Cellular learning theory: theoretical comment on Cole and McNally (2007)

The idea that learning proceeds as a function of the discrepancy (or error) between expected and obtained outcomes is central to many theories of associative learning. However, remarkably little is known about the neurobiological mechanisms that underlie this learning of predictive errors in fear conditioning, a widely used preparation in studies of cellular and molecular mechanisms of memory. In this issue of Behavioral Neuroscience, S. Cole and G. P. McNally demonstrate an important dissociation between the establishment and regulation of predictive error at the cellular level. Their findings have added a level of complexity to currently established views of the function of NMDA and opioid receptors in learning and memory. This commentary discusses some of the implications of these findings for theoretical and neurobiological approaches to memory, as well as current thinking about the cellular circuitry involved in reward learning and drug abuse.     

Synapses, circuits, and the ontogeny of learning

This article summarizes the proceedings of a symposium organized by Mark Stanton and Pamela Hunt and presented at the annual meeting of the International Society for Developmental Psychobiology. The purpose of the symposium was to review recent advances in neurobiological and developmental studies of fear and eyeblink conditioning with the hope of discovering how neural circuitry might inform the ontogenetic analyses of learning and memory, and vice versa. The presentations were: (1) Multiple Brain Regions Contribute to the Acquisition of Pavlovian Fear by Michael S. Fanselow; (2) Expression of Learned Fear: Appropriate to Age of Training or Age of Testing by Rick Richardson; (3) Trying to Understand the Cerebellum Well Enough to Build One by Michael D. Mauk; and (4) The Ontogeny of Eyeblink Conditioning: Neural Mechanisms by John H. Freeman. Taken together, these presentations converge on the conclusions that (1) seemingly simple forms of associative learning are governed by multiple "engrams" and by temporally dynamic interactions among these engrams and other circuit elements and (2) developmental changes in these interactions determine when and how learning emerges during ontogeny.     

The Use of Magnetic Resonance Imaging for Non-Invasive Assessment of Venofer® Biodistribution in Rats

Purpose

The aim of this study was to determine the potential of magnetic resonance imaging to evaluate the biodistribution of exogenous iron within 24 h after one single injection of Venofer® (iron sucrose).

Methods

Venofer® was evaluated in vitro for its ability to generate contrast in MR images. Subsequently, iron disposition was assessed in rats with MRI, in vivo up to 3 h and post mortem at 24 h after injection of Venofer®, at doses of 10- and 40 mg/kg body weight (n?=?2?×?4), or saline (n?=?4).

Results

Within 10–20 min after injection of Venofer®, transverse relaxation rates (R₂) clearly increased, representative of a local increase in iron concentration, in liver, spleen and kidney, including the kidney medulla and cortex. In liver and spleen R₂ values remained elevated up to 3 h post injection, while the initial R₂ increase in the kidney was followed by gradual decrease towards baseline levels. Bone marrow and muscle tissue did not show significant increases in R₂ values. Whole-body post mortem MRI showed most prominent iron accumulation in the liver and spleen at 24 h post injection, which corroborated the in vivo results.

Conclusions

MR imaging is a powerful imaging modality for non-invasive assessment of iron distribution in organs. It is recommended to use this whole-body imaging approach complementary to other techniques that allow quantification of iron disposition at a (sub)cellular level.

     

Assessing exclusionary power of a paternity test involving a pair of alleged grandparents

BACKGROUND: The power of a genetic test battery to exclude a pair of individuals as grandparents is an important consideration for parentage testing laboratories. However, a reliable method to calculate such a statistic with short-tandem repeat (STR) genetic markers has not been presented. STUDY DESIGN AND METHODS: Two formulae describing the random grandparents not excluded (RGPNE) statistic at a single genetic locus were derived: RGPNE = a(4 - 6a + 4a(2)- a(3)) when the paternal obligate allele (POA) is defined and RGPNE = 2[(a + b)(2 - a - b)][1 - (a + b)(2 - a - b)] + [(a + b)(2 - a - b)] when the POA is ambiguous. A minimum number of genetic markers required to yield cumulative RGPNE values of not greater than 0.01 was calculated with weighted average allele frequencies of the CODIS STR loci. RGPNE data for actual grandparentage cases are also presented to empirically examine the exclusionary power of routine casework. RESULTS: A comparison of RGPNE and random man not excluded (RMNE) values demonstrates the increased difficulty involved in excluding two individuals as grandparents compared to excluding a single alleged parent. A minimum of 12 STR markers is necessary to achieve RGPNE values of not greater than 0.01 when the mother is tested; more than 25 markers are required without the mother. Cumulative RGPNE values for each of 22 nonexclusionary grandparentage cases were not more than 0.01 but were significantly weaker when calculated without data from the mother. CONCLUSION: Calculation of the RGPNE provides a simple means to help minimize the potential of false inclusions in grandparentage analyses. This study also underscores the importance of testing the mother when examining the parents of an unavailable alleged father (AF).     

Septal myectomy after previous septal artery ablation in hypertrophic cardiomyopathy

OBJECTIVE: To review our institution's experience with patients who failed to benefit from septal artery ablation, which necessitated subsequent septal myectomy, and to examine reasons for ablation failure and outcome of myectomy after ablation. PARTICIPANTS AND METHODS: Of 550 patients who underwent septal myectomy at Mayo Clinic Rochester between January 1, 1999, and December 31, 2006, 16 (3%) had had a total of 22 previous septal artery ablations. This subset of 16 patients was analyzed and compared with a reference group of 120 patients whose septal artery ablations were performed at our institution during this period. Angiograms obtained during septal ablation were available for 13 (81%) of 16 patients in this series and were reviewed by 2 interventional cardiologists (R.A.N. and S.R.O.). These cardiologists also reviewed preoperative and postoperative echocardiography data, hospital course, and follow-up data to compile a list of characteristics that could have contributed to failed ablation. RESULTS: The median age of the patients at operation was 65 years (interquartile range [IQR], 52-72 years), and interval between ablation and myectomy was 409 days (IQR, 162-568 days). Angiograms revealed 2 failed procedures secondary to technical error. One patient had a relatively large first septal perforator with a large resting gradient. In 10 patients no septal perforators supplying the proximal septum were identified. Postoperatively, mitral regurgitation decreased from 3.00 to 1.00 (P less than .001), and left ventricular outflow tract gradient decreased from 75 mm Hg to 0 mm Hg (IQR, 0-29 mm Hg; P less than .001). Two patients died after surgery: 1 patient developed multiple-organ system failure on postoperative day 7, and 1 patient developed arrhythmia on postoperative day 21. Patients with previous septal artery ablation were older (P=.04), were more likely to have preoperative permanent pacemakers or implantable cardioverter-defibrillators (P=.05), were more likely to require postoperative pacemaker placement (P less than .001), and had higher operative mortality (P less than .001) than control patients. Fourteen patients survived the early recovery phase; 9 were followed up at a median of 1.88 years (IQR, 306 days to 3.3 years). All patients' symptoms improved. Median gradient of the left ventricular outflow tract was 13 mm Hg (IQR, 0-15 mm Hg) at follow-up with mild to moderate (1.6) mitral regurgitation. CONCLUSION: Septal myectomy performed after failed ablation improves gradient and provides excellent relief of symptoms but is associated with a higher incidence of morbidity and mortality.     

Management of Locally Recurrent Retroperitoneal Sarcoma in the Adult: An Updated Consensus Approach from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group

Annals of Surgical Oncology - Surgery is the mainstay of treatment for retroperitoneal sarcoma (RPS), but local recurrence is common. Biologic behavior and recurrence patterns differ significantly...     

Dynamic Nature of the p75 Neurotrophin Receptor in Response to Injury and Disease

Neurotrophins and their respective tropomyosin related kinase (Trk) receptors (TrkA, TrkB, and TrkC) and the p75 neurotrophin receptor (p75^NTR) play a fundamental role in the development and maintenance of the nervous system making them important targets for treatment of neurodegenerative diseases. Whereas Trk receptors are directly activated by specific neurotrophins, the p75^NTR is a multifunctional receptor that exerts its effects via heterodimeric interactions with TrkA, TrkB, TrkC, sortilin or the Nogo receptor to regulate a wide array of cellular functions. By partnering with different receptors the p75^NTR regulates binding of mature versus pro-neurotrophins and activation of different signaling pathways with outcomes ranging from growth and survival to cell death. While the developmental downregulation of the p75^NTR has raised questions regarding its role in the mature nervous system, recent data have revealed widespread expression of low levels, a role in synaptic plasticity and adult neurogenesis and upregulation in response to injury or disease. Studies are needed to better understand these processes, particularly in the damaged nervous system, but will be complicated by expression of p75^NTR on immune cells including macrophages and microglia that are intimately involved in disease and repair processes. Recent approaches that regulate p75^NTR function with small non-peptide ligands have demonstrated potent neuroprotection in models of injury and neurodegenerative diseases that highlight the importance of the p75^NTR as a therapeutic target. Future studies hold the promise of revealing a wealth of information on the multifaceted actions of the p75^NTR that will inform the design of new neurotrophin-based therapies.