Pilots and astronauts experience fluid shifts in variable gravity. Acute effects of fluid shifts on the cardiovascular system were monitored on NASA's KC-135 aircraft during parabolic flight. The variability of R-R intervals in the electrocardiogram was measured as an indication of vagal cardiac neural activity. R-R intervals were measured during the gravity transition from 2-G to 0-G produced by parabolic flight to assess the involvement of the autonomic nervous system in regulating the acute effects of fluid shifts. In seven subjects, a BoMed noninvasive continuous cardiac output monitor (NCCOM 3) monitored thoracic fluid index (TFI, ohms), heart rate (bpm), and cardiac output (1/min). Data were stored on a lap-top computer with the subject in one of four postures: sitting, standing, supine, and semi-supine, during one of four sets of eight to ten parabolas. Five seconds of data were averaged: before parabola onset (1.3-G); parabola entry (1.9-G); 0-G; and parabola exit (1.7-G). Three to eight parabolas were averaged for subjects in each posture; the mean for each posture was calculated. In each of five additional subjects, the coefficient of variation was calculated by dividing mean value by the standard deviation of 3 to 15 R-R intervals. Eight to ten parabolas were averaged for each postural set. Compared with values collected before 0-G, standing values during 0-G showed that the thoracic fluid index decreased 2.5 ohms, heart rate decreased 22 bpm, and cardiac output increased 1 L/min. During sitting, thoracic fluid index decreased 1.25 ohms, heart rate decreased 10 bpm, whereas cardiac output increased 0.5 L/min.(ABSTRACT TRUNCATED AT 250 WORDS)

Chicken ovalbumin upstream promoter-transcription factors (COUP-TFs), orphan members of the nuclear receptor superfamily, play a key role in the regulation of organogenesis, neurogenesis, and cellular differentiation during embryogenic development. COUP-TFs are also involved in the regulation of several genes that encode metabolic enzymes. Although COUP-TFs function as potent transcription repressors, there are at least three different molecular mechanisms of activation of gene expression by COUP-TFs. First, as we have previously shown, COUP-TF is required as an accessory factor for the complete induction of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. This action is mediated by the binding of COUP-TF to the glucocorticoid accessory factor 1 (gAF1) and 3 (gAF3) elements in the phosphoenolpyruvate carboxykinase gene glucocorticoid response unit. In addition, COUP-TF1 binds to DNA elements in certain genes and transactivates directly. Finally, COUP-TF1 serves as a coactivator through DNA-bound hepatic nuclear factor 4. Here we show that the same region of COUP-TFI, located between amino acids 184 and 423, is involved in these three mechanisms of transactivation by COUP-TFI. Furthermore, we show that GRIP1 and SRC-1 potentiate the activity of COUP-TFI and that COUP-TFI associates with these coactivators in vivo using the same region required for transcription activation. Finally, overexpression of GRIP1 or SRC-1 does not convert COUP-TFI from a transcriptional repressor into a transcriptional activator in HeLa cells.

In all oviparous, liver represents one of the main E2-target tissues where estrogen receptor (ER) constitutes the key mediator of estrogen action. The rainbow trout estrogen receptor (rtER) gene expression is markedly up-regulated by estrogens and the sequences responsible for this autoregulation have been located in a 0.2 kb upstream transcription start site within - 40/- 248 enhancer region. Absence of interference with steroid hormone receptors and tissue-specific factors and a conserved basal transcriptional machinery between yeast and higher eukaryotes, make yeast a simple assay system that will enable determination of important cis-acting regulatory sequences within rtER gene promoter and identification of transcription factors implicated in the regulation of this gene. Deletion analysis allowed to show a synergistic effect between an imperfect estrogen-responsive element (ERE) and a consensus half-ERE to achieve a high hormone-dependent transcriptional activation of the rtER gene promoter in the presence of stably expressed rtER. As in mammalian cells, here we observed a positive regulation of the rtER gene promoter by the chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) through enhancing autoregulation. Using a point mutation COUP-TFI mutant unable to bind DNA demonstrates that enhancement of rtER gene autoregulation requires the interaction of COUP-TFI to the DNA. Moreover, this enhancement of transcriptional activation by COUP-TFI requires specifically the AF-1 transactivation function of ER and can be observed in the presence of E2 or 4-hydroxytamoxifen but not ICI 164384. Thus, this paper describes the reconstitution of a hormone-responsive transcription unit in yeast in which the regulation of rtER gene promoter could be enhanced by the participation of cis-elements and/or trans-acting factors, such as ER itself or COUP-TF.

BACKGROUND

The Tilburg frailty indicator (TFI) is a self-report measurement instrument which integrates the physical, psychological and social domains to assess frailty in older adults. The aim of this study was the adaptation of the TFI to a German version and testing of the psychometric properties.

METHODS

This study surveyed 210 individuals aged 64-91 years living at home. The mean age of participants was M = 75.3±5.7 years with 62 % females. The internal consistency was tested with Cronbach's alpha. The test-retest reliability was calculated after 20 weeks. The German TFI was validated using alternative measures for assessment of the quality of life, e.g. Eurohis-QoL-8 and short form health survey (SF-12), the patient health questionnaire (PHQ), the geriatric anxiety inventory short form (GAI-SF), the social support scale (F-Soz-U-K-14) and the resilience scale (RS-11).

RESULTS

The internal consistency was acceptable with a value for Cronbach's alpha of 0.67. The test-retest reliability was good after 5 months α = 0.87 (physical domain r = 0.85, psychological domain r = 0.75 and social domain r = 0.84). The inter-item correlations ranged between - 0.06 and 0.57. Correlations with alternative frailty measures showed good convergent and divergent validity.

CONCLUSIONS

This study showed acceptable psychometric properties of the German adaptation of the TFI which was found to be age and frailty sensitive. The results of the validity of the TFI support the three domains integrated in the frailty score. Further application and testing of the German TFI in primary care and clinical settings are suggested to consolidate the findings.

To study long-term testicular function following the treatment of acute lymphoblastic leukaemia (ALL) in childhood, 37 young adult males were assessed at two separate time points. The initial assessment was made by a wedge testicular biopsy after completion of treatment (median 9.7 years; range 4.1-16.3 years) and the subsequent assessment (median 18.6 years; range 15.4-26.8 years) consisted of the clinical examination of pubertal stage, measurement of serum gonadotrophins and testosterone and, in 19 patients, semen analysis. All 37 men completed pubertal development normally and had a testosterone concentration within the normal adult range. Six men showed evidence of severe damage to the seminiferous epithelium, five were azoospermic and one, who did not provide semen for analysis, had a reduced mean testicular volume (11 mls; normal greater than or equal to 15 mls) and a raised basal FSH level (13 UI 1-1; normal less than or equal to 6 IU 1-1). All six men with germ-cell damage had received either cyclophosphamide or both cyclophosphamide and cytosine arabinoside as part of their chemotherapy regimen. Approximately 10.7 years earlier all 37 men had undergone a testicular biopsy after completion of their chemotherapy. Morphological damage to the seminiferous epithelium had been calculated by estimating the tubular fertility index (TFI), which is the percentage of seminiferous tubules containing identifiable spermatogonia (age-matched normal = 100%).(ABSTRACT TRUNCATED AT 250 WORDS)

Using the yeast one-hybrid approach to screen a human breast tissue hybrid cDNA expression library, we have found that four orphan/nuclear receptors, ERRalpha-1, EAR-2, COUP-TFI (EAR-3), and RARgamma, bind to the silencer (S1) region of the human aromatase gene. S1 down regulates promoters I.3 and II of the human aromatase gene. In this study, the interaction of EAR-2, COUP-TFI, and RARgamma with S1 was confirmed by DNA mobility shift analysis. In contrast to the findings that ERRalpha-1 behaves as a positive regulatory factor, these three nuclear receptors were found, by mammalian cell transfection experiments, to act as negative regulatory factors by binding to S1. Furthermore, the negative action of these three nuclear receptors could override the positive effect of ERRalpha-1. RT-PCR analysis of 11 cell lines and 55 human breast tumor specimens has shown that these nuclear receptors are expressed in human breast tissue. Since EAR-2, COUP-TFI, and RARgamma are expressed at high levels, it is likely that S1 is a negative regulatory element that suppresses aromatase promoters I.3 and II in normal breast tissue. In cancer tissue, S1 may function as a positive element since ERRalpha-1 is expressed, but EAR-2 and RARgamma are only present in a small number of tumor specimens. This hypothesis is sustained by the finding that there is a weak inverse correlation between the expression of COUP-TFI and that of aromatase in breast tumor tissue. Our studies have revealed that estrogen receptor alpha (ERalpha) can also bind to S1, in a ligand-dependent manner. By binding to S1, ERalpha down-regulates the aromatase promoter activity. These results demonstrate that nuclear receptors play important roles in modulating aromatase expression in human breast tissue.

Oxidative stress is a deleterious stressor associated with a plethora of disease and aging manifestations, including neurodegenerative disorders, yet very few factors and mechanisms promoting the neuroprotection of photoreceptor and other neurons against oxidative stress are known. Insufficiency of RAN-binding protein-2 (RANBP2), a large, mosaic protein with pleiotropic functions, suppresses apoptosis of photoreceptor neurons upon aging and light-elicited oxidative stress, and promotes age-dependent tumorigenesis by mechanisms that are not well understood. Here we show that, by downregulating selective partners of RANBP2, such as RAN GTPase, UBC9 and ErbB-2 (HER2; Neu), and blunting the upregulation of a set of orphan nuclear receptors and the light-dependent accumulation of ubiquitylated substrates, light-elicited oxidative stress and Ranbp2 haploinsufficiency have a selective effect on protein homeostasis in the retina. Among the nuclear orphan receptors affected by insufficiency of RANBP2, we identified an isoform of COUP-TFI (Nr2f1) as the only receptor stably co-associating in vivo with RANBP2 and distinct isoforms of UBC9. Strikingly, most changes in proteostasis caused by insufficiency of RANBP2 in the retina are not observed in the supporting tissue, the retinal pigment epithelium (RPE). Instead, insufficiency of RANBP2 in the RPE prominently suppresses the light-dependent accumulation of lipophilic deposits, and it has divergent effects on the accumulation of free cholesterol and free fatty acids despite the genotype-independent increase of light-elicited oxidative stress in this tissue. Thus, the data indicate that insufficiency of RANBP2 results in the cell-type-dependent downregulation of protein and lipid homeostasis, acting on functionally interconnected pathways in response to oxidative stress. These results provide a rationale for the neuroprotection from light damage of photosensory neurons by RANBP2 insufficiency and for the identification of novel therapeutic targets and approaches promoting neuroprotection.

In a companion study published in this issue (p. 83), we showed that chimeric substrates containing 2'-methoxyethyl (MOE) nucleotides inhibited human RNase H1 activity. In this study, we prepared chimeric substrates containing a central DNA region with flanking northern-biased MOE nucleotides hybridized to complementary RNA. Conformationally biased and flexible modified nucleotides were positioned at the junctions between the DNA and MOE residues of the chimeric substrates to modulate the effects of the MOE residues on human RNase H1 activity. The strong northern-biased locked-nucleic acid modification exacerbated the negative effects of the MOE modifications resulting in slower human RNase H1 cleavage rates. Enhanced cleavage rates were observed for the eastern-biased 2'-ara-fluorothymidine and bulge inducing N-methylthymidine modifications positioned at the 5'-DNA/3'-MOE junction as well as the southern-biased 2'-methylthiothymidine and conformationally flexible tetrafluoroindole (TFI) modifications positioned at the 5'-MOE/3'-DNA junction. The heterocycle of the ribonucleotide opposing the TFI deoxyribonucleotide had no effect on the human RNase H1 activity, whereas nucleotide substitutions adjacent the TFI significantly affected the cleavage rate. Mismatch base pair(s) exhibited similar effects on human RNase H1 activity as the TFI modifications. The effects of the TFI modification and mismatch base pair(s) on human RNase H1 activity were influenced by the position of the modification relative to the nucleotides interacting with the catalytic site of the enzyme rather than the juxtaposition of the modification to the MOE residues. Finally, these results provide a method for enhancing the human RNase H1 activity of chimeric antisense oligonucleotides (ASO) as well as the design of more potent ASO drugs.

The present study investigated the relationship between endogenous CCK and serotonin (5-HT) in fat-induced satiety. Male Wistar rats with duodenal cannulas were adapted to eating 6 h/day along with receiving an infusion of saline or one of two isocaloric solutions (10 ml, 1 kcal/ml, 0.45 ml/min) varying in fat and carbohydrate content (20 or 80% energy from fat). Rats were infused 10 min after food presentation. The satiation/satiety response was determined from measures of meal size (MS), intermeal interval (IMI), and total food intake (TFI). Infusion with either fat solution reduced MS compared with saline; however, the 80% fat infusate reduced TFI and lengthened the IMI compared with saline and the 20% fat infusate. CCK and 5-HT involvement in fat-induced satiety was investigated by preceding the 80% fat infusate with CCK and/or 5-HT3 receptor antagonists Devazepide (Dev) and Tropisetron (Trop). A CCK releaser, trypsin inhibitor (TI), was added to the 20% fat infusate to enhance satiety. Pretreatment with Dev or Trop alone attenuated the inhibitory effects of the 80% solution on IMI, whereas reversal of the inhibitory effects on MS and TFI were sensitive only to Dev at the doses provided. Both antagonists together completely blocked the satiating effects of the 80% fat infusate on all feeding variables measured. Addition of TI to the 20% fat infusate lengthened the IMI but did not affect MS or TFI. These results provide evidence for the participation of both endogenous CCK and 5-HT in the satiety response to fat in the intestine.

BACKGROUND

Bevacizumab (BEV) plus triplet chemotherapy can increase efficacy of first-line treatment of metastatic colorectal cancer (MCRC), particularly integrated with secondary liver surgery in liver-limited (L-L) patients. The prognostic value of the KRAS genotype in L-L and other or multiple metastatic (O/MM) MCRC patients treated with the FIr-B/FOx regimen was retrospectively evaluated.

METHODS

Tumoral and metastatic samples were screened for KRAS codon 12 and 13 and BRAF mutations by SNaPshot and/or direct sequencing. Fit MCRC patients <75 years were consecutively treated with FIr-B/FOx regimen: weekly 12-h timed flat-infusion/5-fluorouracil (TFI 5-FU) 900 mg/m2, days 1, 2, 8, 9, 15, 16, 22 and 23; irinotecan (CPT-11) 160 mg/m2 plus BEV 5 mg/kg, days 1, 15; oxaliplatin (OXP) 80 mg/m2, days 8, 22; every 4 weeks. MCRC patients were classified as L-L and O/MM. Activity and efficacy were evaluated and compared using log-rank test.

RESULTS

In all, 59 patients were evaluated: 31 KRAS wild-type (53%), 28 KRAS mutant (47%). At 21.5 months median follow-up, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS wild-type 90%, 14 months, 38 months; KRAS mutant 67%, 11 months, 20 months. PFS and OS were not significantly different. PFS and OS were significantly different in L-L compared to O/MM evaluable patients. In KRAS wild-type patients, clinical outcome of 12 L-L compared to 18 O/MM was significantly different: PFS 21 versus 12 months and OS 47 versus 28 months, respectively. In KRAS mutant patients, the clinical outcome of 13 L-L compared to 14 O/MM was not significantly different: PFS 11 months equivalently and OS 39 versus 19 months, respectively.

CONCLUSIONS

The KRAS genotype wild-type and mutant does not significantly affect different clinical outcomes for MCRC patients treated with the first-line FIr-B/FOx intensive regimen. KRAS wild-type patients with L-L disease may achieve a significantly prolonged clinical outcome due to integration with secondary liver surgery, with respect to KRAS mutant patients.

OBJECTIVE

Caregivers of adolescents and young adults (AYA) with complex medical conditions, including brain tumor survivors, have protracted and often complex roles, yet a gap exists in understanding their perceived competence. The aim of this study is to test a hypothesized model based on the theoretical and empirical literature: better caregiver health, better survivor health, and better family functioning contribute directly to fewer caregiving demands, which in turn contribute to greater caregiver competence.

METHODS

Telephone interviews using structured self-report questionnaires were conducted in this cross-sectional study with a sample of 186 caregivers (mothers) of childhood brain tumor survivors aged 14-40 years old who live with at least one parent. Structural equation modeling (SEM) was used to test the hypothesized model.

RESULTS

The final SEM model suggests that survivor health and family functioning directly predict caregiver competence. Caregiver health indirectly predicts caregiver competence through caregiver demands and then family functioning. Family income directly predicts family functioning. The model showed adequate fit (CFI = 0.905, TFI = 0.880, and RMSEA = 0.081). Overall, the model accounted for 45% of variance in caregiver competence.

CONCLUSIONS

For this sample of caregivers of AYA with medically complex conditions, family functioning and the health of survivors are both important to how they evaluate their skills as caregivers. The results of this study underscore the crucial role of care models that focus on optimizing the health of the survivor, caregiver, and family, along with supporting a family centered approach to their care.

The emerging technique of real-time fMRI neurofeedback trains individuals to regulate their own brain activity via feedback from an fMRI measure of neural activity. Optimum feedback presentation has yet to be determined, particularly when working with clinical populations. To this end, we compared continuous against intermittent feedback in subjects with tinnitus. Fourteen participants with tinnitus completed the whole experiment consisting of nine runs (3 runs × 3 days). Prior to the neurofeedback, the target region was localized within the auditory cortex using auditory stimulation (1 kHz tone pulsating at 6 Hz) in an ON-OFF block design. During neurofeedback runs, participants received either continuous (n = 7, age 46.84 ± 12.01, Tinnitus Functional Index (TFI) 49.43 ± 15.70) or intermittent feedback (only after the regulation block) (n = 7, age 47.42 ± 12.39, TFI 49.82 ± 20.28). Participants were asked to decrease auditory cortex activity that was presented to them by a moving bar. In the first and the last session, participants also underwent arterial spin labeling (ASL) and resting-state fMRI imaging. We assessed tinnitus severity using the TFI questionnaire before all sessions, directly after all sessions and six weeks after all sessions. We then compared neuroimaging results from neurofeedback using a general linear model (GLM) and region-of-interest analysis as well as behavior measures employing a repeated-measures ANOVA. In addition, we looked at the seed-based connectivity of the auditory cortex using resting-state data and the cerebral blood flow using ASL data. GLM group analysis revealed that a considerable part of the target region within the auditory cortex was significantly deactivated during neurofeedback. When comparing continuous and intermittent feedback groups, the continuous group showed a stronger deactivation of parts of the target region, specifically the secondary auditory cortex. This result was confirmed in the region-of-interest analysis that showed a significant down-regulation effect for the continuous but not the intermittent group. Additionally, continuous feedback led to a slightly stronger effect over time while intermittent feedback showed best results in the first session. Behaviorally, there was no significant effect on the total TFI score, though on a descriptive level TFI scores tended to decrease after all sessions and in the six weeks follow up in the continuous group. Seed-based connectivity with a fixed-effects analysis revealed that functional connectivity increased over sessions in the posterior cingulate cortex, premotor area and part of the insula when looking at all patients while cerebral blood flow did not change significantly over time. Overall, these results show that continuous feedback is suitable for long-term neurofeedback experiments while intermittent feedback presentation promises good results for single session experiments when using the auditory cortex as a target region. In particular, the down-regulation effect is more pronounced in the secondary auditory cortex, which might be more susceptible to voluntary modulation in comparison to a primary sensory region.

OBJECTIVE

To compare the transradial approach and transfemoral approach for primary percutaneous coronary intervention (PCI) in Chinese patients with acute myocardium infarction (AMI).

METHODS

From August 2005 to September 2008, we randomly divided 200 AMI patients into transradial intervention (TRI) group and transfemoral intervention (TFI) group. The study took place in the Department of Cardiology, The Tenth People's Hospital, Tongji University, Shanghai, China. During the procedure, the puncture success, procedure success, infarction related artery (IRA), coronary flow, percentage of 3 vessel disease, stent used, and tirofiban used were observed. The procedural time intervals were also recorded. After the procedure, the major adverse cardiac events (MACEs) and the vascular complications were studied. In this trial, the hospital stay was also recorded.

RESULTS

The baseline clinical characteristics of the patients were similar in both groups. There were no statistical differences in IRA, 3 vessel disease, initial and final thrombolysis in myocardial infarction (TIMI) flow, rate of stent and tirofiban used, and procedure rate (p>0.05). No statistical differences were observed in the puncture time, cannulation time, reperfusion time, procedural time, and fluoroscopy time in both groups (p>0.05). There was no statistical difference in the incidence of MACEs between the 2 groups (p>0.05). Not only the vascular complications were lower in the TRI group (p<0.01), but also the total hospital stay was longer in the TFI group than in the TRI group (p<0.001).

CONCLUSIONS

Transradial intervention for Chinese patients with AMI yields comparable procedural success, and has fewer vascular access site complications compared with the TFI group.

BACKGROUND

Transradial coronary intervention has been widely used because of its effects in lowering the incidence of complications in vascular access site and improving patient satisfaction compared to the femoral approach. This study aimed to investigate the safety and feasibility of transradial approach for primary percutaneous coronary intervention (PCI) in elderly patients with acute myocardial infarction (AMI).

METHODS

A total of 103 consecutive elderly patients (age = 65 years) who were diagnosed as having AMI were indicated for PCI. Among them, 57 patients received primary PCI via the transradial approach (transradial intervention, TRI group), and 46 underwent primary PCI via the transfemoral approach (transfemoral intervention, TFI group). The success rate of puncture, puncture time, cannulation time, reperfusion time, the total time for PCI, the success rate of PCI, the use rates of temporary pacemaker and intra-aortic balloon pump (IABP), and the total length of hospital stay of the patients in the two groups were compared. After the procedure, vascular access site complications and major adverse cardiovascular events (MACE) in the two groups in one month were observed.

RESULTS

The success rates of puncture (98.2% vs 100.0%) and PCI (96.5% vs 95.7%) for the patients in the TRI and TFI groups were not statistically significant (P>> 0.05). The puncture time ((2.4 +/- 1.1) vs (2.0 +/- 0.9) minutes), cannulation time ((2.7 +/- 0.5) vs (2.6 +/- 0.5) minutes), reperfusion time ((16.2 +/- 4.5) vs (15.4 +/- 3.6) minutes), total time of the procedure ((44.1 +/- 6.8) vs (41.2 +/- 5.7) minutes), use rates of temporary pacemaker (1.8% vs 2.2%) and IABP (0 vs 2.2%) in the two groups were not statistically significant (P>> 0.05), but the hospital stay of the TFI group was longer than that of the TRI group ((10.1 +/- 4.6) vs (7.2 +/- 2.6) days, P < 0.01). A radial occlusion was observed in the TRI group, but no ischemic syndrome in hand. In the TFI group, 4 patients had hematosis, 1 had pseudoaneurysm, and 1 had major bleeding. Statistical significance in vascular access site complications was seen in the two groups (1.8 % vs 13.1%, P < 0.05). Three patients died in the two groups respectively in one month, and there was no statistical significance in MACE in the two groups (5.3% vs 6.5%, P>> 0.05).

CONCLUSIONS

The transradial approach for primary PCI is safe and feasible for elderly patients with AMI.

OBJECTIVE

To perform a subset analysis of patients with very platinum-sensitive recurrent ovarian cancer (ROC) enrolled in the phase III CALYPSO trial.

METHODS

The international non-inferiority trial enrolled women with ROC that relapsed >6 months following first- or second-line platinum- and paclitaxel-based therapies. Patients were randomised to CD [carboplatin-pegylated liposomal doxorubicin (PLD)] or CP (carboplatin-paclitaxel) and stratified by treatment-free interval (TFI). In this analysis, patients with a TFI)24 months were analysed separately for progression free survival (PFS), the primary endpoint of CALYPSO, overall survival (OS) and safety.

RESULTS

A total of 259 very platinum-sensitive patients were included (n=131, CD; n=128, CP). Median PFS was 12.0 months for the CD arm and 12.3 months for CP [HR=1.05 (95% CI, 0.79-1.40); P=0.73 for superiority] and median OS was 40.2 months for CD and 43.9 for CP [HR=1.18 (95% CI 0.85-1.63); P=0.33 for superiority]. Overall response rates were 42% and 38%, respectively (P=0.46). Toxicities were more common with CP versus CD, including grade 3/4 neutropenia (40.8% versus 27.5%; P=0.025), nausea (4.8% versus 3.1%; P=0.47), allergic reaction (8% versus 3.1%; P=0.082) sensory neuropathy (4.8% versus 2.3%; P=0.27) and grade 2 alopecia (88% versus 9.2%; P<0.001). Grade 3/4 thrombocytopenia (12.2% versus 3.2%; P=0.007) and mucositis (2.3% versus 0%; P=0.089) were more common with CD. Grade 3/4 hand-foot syndrome occurred rarely with CD (3 patients versus 0 in CP arm; P=0.089).

CONCLUSIONS

CP and CD were equally effective treatment regimens for patients with very platinum-sensitive ROC. The favourable risk-benefit profile suggests carboplatin-PLD as treatment of choice for these patients.

OBJECTIVE

To identify risk factors for dental fluorosis that cannot be explained by drinking water fluoride concentration alone.

METHODS

Two hundred eighty-four Tanzanian children ages 9 to 19 (mean 14.0+/-SD 1.69), who were lifetime residents at differing altitudes (Chanika, 100 m; Rundugai, 840 m; and Kibosho, 1,463 m; Sites 1, 2, and 3 respectively) were examined for dental fluorosis and caries. They were interviewed about their food habits, environmental characteristics and use of a fluoride-containing food tenderizer known locally as magadi. Meal, urine, water and magadi samples supplied by the participants were analyzed for fluoride content. Urine samples were also analyzed for creatinine concentration. Four magadi samples from Sites 1 and 3 were analyzed for complete element composition.

RESULTS

Of the 13 water samples from Site 2, 10 contained>> or =4 mg/L F, ranging from 1.26 to 12.36 mg/L with a mean+/-SD of 5.72+/-4.71 mg/L. Sites 1 and 3 had negligible water fluoride of 0.05+/-0.05 and 0.18+/-0.32 mg/L respectively. Mean TFI fluorosis scores (range 0-9) for Site 2 were high: 4.44+/-1.68. In Sites 1 and 3, which both had negligible water fluoride, fluorosis scores varied dramatically: Site 1 mean maximum TFI was 0.01+/-0.07 and Site 3 TFI was 4.39+/-1.52. Mean DMFS was 1.39+/-2.45, 0.15+/-0.73 and 0.19+/-0.61 at Sites 1, 2, and 3, respectively. There were no restorations present. Urinary fluoride values were 0.52+/-0.70, 4.34+/-7.62, and 1.43+/-1.80 mg/L F at Sites 1, 2, and 3, respectively. Mean urinary fluoride values at Site 3 were within the normal urinary fluoride reference value range in spite of pervasive severe pitting fluorosis. Meal and magadi analyses revealed widely varied fluoride concentrations. Concentrations ranged from 0.01 to 22.04 mg/L F for meals and from 189 to 83211 mg/L F for magadi. Complete element analysis revealed the presence of aluminum, iron, magnesium, manganese, strontium and titanium in four magadi samples. There were much higher concentrations of these elements in samples from Site 3, which was at the highest altitude and had severe enamel disturbances in spite of negligible water fluoride concentration. An analysis of covariance model supported the research hypothesis that the three communities differed significantly in mean fluorosis scores (P<0.0001). Controlling for urinary fluoride concentration and urinary fluoride:urinary creatinine ratio, location appeared to significantly affect fluorosis severity. Urinary fluoride:urinary creatinine ratio had a stronger correlation than urinary fluoride concentration with mean TFI fluorosis scores (r=0.43 vs r= 0.25).

CONCLUSIONS

The severity of enamel disturbances at Site 3 (1463 m) was not consistent with the low fluoride concentration in drinking water, and was more severe than would be expected from the subjects' normal urinary fluoride values. Location, fluoride in magadi, other elements found in magadi, and malnutrition are variables which may be contributing to the severity of dental enamel disturbances occurring in Site 3. Altitude was a variable which differentiated the locations.

BACKGROUND

While the impact of various treatments on myeloma patients' health-related quality of life (HRQL) has been reported, the impact of a treatment-free interval (TFI) is currently unclear. The aims of this study were to assess if (1) a TFI is associated with a better HRQL vs. other treatment phases and (2) the length of the TFI influences HRQL.

METHODS

A cross-sectional postal survey was conducted in the UK. The survey was sent to 605 multiple myeloma patients via the charity Myeloma UK and asked patients to rate their HRQL using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), EORTC QLQ-MY20 and the EQ-5D. The results were analysed using ordinary least squares regression.

RESULTS

Surveys of 402 (67 %) were returned; 370 (61 %) were considered eligible for analysis. Results demonstrated that being in a first TFI relative to other treatment phases and experiencing a longer TFI were significantly associated with better HRQL as assessed by various domains of the QLQ-C30, MY20 and EQ-5D.

CONCLUSIONS

Patients enjoy better HRQL when in their first TFI, and the length of the TFI also positively impacts on HRQL This information may be important for patients and their physicians making treatment decisions and has implications for treatment protocols incorporating extended therapy.

Near-infrared fluorescence (NIRF) imaging has great potential for studying physiological and pathophysiological processes noninvasively in several locations of the body. In this study, we evaluated the feasibility of NIRF imaging to visualize fluorescent compounds within the brains of live mice commonly used in brain research. To simulate the presence of a molecular NIRF reporter agent at the site of a lesion, we developed a new in vivo phantom model wherein capsules containing different amounts of an NIRF dye (Cy5.5) were stereotactically implanted deep into the left hemispheres of living mice. To precisely locate the implanted capsules, magnetic resonance imaging (MRI) was performed. Fluorescence reflectance imaging (FRI) and transillumination fluorescence imaging (TFI) were conducted to analyze and compare sensitivity and target-to-background ratios of the two methods. The sensitivities of FRI and TFI to background fluorescence from circulating dye was tested by imaging fluorescent capsules in mice intravenously injected with increasing amounts of long-circulating Cy5.5-dextran. The results show that capsules containing dye amounts as low as 10(-12) mol can be detected. TFI yielded significantly higher target-to-background ratios than FRI at 10(-11) mol (p < .05). Comparatively low amounts of fluorescence in the blood vessels can extinguish the signal. We conclude that keeping the signal from circulating NIRF dye low, NIRF imaging offers high sensitivity in detecting fluorochromes noninvasively within brains of mice, especially by using TFI. This encourages the application of NIRF for molecular imaging in the mouse brain using NIRF reporters.

OBJECTIVE

This study sought to evaluate the costs of transradial percutaneous coronary intervention (TRI) and transfemoral percutaneous coronary intervention (TFI) from a contemporary hospital perspective.

BACKGROUND

Whereas the TRI approach to percutaneous coronary intervention (PCI) has been shown to reduce access-site complications compared with TFI, whether it is associated with lower costs is unknown.

METHODS

TRI and TFI patients were identified at 5 U.S. centers. The primary outcome was the cost of percutaneous coronary intervention (PCI) hospitalization, defined as cost on the day of PCI through hospital discharge. Cost was obtained from each hospital's cost accounting system. Independent costs of TRI were identified using propensity-scoring methods with inverse probability weighting. Secondary outcomes of interest were bleeding, in-hospital mortality, and length of stay, which were stratified by pre-procedural risk and PCI indication.

RESULTS

In 7,121 PCI procedures performed from January 1, 2010, to March 31, 2011, TRI was performed in 1,219 (17%) patients and was associated with shorter lengths of stay (2.5 vs. 3.0 days; p < 0.001) and lower bleeding events (1.1% vs. 2.4%, adjusted odds ratio [OR]: 0.52, 95% confidence interval [CI]: 0.34 to 0.79; p = 0.002). TRI was associated with a total cost savings of $830 (95% CI: $296 to $1,364; p < 0.001), of which $130 (95% CI: -$99 to $361; p = 0.112) were procedural savings and $705 (95% CI: $212 to $1,238; p < 0.001) were post-procedural savings. There was an associated graded increase in savings among patients at higher predicted risk of bleeding: low risk: $642 (95% CI: $43 to $1,236; p = 0.035); moderate risk: $706 (95% CI: $104 to $1,308; p = 0.029); and high risk: $1,621 (95% CI: $271 to $2,971, p = 0.039).

CONCLUSIONS

TRI was associated with a cost savings exceeding $800 per patient relative to TFI. Increased adoption of TRI may result in cost savings at hospitals.

A tessellated fundus is a common characteristic of myopic eyes and is an important clinical marker for the development of retinochoroidal changes. However, the exact cause and significance of tessellated fundi have not been definitively determined. We determined the degree of tessellation in fundi objectively in normal, non-pathological myopic eyes, and correlated the degree of tessellation and the choroidal thickness (CT) and axial length (AL). This was a prospective observational cross sectional study. The eyes were classified subjectively into three groups based on the degree of tessellation observed ophthalmoscopically. Digital color fundus photographs were assessed for the degree of tessellation by ImageJ, an image processing program. Three tessellated fundus indices (TFIs) were calculated and were compared to the three subjectively-determined groups. The subfoveal and nasal CTs were measured in the optical coherence tomographic images. The correlations between the TFIs and the CT were calculated. Additionally, the correlation between the TFIs and the AL was calculated. One hundred right eyes of 100 healthy volunteers (mean age 25.8±3.9 years) were studied. Ophthalmoscopically, 57 eyes were placed in the non-tessellated group, 27 eyes into the weakly tessellated group, and 16 eyes into the strongly tessellated group. There was a significant correlation between the subjective classifications and the TFI values (P<0.05, Kruskal-Wallis test). All of the TFIs were significantly associated with the subfoveal and nasal CT (R = -0.20 to -0.24, P<0.05). The TFIs were not significantly correlated with the ALs. In conclusion, the significant correlation between the subjective and objective classifications of the degree of tessellation indicates that TFIs can be used to classify the degree of tessellation. The results indicate that the differences in the CT account for the degree of tessellation.

Non-invasive renal signatures can help in serial monitoring of diabetic patients. We tested whether urinary exosomal (UE) microRNA (miR) analysis could non-invasively predict renal pathology in diabetic rats during the course of diabetes. Diabetes mellitus (DM) was induced in male Wistar rats by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg body weight). Non-diabetic control (CTRL) rats were injected with vehicle. Insulin (INS) treatment (5U/d, s.c.) was provided to 50% of the DM rats. Urine samples were collected at weeks 3, 6, and 9 following injections and UE prepared. An increase in miR-451-5p and miR-16, observed by pilot small RNA sequencing of UE RNA, was confirmed by quantitative real-time polymerase chain reaction (qPCR) and selected for further study. Subsets of rats were euthanized after 3, 6, and 9 weeks of diabetes for renal pathology analysis, including determination of the tubulointerstitial fibrotic index (TFI) and glomerulosclerotic index (GI) scores. qPCR showed a substantial rise in miR-451-5p in UE from DM rats during the course of diabetes, with a significant rise (median fold change >1000) between 3 and 6 weeks. Moreover, UE miR-451-5p at 6 weeks predicted urine albumin at 9 weeks (r = 0.76). A delayed but significant rise was also observed for miR-16. In contrast, mean urine albumin only increased 21% between 3 and 6 weeks (non-significant rise), and renal TFI and GI were unchanged till 9 weeks. Renal expression of miR-451-5p and miR-16 (at 10 weeks) did not correlate with urine levels, and moreover, was negatively associated with indices of renal pathology (r≥-0.70, p = 0.005 for TFI and r≥-0.6, p≤0.02 for GI). Overall, a relative elevation in renal miR-451-5p and miR-16 in diabetes appeared protective against diabetes-induced kidney fibrosis; while UE miR-451-5p may hold prognostic value as an early and sensitive non-invasive indicator of renal disease.

Early stage estrogen receptor positive (ER+) breast cancer (BCa) treatment is based on the presumed aggressiveness and likelihood of cancer recurrence. Oncotype DX (ODX) and other gene expression tests have allowed for distinguishing the more aggressive ER+ BCa requiring adjuvant chemotherapy from the less aggressive cancers benefiting from hormonal therapy alone. However these tests are expensive, tissue destructive and require specialized facilities. Interestingly BCa grade has been shown to be correlated with the ODX risk score. Unfortunately Bloom-Richardson (BR) grade determined by pathologists can be variable. A constituent category in BR grading is tubule formation. This study aims to develop a deep learning classifier to automatically identify tubule nuclei from whole slide images (WSI) of ER+ BCa, the hypothesis being that the ratio of tubule nuclei to overall number of nuclei (a tubule formation indicator - TFI) correlates with the corresponding ODX risk categories. This correlation was assessed in 7513 fields extracted from 174 WSI. The results suggests that low ODX/BR cases have a larger TFI than high ODX/BR cases (p < 0.01). The low ODX/BR cases also presented a larger TFI than that obtained for the rest of cases (p < 0.05). Finally, the high ODX/BR cases have a significantly smaller TFI than that obtained for the rest of cases (p < 0.01).

The objectives of this study was to test the feasibility and safety of transradial coronary intervention (TRI) in Japanese patients. We compared the results of TRI in 1,791 lesions (1,360 patients) between November 1995 and December 1997 with those of transfemoral coronary intervention (TFI) in 966 lesions (793 patients) between April and October 1995. We also examined the radial artery pulse in 294 patients 1-2 weeks after TRI by palpation and Doppler examination. Arterial puncture, coronary artery cannulation, lesion, and patient success rates were similar in both groups. No significant difference was noted in the major complication rate. Local complications were significantly lower in the TRI group (0.3% vs. 3.3%, P < 0.001). Doppler studies of the radial artery were performed in 294 patients chosen at random. In the first 234 patients, the sheath was pulled out 3 hr after the procedure, and in the last 60 patients, immediately after the procedure; radial artery occlusion rates were 5% and 0%, respectively. In conclusion, TRI seems safe and feasible in Japanese patients.

We demonstrate that chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) mRNA is more abundantly expressed (than COUP-TFI mRNA) in skeletal muscle C2C12 cells and in (type I and II) skeletal muscle tissue from C57BL/10 mice. Consequently, we have utilized the ABI TaqMan Low Density Array (TLDA) platform to analyze gene expression changes specifically attributable to ectopic COUP-TFII (relative to vector only) expression in muscle cells. Utilizing a TLDA-based platform and 5 internal controls, we analyze the entire NR superfamily, 96 critical metabolic genes, and 48 important myogenic regulatory genes on the TLDA platform utilizing 5 internal controls. The low density arrays were analyzed by rigorous statistical analysis (with Genorm normalization, Bioconductor R, and the Empirical Bayes statistic) using the (integromics) statminer software. In addition, we validated the differentially expressed patho-physiologically relevant gene (identified on the TLDA platform) glucose transporter type 4 (Glut4). We demonstrated that COUP-TFII expression increased the steady state levels of Glut4 mRNA and protein, while ectopic expression of truncated COUP-TFII lacking helix 12 (COUP-TFΔH12) reduced Glut4 mRNA expression in C2C12 cells. Moreover, COUP-TFII expression trans-activated the Glut4 promoter (-997/+3), and ChIP analysis identified selective recruitment of COUP-TFII to a region encompassing a highly conserved SP1 binding site (in mouse, rat, and human) at nt positions -131/-118. Mutation of the SpI site ablated COUP-TFII mediated trans-activation of the Glut4 promoter. In conclusion, this study demonstrates that in skeletal muscle cells, COUP-TFII regulates several nuclear hormone receptors, and critical metabolic and muscle specific genes.