BACKGROUND

Frail older people are at high risk of developing adverse outcomes, such as disability, mortality, hospitalization, and institutionalization. Previous research suggests that the Tilburg Frailty Indicator (TFI) is a valid and reliable instrument for measuring frailty. The aim of this study was to adapt and to test the reliability of the Polish version of the TFI.

METHODS

A standard guideline was used for translation and cultural adaptation of the English version of the TFI into Polish. The study included 100 Polish patients (mean age 68.2±6.5 years), among them 42 men and 58 women. Cronbach's alpha was used for analysis of the internal consistency of the TFI.

RESULTS

The mean total TFI score was 6.7±3.1. Forty patients scored ≥5, which corresponded to being frail. Cronbach's alpha reliability coefficients of the instrument ranged from 0.68 to 0.72 and item-total correlation ranged from 0.12 to 0.52.

CONCLUSIONS

The TFI is valid and reproducible for assessment of frailty syndrome among a Polish population. The Polish adaptation of the TFI proved a useful and fast tool for assessing frailty.

OBJECTIVE

To establish whether the prediction of the adverse outcomes disability and six indicators of health care utilization one and two years later by the three frailty domains (physical, psychological, social) of the Tilburg Frailty Indicator (TFI) is improved by adding interview and physical measures of frailty.

METHODS

A representative sample of 245 Dutch community-dwelling persons aged 75 years and older (response rate 53%) participated in 2008, one year later in 2009 (n=179, 73%) and again two years later in 2010 (n=141, 58%). Frailty was assessed with the TFI, an easy to administer self-report measure. Disability was measured using the Groningen Activity Restriction Scale (GARS). Indicators of health care utilization were: visit to a general practitioner (gp), contacts with health care professionals (hcps), hospital admission, receiving personal care, receiving nursing care, and receiving informal care.

RESULTS

After controlling for background characteristics, the TFI predicted disability and the indicators of health care utilization. Interviews and physical measures of frailty improved the prediction of disability. The Hospital Anxiety and Depression Scale (HADS-A) improved the prediction of contacts with hcps, but the interview and physical measures of frailty did not improve the predictions of the other indicators of health care utilization.

CONCLUSIONS

Assessment by the self-report TFI is sufficient for predicting six indicators of health care utilization, but for predicting disability the use of both the TFI and the Timed Up & Go (TUG) test is recommended. It is advisable assessing all three frailty domains when examining frailty and its prediction of adverse outcomes.

Chronic inflammation induced by Chlamydia trachomatis can lead to tubal factor infertility (TFI). To investigate the genetic basis of chlamydial TFI and various manifestations of tubal damage, we studied functional polymorphisms in selected cytokine genes (IL-10 -1082 A/G, -819 T/C, and -592 A/C; IFN-gamma +874 T/A; TNF-alpha -308 G/A; TGF-beta1 codons 10 T/C and 25 G/C; and IL-6 -174 G/C) in 114 women with laparoscopically verified TFI (hereafter known as "cases") and in 176 controls. Evidence of past infection with C. trachomatis was demonstrated in 96 cases by use of a combined test for humoral and cell-mediated immune responses to chlamydial elementary bodies (EBs) and chlamydial heat-shock protein 60 antigens. We found that the IL-10 -1082 AA genotype and the TNF-alpha -308 A allele increased the risk of severe tubal damage in women with infertility associated with C. trachomatis (odds ratio [OR], 7.3 [95% confidence interval {CI}, 1.3-42] and 4.0 [95% CI, 1.0-16], respectively), suggesting that differences in these genes contribute to the wide spectrum of disease manifestations.

OBJECTIVE

Describe the oral health related quality of life among a group of children in rural Uganda and compare impacts on oral health related quality of life associated with dental caries and fluorosis.

METHODS

Cross-sectional clinical and questionnaire analytical study.

METHODS

Proportional sample of 174 12 year olds attending primary schools in a rural sub-county of Uganda.

METHODS

Clinical assessments using WHO basic methods and the Thylstrup and Fejerskov index of Fluorosis (TFI). Child Oral Health Related Quality of Life data collected with self-administered child perception questionnaire (CPQ11-14).

RESULTS

Two thirds of children reported a dental impact 'often' or 'everyday'. The mean number of impacts per child at this threshold was 2.6 and the mean total CPQ11-14 score was 25.8 (sd 21.1). Mean DMFT was 0.68. No children had fillings. Forty-one children had dental fluorosis with 10 having scores greater than 2. CPQ11-14 showed acceptable criterion validity and reliability. The number of sites with gingivitis or the presence of calculus or trauma were not associated with summary measures of CPQ11-14 whereas having any dental caries or treatment experience was associated with higher total scores and more impacts. Socially noticeable fluorosis (TFI >2) was associated with more impacts but not with higher total scores.

CONCLUSIONS

Despite low levels of oral disease these children experience appreciable impacts on oral health related quality of life. The greatest burden was associated with dental caries and to a lesser extent, fluorosis.

Postural tachycardia syndrome (POTS) is characterized by orthostatic dizziness, tremulousness, tachycardia and variable blood pressure changes. Since some POTS patients have a marked reduction in pulse pressure on standing, a major mechanism of their symptoms might be venous pooling. We therefore studied the cardiovascular response to head-up tilt, Valsalva maneuver and deep breathing in: control subjects (n = 11; F = 8; M = 3; 39.2 +/- 14.4 years); patients with orthostatic hypotension secondary to autonomic failure (n = 11; F = 9; M = 2; 61.7 +/- 13.0 years), and patients with POTS (n = 15); F = 13; M = 2; 32.3 +/- 10.6 years). Blood pressure was measured with a Finapres, and cardiac output, stroke volume, end-diastolic volume and thoracic impedance (TFI) were measured by thoracic electrical bioimpedance. During tilt (in contrast to patients with orthostatic hypotensiom), patients with POTS had excessive tachycardia (P < 0.001), a normal to excessive total peripheral resistance increase, and an exaggerated decrease in stroke volume (P < 0.001) and end-diastolic volume (P < 0.001). These findings suggest that sympathetic arteriolar function remains relatively intact but that sympathetic venomotor function is selectively impaired. These findings may have significant implications for the treatment of patients with POTS.

An imperfect estrogen receptor half-site response element direct-repeat, located within the TATA-less promoter of the human luteinizing hormone receptor (hLHR), was identified as an inhibitory site for Sp1/Sp3-driven basal transcription. Isolation of proteins recognizing this site by yeast one-hybrid screening of a human placenta cDNA library revealed three nuclear orphan receptors, EAR2, EAR3/COUP-TFI, and TR4. Electrophoresis mobility shift assays demonstrated that the in vitro translated nuclear orphan receptors specifically bound the direct-repeat motif of the hLHR promoter. Also, endogenous EAR2 and EAR3/COUP-TFI from JAR cell and human testis and TR4 from testes bound this motif in electrophoresis mobility shift assays. Functional analyses in CV-1 cells showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity by up to 70% in a dose-dependent and sequence-specific manner. Conversely, TR4 activated the hLHR promoter activity up to 2.5-fold through binding to the same cis-element. The stimulation was reversed by coexpression of EAR2 or EAR3/COUP-TFI, indicating their competitive binding for this site. Such recognition of a common cognate site by the proteins with antagonistic functions implies that a net regulation of the hLHR gene may result from the relative availability of repressors and activator in a physiological state. This also may contribute to the differential expression of the hLHR gene in gonadal and non-gonadal tissues.

Transcription of luteinizing hormone receptor (LHR) gene is activated by Sp1/Sp3 at two Sp1 sites and is repressed by nuclear orphan receptors EAR2 and EAR3 through a direct-repeat (DR) motif. To elucidate the mechanism of the orphan receptor-mediated gene repression, we explored the functional connection between the orphan receptors and Sp1/Sp3 complex, and its impact on the basal transcription machinery. The Sp1(I) site was identified as critical for the repression since its mutation reduced the inhibition by EAR2 and abolished the inhibition by EAR3. Cotransfection analyses in SL2 cells showed that both Sp1 and Sp3 were required for this process since EAR3 displayed a complete Sp1/Sp3-dependent inhibitory effect. Functional cooperation between Sp1 and DR domains was further supported by mutual recruitment of EAR3 and Sp1/Sp3 bound to their cognate sites. Deletion of EAR3 N-terminal and DNA-binding domains that reduced its interaction with Sp1 impaired its inhibitory effect on human LHR (hLHR) gene transcription. Furthermore, we demonstrate interaction of TFIIB with Sp1/Sp3 at the Sp1(I) site besides its association with EAR3 and the TATA-less core promoter region. Such interaction relied on Sp1 site-bound Sp1/Sp3 complex and adaptor protein(s) present in the JAR nuclear extracts. We further demonstrated that EAR3 specifically decreased association of TFIIB to the Sp1(I) site without interfering on its interaction with the hLHR core promoter. The C-terminal region of EAR3, which did not participate in its interaction with Sp1, was required for its inhibitory function and may affect the association of TFIIB with Sp1. Moreover, perturbation of the association of TFIIB with Sp1 by EAR3 was reflected in the reduced recruitment of RNA polymerase II to the promoter. Overexpression of TFIIB counteracted the inhibitory effect of EAR3 and activated hLHR gene transcription in an Sp1 site-dependent manner. These findings therefore indicate that TFIIB is a key component in the regulatory control of EAR3 and Sp1/Sp3 on the initiation complex. Such cross talk among EAR3, TFIIB, and Sp1/Sp3 reveals repression of hLHR gene transcription by nuclear orphan receptors is achieved via perturbation of communication between Sp1/Sp3 at the Sp1-1 site and the basal transcription initiator complex.

BACKGROUND

Fallopian tube damage and subsequent infertility are common sequelae of upper genital tract infection with Chlamydia trachomatis. This fallopian tube damage is thought to be immune mediated. The 60 kilodalton chlamydial heat shock protein (hsp) may be the key antigen associated with this pathogenic response. Our objective was to study the relationship between antibody response to 60 kilodalton chlamydial hsp and tubal factor infertility (TFI).

METHODS

Twenty-three women with TFI and 33 women with male factor infertility (controls) were studied. Tubal factor infertility was defined as infertility for one year with hydrosalpinx or distal tubal occlusion. Patients' sera were tested for antibodies to the chlamydial hsp using an enzyme-linked immunosorbent assay (ELISA). A stepwise logistic regression was performed by each patient's age, race/ethnicity, self-reported history of chlamydia infection, gonorrhea, or pelvic inflammatory disease (PID), history of ectopic pregnancy, and antibodies to the chlamydial hsp.

RESULTS

Eighteen of the 23 women with TFI had a positive result on the hsp ELISA (78.6%) versus 23.4% of controls. Risk factors for TFI were a history of PID (P = 0.022), "nonwhite" race (P = 0.004), history of ectopic pregnancy (P = 0.027), and antibodies to the 60 kilodalton chlamydial hsp (P < 0.001).

CONCLUSIONS

Antibodies to 60 kilodalton chlamydial hsp are strongly associated with TFI.

Recent literature implicates a regulatory function of the juxtamembrane domain (JMD) in receptor tyrosine kinases. Mutations in the JMD of c-Kit and Flt3 are associated with gastrointestinal stromal tumors and acute myeloid leukemias, respectively. Additionally, autophosphorylated Tyr559 in the JMD of the colony stimulating factor-1 (CSF-1) receptor (CSF-1R) binds to Src family kinases (SFKs). To investigate SFK function in CSF-1 signaling we established stable 32D myeloid cell lines expressing CSF-1Rs with mutated SFK binding sites (Tyr559-TFI). Whereas binding to I562S was not significantly perturbed, Y559F and Y559D exhibited markedly decreased CSF-1-dependent SFK association. All JMD mutants retained intrinsic kinase activity, but Y559F, and less so Y559D, showed dramatically reduced CSF-1-induced autophosphorylation. CSF-1-mediated wild-type (WT)-CSF-1R phosphorylation was not markedly affected by SFK inhibition, indicating that lack of SFK binding is not responsible for diminished Y559F phosphorylation. Unexpectedly, cells expressing Y559F were hyperproliferative in response to CSF-1. Hyperproliferation correlated with prolonged activation of Akt, ERK, and Stat5 in the Y559F mutant. Consistent with a defect in receptor negative regulation, c-Cbl tyrosine phosphorylation and CSF-1R/c-Cbl co-association were almost undetectable in the Y559F mutant. Furthermore, Y559F underwent reduced multiubiquitination and delayed receptor internalization and degradation. In conclusion, we propose that Tyr559 is a switch residue that functions in kinase regulation, signal transduction and, indirectly, receptor down-regulation. These findings may have implications for the oncogenic conversion of c-Kit and Flt3 with JMD mutations.

Neural stem/progenitor cell (NSPC) multipotency is highly regulated so that specific neural networks form during development. NSPCs cannot respond to gliogenic signals without acquiring gliogenic competence and decreasing their neurogenic competence as development proceeds. Coup-tfI and Coup-tfII are triggers of these temporal NSPC competence changes. However, the downstream effectors of Coup-tfs that mediate the neurogenic-to-gliogenic competence transition remain unknown. Here, we identified the microRNA-17/106 (miR-17/106)-p38 axis as a critical regulator of this transition. Overexpression of miR-17 inhibited the acquisition of gliogenic competence and forced stage-progressed NSPCs to regain neurogenic competence without altering the methylation status of a glial gene promoter. We also identified Mapk14 (also known as p38) as a target of miR-17/106 and found that Mapk14 inhibition restored neurogenic competence after the neurogenic phase. These results demonstrate that the miR-17/106-p38 axis is a key regulator of the neurogenic-to-gliogenic NSPC competence transition and that manipulation of this axis permits bidirectional control of NSPC multipotency.

Optic nerve atrophy and hypoplasia can be primary disorders or can result from trans-synaptic degeneration arising from cerebral visual impairment (CVI). Here we report six individuals with CVI and/or optic nerve abnormalities, born after an uneventful pregnancy and delivery, who have either de novo heterozygous missense mutations in NR2F1, also known as COUP-TFI, or deletions encompassing NR2F1. All affected individuals show mild to moderate intellectual impairment. NR2F1 encodes a nuclear receptor protein that regulates transcription. A reporter assay showed that missense mutations in the zinc-finger DNA-binding domain and the putative ligand-binding domain decrease NR2F1 transcriptional activity. These findings indicate that NR2F1 plays an important role in the neurodevelopment of the visual system and that its disruption can lead to optic atrophy with intellectual disability.

Tubal factor infertility (TFI) represents 36% of female infertility and genital infection by Chlamydia trachomatis (C. trachomatis) is a major cause. Although TFI is associated with host inflammatory responses to bacterial components, the molecular pathogenesis of Chlamydia-induced infertility remains poorly understood. We investigated the hypothesis that activation of specific cysteine proteases, the caspases, during C. trachomatis genital infection causes the disruption of key fertility-promoting molecules required for embryo development and implantation. We analyzed the effect of caspase inhibition on infertility and the integrity of Dicer, a caspase-sensitive, fertility-promoting ribonuclease III enzyme, and key micro-RNAs in the reproductive system. Genital infection with the inflammation- and caspase-inducing, wild-type C. trachomatis serovar L2 led to infertility, but the noninflammation-inducing, plasmid-free strain did not. We confirmed that caspase-mediated apoptotic tissue destruction may contribute to chlamydial pathogenesis. Caspase-1 or -3 deficiency, or local administration of the pan caspase inhibitor, Z-VAD-FMK into normal mice protected against Chlamydia-induced infertility. Finally, the oviducts of infected infertile mice showed evidence of caspase-mediated cleavage inactivation of Dicer and alteration in critical miRNAs that regulate growth, differentiation, and development, including mir-21. These results provide new insight into the molecular pathogenesis of TFI with significant implications for new strategies for treatment and prevention of chlamydial complications.

This manuscript reports the consensus statements regarding recurrent ovarian cancer (ROC), reached at the fifth Ovarian Cancer Consensus Conference (OCCC), which was held in Tokyo, Japan, in November 2015. Three important questions were identified: (i) What are the subgroups for clinical trials in ROC? The historical definition of using platinum-free interval (PFI) to categorise patients as having platinum-sensitive/resistant disease was replaced by therapy-free interval (TFI). TFI can be broken down into TFIp (PFI), TFInp (non-PFI) and TFIb (biological agent-free interval). Additional criteria to consider include histology, BRCA mutation status, number/type of previous therapies, outcome of prior surgery and patient reported symptoms. (ii) What are the control arms for clinical trials in ROC? When platinum is considered the best option, the control arm should be a platinum-based therapy with or without an anti-angiogenic agent or a poly (ADP-ribose) polymerase (PARP) inhibitor. If platinum is not considered the best option, the control arm could include a non-platinum drug, either as single agent or in combination. (iii) What are the endpoints for clinical trials in ROC? Overall survival (OS) is the preferred endpoint for patient cohorts with an expected median OS < or = 12 months. Progression-free survival (PFS) is an alternative, and it is the preferred endpoint when the expected median OS is>> 12 months. However, PFS alone should not be the only endpoint and must be supported by additional endpoints including pre-defined patient reported outcomes (PROs), time to second subsequent therapy (TSST), or time until definitive deterioration of quality of life (TUDD).

The cerebral cortex is divided into many functionally distinct areas. The emergence of these areas during neural development is dependent on the expression patterns of several genes. Along the anterior-posterior axis, gradients of Fgf8, Emx2, Pax6, Coup-tfi, and Sp8 play a particularly strong role in specifying areal identity. However, our understanding of the regulatory interactions between these genes that lead to their confinement to particular spatial patterns is currently qualitative and incomplete. We therefore used a computational model of the interactions between these five genes to determine which interactions, and combinations of interactions, occur in networks that reproduce the anterior-posterior expression patterns observed experimentally. The model treats expression levels as Boolean, reflecting the qualitative nature of the expression data currently available. We simulated gene expression patterns created by all possible networks containing the five genes of interest. We found that only of these networks were able to reproduce the experimentally observed expression patterns. These networks all lacked certain interactions and combinations of interactions including auto-regulation and inductive loops. Many higher order combinations of interactions also never appeared in networks that satisfied our criteria for good performance. While there was remarkable diversity in the structure of the networks that perform well, an analysis of the probability of each interaction gave an indication of which interactions are most likely to be present in the gene network regulating cortical area development. We found that in general, repressive interactions are much more likely than inductive ones, but that mutually repressive loops are not critical for correct network functioning. Overall, our model illuminates the design principles of the gene network regulating cortical area development, and makes novel predictions that can be tested experimentally.

A method of computed tomography (CT) image analysis of lumbar vertebrae has been developed, providing a visualization of the trabecular network as it is represented in a 1.5 mm-thick CT image. We measured the length of the network and the number of discontinuities found in the image. The ratio of these measurements was called the "trabecular fragmentation index" (TFI). CT images from 71 women between the ages of 50 and 59, and 94 women between the ages of 60 and 69 were divided into three groups according to quantitative computed tomography (QCT) vertebral density and to the presence or absence of crushing and fractures. The measure of the network length versus the vertebral area was significantly higher in normal subjects than in osteoporotics. A TFI threshold at 0.195 could separate the normal subjects, regardless of the decade, from osteoporotic ones. In females between 50 and 69 years of age, TFI was 0.166 (SD = 0.031) for the normal group and 0.248 (SD = 0.082) for osteoporotics. The osteopenic group without fractures but low bone mineral density (BMD) showed an intermediate TFI of 0.195 (SD = 0.05), placing this population on both sides of the threshold. Correlation between TFI and BMD was only -0.60. TFI could provide new information in vivo about the state of trabecular structure, particularly in the osteopenic group.

BACKGROUND

Over the years, a plethora of frailty assessment tools has been developed. These instruments can be basically grouped into two types of conceptualizations - unidimensional, based on the physical-biological dimension - and multidimensional, based on the connections among the physical, psychological, and social domains. At present, studies on the comparison between uni- and multidimensional frailty measures are limited.

OBJECTIVE

The aims of this paper were: 1) to compare the prevalence of frailty obtained using a uni- and a multidimensional measure; 2) to analyze differences in the functional status among individuals captured as frail or robust by the two measures; and 3) to investigate relations between the two frailty measures and disability.

METHODS

Two hundred and sixty-seven community-dwelling older adults (73.4±6 years old, 59.9% of women) participated in this cross-sectional study. The Cardiovascular Health Study (CHS) index and the Tilburg Frailty Indicator (TFI) were used to measure frailty in a uni- and multidimensional way, respectively. The International Physical Activity Questionnaire, the Center of Epidemiologic Studies Depression scale, and the Loneliness Scale were administered to evaluate the functional status. Disability was assessed using the Groningen Activity Restriction Scale. Data were treated with descriptive statistics, one-way analysis of variance, correlations, and receiver operating characteristic analyses through the evaluation of the areas under the curve.

RESULTS

Results showed that frailty prevalence rate is strictly dependent on the index used (CHS =12.7%; TFI =44.6%). Furthermore, frail individuals presented differences in terms of functional status in all the domains. Frailty measures were significantly correlated with each other (r=0.483), and with disability (CHS: r=0.423; TFI: r=0.475). Finally, the area under the curve of the TFI (0.833) for disability was higher with respect to the one of CHS (0.770).

CONCLUSIONS

Data reported here confirm that different instruments capture different frail individuals. Clinicians and researchers have to consider the different abilities of the two measures to detect frail individuals.

The chicken ovalbumin upstream promoter-transcription factors (COUP-TFs) are "orphan" members of the nuclear hormone receptor (NR) superfamily. COUP-TFs are involved in organogenesis and neurogenesis. However, their role in skeletal muscle (and other major mass tissues) and metabolism remains obscure. Skeletal muscle accounts for approximately 40% of total body mass and energy expenditure. Moreover, this peripheral tissue is a primary site of glucose and fatty acid utilization. We utilize small interfering RNA (siRNA)-mediated attenuation of Coup-TfI and II (mRNA and protein) in a skeletal muscle cell culture model to understand the regulatory role of Coup-Tfs in this energy demanding tissue. This targeted NR repression resulted in the significant attenuation of genes that regulate lipid mobilization and utilization (including Pparalpha, Fabp3, and Cpt-1). This was coupled to reduced fatty acid beta-oxidation. Additionally we observed significant attenuation of Ucp1, a gene involved in energy expenditure. Concordantly, we observed a 5-fold increase in ATP levels in cells with siRNA-mediated repression of Coup-TfI and II. Furthermore, the expression of "classical" liver X receptor (LXR) target genes involved in reverse cholesterol transport (Abca1 and Abcg1) were both significantly repressed. Moreover, we observed that repression of the Coup-Tfs ablated the activation of Abca1, and Abcg1 mRNA expression by the selective LXR agonist, T0901317. In concordance, Coup-Tf-siRNA-transfected cells were refractory to Lxr-mediated reduction of total intracellular cholesterol levels in contrast to the negative control cells. In agreement Lxr-mediated activation of the Abca1 promoter in Coup-Tf-siRNA cells was attenuated. Collectively, these data suggest a pivotal role for Coup-Tfs in the regulation of lipid utilization/cholesterol homeostasis in skeletal muscle cells and the modulation of Lxr-dependent gene regulation.

An instrument has been designed and constructed that facilitates the measurement of in vivo tear film topology, thickness, and wetting, using the principles of thin film interferometry. The use of this tear film interferometer (TFI) allows objective evaluation of the breakup characteristics of the tear film on contact lens surfaces and provides a means for examining the dynamic changes in thickness, thickness distribution, and wetting properties during sequential interblink periods. The effects of contact lens material, wetting solutions, and cleaning regimens can be compared objectively. The instrument is easy to use, no additives to the natural tear fluid are required.

BACKGROUND

Exposure of the fingers to severe cold leads to cold-induced vasodilation (CIVD). The influence of ambient temperature on the CIVD-response is well understood and documented, but the response of CIVD to hyperthermia and mild hypothermia has rarely been investigated.

METHODS

To investigate the influence of body thermal status on the CIVD response, eight subjects immersed their right hand in 5 degrees C water for 40 min during mild hypothermia (C), thermoneutrality (N) and hyperthermia (W). The mean skin temperature of the body (Tsk), the esophageal temperature (Tes), the temperature of the volar side of the distal phalanx of each immersed finger (Tfi) and the skin perfusion of the immersed middle finger (Qsk) were continuously measured.

RESULTS

During the W condition the body temperatures were higher (Tes: 38.0+/-0.1 degrees C; Tsk: 37.9+/-0.7 degrees C) than during N (Tes: 36.8+/-0.2 degrees C; Tsk: 31.8+/-0.7 degrees C) and during C (Tes: 36.1+/-0.8 degrees C; Tsk: 21.2+/-1.9 degrees C). Tfi and Qsk were higher during the W condition (Tfi: 16.5+/-2.3 degrees C; Qsk: 133+/-53 perfusion units (PU)) than during N (Tfi: 8.1+/-1.7 degrees C; Qsk: 57+/-39 PU) and during C (Tfi: 6.8+/-1.2 degrees C; Qsk: 22+/-14 PU). The onset time of CIVD was significantly prolonged in condition C (13.0+/-3.8 min) as compared with N (7.2+/-2.2 min).

CONCLUSIONS

It was concluded that the CIVD response is significantly affected by body core and skin temperatures.

A number of nuclear receptors, including retinoic acid receptors (RARs), retinoid-X receptors (RXRs), hepatocyte nuclear factor 4 (HNF-4), chicken ovalbumin upstream promoter transcription factor I (COUP-TFI), apolipoprotein regulatory protein 1 (ARP-1) and peroxisome proliferator-activated receptor (PPAR), bind to response elements comprised of two core motifs, 5'-RG(G/T)TCA, or a closely related sequence separated by 1 nt (DR1 elements). The potential role of the precise sequence of the core motif as well as the spacer nucleotide in determining specificity and promiscuity of receptor-response element interactions was investigated. We show here that nucleotides at base positions 1, 2 and 4 of the core motif as well as the spacer nucleotide determine the binding preference of HNF-4 and ARP-1 homodimers and RAR:RXR and PPAR:RXR heterodimers. In transfection experiments transcriptional activation by HNF-4 and PPAR:RXR and repression by ARP-1 correlated with the relative in vitro binding affinity provided the element was located within the proper promoter context. Furthermore, promoter context also determined whether an element that binds to HNF-4 and PPAR:RXR with equal affinity functions as an HNF-4 response element or PPAR response element. Thus, apart from the element-specific differences in affinity for the receptors, additional promoter-specific transcription factors that interact with HNF-4 and PPAR:RXR determine the specificity of transcriptional response through DR1-type elements.

Transradial coronary intervention (TRI) can be performed in elective patients with low incidence of access site complications. However, the feasibility of primary stent implantation by TRI is still not clear in patients with acute myocardial infarction (AMI). We prospectively randomized 149 patients out of 213 patients with AMI within 12 hr from onset into two groups: 77 patients treated by TRI (TRI group) and 72 patients by transfemoral coronary intervention (TFI; TFI group). We compared the incidences of major adverse cardiac events (MACE; repeat MI, target lesion revascularization, and cardiac death) during the initial hospitalization and 9-month follow-up periods in both groups. There were one patient who crossed over to the opposite arm, and two patients with severe bleeding complications in the TFI group. Background characteristics of patients were similar between the two groups. The success rate of reperfusion and the incidence of in-hospital MACE were similar in both groups (96.1% and 5.2% vs. 97.1% and 8.3% in TRI and TFI groups, respectively). In selected patients with AMI, primary stent implantation by TRI is feasible as compared to TFI.

Cystatin C, a cysteine protease inhibitor produced by the choroid plexus and found in CSF at high concentrations, may have an important role in brain injury. We used the two-vessel occlusion model with hypotension to induce transient forebrain ischemia (TFI) in rats for 10 min and then examined cystatin C immuno-like reactivity (CC-IR) after 1, 3, 7 and 14 days of recovery. Our results reveal that CC-IR was minimal or absent in the hippocampus of normal and 1 day post-ischemic animals. However, CC-IR was present in CA1 pyramidal cells and a small number of reactive glia of the stratum radiatum (SR) and stratum oriens (SO) at 3, 7 and 14 days post-ischemia. Histological assessment of the hippocampus indicates that CC-IR was localized in morphologically degenerative neurons. This distinct temporal expression of cystatin C in the rat hippocampus is concurrent with delayed neuronal death following TFI. Thus, these results indicate that cystatin C and/or its substrates may be important components of the post-ischemic neurodegenerative and repair process.

A mutant herpes simplex virus type 1, termed delta Tfi, with a 350 bp deletion of the Sp1, NF-kappaB, TAATGARATs, C/EBP and F2 DNA-binding elements from -420 to -70 relative to the transcriptional start site of ICPO (Vmw 110), was generated and characterized. The efficiency of plating of delta Tfi was reduced on Vero cells and it expressed correctly initiated ICPO RNA in the presence of cycloheximide, although RNA levels were 2.5-fold lower than with wild-type (KOS) and marker-rescued (delta TfiR) viruses. This was consistent with a demonstrated reduction in ICPO protein expression for delta Tfi at early times post-infection and a 3-fold reduction in ICPO-dependent transactivation of the ICP6 promoter. KOS, delta Tfi and delta TfiR replication in murine corneas and trigeminal ganglia were comparable when measured on a complementing cell line, but delta Tfi titres appeared 15- to 50-fold lower when measured on Vero cells. delta Tfi was correspondingly less virulent than wild-type or marker-rescued viruses in both immunocompetent and SCID mice. delta Tfi, however, established and reactivated from latency with efficiencies comparable to wild-type and marker-rescued viruses. These results demonstrate that although this deletion of the ICPO promoter results in lower levels of ICPO in vitro and decreased virulence in vivo, the establishment of and reactivation from latency are unaffected. This indicates that elements which regulate ICPO expression and virulence during acute infection may be distinct from those involved in reactivation.

BACKGROUND

Serum antibodies against major outer membrane protein (MOMP) and heat shock protein 60 (HSP60) from Chlamydia trachomatis are correlated with sequelae following infection. Since bacterial and human HSP60 share considerable sequence homology, cross-reactivity to human HSP60 is suggested as being involved in tubal factor infertility (TFI). The aim was to investigate whether antibodies to human HSP60 are associated with TFI, and to evaluate antibody testing in TFI diagnosis.

METHODS

Serum levels of antibodies against chlamydial MOMP and HSP60 from C. trachomatis, Salmonella enterica Enteritidis, Campylobacter jejuni and human HSP60 were analysed by enzyme-linked immunosorbent assay in three groups of infertile women: women with TFI (n = 70), controls with normal fallopian tubes (control group 1, n = 92) and a subgroup of women with normal fallopian tubes and sero-positive for either chlamydial MOMP or chlamydial HSP60 (control group 2, n = 28).

RESULTS

Serum levels of immunoglobulin (Ig)G1 and IgG3 antibodies against MOMP and HSP60 from C. trachomatis were elevated in patients with TFI compared with non-TFI individuals (group 1; P < 0.001), while levels of IgG3 against MOMP and IgG1 against HSP60 were higher in the TFI group compared with control group 2 (P = 0.04 and P = 0.03, respectively). Levels of antibodies against human HSP60 did not differ between groups.

CONCLUSIONS

Our findings confirm an association between TFI and antibodies to MOMP and HSP60 from C. trachomatis, suggesting antibody testing as a supplement in TFI diagnosis. No connection was observed between TFI and antibodies to human HSP60, pointing to an infectious rather than an autoimmune inflammation as the cause of TFI.