Miracle-dz/UniFAR-FTUs huggingface dataset:
Antisense depletion of beta‐subunits modulates the biophysical and pharmacological properties of neuronal calcium channels.

1. The role of the voltage‐dependent calcium channel (VDCC) beta‐subunit has been examined in cultured rat dorsal root ganglion neurones (DRGs). An antipeptide antibody was raised and this recognized proteins corresponding to beta‐subunits in a number of preparations. Immunoreactivity for the VDCC beta‐subunit in DRGs was concentrated on the internal side of the plasma membrane but was also present in the cytoplasm. 2. A twenty‐six‐mer antisense oligonucleotide with homology to all published VDCC beta‐subunit sequences was microinjected into individual cells, and maximal depletion of VDCC beta‐subunit immunoreactivity was observed after 108 h suggesting a half‐life for the turnover of the beta‐subunit greater than 50 h. No depletion was obtained with nonsense oligonucleotide. 3. The effect of depletion of VDCC beta‐subunit immunoreactivity on calcium channel currents in these cells was a reduction in amplitude of the maximum current of about 47%, and a shift in the voltage dependence of current activation of about +7 mV. These effects are the converse of those observed following co‐expression of cloned beta‐ with alpha 1‐subunits in oocytes and other expression systems. 4. The ability of the 1,4‐dihydropyridine (DHP) agonist Bay K 8644 to enhance calcium channel currents was greatly reduced following depletion of beta‐subunit immunoreactivity. This result is in agreement with the finding in several systems that co‐expression of the beta‐subunit with alpha 1‐subunits results in an increased number of DHP binding sites. 5. These results show that calcium channel beta‐subunits form part of native neuronal calcium channels and modify their biophysical and pharmacological properties.
Quality of Life After Complete Lymphadenectomy for Vulvar Cancer: Do Women Prefer Sentinel Lymph Node Biopsy?

Objectives Leg lymphoedema occurs in up to 60% of women after a complete inguinal-femoral lymphadenectomy for vulvar cancer. To avoid lymphoedema, sentinel lymph node biopsy has become the preferred method of staging. However, false-negative results may influence survival, making the sentinel node procedure unacceptable to many fully informed women. The aims of this study were to measure the quality of life (QoL) in women after a complete lymphadenectomy for vulvar cancer and to quantify the risk to survival these women would be prepared to take with sentinel node biopsy. Materials and Methods Sixty women who had a complete lymphadenectomy for early-stage vulvar cancer participated in structured interviews. The severity of lymphoedema symptoms was recorded. The QoL-adjusted survival was measured using the Utility-Based Questionnaire-Cancer, a cancer-specific validated QoL instrument. The women stated their preference for sentinel node biopsy or complete lymphadenectomy. A “standard-gamble” preference table was used to quantify the degree of risk to survival they would take to avoid lymphoedema. Results Seventy-three percent of women reported lymphoedema after complete lymphadenectomy. Women with lymphoedema or leg pain had significantly worse scores for QoL in terms of social activity as well as physical and sexual function. Overall, 80% of women would choose complete lymphadenectomy rather than sentinel node biopsy if the risk of missing a positive lymph node was higher than 1 in 100, but if the risk of missing a positive lymph node was lower than 1 in 100, almost one third of the women would prefer sentinel node biopsy. Conclusions Although women treated for early-stage vulvar cancer report reduced QoL after complete lymphadenectomy, most would choose complete lymphadenectomy over sentinel node biopsy. However, there is an individual level of risk that each woman can define with regard to her preference for the sentinel node procedure. Women with early-stage vulvar cancer should be offered an informed choice between complete lymphadenectomy or sentinel node biopsy.
The Value of a Baseline Caries Risk Assessment Model in the Primary Dentition for the Prediction of Caries Incidence in the Permanent Dentition

To establish a reliable screening method for caries prediction and to identify predominant risk factors, this study tested whether a cross–sectional caries risk model assessed at age 7 could be used to predict future caries onset in the permanent first molars at age 10 in 3,303 children born in 1989. As prediction variables, assessing the believed risk, baseline data at age 7 on oral health status, oral hygiene level, oral health behaviour and sociodemographic factors were used. The real risk, based on data collected for the first permanent molars during the follow–up, was assessed by different approaches. Cumulative incidence during the 3–year observation period was 31.6%, ranging from 22.4% in the believed low–risk group to 43.2% in the believed high–risk group. A stepwise logistic regression analysis was performed with net caries increment as outcome measure, adjusted for the real time at risk, using eruption times. Baseline dmfs and occlusal and buccal plaque indices were highly significant for having a high caries increment in permanent first molars with respective odds ratios of 1.07, 1.43 and 1.35. Brushing less than once a day and the daily use of sugar–containing drinks between meals were confirmed as risk factors (OR 2.43 and 1.25, respectively). The logistic regression analysis provided a sensitivity of 59–66% and a specificity of 65.7–72.8%, which indicates that the risk marker did not have an important predictive power. None of the socio–demographic and behavioural variables had enough predictive power at community level to be useful for identifying caries susceptible children. Even the power of dmfs at baseline must be considered modest.
Chromium allergy in consecutive patients in a country where ferrous sulfate has been added to cement since 1981

Cement eczema used to be a common occupational disease in Denmark. Since 1981, ferrous sulfate has been added to all cement produced in Denmark to reduce the amount of soluble hexavalent chromate to below 2 mg/kg (2 ppm). The aim of the study was to analyse a material of consecutive chromate‐sensitive patients in an urban tertiary referral centre with respect to primary cause of sensitization, in a geographical area where the risk of chromate exposure from cement had been reduced. In the 6‐year period January 1989 to December 1994, a total of 4511 patients were patch tested with the European standard series, including chromate. 79 patients, 31 male and 48 female, were diagnosed as chromate sensitive. Relevant chromate exposure was established in 34 of these 79 patients. Leather was the most frequent source of chromate sensitization (19 out of 34) (47%). Chromate sensitization from cement was considered likely in 10 out of 34 subjects. Of these, 7 had been sensitized before 1981, 2 had been sensitized by non‐occupational exposure to cement, and only 1 had been sensitized from occupational cement exposure in the 6‐year period.
Palaeogeographic controls on climate and proxy interpretation

Abstract. During the period from approximately 150 to 35 million years ago, the Cretaceous–Paleocene–Eocene (CPE), the Earth was in a “greenhouse” state with little or no ice at either pole. It was also a period of considerable global change, from the warmest periods of the mid-Cretaceous, to the threshold of icehouse conditions at the end of the Eocene. However, the relative contribution of palaeogeographic change, solar change, and carbon cycle change to these climatic variations is unknown. Here, making use of recent advances in computing power, and a set of unique palaeogeographic maps, we carry out an ensemble of 19 General Circulation Model simulations covering this period, one simulation per stratigraphic stage. By maintaining atmospheric CO2 concentration constant across the simulations, we are able to identify the contribution from palaeogeographic and solar forcing to global change across the CPE, and explore the underlying mechanisms. We find that global mean surface temperature is remarkably constant across the simulations, resulting from a cancellation of opposing trends from solar and palaeogeographic change. However, there are significant modelled variations on a regional scale. The stratigraphic stage–stage transitions which exhibit greatest climatic change are associated with transitions in the mode of ocean circulation, themselves often associated with changes in ocean gateways, and amplified by feedbacks related to emissivity and planetary albedo. We also find some control on global mean temperature from continental area and global mean orography. Our results have important implications for the interpretation of single-site palaeo proxy records. In particular, our results allow the non-CO2 (i.e. palaeogeographic and solar constant) components of proxy records to be removed, leaving a more global component associated with carbon cycle change. This “adjustment factor” is used to adjust sea surface temperatures, as the deep ocean is not fully equilibrated in the model. The adjustment factor is illustrated for seven key sites in the CPE, and applied to proxy data from Falkland Plateau, and we provide data so that similar adjustments can be made to any site and for any time period within the CPE. Ultimately, this will enable isolation of the CO2-forced climate signal to be extracted from multiple proxy records from around the globe, allowing an evaluation of the regional signals and extent of polar amplification in response to CO2 changes during the CPE. Finally, regions where the adjustment factor is constant throughout the CPE could indicate places where future proxies could be targeted in order to reconstruct the purest CO2-induced temperature change, where the complicating contributions of other processes are minimised. Therefore, combined with other considerations, this work could provide useful information for supporting targets for drilling localities and outcrop studies.
Childhood cancer in Côte d'Ivoire, 1995 - 2004: challenges and hopes.

BACKGROUND There is insufficient research into the state of paediatric oncology in African countries. OBJECTIVES The purpose of this study was to analyse the state of paediatric oncology between 1995 and 2004 in Côte d'Ivoire. METHODS This retrospective descriptive study analysed all patients under the age of 18 who were diagnosed with cancer in Côte d'Ivoire over a period of 10 years (January 1995 - December 2004) with regard to demographics, types of pathology, delay in diagnosis and treatment, treatment modalities, abandonment of treatment and survival rate. RESULTS Of 405 patients diagnosed with cancer, 331 were included in the study. Burkitt's lymphoma was the most common malignancy (73.6%), followed by nephroblastoma (14.5%) and acute leukaemia (4%). Delay in diagnosis occurred in 38.7% of cases and ranged from 1 to 3 months; the average delay from diagnosis to starting treatment was 18 days. An abdominal mass and swelling of the jaw were the most common clinical presentations. Almost half of the patients (48.6%) were lost to follow-up and over a third (39.3%) died shortly after admission owing to advanced disease. The overall survival rate was 9.4%. CONCLUSIONS Cancer in children in Côte d'Ivoire was dominated by Burkitt's lymphoma. The rate of loss to follow-up of almost 50% is grounds for concern. The overall survival rate of 9.4% is very low, but such figures are not uncommon for African countries. Collaboration within the Franco-African Group of Paediatric Oncology has contributed to improving the management of children with cancer.
Cancer risk after renal transplantation in Japan

Excess of cancer in patients receiving renal transplantation is well‐known in Western countries, but information in Japan remains limited. Our study examined whether excess risk is found in patients receiving renal transplantation in Japan. Between 1970 and 1995, 1155 males and 589 females underwent renal transplantation in 6 hospitals, and a total of 12,982 person‐years of observation was accumulated. Malignancies developed in 2.6% of patients; O/E ration was 2.78. Median interval from renal transplantation to tumor development was 58 months. The interval in the patients receiving medication with cyclosporine‐A (CyA) (median, 42.5 months) was significantly shorter than that with non‐CyA (median, 95.5 months). Median age at the diagnosis of malignancy was 40 years, which is much younger than that in the general population. Relative risk was highest in renal cancer, followed by thyroid cancer, malignant lymphoma and uterine cancer. A distribution of malignancies was different from that reported from Western countries. These findings showed the excess risk of malignancies in Japan with renal transplants, especially in male patients, similar to that observed in Western countries, though the types of malignancy were different. Int. J. Cancer 71:517‐520, 1997. © 1997 Wiley‐Liss, Inc.
Clinical Course in Patients Seeking Primary Care for Back or Neck Pain: A Prospective 5-Year Follow-Up of Outcome and Health Care Consumption with Subgroup Analysis

Study Design. Prospective follow-up. Objective. To describe the 5-year clinical course in a cohort of patients treated for back or neck pain in primary care and compare results with the 1-year outcome both for the whole group and for subgroups. Summary of Background Data. A randomized study showed a decrease in perceived pain and disability after treatment by chiropractic or physiotherapy, but many reported recurrence or continual pain at the 1-year follow-up. Knowledge of the clinical course over longer follow-up periods is limited. Methods. A 5-year follow-up questionnaire was sent to 314 individuals. Main outcome measures were pain intensity, Oswestry score, and general health. Recurrence, health care consumption, and other measures were described. Results. Fifty-two percent of respondents reported pain (visual analog scale, >10 mm) and back-related disability (Oswestry, >10%) at the 5-year follow-up. This was similar to 1-year results, and 84% of these were the same individuals. Sixty-three percent reported recurrence or continual pain, and 32% reported health care consumption at the 5-year follow-up. Conclusions. In a cohort of individuals of working age seeking primary care for nonspecific back or neck pain, it can be expected that about half of the population will report pain and disability at the 5-year follow-up. A significant proportion will report recurrence or continual pain and health care consumption. Pain and disability were associated with recurrence or continual pain and health care consumption. Further analysis is needed to identify additional predictors for 5-year outcome, taking into account 1-year follow-up results. Since many patients will have recurrence or continual pain, health policies and clinical decision models for long-term outcome must allow for these aspects.
Grapefruit juice-drug interaction studies as a method to assess the extent of intestinal availability: utility and limitations.

This study aims to assess utility and limitations of grapefruit juice (GFJ) interaction studies as alternative in vivo approach to estimate intestinal availability (F(G)) in comparison to the predominantly used i.v. /oral method. The F(G) estimates were obtained from the ratio of AUC in the control and the GFJ group reported previously. Due to large variability in the study design, the following inclusion criteria were applied for the selection of clinical studies: no change in elimination half-life in the presence of GFJ, administration of GFJ with or up to 4 h before drug intake, and a reported significant increase in AUC in the presence of GFJ. Weighted mean F(G) values were compared to estimates from i.v. /oral data. Additionally, inter-study and inter-individual variation of GFJ F(G) estimates was assessed by meta-analysis for drugs with multiple studies reported. F(G) values ranged from 0.07 to 0.92 for lovastatin and quinidine, respectively. Overall, the inter-individual variation in GFJ F(G) estimates (16-54%) was higher than the inter-study (5.7-39%) with the exception of nisoldipine and simvastatin where inter-study variations of 53-88% were observed. Weighted average GFJ F(G) estimates were comparable to i.v. /oral, supporting the application of this approach as an alternative to i.v. /oral data for predominantly metabolised drugs (r(2) = 0.65; n=10). In contrast, this approach is of limited use for drugs whose disposition is co-dependent on efflux/uptake transporters and metabolic enzymes. An area of high intestinal extraction (F(G) < or = 0.25) is identified as problematic, as availability of conclusive data is limited in this area.
MCF-7 breast cancer cells selected for tamoxifen resistance acquire new phenotypes differing in DNA content, phospho-HER2 and PAX2 expression, and rapamycin sensitivity

Patients with estrogen receptor-positive (ER+) breast cancers are often treated with aromatase inhibitors or by anti-estrogens such as tamoxifen to prevent disease recurrence. Resistant tumors nevertheless develop and it is commonly assumed that they arise by the induction of mutations. However, it is also possible that resistant tumors grow from pre-existing variant populations within the original tumor. We have investigated this possibility in the case of the MCF-7 breast cancer cell line. The line was cultured for a prolonged period either in the presence of tamoxifen to block the action of oestrogen or in the absence of estrogen to mimic the action of oophorectomy or treatment with aromatase inhibitors. Both treatments led to growth inhibition followed by eventual outgrowth of sub-lines. Five of these sub-lines were developed and characterized for sensitivity to tamoxifen and to the antibiotic rapamycin, expression of HER2 and PAX2, and phosphorylation of Akt, p70S6K, 4E-BP1, rpS6, EGFR1, Erk and HER2. All six lines were ER+ and could be divided into four phenotypes distinguished by cell volume, DNA content (ploidy) and cell cycle time. In two cases, selection with tamoxifen and selection in the absence of estrogen produced similar phenotypes. Rapamycin resistance was a feature of the sub-lines developed under estrogen deprivation and was associated with loss of active phospho-HER2 and acquisition of PAX2 expression. The results support the conclusion that the MCF-7 cell line is heterogeneous and that the selection conditions allow the growth of pre-existing phenotypes.
Histologic changes in transplanted expanded polytetrafluoroethylene in an animal model

Several materials have been used for nasal augmentation surgery. Expanded polytetrafluoroethylene (e‐PTFE) (Gore‐Tex; W. L. Gore & Associates, Flagstaff, AZ) has proven to be an ideal synthetic material for nasal augmentation. Gore‐Tex contains numerous pores that stabilize an implant, but this advantage has been tempered by unpredictable outcomes. The purpose of this study was to evaluate morphologic and histologic changes in nonreinforced Gore‐Tex in a rabbit model.
Skeletal muscle plasticity with marathon training in novice runners

The purpose of this study was to investigate leg muscle adaptation in runners preparing for their first marathon. Soleus and vastus lateralis (VL) biopsies were obtained from six recreational runners (23 ± 1 years, 61 ± 3 kg) before (T1), after 13 weeks of run training (T2), and after 3 weeks of taper and marathon (T3). Single muscle fiber size, contractile function (strength, speed, and power) and oxidative enzyme activity [citrate synthase (CS)] were measured at all three time points, and fiber type distribution was determined before and after the 16‐week intervention. Training increased VO2max∼9% (P<0.05). All soleus parameters were unchanged. VL MHC I fiber diameter increased (+8%; P<0.05) from T1 to T2. VL MHC I Vo (−12%), MHC I power (−22%) and MHC IIa power (−29%) were reduced from T1 to T2 (P<0.05). No changes in VL single fiber contractile properties were observed from T2 to T3. No change was observed in soleus CS activity, whereas VL CS activity increased 66% (P<0.05). Our observations indicate that modest marathon training elicits very specific skeletal muscle adaptations that likely support the ability to perform 42.2 km of continuous running – further strengthening the existing body of evidence for skeletal muscle specificity.
Elevated Urinary Albumin Excretion Is Associated With Impaired Arterial Dilatory Capacity in Clinically Healthy Subjects

BackgroundElevated urinary albumin excretion (UAE) predicts atherosclerotic cardiovascular disease. It is hypothesized that elevated UAE is associated with a generalized vascular dysfunction. This study tested this hypothesis for conduit arteries. Methods and ResultsClinically healthy subjects were selected: 19 with UAE >90th percentile in the background population (6.6 &mgr;g/min<UAE<150 &mgr;g/min) and 41 with normoalbuminuria (UAE <6.6 &mgr;g/min). External ultrasound was used to measure the dilatory response of the brachial artery to postischemic increased blood flow (endothelium-dependent, flow-associated dilation) and to nitroglycerin (endothelium-independent, nitroglycerin-induced dilation). Plasma concentrations of the endothelial markers nitrate/nitrite, thrombomodulin, and von Willebrand factor antigen were also measured. Both flow-associated and nitroglycerin-induced dilations were significantly impaired in subjects with elevated UAE as compared with normoalbuminuric control subjects: 102.0±1.0% (mean±SEM) versus 104.3±0.6% (P <0.05) and 120.1±1.5% versus 123.8±1.0% (P <0.05). No differences in the plasma concentrations of endothelial markers were found. ConclusionsSlightly elevated UAE is associated with impaired conduit arterial dilatory capacity in clinically healthy subjects, and this impairment may be explained by a reduced dilatory response to nitric oxide of both endogenous and exogenous origin. Impaired arterial dilatory capacity may contribute to the increased cardiovascular risk in subjects with elevated UAE.
Involvement of human ORC and TRF2 in pre‐replication complex assembly at telomeres

The origin recognition complex (ORC) binds to replication origins to regulate the cell cycle‐dependent assembly of pre‐replication complexes (pre‐RCs). We have found a novel link between pre‐RC assembly regulation and telomere homeostasis in human cells. Biochemical analyses showed that human ORC binds to TRF2, a telomere sequence‐binding protein that protects telomeres and functions in telomere length homeostasis, via the ORC1 subunit. Immunostaining further revealed that ORC and TRF2 partially co‐localize in nuclei, whereas chromatin immunoprecipitation analyses confirmed that pre‐RCs are assembled at telomeres in a cell cycle‐dependent manner. Over‐expression of TRF2 stimulated ORC and MCM binding to chromatin and RNAi‐directed TRF2 silencing resulted in reduced ORC binding and pre‐RC assembly at telomeres. As expected from previous reports, TRF2 silencing induced telomere elongation. Interestingly, ORC1 silencing by RNAi weakened the TRF2 binding as well as the pre‐RC assembly at telomeres, suggesting that ORC and TRF2 interact with each other to achieve stable binding. Furthermore, ORC1 silencing also resulted in modest telomere elongation. These data suggest that ORC might be involved in telomere homeostasis in human cells.