A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage

Inhibition of the ternary protein complex of the synaptic scaffolding protein postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS), and the N-methyl-D-aspartate (NMDA) receptor is a potential strategy for treating ischemic brain damage, but high-affinity inhibitors are lacking. Here we report the design and synthesis of a novel dimeric inhibitor, Tat-NPEG4(IETDV)(2) (Tat-N-dimer), which binds the tandem PDZ1-2 domain of PSD-95 with an unprecedented high affinity of 4.6 nM, and displays extensive protease-resistance as evaluated in vitro by stability-measurements in human blood plasma. X-ray crystallography, NMR, and small-angle X-ray scattering (SAXS) deduced a true bivalent interaction between dimeric inhibitor and PDZ1-2, and also provided a dynamic model of the conformational changes of PDZ1-2 induced by the dimeric inhibitor. A single intravenous injection of Tat-N-dimer (3 nmol/g) to mice subjected to focal cerebral ischemia reduces infarct volume with 40% and restores motor functions. Thus, Tat-N-dimer is a highly efficacious neuroprotective agent with therapeutic potential in stroke.     

Body mass index in male and female children with pervasive developmental disorders

Background: The aim of the present study was to evaluate body mass index (BMI) of children with a pervasive developmental disorder (PDD) attending two university clinics during the 1960–84 period.
Methods: BMI derived from medical records of 83 consecutively admitted children with atypical autism and 115 children with Asperger syndrome were compared with the corresponding BMI percentiles in an age- and sex-matched reference population.
Results: The BMI distribution of the boys, but not the girls, in both diagnostic categories was significantly lower than those of the age-matched reference populations. Approximately 15% of the boys had a BMI below the fifth percentile.
Conclusions: The present findings are comparable to the results of other studies. Particular attention is given to low BMI as a potential endophenotype in boys with PDD.     

Diagnosing dental caries in populations with different levels of dental fluorosis

The aim of this study was to assess the reliability of the Nyvad visual–tactile caries-diagnostic criteria when used among children who have been lifelong residents in areas with 'optimal' or low concentrations of fluoride in the drinking water. In each of two areas with drinking water fluoride concentrations of 0.3 and 1.1 ppm (0.3 and 1.1 mg/l) fluoride, respectively, 150 children were clinically examined twice, 2 wk apart, for dental fluorosis, using the Thylstrup-Fejerskov index (TF index), and for dental caries using the Nyvad visual–tactile caries criteria. The prevalence of dental fluorosis was 45% in the 1.1 ppm fluoride area and 21% in the 0.3 ppm fluoride area. When the results of the duplicate caries recordings were compared at the surface level, only minute differences were observed in the percentage agreement (91.7 and 90.7%, respectively) and in the kappa values (0.73 and 0.72, respectively). When individual DFS counts were compared across examinations using Bland–Altman plots and estimation of prediction intervals for the differences, we observed a greater variability of the differences between recordings among children from the low-fluoride area. Contrary to our expectations, a pronounced dental fluorosis background did not reduce the reliability of the caries recordings, which appeared to be slightly less reliable at very low levels of dental fluorosis.     

IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin

Hypoferremia is a common response to systemic infections or generalized inflammatory disorders. In mouse models, the development of hypoferremia during inflammation requires hepcidin, an iron regulatory peptide hormone produced in the liver, but the inflammatory signals that regulate hepcidin are largely unknown. Our studies in human liver cell cultures, mice, and human volunteers indicate that IL-6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL-6-hepcidin axis is responsible for the hypoferremia of inflammation.     

Challenges in community health nursing of old migrant patients in Norway - an exploratory study

Old people of non-western minority backgrounds are an invisible group in Norway in several ways: in the national debate about the ageing population, in geriatric health care services, and in the general picture of ethnic minorities. There is a lack of knowledge about health and care amongst old migrants. This study aimed at exploring nurse managers' perceptions of the content of community health nursing care of older people from non-western countries of origin, and the challenges associated with caring for this group of patients. The study took place in a medium-sized Norwegian community, a mostly urban area with surrounding rural areas. The community health nursing system was organized in six districts with nurses in management positions, covering nursing homes, special housing and home-based care. Data were collected by a questionnaire with structured and open-ended questions answered by 18 nurse managers. The data provided scarce information, but indicated a lack of systematic cultural care assessments. Community health nursing of old non-western migrant patients was described as deficient and a demanding burden. The challenges were captured in four themes: language barriers, family involvement in care, deficiencies in cultural competency and the need for development. Increased competency, action and local responsibility were identified as propositions to manage the challenges. The lack of awareness and knowledge concerning cultural issues found in this study highlights the need for further development and research on this topic.     

The Expression of IL-6 by Osteoblasts Is Increased in Healthy Elderly Individuals: Stimulated Proliferation and Differentiation Are Unaffected by Age

Increasing age is associated with reduced bone mineral content and increased risk of fractures. This is caused by a relative insufficiency of osteoblasts compared with osteoclasts. We therefore wanted to examine the potential differences in proliferation, differentiation, and expression of cytokines between human osteoblasts (hOBs) obtained from young and elderly individuals. Cultures of hOBs were obtained from 11 elderly (73–85 years) and 15 young (21–27 years) healthy individuals. The cells were stimulated with hGH, IGF-I, hGH + IGF-I, and TGF-β1. Proliferation was evaluated by thymidine incorporation, and differentiation was evaluated by alkaline phosphatase, OPG, and PINP production. Expression of IL-6, TGF-β1, OPG, and RANKL was investigated using real-time PCR and three carefully selected housekeeping genes. Combined stimulation with hGH and IGF-I increased proliferation without differences between hOBs obtained from young and elderly individuals. hOBs from young individuals responded to stimulation with vitamin D with a more pronounced increase in alkaline phosphatase: 107 ± 17% vs. 43 ± 5%, P < 0.01. Stimulation with TGF-β1 decreased OPG production by hOBs from elderly individuals but not from young individuals, P < 0.05. hOBs from elderly individuals expressed significantly higher amounts of IL-6 mRNA (P < 0.05) and less OPG and TGF-β1 mRNA (P = 0.08 and P = 0.08, respectively) compared with hOBs from young individuals. In conclusion, hOBs from elderly individuals express more IL-6 mRNA and less OPG and TGF-β1 mRNA than hOBs from young individuals. This could partly explain the reduced bone mass and increased fracture risk seen in the elderly. hOBs from young and elderly individuals responded similarly to short-term stimulation of proliferation and differentiation.     

Strontium and Bone Nanostructure in Normal and Ovariectomized Rats Investigated by Scanning Small-Angle X-Ray Scattering

The effect of SrCl₂ treatment on bone nanostructure in a rat ovariectomy model was studied using scanning small-angle X-ray scattering (sSAXS). Twelve 6-month-old female Wistar rats were used. Six animals were ovariectomized (+ovx) and six were left intact after sham surgery (−ovx). Six animals, three +ovx and three −ovx, were treated with 4 mmol SrCl₂ (aq)/kg/day (+Sr), whereas the remaining six received placebo (−Sr) for 140 days. Rats were labeled with flourochromes at days 7, 126, and 136. Femoral cross sections were studied using fluorescence microscopy, scanning electron microscopy including energy-dispersive X-ray analysis, and sSAXS. The SAXS data comprised about 5,500 measurements and provided information about mineral crystal thickness and orientation in new and old bone. The newly formed bone contained higher levels of Sr²⁺ in +Sr than in −Sr animals, indicating that the Sr²⁺ was incorporated into the new bone. Mineral plates were significantly thicker in old bone, 2.62 nm (95% CI 2.58–2.66), than in new bone, 2.41 nm (95% CI 2.36–2.46). Surprisingly, mineral plates in new bone were significantly thicker (2.52 [95% CI 2.47–2.57] nm vs. 2.41 [95% CI 2.36–2.46] nm, P = 0.017) in +ovx rats than in −ovx rats. However, no significant effect of SrCl₂ on mineral plate thicknesses in new bone was observed. The statistical model yielded estimates of the difference in bone mineral plate thickness induced by Sr. The estimated effect of Sr was −0.09 (95% CI −0.21 to 0.03) and 0.02 (95% CI −0.10 to 0.14) nm for new bone in −ovx and +ovx rats, respectively.     

Change processes in residential cognitive therapy for bulimia nervosa

The purpose of the study was to examine the relationships of process variables derived from the cognitive model of bulimia nervosa (BN) and weekly outcome. The participants were 39 patients with BN or subthreshold bulimia consecutively admitted to an inpatient treatment program for bulimia. Theory‐derived process and outcome variables were measured repeatedly during the course of therapy with a gap of a week between each measurement. The data were analysed with time series methods (ARIMA). Weekly variations in the process variables: self‐efficacy about resisting binge eating, dysfunctional beliefs, negative affect and positive affect influenced variations in subsequent outcome, whereas weekly outcome did not influence subsequent process. These results are consistent with the cognitive model of BN and suggest that self‐efficacy, dysfunctional beliefs, negative affect and positive affect are potential targets for treatment that need further investigation. Copyright © 2010 John Wiley & Sons, Ltd and Eating Disorders Association.