As part of an epidemiological study on the oral health of Flemish schoolchildren, fluoride use was studied together with risk factors (medical history, tap water fluoride concentration, use of fluoride supplements, toothpaste and brushing habits). Fluorosis was scored according to the Thylstrup-Fejerskov index (TFI) in children aged 11 years (4,128 children examined). Explanatory variables were recorded yearly, starting at the age of 7. Earliest toothpaste use was reported at the age of 1. By age 7, 99.7% of the children reported the use of toothpaste (90% fluoride-containing), but only 13.9% reported using a pea-sized amount. At age 7, 66% of the children had received systemic fluoride supplements during at least part of their childhood. At 11 years, 92% of the children used a fluoride-containing toothpaste and 6% still received systemic fluoride supplements. Fluorosis was present in about 10% of all the children examined, mainly TFI score 1 (7.3% in upper central incisors). Logistic regression established tooth brushing frequency and fluoride supplement use, in addition to tap water fluoride concentrations above 0.7 mg/l, as significant risk factors when the presence of fluorosis on at least one tooth was used as outcome variable. Children having fluorosis had a lower risk of caries, both in the primary (median dmft 1, range 0-10 vs. 2, range 0-12) and permanent dentition (median DMFT 0, range 0-5 vs. 0, range 0-11).

Revascularization of ischemic skeletal muscle is governed by a balance between pro- and antiangiogenic factors in multiple cell types but particularly in myocytes and endothelial cells. Whereas the regulators of proangiogenic factors are well defined (e.g., hypoxia-inducible factor [HIF]), the transcriptional pathways encoding antiangiogenic factors remain unknown. We report that the transcriptional cofactor PGC1β drives an antiangiogenic gene program in muscle and endothelial cells. PGC1β transcriptionally represses proangiogenic genes (e.g., Vegfc, Vegfd, Pdgfb, Angpt1, Angpt2, Fgf1, and Fgf2) and induces antiangiogenic genes (e.g., Thbs1, Thbs2, Angstat, Pedf, and Vash1). Consequently, muscle-specific PGC1β overexpression impairs muscle revascularization in ischemia and PGC1β deletion enhances it. PGC1β overexpression or deletion in endothelial cells also blocks or stimulates angiogenesis, respectively. PGC1β stimulates the antiangiogenic genes partly by coactivating COUP-TFI. Furthermore, proangiogenic stimuli such as hypoxia, hypoxia-mimetic agents, and ischemia decrease PGC1β expression in a HIF-dependent manner. PGC1β is an antiangiogenic transcriptional switch that could be targeted for therapeutic angiogenesis.

Chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) is an orphan nuclear receptor essential for neurogenesis, organogenesis, and cell fate determination. CYP17 gene transcription has recently been shown to be activated by SF-1 (steroidogenic factor-1) binding to a cyclic AMP-responsive sequence within the promoter region of the gene, and inhibited by COUP-TF binding to the sequence. Thus, COUP-TF and SF-1 act as a transcriptional repressor and activator, respectively, of CYP17 gene expression. Transcriptional repression by COUP-TFI is mediated by corepressors, N-CoR (nuclear receptor-corepressor) and SMRT (silencing mediator for retinoid and thyroid hormone-receptor), whereas transcriptional activation by SF-1 is mediated by coactivator SRC-1 (steroid receptor coactivator-1). We therefore examined the expression of COUP-TFI, SF-1, SRC-1, N-CoR, and SMRT in a variety of adrenocortical adenomas and compared the results with CYP17 mRNA levels. We found significantly high COUP-TFI mRNA expression in nonfunctional adenomas (n=8: 220+/-16%; normal 96+/-4%), a deoxycorticosterone-producing adenoma (n=1: 200%), and a pre-clinical Cushing's adenoma (n=1: 280%), intermediate COUP-TFI expression in cortisol-producing adenomas (n=8: 63+/-5%), and low COUP-TFI expression in aldosterone-producing adenomas (n=8: 49+/-4%). In contrast to COUP-TFI, SF-1 mRNA expression did not vary significantly among adrenals. We did not detect the expected negative correlation between COUP-TFI and CYP17 mRNA levels in adrenocortical adenomas. High COUP-TFI expression was associatedwith a nonfunctioning phenotype. Interestingly, the pattern of COUP-TFI expression was similar to the profile of N-CoR expression, but not of SMRT expression. These results indicate that COUP-TFI and N-CoR may play a role in steroidogenesis by human adrenocortical adenomas.

OBJECTIVE

• To investigate the effect of presence and extent of tumour fat invasion (TFI) - perinephric invasion (PFI), renal sinus fat invasion (RSFI) or both PFI and RSFI - on cancer-specific mortality (CSM) in patients with renal cell carcinoma (RCC) and venous tumour thrombus (VTT).

METHODS

• We examined 184 consecutive patients with RCC with VTT treated with nephrectomy between 1987 and 2007. Associations with CSM were evaluated by univariable and multivariable Cox proportional hazard models.

RESULTS

• Median follow up was 21 months. The 5-year CSM-free survival estimates were 75%, 36% and 20% in patients with VTT without TFI, those with VTT with PFI or RSFI, and those with VTT with both PFI and RSFI, respectively (P < 0.001). In multivariable analyses, presence of either PFI or RSFI was associated with a two-fold increased risk of CSM, whereas presence of both PFI and RSFI was associated with a three-fold increased risk of CSM, relative to VTT-only cases. • The inclusion of the variable describing the presence and extent of TFI in a base model including pT stage, Fuhrman grade and presence of nodal disease and metastatic disease significantly increased the accuracy in predicting CSM (+2.1%; P < 0.001) in patients with VTT.

CONCLUSIONS

• Patients affected by RCC with VTT and TFI have a higher risk of CSM relative to cases with VTT only. Patients with both PFI and RSFI showed increased CSM compared with patients with either PFI or RSFI. • Our results suggest TFI should be accurately evaluated and included in routine pathological reports to provide better patient risk stratification.

Chlamydia trachomatis-induced fallopian tube damage leading to tubal factor infertility (TFI) is linked with TNF, IL-10, and probably IFNG gene polymorphisms. The aim of this study was to clarify the contribution of these cytokine gene polymorphisms to interindividual variation in C trachomatis-specific immune responses and the cross-regulation of secreted cytokines and single nucleotide polymorphisms (SNPs). Cytokine polymorphisms (IL-10 -1082A/G, -819T/C, and -592A/C, IFNG +874T/A, and TNF -308G/A) were genotyped by polymerase chain reaction in 139 women. C trachomatis-specific immune responses were measured using lymphocyte proliferation (LP) induced by C trachomatis E and F strains and chlamydial heat shock protein 60 antigens. Cytokine secretion was measured in culture supernatants of infected and uninfected mononuclear leukocytes. IL-10 -1082/-819/-592 and IFNG +874 SNPs were associated with the intensity of LP responses to C trachomatis antigens. These cytokines also interact with each other and a cumulative effect of IL-10 -1082 and IFNG +874 genotypes was seen in LP responses to C trachomatis antigens. Our data suggest that interleukin-10 and interferon-γ regulate C trachomatis-specific immune responses in humans and that genetic variation in the expression of their coding genes explains interindividual variation in host immune responses to C trachomatis infection.

BACKGROUND

To date, no continuous scale exists for measuring the severity of dental fluorosis (DF).

OBJECTIVE

The authors developed and validated a visual analog scale (VAS) for DF. They tested the scale in clinical (DF-endemic area) and laboratory settings.

METHODS

Dentists and nondentists (23 per group) were asked to grade the DF severity in photographs of 23 anterior teeth with different DF levels (using a 100-millimeter VAS) to create a VAS for DF. Statistical analysis was performed to validate the new scale. The authors used clinical and laboratory (unerupted third molars) analyses to assess the usefulness of the VAS.

RESULTS

The authors used an intraclass correlation coefficient (ICC) to assess the interexaminer (ICC = .79: good agreement) and intraexaminer (.88 < ICC < .97: excellent agreement) reliability during creation of the scale. They used the Spearman rank correlation (r(s)) to validate the VAS against the gold standards (that is, the Thylstrup-Fejerskov index [TFI] and Dean's index [DI]) (the results showed excellent or good correlation for 45 examiners). Two dentist examiners clinically tested the new VAS, and the results showed excellent (r(s) = .922, P < .001) correlation and excellent ICC between the examiners (ICC = .96), as well as good ICC between the TFI and the VAS for DF (ICC = .6). The laboratory study showed better correlation between fluoride concentration and the VAS for DF than between fluoride concentration and the TFI.

CONCLUSIONS

Because of its simplicity, precision and utility in statistical applications, the VAS for DF can be useful in DF studies.

OBJECTIVE

To evaluate the relationship between fluoride intake and dental fluorosis in permanent central incisors and first molars.

METHODS

Fluoride intake (mg F/kg body weight/day) from diet, dentifrice and both combined was determined on a single occasion in 1998 among children aged 19-39 months living in two fluoridated Brazilian communities (0.6-0.8 ppm F). Six years later, when the permanent teeth of these children had erupted (central incisors and first molars), 49 children aged 7-9 years [20 girls (40.8%) and 29 boys (58.2%)] were evaluated for dental fluorosis. To test the association between fluorosis and fluoride intake, children were dichotomized into two groups, cases (children with dental fluorosis on at least two teeth, TFI>> or =1) and noncases (children without dental fluorosis, TFI = 0).

RESULTS

Among the case group (n = 29), median fluoride doses from diet, dentifrice and combined were 0.031, 0.050 and 0.083 mg F/kg/day, respectively. Among the noncase group (n = 20), median fluoride doses were 0.029, 0.049, 0.084 mg F/kg/day, respectively. There was no association between dental fluorosis in permanent teeth and fluoride intake from diet, dentifrice and combined (p>> 0.05).

CONCLUSIONS

There was no difference between children with and without fluorosis in the permanent central incisors and first molars regarding fluoride intake. However, this study has limitations that must be recognized: fluoride intake was only measured once, and there were no children in the sample with severe degrees of dental fluorosis.

Neural stem cells (NSCs) persist in the adult mammalian subventricular zone (SVZ) of the lateral ventricle. Primary NSCs generate rapidly dividing intermediate progenitor cells, which in turn generate neuroblasts that migrate along the rostral migratory stream (RMS) to the olfactory bulb (OB). Here, we have examined the role of the COUP-TFI and COUP-TFII orphan nuclear receptor transcription factors in mouse OB interneuron development. We observed that COUP-TFI is expressed in a gradient of low rostral to high caudal within the postnatal SVZ neural stem/progenitor cells. COUP-TFI is also expressed in a large number of migrating neuroblasts in the SVZ and RMS, and in mature interneurons in the OB. By contrast, very few COUP-TFII-expressing (+) cells exist in the SVZ-RMS-OB pathway. Conditional inactivation of COUP-TFI resulted in downregulation of tyrosine hydroxylase expression in the OB periglomerular cells and upregulation of COUP-TFII expression in the SVZ, RMS and OB deep granule cell layer. In COUP-TFI/COUP-TFII double conditional mutant SVZ, cell proliferation was increased through the upregulation of the proneural gene Ascl1. Furthermore, COUP-TFI/II-deficient neuroblasts had impaired migration, resulting in ectopic accumulation of calretinin (CR)+ and NeuN+ cells, and an increase in apoptotic cell death in the SVZ. Finally, we found that most Pax6+ and a subset of CR+ granular cells were lost in the OB. Taken together, these results suggest that COUP-TFI/II coordinately regulate the proliferation, migration and survival of a subpopulation of Pax6+ and CR+ granule cells in the OB.

OBJECTIVE

To evaluate the impact of a Mindfulness Based Stress Reduction (MBSR) program in patients with chronic bothersome tinnitus on the (1) severity of symptoms of tinnitus and (2) functional connectivity in neural attention networks.

METHODS

Open-label interventional pilot study.

METHODS

Outpatient academic medical center.

METHODS

A total of 13 adult participants with a median age of 55 years, suffering from bothersome tinnitus.

METHODS

An 8-week MBSR program was conducted by a trained MBSR instructor. The primary outcome measure was the difference in patient-reported tinnitus symptoms using the Tinnitus Handicap Index (THI) and Tinnitus Functional Index (TFI) between pre-intervention, post-MBSR, and 4-week post-MBSR assessments. Secondary outcomes included change in measurements of depression, anxiety, mindfulness, and cognitive abilities. Functional connectivity magnetic resonance imaging (MRI) was performed at pre- and post-MBSR intervention time points to serve as a neuroimaging biomarker of critical cortical networks.

RESULTS

Scores on the THI and TFI showed statistically significant and clinically meaningful improvement over the course of the study with a median ΔTHI of -16 and median ΔTFI of -14.8 between baseline and 4-week follow-up scores. Except for depression, there was no significant change in any of the secondary outcome measures. Analysis of the resting state functional connectivity MRI (rs-fcMRI) data showed increased connectivity in the post-MBSR group in attention networks but not the default network.

CONCLUSIONS

Participation in an MBSR program is associated with decreased severity in tinnitus symptoms and depression and connectivity changes in neural attention networks. MBSR is a promising treatment option for chronic bothersome tinnitus that is both noninvasive and inexpensive.

The thyroid function was evaluated in a study group of 226 breast cancer patients and in control groups, consisting of 125 patients with various other malignancies, 61 women with benign breast disease and 166 healthy blood donors. The mean serum concentrations of total T3 and T4 were significantly higher in the breast cancer group than in the controls. The mean TFI (thyroid function index), measured by two indirect techniques (T3RU, T4/TBG) or by direct free T4 measurement, was also significantly higher in this group of patients than in controls. Individual values of TFI exceeding the upper limit of the normal range were related with elevated total T4 levels and not with abnormal concentrations of total TBG. Eight women with breast cancer (3.5%) and one patient with head and neck cancer were clinically hyperthyroid. No case of overt hypothyroidism was observed. There was no relation between thyroid function and spread of the disease (TNM). The control groups, including patients with other-than-breast cancers, did not show any significant modification of the thyroid function tests. In the present study, breast cancer patients, as a group, show a thyroid dysfunction distinct from the non-specific abnormalities (low T3 syndrome) frequently observed in patients with a variety of acute or chronic non-thyroidal illnesses.

OBJECTIVE

Female infertility patients with diverse etiologies show increased production of autoantibodies.

METHODS

Immunoblot analysis of sera from patients with endometriosis and tubal factor infertility (TFI) and mass spectrometry identification of candidate antigens.

RESULTS

The immunoblot results demonstrated the presence of IgA and IgG anti-endometrial antibodies (AEA) to various antigens at molecular weights ranging from 10 to 200 kDa. Differences were detected in certain AEA reactions between the patients' groups and particular AEA were associated with in vitro fertilization (IVF) implantation failure. IgA AEA to a 47-kDa protein were more prevalent in TFI patients and were associated with unsuccessful IVF treatment. This antigen was subsequently identified as alpha-enolase.

CONCLUSIONS

Determination of the presence and spectra of AEA in patients with endometriosis and TFI undergoing IVF may be a useful marker to predict their pregnancy outcome.

Chlamydia trachomatis is the causative agent of the most frequently reported bacterial sexually transmitted infection, the total burden of which is underestimated due to the asymptomatic nature of the infection. Untreated C. trachomatis infections can cause significant morbidities, including pelvic inflammatory disease and tubal factor infertility (TFI). The human immune response against C. trachomatis, an obligate intracellular bacterium, is poorly characterized but is thought to rely on cell-mediated immunity, with CD4(+) and CD8(+) T cells implicated in protection. In this report, we present immune profiling data of subjects enrolled in a multicenter study of C. trachomatis genital infection. CD4(+) and CD8(+) T cells from subjects grouped into disease-specific cohorts were screened using a C. trachomatis proteomic library to identify the antigen specificities of recall T cell responses after natural exposure by measuring interferon gamma (IFN-γ) levels. We identified specific T cell responses associated with the resolution of infection, including unique antigens identified in subjects who spontaneously cleared infection and different antigens associated with C. trachomatis-related sequelae, such as TFI. These data suggest that novel and unique C. trachomatis T cell antigens identified in individuals with effective immune responses can be considered as targets for vaccine development, and by excluding antigens associated with deleterious sequelae, immune-mediated pathologies may be circumvented.

In the dentate gyrus (DG) of the mouse hippocampus, neurogenesis and astrogliogenesis persist throughout life. Adult-born neurons and astrocytes originate from multipotent neural stem cells (NSCs) whose activity is tightly regulated within the neurogenic niche. However, the cell-intrinsic mechanisms controlling neuron-glia NSC fate choice are largely unknown. Here, we show COUP-TFI/NR2F1 expression in DG NSCs and its downregulation upon neuroinflammation. By using in vivo inducible knockout lines, a retroviral-based loss-of-function approach and genetic fate mapping, we demonstrate that COUP-TFI inactivation in adult NSCs and/or mitotic progenitors reduces neurogenesis and increases astrocyte production without depleting the NSC pool. Moreover, forced COUP-TFI expression in adult NSCs/progenitors decreases DG astrogliogenesis and rescues the neuro-astrogliogenic imbalance under neuroinflammation. Thus, COUP-TFI is necessary and sufficient to promote neurogenesis by suppressing astrogliogenesis. Our data propose COUP-TFI as a central regulator of the neuron-astroglia cell fate decision and a key modulator during neuroinflammation in the adult hippocampus.

OBJECTIVE

The present study aimed, first, to compare the ability to predict falls over 12 months for three measures - mobility, balance and frailty. Second, among the three domains of frailty - physical, psychological and social - we investigated what is the strongest predictor of falls.

METHODS

A total of 192 community-dwelling older adults (age 73.0 ± 6.2 years; 62% women) were involved in this longitudinal study. The Timed Up and Go (TUG) test, One Leg Standing (OLS) test and the Tilburg Frailty Indicator (TFI) were respectively used to measure mobility, balance and frailty. The TFI is a questionnaire based on a multidimensional conceptualization of frailty consisting of 15 items in three domains (physical, psychological and social). Falls were self-reported during the 12-month follow up. Logistic regression models, adjusted for interesting variables, were carried out to predict the risk of falls.

RESULTS

History of falls and chronic conditions were the indicators more strongly related with falls over 12 months. The TFI resulted as a stronger predictor of falls when compared with the TUG and OLS tests. The explained variance of the three models was 31.2%, 22.4% and 22.2%, respectively. The TFI was significantly associated with falls (P < 0.001), whereas the TUG and the OLS were not (P>> 0.05). Among the three frailty domains, physical (P < 0.001) and psychological (P = 0.041) domains were significant predictors of falls.

CONCLUSIONS

The findings showed that the TFI might be an effective tool for predicting falls at 12 months in aged populations, probably because it is able to capture the multifactorial facets that can lead to falls. Geriatr Gerontol Int 2017; 17: 1463-1469.

The response of 6 human colorectal tumour xenografts to 7 cytotoxic agents have been established. Tumour responses have been quantified by growth inhibition, and the time taken for 3H-thymidine fractional incorporation (TFI) to recover to the control value after treatment. The chemosensitivity of each tumour line to a spectrum of agents was individual, and no pattern of response which would allow prediction of individual agent efficacy was apparent. Cyclophosphamide, methyl-CCNU and 5-fluorouracil produced marked growth inhibition in individual tumour lines, whereas actinomycin-D, cis-dichlorodiammine platinum, doxorubicin and pentamethylmelamine showed little activity. Data presented agree with clinical evaluation for single-agent therapy. The uptake and incorporation of radiolabelled 5-fluorouracil into 4 tumour lines is reported. No marked differences between 3 FU-insensitive lines and 1 sensitive line have been observed.

The octapeptide hormone, angiotensin II (AngII) and ACTH stimulate mineralocorticoid biosynthesis in the zona glomerulosa of the adrenal cortex in part by promoting the transcription of the gene coding for the steroidogenic acute regulatory (StAR) protein. We have examined whether chicken ovalbumin upstream promoter-transcription factor (COUP-TF), a member of the orphan nuclear receptor family of transcription factors, is involved in this transcriptional regulation. We analyzed COUP-TF and StAR mRNA and protein levels in bovine adrenal glomerulosa cells in primary culture. COUP-TF protein was readily detectable in nonstimulated cells, and AngII markedly reduced its expression in a time- and concentration-dependent manner (IC50 = 1 nm), to 46 +/- 4.4% of control levels after 6 h, (n = 3; P < 0.01). This repression was paralleled by a marked decrease in COUP-TF mRNA levels, reaching 18 +/- 8.8% of controls (n = 3, P < 0.01) after 6 h and by a 20-fold increase in aldosterone output. In bovine glomerulosa cells overexpressing COUP-TFI and -II, the induction of StAR mRNA and protein elicited by AngII was completely suppressed to control levels, and the aldosterone response was significantly reduced (from 4.8 +/- 1.1-fold the basal value in mock-infected cells to 1.9 +/- 0.5-fold and 2.2 +/- 0.7-fold in COUP-TFI- and COUP-TFII-expressing cells, respectively; n = 3; P < 0.01 for both differences). Finally, by using electrophoretic mobility shift assays and chromatin immunoprecipitation, we have shown a direct interaction between COUP-TF and the proximal StAR promoter. These results suggest that COUP-TF exerts a tonic inhibition on steroidogenesis by repressing StAR protein expression and that activators of aldosterone biosynthesis lift this inhibition in part by repressing COUP-TF levels.

Poor water quality and under nutrition are important factors affecting the health of many communities in developing countries. The aims of this study were: i) to describe the fluoride water concentration and the hydrogeological conditions in a region of a state located in the central in Mexico ii) to measure the association between undernutrition and dental fluorosis in children living in communities with different drinking water fluoride concentrations in a state located in the central region of Mexico.

METHODS

Field work was performed in the region to identify the prevailing groundwater flow characteristics and water wells were sampled to analyze water fluoride concentration. Children were selected from three communities that had different drinking water fluoride concentrations (i.e., 0.56, 0.70 and 1.60 mg/l). Fluoridated salt was available in these communities. The Thylstrup-Fejerskov Index (TFI) was used to assess dental fluorosis. Categories four or higher of this index involve changes in the entire tooth surface (ITF ≥ 4). The weight and height of the children were measured. The assessment of undernutrition was based on the World Health Organization criteria: children were classified as being at risk of low-height (Height-for-Age Z score < − 1.0 SD) and having low-height (Height-for-Age Z score < − 2.0 SD) for age and sex, the same cutoff points of the Z score were used to classify "risk of low-weight" and" low-weight children".

RESULTS

In the region the mineralization of the water captured by the wells is the result of a reaction with volcanic materials. The water fluoride concentration in the region ranged from 0.2 to 1.6 mg/l. A total of 734 schoolchildren participated in the study. The percentage of children in fluorosis categories (ITF ≥ 4) was 15.9%, 21.1% of the children were at risk of low height-for-age, and 8.0% had low height-for-age. The percentage of children with fluorosis (ITF ≥ 4) was 6.3%, 9.1% and 31.9% (p ˂ 0.001) and low high-for-age was 2.9%, 2.5% and 8.4% (p ˂ 0.001), for the communities with F concentrations of 0.56 mg/l, 0.70 mg/l and 1.6 mg/l, respectively. The logistic regression model showed an association between dental fluorosis (TFI ≥ 4) and low height-for-age (OR 2.09, p = 0.022) after adjusting for sex, number of teeth erupted, source of drinking water, use of fluoridated toothpaste and tap water fluoride concentration in the community.

CONCLUSIONS

Children with low height-for-age were more likely to have dental fluorosis in the TFI categories that affect the entire tooth surface. The results suggest that subpopulations with chronic undernutrition are more susceptible to dental fluorosis.

CDK4 & 6 inhibitors have enhanced the effectiveness of endocrine therapy (ET) in patients with advanced breast cancer (ABC). This paper presents exploratory analyses examining patient and disease characteristics that may inform in whom and when abemaciclib should be initiated. MONARCH 2 and 3 enrolled women with HR+, HER2- ABC. In MONARCH 2, patients whose disease had progressed while receiving ET were administered fulvestrant+abemaciclib/placebo. In MONARCH 3, patients received a nonsteroidal aromatase inhibitor+abemaciclib/placebo as initial therapy for advanced disease. A combined analysis of the two studies was performed to determine significant prognostic factors. Efficacy results (PFS and ORR in patients with measurable disease) were examined for patient subgroups corresponding to each significant prognostic factor. Analysis of clinical factors confirmed the following to have prognostic value: bone-only disease, liver metastases, tumor grade, progesterone receptor status, performance status, treatment-free interval (TFI) from the end of adjuvant ET, and time from diagnosis to recurrence. Prognosis was poorer in patients with liver metastases, progesterone receptor-negative tumors, high grade tumors, or short TFI (<36 months). Benefit (PFS hazard ratio, ORR increase) from abemaciclib was observed in all patient subgroups. Patients with indicators of poor prognosis had the largest benefit from the addition of abemaciclib. However, in MONARCH 3, for patients with certain good prognostic factors (TFI ≥ 36 months, bone-only disease) ET achieved a median PFS of >20 months. These analyses identified prognostic factors and demonstrated that patients with poor prognostic factors derived the largest benefit from the addition of abemaciclib.

Ceramide is the central lipid in the sphingolipid metabolism. Ceramide kinase (CERK) and its product, ceramide 1-phosphate, have been implicated in various cellular functions. However, the regulatory mechanism of CERK gene expression remains to be determined. Here, we examined CERK mRNA level during all-trans retinoic acid (ATRA)-induced differentiation of a human neuroblastoma cell line, SH-SY5Y. ATRA reduced CERK mRNA and protein levels. Over-expression and small interfering RNA (siRNA) of CERK revealed that CERK is inhibitory against ATRA-induced neuronal differentiation and cell growth arrest. ATRA inhibited the transcriptional activity of 5'-promoter of CERK. Truncation and mutation study suggests that ATRA-responsible region was mainly located in the tandem retinoic acid responsive elements (RARE) between -40 bp and the first exon. The electrophoresis mobility shift assay revealed that ATRA produced two retarded bands, which were erased by antibody against chicken ovalbumin upstream promoter transcription factor I (COUP-TFI), RARalpha, and RXRalpha, respectively. DNA pull-down assay confirmed increased binding of these transcription factors to RARE. Transient expression of RAR, RXR, and COUP-TFI and siRNA transfection of these genes revealed that COUP-TFI inhibited CERK mRNA. Furthermore, chromatin immunoprecipitation assay showed the recruitment of co-repressors as well as three transcription factors. These results suggest that COUP-TFI was the ATRA-responsive suppressive transcription factor of CERK gene transcription.

The objectives of this study were to provide reference values of the Tilburg Frailty Indicator (TFI) for community-dwelling older people by age, sex, marital status, ethnicity, education, income, and residence, and examine the effects of these seven socio-demographic variables on frailty.

47,768 individuals aged 65 years and older living in the Netherlands completed a health questionnaire (58.5% response rate), including the TFI. The TFI is a self-report questionnaire for measuring frailty, developed from an integral approach of frailty, including physical, psychological, and social domains.

Reference values were provided for men and women separately, as a function of age. We found associations of all socio-demographic variables with frailty, also after controlling for the effects of age. These associations held for both sexes and for big cities as wells as more rural areas. For instance, the effect of age was large for total and physical frailty, women were more frail than men, and some very large average frailty differences between the ethnic groups were found, with autochthon people having the lowest frailty score.

In conclusion, this study offers reference values of the TFI by socio-demographic characteristics and explains frailty using these characteristics. This information will support researchers, policymakers and health care professionals in interpreting scores of the TFI, which may guide their efforts to reduce frailty and its adverse outcomes.

OBJECTIVE

To translate the Tilburg Frailty Indicator (TFI) into Chinese and assess its reliability and validity.

METHODS

A sample of 917 community-dwelling older people, aged ≥60 years, in a Chinese city was included between August 2015 and March 2016. Construct validity was assessed using alternative measures corresponding to the TFI items, including self-rated health status (SRH), unintentional weight loss, walking speed, timed-up-and-go tests (TUGT), making telephone calls, grip strength, exhaustion, Short Portable Mental Status Questionnaire (SPMSQ), Geriatric Depression scale (GDS-15), emotional role, Adaptability Partnership Growth Affection and Resolve scale (APGAR) and Social Support Rating Scale (SSRS). Fried's phenotype and frailty index were measured to evaluate criterion validity. Adverse health outcomes (ADL and IADL disability, healthcare utilization, GDS-15, SSRS) were used to assess predictive (concurrent) validity.

RESULTS

The internal consistency reliability was good (Cronbach's α=0.71). The test-retest reliability was strong (r=0.88). Kappa coefficients showed agreements between the TFI items and corresponding alternative measures. Alternative measures correlated as expected with the three domains of TFI, with an exclusion that alternative psychological measures had similar correlations with psychological and physical domains of the TFI. The Chinese TFI had excellent criterion validity with the AUCs regarding physical phenotype and frailty index of 0.87 and 0.86, respectively. The predictive (concurrent) validities of the adverse health outcomes and healthcare utilization were acceptable (AUCs: 0.65-0.83).

CONCLUSIONS

The Chinese TFI has good validity and reliability as an integral instrument to measure frailty of older people living in the community in China.

OBJECTIVE

The physiological regulation of total body water and fluid concentrations is complex and dynamic. The human daily water requirement varies because of differences in body size, dietary solute load, exercise, and activities. Although chronically concentrated urine increases the risk of renal diseases, an empirical method to determine inadequate daily water consumption has not been described for any demographic group; instead, statistical analyses are applied to estimate nutritional guidelines (i.e., adequate intake). This investigation describes a novel empirical method to determine the 24-h total fluid intake (TFI; TFI = water + beverages + moisture in food) and 24-h urine volume, which correspond to inadequate 24-h water intake (defined as urine osmolality of 800 mOsm/kg; U800).

METHODS

Healthy young women (mean ± standard deviation; age, 20 ± 2 y, mass, 60.8 ± 11.7 kg; n = 28) were observed for 7 consecutive days. A 24-h urine sample was analyzed for volume and osmolality. Diet records were analyzed to determine 24-h TFI.

RESULTS

For these 28 healthy young women, the U800 corresponded to a TFI ≥2.4 L/d (≥39 mL/kg/d) and a urine volume ≥1.3 L/d.

CONCLUSIONS

The U800 method could be employed to empirically determine 24-h TFI and 24-h urine volumes that correspond to inadequate water intake in diverse demographic groups, residents of specific geographic regions, and individuals who consume specialized diets or experience large daily water turnover. Because laboratory expertise and instrumentation are required, this technique provides greatest value in research and clinical settings.

Reliable data at population level are essential to firmly establish links between fluid intake, hydration and health, investigate dose-response relationships and develop meaningful public health strategies or reference intake values. However, limited research exists regarding the most appropriate methodology for assessing beverage or total fluid intake (TFI). To date, methodologies have been developed to assess food and nutrient intake without due consideration of water or fluid intake behavior. A recent crossover study showed that a 24-hour food recall significantly underestimated mean TFI by 382 ml (95% CI 299-465) compared with a fluid specific 7-day record. The authors postulated that this average difference was mainly the result of missed drinking acts between meals a 24-hour recall was used. Using a 7-day record administered in paper form or on-line has also been shown to lead to a significantly different mean TFI of 129 ml. Therefore, the choice of methodology might result in measurement errors that limit between-survey or between-country comparisons. Such errors may contribute to variations in estimates of TFI that cannot be explained by differences in climate, physical activity or cultural habits. A recent survey confirmed the variation in methodologies used in European national dietary surveys. Since these surveys form the basis for setting adequate intakes for total water intake, measurement error between surveys should be limited, highlighting the need for the development of a consistent methodology that is validated for water and TFI estimation.

Objective: The need for validated measures enabling clinicians to classify tinnitus patients according to the severity of tinnitus and screen the progress of therapies in our country led us to translate into Polish and to validate two tinnitus questionnaires, namely the Tinnitus Handicap Inventory (THI) and the Tinnitus Functional Index (TFI). Design: The original English versions of the questionnaires were translated into Polish and translated back to English by three independent translators. These versions were then finalized by the authors into a Polish THI (THI-Pl) and a Polish TFI (TFI-Pl). Participants from three laryngological centers in Poland anonymously answered the THI-Pl (N = 98) and the TFI-Pl (N = 108) in addition to the Polish versions of the Center for Epidemiologic Studies Depression Scale as a measure of self-perceived level of depression, and the Satisfaction With Life Scale to assess self-perceived quality of life. Both were used to determine discriminant validity. Two Visual Analog Scales were used to measure tinnitus annoyance and tinnitus loudness in order to determine convergent validity. Results: Similar to the original version of the THI, the THI-Pl showed a high internal consistency (Cronbach's α = 0.93). The exploratory factor analysis revealed that the questionnaire has a three-factorial structure that does not correspond to the original division for functional, catastrophic, and emotional subscales. Convergent and discriminant validities were confirmed. The TFI-Pl showed high internal consistency (Cronbach's α = 0.96) with the reliability ranging from 0.82 to 0.95 for its different subscales. Factor analysis confirmed an eight-factorial structure with factors assigning all items to appropriate subscales reported in the original version of the questionnaire. Discriminant and convergent validities were also confirmed for the TFI-Pl. Conclusion: We translated and validated the Polish versions of the THI and the TFI to make them suitable for clinical use in Poland.