%) reported coughing with a duration of three weeks or longer (259 men and 300 women). A large proportion of individuals with a cough for more than three weeks had limited knowledge of the causes, transmission modes, symptoms, and curability of TB. Men had a significantly higher knowledge score than women (3.04 vs 2.55). Better knowledge was significantly related to seeking healthcare and seeking hospital care. More men than women did not take any health care action at all.

CONCLUSIONS

Health education for TB thus seems to be useful, but efforts must be made to ensure that both men and women in different socioeconomic contexts can access the information.

It is believed that interactions among genes (epistasis) may play an important role in susceptibility to common diseases (Moore and Williams [2002]. Ann Med 34:88-95; Ritchie et al. [2001]. Am J Hum Genet 69:138-147). To study the underlying genetic variants of diseases, genome-wide association studies (GWAS) that simultaneously assay several hundreds of thousands of SNPs are being increasingly used. Often, the data from these studies are analyzed with single-locus methods (Lambert et al. [2009]. Nat Genet 41:1094-1099; Reiman et al. [2007]. Neuron 54:713-720). However, epistatic interactions may not be easily detected with single-locus methods (Marchini et al. [2005]. Nat Genet 37:413-417). As a result, both parametric and nonparametric multi-locus methods have been developed to detect such interactions (Heidema et al. [2006]. BMC Genet 7:23). However, efficiently analyzing epistasis using high-dimensional genome-wide data remains a crucial challenge. We develop a method based on Bayesian networks and the minimum description length principle for detecting epistatic interactions. We compare its ability to detect gene-gene interactions and its efficiency to that of the combinatorial method multifactor dimensionality reduction (MDR) using 28,000 simulated data sets generated from 70 different genetic models We further apply the method to over 300,000 SNPs obtained from a GWAS involving late onset Alzheimer's disease (LOAD). Our method outperforms MDR and we substantiate previous results indicating that the GAB2 gene is associated with LOAD. To our knowledge, this is the first successful model-based epistatic analysis using a high-dimensional genome-wide data set.

To determine the relationship between femoral neck geometry and the risk of hip fracture in post-menopausal Caucasian women, we conducted a retrospective study comparing the femoral neck dimensions of 62 hip fracture cases to those of 608 randomly selected controls. Measurements were made from dual-energy X-ray absorptiometry scans (Lunar DPX-L), using the manufacturer's ruler function, and included: hip axis length (HAL), femoral neck axis length (FNAL), femoral neck width (FNW), femoral shaft width (FSW), medial femoral shaft cortical thickness (FSCT(med)), and lateral femoral shaft cortical thickness (FSCT(lat)). The fracture group was older (median age 78.3 years vs 73.8 years), lighter (median weight 59.9 kg vs 64.5 kg), and, after adjustment for age, taller (mean height 158.7+/-0.8 cm vs 156.7+/-0.2 cm) than the controls. Furthermore, bone mineral density was lower in this group (0.682+/-0.016 g/cm(2) vs 0.791+/-0.006 g/cm(2)). After adjustment for age, bone mineral content (BMC) or height, hip fracture patients had greater FNW (up to 6.6%) and FSW (up to 6.3%) than did the controls. Each standard deviation increase in FNW and FSW was associated with a 1.7-fold (95% CI 1.3-2.3) and a 2.4-fold (95% CI 1.8-3.2) increase in the fracture risk, respectively. BMC-adjusted FNAL was greater in the fracture group (+2.1%) than in the controls, while the age-adjusted FSCT(med) was reduced (-7.2%). There was a trend towards longer HAL (up to 2.1%) after adjustment for age or BMC, and thinner age-adjusted FSCT(lat) (-1.7%) in fracture patients that did not reach statistical significance. In multivariate analysis, the risk of hip fracture was predicted by the combination of age, FNW, FSW, BMC and FSCT(med). HAL was not analyzed because of the small number of HAL measurements among fracture cases. We conclude that post-menopausal women with hip fractures have wider femoral necks and shafts, thinner femoral cortices and longer femoral neck axis lengths than do women with no fractures. Alteration in hip geometry is associated with the risk of hip fracture.

Deletions of chromosome 18q are among the most common segmental aneusomies compatible with life. The estimated frequency is approximately 1/40,000 live births [Cody JD, Pierce JF, Brkanac Z, Plaetke R, Ghidoni PD, Kaye CI, Leach RJ. 1997. Am. J. Med. Genet. 69:280-286]. Most deletions are terminal encompassing as much as 36 Mb, but interstitial deletions have also been reported. We have evaluated 42 subjects with deletions of 18q at our institution. This is the largest number of individuals with this chromosome abnormality studied by one group of investigators. Here we report the physical findings in these individuals. We have compared our findings with those of previously reported cases and have found a significantly different incidence of several minor anomalies in our subjects. We also describe here several anomalies not previously reported in individuals with deletions of 18q, including short frenulum, short palpebral fissures, disproportionate short stature, overlap of second and third toes, and a prominent abdominal venous pattern. Characteristics found in subjects were analyzed for correlation with cytogenetic breakpoints. Several traits were found to correlate with the extent of the deletion. Large deletions were associated with significantly decreased head circumference and ear length as well as the presence of proximally placed and/or anomalous thumbs. Individuals with the smallest deletions were more likely to have metatarsus adductus. Although relatively few genotype/phenotype correlations were apparent, these data demonstrate that correlations with breakpoint are possible. This implies that more correlations will become evident when the more precise molecularly based genotyping is completed. These correlations will identify critical regions on the chromosome in which genes responsible for specific abnormal phenotypes are located.

Weight-bearing activity provides an osteogenic stimulus, while effects of swimming on bone are unclear. We evaluated bone mineral density (BMD) and markers of bone turnover in female athletes (n = 41, age 20.7 yr) comparing three impact groups, high impact (High, basketball and volleyball, n = 14), medium impact (Med, soccer and track, n = 13), and nonimpact (Non, swimming, n = 7), with sedentary age-matched controls (Con, n = 7). BMD was assessed by dual-energy X-ray absorptiometry at the lumbar spine, femoral neck (FN), Ward's triangle, and trochanter (TR); bone resorption estimated from urinary cross-linked N-telopeptides (NTx); and bone formation determined from serum osteocalcin. Adjusted BMD (g/cm; covariates: body mass index, weight, and calcium and calorie intake) was greater at the FN and TR in the High group (1.27 +/- 0.03 and 1.05 +/- 0.03) than in the Non (1.05 +/- 0.04 and 0.86 +/- 0.04) and Con (1.03 +/- 0.05 and 0.85 +/- 0.05) groups and greater at the TR in the Med group (1.01 +/- 0.03) than in the Non (0.86 +/- 0.04) and Con (0.85 +/- 0.05) groups. Total body BMD was higher in the High group (4.9 +/- 0.12) than in the Med (4.5 +/- 0.12), Non (4.2 +/- 0.14), and Con (4.1 +/- 0.17) groups and greater in the Med group than in the Non and Con groups. Bone formation was lower in the Non group (19.8 +/- 2.6) than in the High (30.6 +/- 3.0) and Med (32.9 +/- 1.9, P < or = 0.05) groups. No differences in a marker of bone resorption (NTx) were noted. This indicates that women who participate in impact sports such as volleyball and basketball had higher BMDs and bone formation values than female swimmers.

In MRI and fMRI, images or voxel measurement are complex valued or bivariate at each time point. Recently, (Rowe, D.B., Logan, B.R., 2004. A complex way to compute fMRI activation. NeuroImage 23 (3), 1078-1092) introduced an fMRI magnitude activation model that utilized both the real and imaginary data in each voxel. This model, following traditional beliefs, specified that the phase time course were fixed unknown quantities which may be estimated voxel-by-voxel. Subsequently, (Rowe, D.B., Logan, B.R., 2005. Complex fMRI analysis with unrestricted phase is equivalent to a magnitude-only model. NeuroImage 24 (2), 603-606) generalized the model to have no restrictions on the phase time course. They showed that this unrestricted phase model was mathematically equivalent to the usual magnitude-only data model including regression coefficients and voxel activation statistic but philosophically different due to it derivation from complex data. Recent findings by (Hoogenrad, F.G., Reichenbach, J.R., Haacke, E.M., Lai, S., Kuppusamy, K., Sprenger, M., 1998. In vivo measurement of changes in venous blood-oxygenation with high resolution functional MRI at .95 Tesla by measuring changes in susceptibility and velocity. Magn. Reson. Med. 39 (1), 97-107) and (Menon, R.S., 2002. Postacquisition suppression of large-vessel BOLD signals in high-resolution fMRI. Magn. Reson. Med. 47 (1), 1-9) indicate that the voxel phase time course may exhibit task related changes. In this paper, a general complex fMRI activation model is introduced that describes both the magnitude and phase in complex data which can be used to specifically characterize task related change in both. Hypotheses regarding task related magnitude and/or phase changes are evaluated using derived activation statistics. It was found that the Rowe-Logan complex constant phase model strongly biases against voxels with task related phase changes and that the current very general complex linear phase model can be cast to address several different hypotheses sensitive to different magnitude/phase changes.

OBJECTIVE

To explore the use of an observational, cognitive-based approach for differentiating between successful, suboptimal, and failed entry of coded data by clinicians in actual practice, and to detect whether causes for unsuccessful attempts to capture true intended meaning were due to terminology content, terminology representation, or user interface problems.

METHODS

Observational study with videotaping and subsequent coding of data entry events in an outpatient clinic at New York Presbyterian Hospital.

METHODS

Eight attending physicians, 18 resident physicians, and 1 nurse practitioner, using the Medical Entities Dictionary (MED) to record patient problems, medications, and adverse reactions in an outpatient medical record system.

METHODS

Classification of data entry events as successful, suboptimal, or failed, and estimation of cause; recording of system response time and total event time.

RESULTS

Two hundred thirty-eight data entry events were analyzed; 71.0 percent were successful, 6.3 percent suboptimal, and 22.7 percent failed; unsuccessful entries were due to problems with content in 13.0 percent of events, representation problems in 10.1 percent of events, and usability problems in 5.9 percent of events. Response time averaged 0.74 sec, and total event time averaged 40.4 sec. Of an additional 209 tasks related to drug dose and frequency terms, 94 percent were successful, 0.5 percent were suboptimal, and 6 percent failed, for an overall success rate of 82 percent.

CONCLUSIONS

Data entry by clinicians using the outpatient system and the MED was generally successful and efficient. The cognitive-based observational approach permitted detection of false-positive (suboptimal) and false-negative (failed due to user interface) data entry.

In functional magnetic resonance imaging, voxel time courses after Fourier or non-Fourier "image reconstruction" are complex valued as a result of phase imperfections due to magnetic field inhomogeneities. Nearly all fMRI studies derive functional "activation" based on magnitude voxel time courses [Bandettini, P., Jesmanowicz, A., Wong, E., Hyde, J.S., 1993. Processing strategies for time-course data sets in functional MRI of the human brain. Magn. Reson. Med. 30 (2): 161-173 and Cox, R.W., Jesmanowicz, A., Hyde, J.S., 1995. Real-time functional magnetic resonance imaging. Magn. Reson. Med. 33 (2): 230-236]. Here, we propose to directly model the entire complex or bivariate data rather than just the magnitude-only data. A nonlinear multiple regression model is used to model activation of the complex signal, and a likelihood ratio test is derived to determine activation in each voxel. We investigate the performance of the model on a real dataset, then compare the magnitude-only and complex models under varying signal-to-noise ratios in a simulation study with varying activation contrast effects.

BACKGROUND

At present the computational gene identification methods in microbial genomes have a high prediction accuracy of verified translation termination site (3' end), but a much lower accuracy of the translation initiation site (TIS, 5' end). The latter is important to the analysis and the understanding of the putative protein of a gene and the regulatory machinery of the translation. Improving the accuracy of prediction of TIS is one of the remaining open problems.

RESULTS

In this paper, we develop a four-component statistical model to describe the TIS of prokaryotic genes. The model incorporates several features with biological meanings, including the correlation between translation termination site and TIS of genes, the sequence content around the start codon; the sequence content of the consensus signal related to ribosomal binding sites (RBSs), and the correlation between TIS and the upstream consensus signal. An entirely non-supervised training system is constructed, which takes as input a set of annotated coding open reading frames (ORFs) by any gene finder, and gives as output a set of organism-specific parameters (without any prior knowledge or empirical constants and formulas). The novel algorithm is tested on a set of reliable datasets of genes from Escherichia coli and Bacillus subtillis. MED-Start may correctly predict 95.4% of the start sites of 195 experimentally confirmed E.coli genes, 96.6% of 58 reliable B.subtillis genes. Moreover, the test results indicate that the algorithm gives higher accuracy for more reliable datasets, and is robust to the variation of gene length. MED-Start may be used as a postprocessor for a gene finder. After processing by our program, the improvement of gene start prediction of gene finder system is remarkable, e.g. the accuracy of TIS predicted by MED 1.0 increases from 61.7 to 91.5% for 854 E.coli verified genes, while that by GLIMMER 2.02 increases from 63.2 to 92.0% for the same dataset. These results show that our algorithm is one of the most accurate methods to identify TIS of prokaryotic genomes.

BACKGROUND

The program MED-Start can be accessed through the website of CTB at Peking University: http://ctb.pku.edu.cn/main/SheGroup/MED_Start.htm.

The relationships between brain activity and accompanying hemodynamic and metabolic alterations, particularly between the cerebral metabolic rate of oxygen utilization (CMR(O2)) and cerebral blood flow (CBF), are not thoroughly established. CMR(O2) is closely coupled to the rate of tricarboxylic acid (TCA) cycle flux. In this study, the changes in glutamate labeling during (13)C labeled glucose administration were determined in the human brain as an index of alterations in neuronal TCA cycle turnover during increased neuronal activity. Two-volume (1)H-[(13)C] MR spectroscopy (MRS) of the visual cortex was combined with functional MRI (fMRI) at 4 Tesla. Hemifield visual stimulation was employed to obtain data simultaneously from activated and control regions located symmetrically in the two hemispheres of the brain. The results showed that the fractional change in the turnover rate of C4 carbon of glutamate was less than that of CBF during visual stimulation. The fractional changes in CMR(O2) (Delta CMR(O2)) induced by activation must be equal to or less than the fractional change in glutamate labeling kinetics. Therefore, the results impose an upper limit of approximately 30% for Delta CMR(O2) and demonstrate: 1) that fractional CBF increases exceed Delta CMR(O2) during elevated activity in the visual cortex, and 2) that such an unequal change would explain the observed positive blood oxygenation level dependent (BOLD) effect in fMRI. Magn Reson Med 45:349-355, 2001.

In imaging of hyperpolarized noble gases, a knowledge of the diffusion coefficient (D) is important both as a contrast mechanism and in the design of pulse sequences. We have made diffusion coefficient maps of both hyperpolarized (3)He and (129)Xe in guinea pig lungs. Along the length of the trachea, (3)He D values were on average 2.4 cm(2)/sec, closely reproducing calculated values for free gas (2.05 cm(2)/sec). The (3)He D values measured perpendicular to the length of the trachea were approximately a factor of two less, indicating restriction to diffusion. Further evidence of restricted diffusion was seen in the distal pulmonary airspaces as the average (3)He D was 0.16 cm(2)/sec. An additional cause for the smaller (3)He D in the lung was due to the presence of air, which is composed of heavier and larger gases. The (129)Xe results show similar trends, with the trachea D averaging 0.068 cm(2)/sec and the lung D averaging 0.021 cm(2)/sec. Magn Reson Med 42:721-728, 1999.