Evidence for phosphorylation of pancreatic islet pyruvate kinase

Rabbit pancreatic islet cytosol catalyzes the calcium-activated phosphorylation by [gamma 32P]ATP of a protein with a molecular weight of 57,000 that is precipitated with antipyruvate kinase antibodies. We were unable to demonstrate that phosphorylation in the presence of calcium or cAMP had any immediate effect on rat pancreatic islet pyruvate kinase activity. This finding is consistent with our inability to confirm the finding of others that pancreatic islets contain phosphoenolpyruvate carboxykinase activity (Diabetes, 34:246, 1985). Since the carboxykinase catalyzes phosphoenolpyruvate formation and pyruvate kinase catalyzes essentially the opposite reaction, if the carboxykinase were present in the beta cell, pyruvate kinase would need to be inhibited to prevent recycling of phosphoenolpyruvate.     

Blockade of Glutamate Receptors and Barbiturate Anesthesia: Increased Sensitivity to Pentobarbital-induced Anesthesia Despite Reduced Inhibition of AMPA Receptors in GluR2 Null Mutant Mice

Background: Barbiturates enhance [gamma]-aminobutyric acid type A (GABAA) receptor function and also inhibit the [alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of glutamate receptor. The relative contribution of these actions to the behavioral properties of barbiturates is not certain. Because AMPA receptor complexes that lack the GluR2 subunit are relatively insensitive to pentobarbital inhibition, GluR2 null mutant mice provide a novel tool to investigate the importance of AMPA receptor inhibition to the anesthetic effects of barbiturates.

Methods: GluR2 null allele (-/-), heterozygous (+/-), and wild-type (+/+) mice were injected with pentobarbital (30 and 35 mg/kg intraperitoneally). Sensitivity to anesthetics was assessed by measuring the latency to loss of righting reflex, sleep time, and the loss of corneal, pineal, and toe-pinch withdrawal reflexes. In addition, patch-clamp recordings of acutely dissociated CA1 hippocampal pyramidal neurons from (-/-) and (+/+) mice were undertaken to investigate the effects of barbiturates on kainate-activated AMPA receptors and GABA-activated GABAA receptors.

Results: Behavioral tests indicate that sensitivity to pentobarbital was increased in (-/-) mice. In contrast, AMPA receptors from (-/-) neurons were less sensitive to inhibition by pentobarbital (concentrations that produced 50% of the maximal inhibition [IC50], 301 vs. 51 [mu]M), thiopental (IC50, 153 vs. 34 [mu]M), and phenobarbital (IC50, 930 vs. 205 [mu]M) compared with wild-type controls, respectively. In addition, the potency of kainate was greater in (-/-) neurons, whereas no differences were observed for the potentiation of GABAA receptors by pentobarbital.     

Periacetabular osteotomy in the treatment of neurogenic acetabular dysplasia

We carried out the Bernese periacetabular osteotomy for the treatment of 13 dysplastic hips in 11 skeletally mature patients with an underlying neurological diagnosis. Seven hips had flaccid paralysis and six were spastic. The mean age at the time of surgery was 23 years and the mean length of follow-up was 6.4 years. Preoperatively, 11 hips had pain and two had progressive subluxation. Before operation the mean T?nnis angle was 33 degrees, the mean centre-edge angle was -10 degrees, and the mean extrusion index was 53%. Postoperatively, they were 8 degrees, 25 degrees and 15%, respectively. Pain was eliminated in 7 patients and reduced in four in those who had preoperative pain. One patient developed pain secondary to anterior impingement from excessive retroversion of the acetabulum. Four required a varus proximal femoral osteotomy at the time of the pelvic procedure and one a late varus proximal femoral osteotomy for progressive subluxation. Before operation no patient had arthritis. At the most recent follow-up one had early arthritis of the hip (T?nnis grade I) and one had advanced arthritis (T?nnis grade III). Our results suggest that the Bernese periacetabular osteotomy can be used successfully to treat neurogenic acetabular dysplasia in skeletally mature patients.     

A novel <Emphasis Type="Italic">KCNA1</Emphasis> mutation in a family with episodic ataxia and malignant hyperthermia

Episodic ataxia type 1 (EA1) is an autosomal dominant channelopathy caused by mutations in KCNA1, which encodes the voltage-gated potassium channel, Kv1.1. Eleven members of an EA family were evaluated with molecular and functional studies. A novel c.746T>G (p.Phe249Cys) missense mutation of KCNA1 segregated in the family members with episodic ataxia, myokymia, and malignant hyperthermia susceptibility. No mutations were found in the known malignant hyperthermia genes RYR1 or CACNA1S. The Phe249Cys-Kv1.1 channels did not show any currents upon functional expression, confirming a pathogenic role of the mutation. Malignant hyperthermia may be a presentation of KCNA1 mutations, which has significant implications for the clinical care of these patients and illustrates the phenotypic heterogeneity of KCNA1 mutations.     

Selective attrition and intraindividual variability in response time moderate cognitive change

Objectives: Selection of a developmental time metric is useful for understanding causal processes that underlie aging-related cognitive change and for the identification of potential moderators of cognitive decline. Building on research suggesting that time to attrition is a metric sensitive to non-normative influences of aging (e.g., subclinical health conditions), we examined reason for attrition and intraindividual variability (IIV) in reaction time as predictors of cognitive performance. Method: Three hundred and four community dwelling older adults (64–92 years) completed annual assessments in a longitudinal study. IIV was calculated from baseline performance on reaction time tasks. Multilevel models were fit to examine patterns and predictors of cognitive change. Results: We show that time to attrition was associated with cognitive decline. Greater IIV was associated with declines on executive functioning and episodic memory measures. Attrition due to personal health reasons was also associated with decreased executive functioning compared to that of individuals who remained in the study. Discussion: These findings suggest that time to attrition is a useful metric for representing cognitive change, and reason for attrition and IIV are predictive of non-normative influences that may underlie instances of cognitive loss in older adults.     

Threat-related amygdala functional connectivity is associated with 5-HTTLPR genotype and neuroticism

Communication between the amygdala and other brain regions critically regulates sensitivity to threat, which has been associated with risk for mood and affective disorders. The extent to which these neural pathways are genetically determined or correlate with risk-related personality measures is not fully understood. Using functional magnetic resonance imaging, we evaluated independent and interactive effects of the 5-HTTLPR genotype and neuroticism on amygdala functional connectivity during an emotional faces paradigm in 76 healthy individuals. Functional connectivity between left amygdala and medial prefrontal cortex (mPFC) and between both amygdalae and a cluster including posterior cingulate cortex, precuneus and visual cortex was significantly increased in 5-HTTLPR S′ allele carriers relative to L_AL_A individuals. Neuroticism was negatively correlated with functional connectivity between right amygdala and mPFC and visual cortex, and between both amygdalae and left lateral orbitofrontal (lOFC) and ventrolateral prefrontal cortex (vlPFC). Notably, 5-HTTLPR moderated the association between neuroticism and functional connectivity between both amygdalae and left lOFC/vlPFC, such that S′ carriers exhibited a more negative association relative to L_AL_A individuals. These findings provide novel evidence for both independent and interactive effects of 5-HTTLPR genotype and neuroticism on amygdala communication, which may mediate effects on risk for mood and affective disorders.     

ACR appropriateness criteria(®) ductal carcinoma in situ

Abstract: Ductal carcinoma in situ (DCIS) describes a wide spectrum of non‐invasive tumors which carry a significant risk of invasive relapse, thus prevention of local recurrence is vital. For appropriate patients with limited disease, management with breast conserving surgery (BCS) followed by whole‐breast radiation (RT) is supported by multiple Phase III studies, but mastectomy may be appropriate in selected patients. Omission of RT may also be reasonable in some patients, though which criteria are to be utilized remain unclear, and the existing data are contradictory with limited follow‐up. Various RT techniques such as boost to the tumor bed, partial breast radiation or hypofractionated, whole‐breast RT are increasingly utilized but the data to support their use specifically in DCIS is limited. Tamoxifen also increases local control for ER + DCIS, adding to the complexity of the local treatment management. This article reviews the existing scientific evidence, the controversies surrounding local management, and clinical guidelines for DCIS based on the group consensus by the ACR Breast Expert Panel. The American College of Radiology Appropriateness Criteria are evidence‐based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer‐reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.     

In Vivo Oxidation and Surface Damage in Retrieved Ethylene Oxide-sterilized Total Knee Arthroplasties

Background

Gas sterilization (eg, ethylene oxide [EtO] and gas plasma) was introduced for polyethylene to reduce oxidation due to free radicals occurring during radiation sterilization. Recently, oxidation has been observed in polyethylenes with undetectable levels of free radicals, which were expected to be oxidatively stable. It is unclear whether in vivo oxidation will occur in unirradiated inserts sterilized with EtO.

Questions/purposes

Methods

We collected 20 EtO-sterilized tibial inserts at revision surgeries. We assessed oxidative using Fourier transform infrared spectroscopy and mechanical properties using the small punch test. Surface damage was assessed using damage scoring techniques and micro-CT.

Results

Oxidation indexes were low and uniform between the regions. The subtle changes did not affect the mechanical properties of the polymer. The dominant surface damage modes included burnishing, abrasion, and third-body wear. There was no evidence of delamination in the retrievals.

Conclusions

The retrieved EtO-sterilized UHMWPE retrievals remained stable with respect to both oxidative and mechanical properties for up to 10 years in vivo. We did observe slight measurable amounts of oxidation in the inserts; however, it was far below levels that would be expected to compromise the strength of the polymer.

Clinical Relevance

Due to the stable oxidative and mechanical properties, EtO-sterilized tibial components appear to be an effective alternative to gamma-sterilized inserts, at least in short-term implantations.