Search

Kathryn Gray,1 Linda H Ficociello,2 Abigail E Hunt,1 Claudy Mullon,2 Steven M Brunelli1 1DaVita Clinical Research, Minneapolis, MN, USA; 2Medical Department, Fresenius Medical Care Renal Therapies Group, Waltham, MA, USA Background: Phosphate binders are widely used to achieve serum phosphorus control in patients with end-stage renal disease. However, the large pill burden associated with these medications may decrease adherence to therapy. In clinical trials, sucroferric oxyhydroxide (SO) demonstrated equivalent control of serum phosphorus to sevelamer, with a lower daily pill burden. We examined changes in phosphate binder pill burden, medication possession ratio (MPR), and phosphorus control among in-center hemodialysis (ICHD) patients converting to SO from another phosphate binder as part of routine care. Materials and methods: Patients included in this retrospective analysis (N=490) were ≥18 years old, received ICHD at a large dialysis organization (LDO), and were enrolled in the LDO’s pharmacy service. Patients converting to SO were those who had supply of another phosphate binder, received a first prescription fill for SO, and subsequently did not refill the non-SO phosphate binder. Patients were followed over the 6 months before and 6 months following the first SO fill and were censored from the analysis upon modality change, loss to follow-up, discontinuation of SO, or fill of a prescription for another phosphate binder after SO initiation (number censored=361). Outcome measures assessed were total phosphate binder pill burden and MPR, serum phosphorus, and percentage of patients with serum phosphorus ≤5.5 mg/dL. Results: Among patients converting to SO, mean phosphate binder pill burden was 10.8 pills/day during baseline; this decreased to 5.5 pills/day during follow-up (P

Steven M Brunelli,1 Levi Njord,2 Abigail E Hunt,1 Scott P Sibbel1 1DaVita Clinical Research®, Minneapolis, MN, USA; 2DaVita HealthCare Partners, Inc, Denver, CO, USA Background and objectives: Catheter-related bloodstream infections (CRBSIs) are common in hemodialysis patients using central venous catheters, and catheter occlusion also occurs frequently. The Tego needlefree connector was developed to reduce the incidence of these complications; however, existing studies of its effectiveness and safety are limited. Materials and methods: This retrospective analysis compared outcomes among patients of a large dialysis organization receiving in-center hemodialysis using a central venous catheter with either the Tego connector or standard catheter caps between October 1 and June 30, 2013. Incidence rates for intravenous (IV) antibiotic starts, receipt of an IV antibiotic course, positive blood cultures, mortality, and missed dialysis treatments were calculated, and incidence-rate ratios (IRRs) were estimated using Poisson regression models. Utilization of erythropoiesis-stimulating agents (ESAs) and thrombolytics was described for each patient-month and compared using mixed linear models. Models were run without adjustment, adjusted for covariates that were imbalanced between cohorts, or fully adjusted for all potential confounders. Results: The analysis comprised 10,652 Tego patients and 6,493 controls. Tego use was independently associated with decreased risk of CRBSI, defined by initiation of IV antibiotics (adjusted IRR 0.92, 95% confidence interval [CI] 0.87–0.97) or initiation of IV antibiotic course (adjusted IRR 0.89, 95% CI 0.84–0.95). Tego use was independently associated with decreased rate of missed dialysis treatments (adjusted IRR 0.98, 95% CI 0.97–1.00); no significant difference between Tego and control cohorts was observed with respect to mortality. Tego use was associated with decreased likelihood of thrombolytic use (adjusted per-month probability of 5.6% versus 6.2% for controls) and lower utilization of ESAs in study months 7–9. Conclusion: Use of the Tego connector may reduce the risk of CRBSI and result in lower utilization of thrombolytics, antibiotics, and ESAs, as well as fewer missed dialysis treatments. Keywords: catheter, dialysis, end-stage renal disease, ESA, infection, mortality

Postoperation gastric bypass patients completed a 47-item nutrition-related quality of life (NQOL) survey. No correlation was found between percentage weight loss and scores for NQOL. However, significant differences in NQOL were found when participants were divided into 4 groups on the basis of time since surgery. Significantly lower NQOL scores were found in the group 19-36 months since surgery versus those who had more recently had surgery. To promote increased quality of life after laparoscopic gastric bypass, nutrition counseling should address the need for permanent changes in dietary intake and participation in a lifelong exercise program for long-term success with maintenance of weight loss. Patients should also be encouraged to seek the help of an eating disorder specialist if an eating disorder is present. [ABSTRACT FROM AUTHOR]

PURPOSE: The purpose of this study was to determine if registered dietitian (RD) and registered nurse (RN) certified diabetes educators (CDEs) provide similar recommendations regarding carbohydrates and dietary supplements to individuals with diabetes. METHODS: A survey was mailed to CDEs in the southern United States. Participants were asked to indicate their recommendations for use of carbohydrates, fiber, artificial sweeteners, and 12 selected dietary and herbal supplements when counseling individuals with diabetes. RESULTS: The survey sample consisted of 366 CDEs: 207 were RNs and 159 were RDs. No statistically significant differences were found between RNs and RDs in typical carbohydrate recommendations for treatment of diabetes. However, RDs were more likely than RNs to make recommendations for fiber intake or use of the glycemic index. A significant difference also was found in the treatment of hypoglycemia: RNs were more likely than RDs to recommend consuming a carbohydrate source with protein to treat hypoglycemia. CONCLUSIONS: Although some differences existed, RD and RN CDEs are making similar overall recommendations in the treatment of individuals with diabetes. [ABSTRACT FROM AUTHOR]

PURPOSE: The purposes of this research were to (1) identify factors that contribute to the barriers to dietary adherence in individuals with diabetes identified 1998 study and (2) obtain recommendations frog registered dietitians for strategies to overcome the barriers. METHODS: A 10-item, open-ended telephone questionnaire was used to obtain information. The sample included 75 registered dietitians who participated in a previous survey to identify barriers and agreed to a follow-up telephone interview. RESULTS: Of the 75 participants, 28% reported spending S hours or less per week counseling individuals with diabetes, 64% spent between 6 and 30 hours, and 8% spent more than 31 hours l week. Almost half of the participants (47%) were certified diabetes educators. Factors identified as the greatest contributors to the barriers being evaluated included lack of time, lack of symptoms, lack of education (including follow-up), poor sel-festeem/lack of empowerment, and misinformation from family/peers/others with diabetes. The primary recommendations for overcoming each of these barriers included individualizing meal plans and planning ahead, teaching about complications, and setting obtainable goals. CONCLUSIONS: The registered dietitians who were surveyed emphasized the importance of individualizing dietary counseling. [ABSTRACT FROM AUTHOR]

The purposes of this study were to determine the use and perceived effectiveness of motivational strategies used by dietitians and to evaluate dietitians' perceptions of barriers to client compliance. A three-part questionnaire with 32 motivational strategies, 16 barriers to adherence, and demographic information was designed and mailed to 862 members of the American Dietetic Association's Diabetes Care and Education Dietetic Practice Group. Statistical analyses included frequency distributions, chi-square analysis, and factor analysis. Only 13 of the 32 motivational strategies were used frequently by 50% or more of the dietitians. The main strategy based on perceived effectiveness was 'Tailor the diet to the client's lifestyle.' Strategies perceived as effective also were used frequently by a majority of the dietitians. There were differences in use of strategies based on practice setting, CDE certification, and education level. The most significant barrier to adherence was 'Complications with lifestyle/competing demands.' Factor analysis revealed nine factors for motivational strategies and five factors for barriers to adherence. [ABSTRACT FROM AUTHOR]

KCTD family proteins typically assemble into cullin-RING E3 ligases. KCTD1 is an atypical member that functions instead as a transcriptional repressor. Mutations in KCTD1 cause developmental abnormalities and kidney fibrosis in scalp-ear-nipple syndrome. Here, we present unexpected mechanistic insights from the structure of human KCTD1. Disease-causing mutation P20S maps to an unrecognized extension of the BTB domain that contributes to both its pentameric structure and TFAP2A binding. The C-terminal domain (CTD) shares its fold and pentameric assembly with the GTP cyclohydrolase I feedback regulatory protein (GFRP) despite lacking discernible sequence similarity. Most surprisingly, the KCTD1 CTD establishes a central channel occupied by alternating sodium and iodide ions that restrict TFAP2A dissociation. The elucidation of the structure redefines the KCTD1 BTB domain fold and identifies an unexpected ion-binding site for future study of KCTD1's function in the ectoderm, neural crest, and kidney., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

We present a case report of diffuse alveolar hemorrhage (DAH), which presented with massive hemoptysis and impending airway compromise. A previously healthy 33-year-old female presented to the emergency department with dyspnea, chest pain, and massive hemoptysis. Due to impending respiratory failure, the patient was placed on mechanical ventilation and a bronchoscopy revealed a diagnosis of DAH. Throughout the hospital course, the patient received antibiotics, steroids, fresh frozen plasma (FFP), cryoprecipitate, tranexamic acid (TXA), and multiple blood transfusions. The patient was subsequently placed on extracorporeal membrane oxygenation (ECMO), but despite these life-saving measures, the patient died less than 48 hours after her initial presentation. This case serves as a harrowing reminder of DAH's destructive capabilities and the importance of rapid, aggressive management., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Hunt et al.)

Introduction: KCTD15 encodes an oligomeric BTB domain protein reported to inhibit neural crest formation through repression of Wnt/beta-catenin signalling, as well as transactivation by TFAP2. Heterozygous missense variants in the closely related paralogue KCTD1 cause scalp-ear-nipple syndrome., Methods: Exome sequencing was performed on a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. Identification of a de novo missense substitution within KCTD15 led to targeted sequencing of DNA from a similarly affected sporadic patient, revealing a different missense mutation. Structural and biophysical analyses were performed to assess the effects of both amino acid substitutions on the KCTD15 protein., Results: A heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain of KCTD15 was identified in an affected father and daughter and segregated with the phenotype. In the sporadically affected patient, a de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was present in KCTD15. Both substitutions were found to perturb the pentameric assembly of the BTB domain. A crystal structure of the BTB domain variant p.(Gly88Asp) revealed a closed hexameric assembly, whereas biophysical analyses showed that the p.(Asp104His) substitution resulted in a monomeric BTB domain likely to be partially unfolded at physiological temperatures., Conclusion: BTB domain substitutions in KCTD1 and KCTD15 cause clinically overlapping phenotypes involving craniofacial abnormalities and cutis aplasia. The structural analyses demonstrate that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Broad-spectrum antimicrobials are commonly used without indication and contribute to antimicrobial resistance (AMR). We implemented a syndrome-based stewardship intervention in a community hospital that targeted common infectious syndromes and antipseudomonal beta-lactam (APBL) use. Our intervention successfully reduced AMR, C. difficile rates, use of APBLs, and cost., Competing Interests: All authors report no conflicts of interest relevant to this article., (© The Author(s) 2024.)

Certain styles of children's shoes reduce 1st metatarsophalangeal joint (MTPJ) and midfoot motion during propulsion of walking. However, no studies have investigated if the splinting effect of shoes on children's 1st MTPJ and midfoot motion occurs during running. This study investigated the effect of sports shoes on multi-segment foot kinematics of children during propulsion of walking and running. Twenty children walked and ran at a self-selected velocity while barefoot and shod in a random order. Reflective markers were used to quantify sagittal plane motion of the 1st MTPJ and three-dimensional motion of the midfoot and ankle. Gait velocity increased during shod walking and running and was considered a covariate in the statistical analysis. Shoes reduced 1st MTPJ motion during propulsion of walking from 36.0° to 10.7° and during running from 31.5° to 12.6°. Midfoot sagittal plane motion during propulsion reduced from 22.5° to 6.2° during walking and from 27.4° to 9.6° during running. Sagittal plane ankle motion during propulsion increased during shod running from 26.7° to 34.1°. During propulsion of walking and running, children's sports shoes have a splinting effect on 1st MTPJ and midfoot motion which is partially compensated by an increase in ankle plantarflexion during running., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: The effect of footwear on the gait of children is poorly understood. This systematic review synthesises the evidence of the biomechanical effects of shoes on children during walking and running., Methods: Study inclusion criteria were: barefoot and shod conditions; healthy children aged ≤ 16 years; sample size of n > 1. Novelty footwear was excluded. Studies were located by online database-searching, hand-searching and contact with experts. Two authors selected studies and assessed study methodology using the Quality Index. Meta-analysis of continuous variables for homogeneous studies was undertaken using the inverse variance approach. Significance level was set at P < 0.05. Heterogeneity was measured by I2. Where I2 > 25%, a random-effects model analysis was used and where I2 < 25%, a fixed-effects model was used., Results: Eleven studies were included. Sample size ranged from 4-898. Median Quality Index was 20/32 (range 11-27). Five studies randomised shoe order, six studies standardised footwear. Shod walking increased: velocity, step length, step time, base of support, double-support time, stance time, time to toe-off, sagittal tibia-rearfoot range of motion (ROM), sagittal tibia-foot ROM, ankle max-plantarflexion, Ankle ROM, foot lift to max-plantarflexion, 'subtalar' rotation ROM, knee sagittal ROM and tibialis anterior activity. Shod walking decreased: cadence, single-support time, ankle max-dorsiflexion, ankle at foot-lift, hallux ROM, arch length change, foot torsion, forefoot supination, forefoot width and midfoot ROM in all planes. Shod running decreased: long axis maximum tibial-acceleration, shock-wave transmission as a ratio of maximum tibial-acceleration, ankle plantarflexion at foot strike, knee angular velocity and tibial swing velocity. No variables increased during shod running., Conclusions: Shoes affect the gait of children. With shoes, children walk faster by taking longer steps with greater ankle and knee motion and increased tibialis anterior activity. Shoes reduce foot motion and increase the support phases of the gait cycle. During running, shoes reduce swing phase leg speed, attenuate some shock and encourage a rearfoot strike pattern. The long-term effect of these changes on growth and development are currently unknown. The impact of footwear on gait should be considered when assessing the paediatric patient and evaluating the effect of shoe or in-shoe interventions.

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) holds promise for the treatment of tumors; however, many tumors are resistant to TRAIL alone. We previously showed that resistant malignant mesothelioma cells are sensitized to TRAIL-induced apoptosis by diverse toxic insults including chemotherapy, irradiation, or protein translation inhibitors such as cycloheximide. In seeking nontoxic sensitizers for TRAIL, we tested the protein translation inhibitor anisomycin at subtoxic concentrations 10- to 100-fold below those reported to inhibit protein translation. At these low concentrations (25 ng/mL), anisomycin potently and rapidly sensitized mesothelioma cells to TRAIL-induced apoptosis. Moreover, such sensitization occurred in malignant but not in nonmalignant mesothelial cells. Sensitization by anisomycin was dependent on Bid, indicating a role for mitochondrial amplification in the apoptotic synergy with TRAIL signaling. Consistent with this, we found that anisomycin induces rapid accumulation of the BH3-only protein Bim; moreover, small interfering RNA knockdown of Bim inhibits anisomycin-induced sensitization. Bim accumulation seems not to be transcriptional; instead, it is associated with Bim phosphorylation and increased stability, both consistent with the activation of c-jun NH2-terminal kinase signals by anisomycin. Overall, our data indicate that the rapid and selective sensitization by anisomycin in mesothelioma cells is mediated by posttranslational potentiation of Bim, which primes the cells for apoptosis via the death receptor pathway. Such subtoxic approaches to sensitization may enhance the value of TRAIL in cancer therapy.

Haematological and biochemical data were collected over a period of six years from grey seal (Halichoerus grypus) pups undergoing rehabilitation. Pups bled during the first three days were allocated retrospectively to one of seven clinical groups and statistical analyses were carried out on six of these groups (130 pups). Compared with reference ranges, all the groups had lower mean packed-cell volumes (pcv), red blood cell (rbc) counts haemoglobin and albumin levels, pups with severe trauma had higher total white blood cell (wbc) and neutrophil counts, pups with severe trauma and malnourished pups had higher total bilirubin levels, and pups in all the clinical groups except those with severe trauma had lower sodium levels. There were significant differences (P<0.05) between some clinical groups for mean pcv, rbc counts, all wbc counts except monocytes, haemoglobin, total bilirubin, creatine kinase, amylase and potassium levels. Forty-nine pups were bled more than once during the first 10 days of rehabilitation for haematology, and 11 were bled more than once for biochemistry. There were significant decreases (P<0.05) during this period in pcv, and in the activities of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatine kinase and lactate dehydrogenase, and significant increases in all wbc counts, total protein, globulin, amylase and calcium levels.

We have analyzed the transcriptional start sites of the rat ARF gene and the amino acid sequence of the rat ARF tumor suppressor protein. The 5' end of the ratARF gene is similar to that of a number of cellular housekeeping genes in that it is CG-rich and does not contain an upstream TATA box motif to define a precise transcriptional start site. The transcription of the rat ARF gene is initiated at multiple start sites with one major start site accounting for 41% of transcription. The rat ARF protein contains two methionine ATG codons at its amino terminus separated by 10 amino acids. The translation of the major endogenous ARF protein species is initiated from the upstream methionine ATG codon. The upstream methionine ATG codon is predominantly used, despite the fact that it is both very close to the major transcriptional start site (6 bases downstream) and is in a less favorable nucleic acid sequence context than the downstream ATG, relative to the ideal sequence postulated for efficient initiation of translation. The downstream, inefficient rat ARF ATG is equivalent to the major mouse ARF ATG start codon. Both of these closely spaced ATGs can be utilized as a translational start codon to produce a nucleolar-localized ARF protein which can induce a p53-dependent inhibition of cell division and transcriptional activation of p53 in the absence of p53 stabilization.

Objective: The purpose of this study was to determine whether a relationship exists between nutrition status and food security of patients on hemodialysis (HD)., Design: A descriptive correlation study., Setting: This study consisted of HD patients undergoing treatment at three northeast Louisiana dialysis centers., Patients: Ninety-eight HD patients participated in the study. The mean age of subjects was 59.1 +/- 14.2 years. The sample was 44% white and 56% black; 49% male and 51% female., Results: Multiple linear regression and chi2 analysis were used to assess relationships between demographics and food insecurity scores and Subjective Global Assessment scores. Race significantly predicted food insecurity (beta = 0.248; P = .019), with black patients being more food insecure than white subjects. A significant positive relationship was found between the level of education and Subjective Global Assessment scores (beta = 0.222; P = .037). In this sample, 16.3% of the subjects were found to be food insecure, and 64.3% of the patients were mildly to moderately malnourished, whereas another 13.3% were severely malnourished., Conclusions: Future research in this area should include food security questions related to the ability to obtain foods for health. Renal health care professionals should assess patients for possible food insecurity so that appropriate interventions can be implemented.

The death ligand, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), has shown great promise for inducing apoptosis selectively in tumors. Although many tumor cells are resistant to TRAIL-induced apoptosis alone, they can often be sensitized by co-treatment with DNA-damaging agents such as etoposide. However, the molecular mechanism underlying this therapeutically important synergy is unknown. We explored the mechanism mediating TRAIL-DNA damage apoptotic synergy in human mesothelioma cells, a tumor type particularly refractory to existing therapies. We show that Bid, a cytoplasmic Bcl-2 homology domain 3-containing protein activated by caspase 8 in response to TRAIL ligation, is essential for TRAIL-etoposide apo-ptotic synergy and, furthermore, that exposure to DNA damage primes cells to induction of apoptosis by otherwise sublethal levels of activated Bid. Finally, we show that the extensive caspase 8 cleavage seen during TRAIL-etoposide synergy is a consequence and not a cause of the apoptotic cascade activated downstream of Bid. These data indicate that TRAIL-etoposide apoptotic synergy arises because DNA damage increases the inherent sensitivity of cells to levels of TRAIL-activated Bid that would otherwise be insufficient for apoptosis. Such studies indicate how the adroit combination of differing proapoptotic and sublethal signals can provide an effective strategy for treating refractory tumors.

TNF-alpha is a key factor in a variety of inflammatory diseases. This study examines the role of p38 MAPK in the regulation of TNF-alpha in primary human cells relevant to inflammation, e.g., macrophages and rheumatoid synovial cells. Using a dominant negative variant (D168A) of p38 MAPK and a kinase inhibitor, SB203580, we confirm in primary human macrophages that p38 MAPK regulates TNF-alpha production using a posttranscriptional mechanism requiring the 3' untranslated region of the gene. However, in LPS-activated primary human macrophages we also detect a second previously unidentified mechanism, the p38 MAPK modulation of TNF-alpha transcription. This is mediated through p38 MAPK regulation of NF-kappaB. Interestingly this mechanism was not observed in rheumatoid synovial cells. Importantly however, the dominant negative mutant of p38 MAPK, but not SB203580 was effective at inhibiting spontaneous TNF-alpha production in these ex vivo rheumatoid synovial cell cultures. These data indicate there are potential major differences in the role of p38 MAPK in inflammatory signaling that have a bearing on the use of this kinase as a target for therapy. These results indicate despite disappointing results with p38 MAPK inhibitors in the clinic, this kinase is a valid target in rheumatoid disease.

Objective: To compare walking stance phase rearfoot and forefoot motion, ankle joint moments and extrinsic foot muscle EMG profiles between normal and pes planus feet., Design: A cross-sectional comparative study., Background: Musculoskeletal conditions are often attributed to pes planus, in which motion is assumed to be excessive and the muscle control inadequate. However, many of the speculated differences in mechanics and control between the normal and the pes planus foot have not been quantified., Methods: Kinematic and kinetic data were obtained from video recordings of skin surface markers and a force plate, and EMG was recorded with surface electrodes. Analysis of variance was carried out to compare the group profiles., Results: In the pes planus group: the forefoot was less adducted (P < .05) at toe-off, and total transverse plane range of motion, at 8 degrees versus 10 degrees, was less (P < .01); the peak plantarflexor ankle moment at push-off was greater (P < .05); the invertor moment was greater at foot flat (P < .05); for the EMG profiles, activity early in stance, relative to the mean stance phase activity was higher (P < .01) in tibialis anterior and lower (P < .05) in the peronei, soleus and medial and lateral gastrocnemius., Conclusions: Despite reaching statistical significance, the group differences were small for the task of laboratory walking at a natural pace. The main implications of the differences were for restraint of motion. The expectations of excessive motion and muscle effort in the pes planus group were therefore not substantiated., Relevance: Symptomatic pes planus subjects did not reveal the expected biomechanical differences from normal subjects. The underlying causes of symptoms were not identifiable.

Objective: The purpose of this study was to evaluate the effectiveness of 20 to 30 minutes per month of additional diet education on monthly laboratory values (phosphorus, calcium, parathyroid hormone, and calcium/phosphorus product) and knowledge of dietary phosphorus management in hemodialysis patients with hyperphosphatemia., Design: A quasi-experimental design., Setting: Three outpatient dialysis centers owned by the same corporation in 1 southern state., Patients: Based on a 3-month average serum phosphorus >6.0 mg/dL, 70 patients were selected for participation; 63 dialysis patients completed the study, 32 in the experimental group and 31 in the control group., Intervention: All patients completed a before-and-after knowledge test and had monthly blood samples drawn. Each month, the same registered dietitian provided the routine laboratory results review with control group. The experimental group received the routine laboratory review plus 20 to 30 minutes of additional diet education specifically targeting phosphorus. Main outcome measures Before-and-after knowledge test results and baseline and final serum calcium, phosphorus, parathyroid hormone, and calcium/phosphorus product levels., Results: At baseline, there were no significant differences in any of the laboratory values, but the knowledge level of the experimental group was greater (P <.05) After 6 months, gains in knowledge were significantly higher in the intervention group, and the serum phosphorus and calcium/phosphorus product levels were significantly lower (P <.01) than in the control group., Conclusion: Based on this research, those patients who received extra education monthly showed positive changes, which may be beneficial in reducing hyperphosphatemia.

p38 MAPK was originally characterized as a stress-induced kinase, along with JNK. Subsequently, p38 MAPK was found to be activated by stimuli other than cellular stress, such as growth factors and mitogens, like interleukin (IL)-2, IL-7 and IL-3. A notable exception was IL-4, as studies in mast cells showed no activation of p38 MAPK by this cytokine. In this study we show that the regulation of p38 MAPK is cell type dependent. Like other cytokines that signal through the gamma (gamma)(c), IL-4 can activate p38 MAPK in the CT6 T-cell line and BA/F3 pro-B-cells. However, IL-4 was unable to activate p38 MAPK in the murine macrophage cell line, RAW 264.7 and, indeed, prolonged exposure of cells to IL-4 results in suppression of LPS-induced MAPK activation. This result correlates with the well defined inhibitory effect of IL-4 on tumour necrosis factor alpha (TNFalpha) production. In contrast, studies in primary human monocytes showed that prolonged exposure to IL-4 resulted in enhanced activation of LPS-stimulated p38 MAPK; this correlated with an enhanced TNFalpha production. These data highlight the complexity of IL-4 signalling mechanisms, the diversity that can exist in the regulation of a given signalling pathway by a given cytokine and, furthermore, indicate the problems that can arise from extrapolation between different cell systems.

We examined whether exposure to polychlorinated biphenyls (PCBs) around puberty would produce hyperactivity and impulsiveness in adult Sprague-Dawley rats. Randomly assigned groups consumed food containing environmental concentrations of Aroclor 1248, PCB-contaminated St. Lawrence River carp, or corn oil (control). All received operant training to a final multiple (mult) 120-s, fixed interval (FI), 5-min extinction (EXT) schedule. Pressing rates of both exposed groups for drops of water averaged more than 1.5 times that of controls, especially toward the end of the 120-s interval. This overactivity included bursts with short (< or =0.5 s) interresponse times (IRTs), behavior characteristic of hyperactive boys and genetically hyperactive rats. The exposed groups also overreacted to the decreases in reinforcement density associated with transition to the final schedule. The results were interpreted in terms of the possible alterations in the animals' reinforcement mechanisms and the possible neurotoxic effects of PCB exposure.

The objectives of this study were to evaluate test characteristics, such as normality of distribution, variation, and repeatability, of simple fasting measures of insulin sensitivity and to use the results to choose among these measures. Duplicate fasting samples of insulin and glucose were collected before 4 h of euglycemic hyperinsulinemic clamping using insulin infusion rates ranging from 40-600 mU/m2 x min. Currently recommended estimates of insulin sensitivity, including the fasting insulin, 40/insulin, the homeostasis model assessment, the logarithmic transformation of the homeostasis model assessment, and the Quantitative Insulin Sensitivity Check Index, were evaluated. The normality of distribution and the variability of the tests (coefficient of variation and discriminant ratio) were compared between the measures and against the "gold standard" hyperinsulinemic clamp. Data from 253 clamp studies in 152 subjects were examined, including 79 repeated studies for repeatability analysis. In subjects ranging from lean to diabetic, the log transformed fasting measures combining insulin and glucose had normal distributions and test characteristics superior to the other simple indices (logarithmic transformation of the homeostasis model assessment coefficient of variation, 0.55; discriminant ratio, 13; Quantitative Insulin Sensitivity Check Index coefficient of variation, 0.05; discriminant ratio, 10) and statistically comparable to euglycemic hyperinsulinemic clamps (coefficient of variation, 0.10; discriminant ratio, 6.4). These favorable characteristics helped explain the superior correlations of these measures with the hyperinsulinemic clamps among insulin-resistant subjects. Furthermore, therapeutic changes in insulin sensitivity were as readily demonstrated with these simple measures as with the hyperinsulinemic clamp. The test characteristics of the logarithmic transformation of the homeostasis model assessment and the Quantitative Insulin Sensitivity Check Index are superior to other simple indices of insulin sensitivity. This helps explain their excellent correlations with formal measures both at baseline and with changes in insulin sensitivity and supports their broader application in clinical research.

Objective: To compare the magnitude and patterns of motion of the rearfoot segment relative to the leg, forefoot segment relative to the rearfoot, height change in the medial longitudinal arch and ground reaction forces of normal adult males during the stance phase of walking., Background: Knowledge of normal motion of the rearfoot and forefoot segments and of the arch during stance phase is important in clinical management., Methods: Motion data were obtained from surface markers, and force data from a force plate, from the right limb of participants while walking at a self-selected pace., Results: Stance phase range of motion across sagittal, frontal and transverse planes was 12 degrees, 4 degrees and 10 degrees for the forefoot, compared to 22 degrees, 8 degrees and 10 degrees for the rearfoot. Most motion occurred at the beginning and end of stance phase when support was via only the rearfoot or forefoot, and when forces were maximal. Arch height decreased from heel contact and increased after heel rise to its maximum at toe-off., Conclusions: The extent of forefoot segment motion confirms the significance of midfoot joints to normal foot function. Between foot flat and heel rise, the forefoot pattern of motion is indicative of foot stability. Typical foot motion does not obey descriptions of triplanar motion such as 'pronation' and 'supination'., Relevance: Typical stance phase foot motion has been described according to a forefoot:rearfoot model and rearfoot:leg model of motion, together with profiles of medial longitudinal arch height and ground reaction forces. This information can be applied in the management of foot dysfunction and should stimulate research into midfoot motion and overall control of the foot.

As part of a project of decrease fat, cholesterol, and sodium in soldiers' diets, new ethnic and breakfast items were developed and standardized for 100 portions. Acceptability data were collected after initial recipe development, during recipe validation at a collaborating university, and in an actual Army garrison. Acceptability was determined using a nine-point hedonic scale; products rating > or = 6.0 in initial tests were prepared in garrison. Acceptability data were compared among test settings, ethnic categories, and food type. When grouped by ethnic categories, acceptability ratings varied more than when grouped by food type. Ratings varied most between development and validation settings (7.2 vs. 6.6; p < 0.05) and least between validation and actual Army settings (6.6 vs. 6.6; not significant). Because acceptability ratings were similar between the validation site and the Army garrison, future recipe development may continue without additional testing at actual Army garrisons, leading to more timely armed forces recipe file additions.

This study examined stance phase foot kinematics, kinetics and electromyographic (EMG) activity of extrinsic muscles of 18 healthy males. Three-dimensional kinematic and kinetic data were obtained via video analysis of surface markers and a force plate. Ankle joint moments are described about orthogonal axes in a segmental coordinate system. Kinematic data comprise rearfoot and forefoot motion, described about axes of a joint coordinate system, and medial longitudinal arch height. Surface EMG was obtained for tibialis anterior, soleus, gastocnemius medialis and lateralis, peroneus longus and peroneus brevis and extensor digitorum longus. It was concluded that the demands on the controlling muscles are greatest prior to foot flat and after heel rise. Tibialis anterior restrained rearfoot plantarflexion from heel contact to 10% stance, and eversion between 10% stance and footflat. Activity in peroneus longus was consistent with its role in causing eversion after heel contact, then as a stabiliser of the forefoot after heel rise. Activity in peroneus brevis suggested a role in restraining lateral rotation of the leg over the foot, late in stance.

The aim of this study was to identify the melatonin receptor type(s) (MT(1) or MT(2)) mediating circadian clock resetting by melatonin in the mammalian suprachiasmatic nucleus (SCN). Quantitative receptor autoradiography with 2-[(125)I]iodomelatonin and in situ hybridization histochemistry, with either (33)P- or digoxigenin-labeled antisense MT(1) and MT(2) melatonin receptor mRNA oligonucleotide probes, revealed specific expression of both melatonin receptor types in the SCN of inbred Long-Evans rats. The melatonin receptor type mediating phase advances of the circadian rhythm of neuronal firing rate in the SCN slice was assessed using competitive melatonin receptor antagonists, the MT(1)/MT(2) nonselective luzindole and the MT(2)-selective 4-phenyl-2-propionamidotetraline (4P-PDOT). Luzindole and 4P-PDOT (1 nM-1 microM) did not affect circadian phase on their own; however, they blocked both the phase advances (approximately 4 h) in the neuronal firing rate induced by melatonin (3 pM) at temporally distinct times of day [i.e., subjective dusk, circadian time (CT) 10; and dawn, CT 23], as well as the associated increases in protein kinase C activity. We conclude that melatonin mediates phase advances of the SCN circadian clock at both dusk and dawn via activation of MT(2) melatonin receptor signaling.

Pyridinyl imidazole inhibitors, particularly SB203580, have been widely used to elucidate the roles of p38 mitogen-activated protein (MAP) kinase (p38/HOG/SAPKII) in a wide array of biological systems. Studies by this group and others have shown that SB203580 can have antiproliferative activity on cytokine-activated lymphocytes. However, we recently reported that the antiproliferative effects of SB203580 were unrelated to p38 MAP kinase activity. This present study now shows that SB203580 can inhibit the key cell cycle event of retinoblastoma protein phosphorylation in interleukin-2-stimulated T cells. Studies on the proximal regulator of this event, the phosphatidylinositol 3-kinase/protein kinase B (PKB)(Akt/Rac) kinase pathway, showed that SB203580 blocked the phosphorylation and activation of PKB by inhibiting the PKB kinase, phosphoinositide-dependent protein kinase 1. The concentrations of SB203580 required to block PKB phosphorylation (IC(50) 3-5 microM) are only approximately 10-fold higher than those required to inhibit p38 MAP kinase (IC(50) 0.3-0.5 microM). These data define a new activity for this drug and would suggest that extreme caution should be taken when interpreting data where SB203580 has been used at concentrations above 1-2 microM.

Clinicians commonly assess static alignment of the foot with the assumption that it is predictive of its movement during walking and the risk of injury. This study investigated the relationship between clinical measures of calcaneal deviation and medial arch angle in standing and three-dimensional rearfoot movement during the stance phase of walking in 19 young healthy males. Correlations were performed among the variables of maximum eversion, maximum abduction, the range of inversion-eversion and the range of abduction-adduction. The only significant correlation was between calcaneal deviation and maximum eversion (r = 0.46, p < 0.05). We concluded that the static measures of calcaneal deviation and medial arch angle are limited in their ability to predict three-dimensional rearfoot movement during walking in asymptomatic people.

We have shown recently that interleukin (IL)-2 activates the mitogen-activated protein (MAP) kinase family members p38 (HOG1/stress-activated protein kinase II) and p54 (c-Jun N-terminal kinase/stress-activated protein kinase I). Furthermore, the p38 MAP kinase inhibitor SB203580 inhibited IL-2-driven T cell proliferation, suggesting that p38 MAP kinase might be involved in mediating proliferative signals. In this study, using transfected BA/F3 cell lines, it is shown that both the acidic domain and the membrane-proximal serine-rich region of the IL-2Rbeta chain are required for p38 and p54 MAP kinase activation and that, as for p42/44 MAP kinase, this activation requires the Tyr338 residue of the acidic domain, the binding site for Shc. It is well established that the acidic domain of the IL-2Rbeta chain is dispensable for IL-2-driven proliferation, and thus our observations suggest that neither p38 nor p54 MAP kinase activation is required for IL-2-driven proliferation of BA/F3 cells. In addition, the tetravalent guanylhydrazone inhibitor of proinflammatory cytokine production, CNI-1493, can block the activation of p54 and p38 MAP kinases by IL-2 but has no effect on IL-2-driven proliferation of BA/F3 cells, activated primary T cells, or a cytotoxic T cell line. Furthermore, our observations provide evidence for the existence of an additional, unknown target of the p38 MAP kinase inhibitor SB203580, the activation of which is essential for mitogenic signaling by IL-2.

Recently, educational policymakers have emphasized the need for undergraduate programs to develop in their graduates generic skills and attributes beyond discipline-specific skills and knowledge. The generic skills and attributes should mesh with the requirements of the workplaces where the graduates will find employment. The present study examined the impact of curricular revisions to a program of study for speech pathologists on the perceptions of the graduates regarding their preparation in appropriate skill and knowledge domains. The curricular revisions sought to develop independent learning, critical thinking, research and evaluation skills, written and oral communication skills, and skills for seeking and providing support to peers. Seventy-eight graduates of the earlier program and 21 graduates of the revised program offered by the School of Communication Disorders at The University of Sydney completed a 52-item questionnaire concerning the extent to which the program had equipped them for the workplace. Eleven scales were derived from the questionnaire responses, reflecting skills endorsed by university educators and workplace supervisors of allied health professionals as being necessary for success in the workplace. The relative levels of perceived preparation on the 11 dimensions were similar across graduates of the revised program and those of the earlier program. Graduates of the revised program were significantly more positive about their preparation on five of the 11 dimensions, compared with earlier graduates of approximately equivalent age and experience. The dimensions where differences were observed generally reflected those targeted by the curricular revisions.

The research reported in this article was undertaken to assess the perceptions of health science graduates in the fields of health information management, occupational therapy, orthoptics, physiotherapy, and speech pathology regarding their perceptions of the adequacy of undergraduate preparation in meeting the demands of a changing health care environment. An instrument was devised for use by graduates on the basis of the skills and workplace behaviours specified by experienced practitioners in the above fields as necessary in newly recruited graduates. A total of 527 health science graduates completed the 52 item instrument. The statistical analyses indicated that 11 factors define the adequacy of graduates' preparation for the workplace. Health science graduates perceived themselves to have been more thoroughly prepared on certain workplace dimensions than on others. Specifically, graduates perceived themselves to be ill-equipped on dimensions concerned with workplace management, knowledge of the health industry, and coping in the workplace. Graduates also perceived themselves to be inadequately prepared in terms of communicating with clients, health professionals, and the general public. The strengths of their courses were perceived to be in completing essential tasks, having confidence in the clinical role, in ethical practice, in pursuit and application of knowledge, and having a realistic expectation of the workplace role. The results are discussed in terms of the need to address curriculum changes.

Nocturnal synthesis of the pineal hormone melatonin (MEL) is regulated by the circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. We examined the hypothesis that MEL can feed back to regulate the SCN using a brain slice preparation from rat. We monitored the SCN ensemble firing rate and found that MEL advanced the time of peak firing rate by more than 3 h at restricted circadian times (CTs) near subjective dusk [CT 10-14 (10-14 h after lights on)] and dawn (CT 23-0) on days 2 and 3 after treatment. The effect of MEL at CT 10 was blocked by pertussis toxin. The protein kinase C (PKC) activator, 12-O-tetradecanoylphorbol 13-acetate, reset the SCN firing rate rhythm with a profile of temporal sensitivity congruent with that of MEL. Two specific PKC inhibitors, calphostin C and chelerythrine chloride, independently blocked MEL-induced phase advances at each sensitive period. Furthermore, MEL administration increased PKC phosphotransferase activity transiently to 200% at CT 10 and CT 23, but not at CT 6. These data demonstrate that 1) MEL can directly modulate the circadian timing of the SCN within two windows of sensitivity corresponding to dusk and dawn; and 2) MEL alters SCN cellular function via a pertussis toxin-sensitive G protein pathway that activates PKC.

The response times of 17 introverts and 24 extroverts to red and blue stimulus lights were compared. While no differences were found between the groups, introverts responded faster to the presentation of the red stimulus light than the blue one.

Some mute swans have been found to have higher levels of radio-iodine in their thyroids than farm and wildlife animals. In the East Midlands of the U.K., elevated levels were confined to swans inhabiting major rivers like the Trent and Soar where the highest values occurred in thyroids collected downstream from sewage and water reclamation works. Comparing the concentrations of 125I and 131I in blanket weed, which is a food source of the swan, and river water samples collected from above, below and in such effluents, showed that radio-iodine enters the river via these routes. The environmental pathway is sewage effluent--(water reclamation)--river water--river weed--swan. The radioactivity originates from the widespread use of radio-iodine in hospitals and analytical laboratories where much of the liquid and soluble waste is discarded into the sewage drain system. With a simple counting assembly consisting of a heavily shielded thin NaI(Tl) crystal detector attached to a 2-channel scaler-timer it was possible to check large numbers of swan thyroid glands. Although relatively high count rates were frequently obtained the levels of radio-iodine in thyroids were too low to affect the health and well-being of the swan.

Serum copper values were determined on composite samples from cattle herds in the Midland counties of Derbyshire, Leicestershire and Nottinghamshire. Sampling took place over a period of 17 months and the results indicate that hypocupraemia existed in many herds. The lowest values were found in heifer group samples and the lowest of these was found in Derbyshire. The geographical and management factors which may affect the copper status of herds in this area are discussed.

We evaluated the vestibulo-ocular reflex (VOR) in 50 normal human subjects, uniformly distributed in age 20-59 years, and evenly distributed in sex by decade, using sinusoidal rotation over the frequency range of 0.005 to 1.0 Hz and three peak amplitudes of 25, 50, and 100 deg/sec. Age variations. The gain magnitude of the normal human VOR appears to decrease with increasing age. This trend becomes statistically significant at p less than 0.05 for the 0.005 and 0.01 Hz test points. Sex-related variations. There were no statistically significant differences in gain magnitude between the sexes but females had higher average gains than males for the lowest test frequencies. The phase data showed a trend with the average phase points for females being less than those for males. This difference was statistically significant at p less than 0.05 for the 0.005 Hz test frequency. Dynamic range. Increasing the stimulus amplitude by a factor of four yielded a small but statistically significant decrease in gain magnitude, thus suggesting a mild saturation-type of nonlinearity.