PET imaging of acetylcholinesterase inhibitor‐induced effects on α4β2 nicotinic acetylcholine receptor binding

Acetylcholinesterase inhibitors (AChEIs) are drugs that increase synaptic acetylcholine (ACh) concentrations and are under investigation as treatments for symptoms accompanying Alzheimer's disease. The goal of this work was to use PET imaging to evaluate alterations of in vivo α4β2 nicotinic acetylcholine receptor (nAChR) binding induced by the AChEIs physostigmine (PHY) and galanthamine (GAL). The α4β2 nAChR‐specific radioligand [¹⁸F]nifene was used to examine the effects of 0.1–0.2 mg/kg PHY, 5 mg/kg GAL, and saline in three separate experiments all performed on each of two rat subjects. A 60‐min bolus‐infusion protocol was used with drug administered after 30 min. Data from the thalamus and cortex were analyzed with a graphical model accounting for neurotransmitter activation using the cerebellum as a reference region to test for transient competition with bound [¹⁸F]nifene. Significant [¹⁸F]nifene displacement was detected in both regions during one PHY and both GAL studies, while no significant competition was observed in both saline studies. This preliminary work indicates the viability of [¹⁸F]nifene in detecting increases in synaptic ACh induced by AChEIs. Synapse 67:882–886, 2013. © 2013 Wiley Periodicals, Inc.     

Chronic ethanol and withdrawal differentially modulate pre- and postsynaptic function at glutamatergic synapses in rat basolateral amygdala

Withdrawal anxiety is a significant factor contributing to continued alcohol abuse in alcoholics. This anxiety is long-lasting, can manifest well after the overt physical symptoms of withdrawal, and is frequently associated with relapse in recovering alcoholics. The neurobiological mechanisms governing these withdrawal-associated increases in anxiety are currently unknown. The basolateral amygdala (BLA) is a major emotional center in the brain and regulates the expression of both learned fear and anxiety. Neurotransmitter system alterations within this brain region may therefore contribute to withdrawal-associated anxiety. Because evidence suggests that glutamate-gated neurotransmitter receptors are sensitive to acute ethanol exposure, we examined the effect of chronic intermittent ethanol (CIE) and withdrawal (WD) on glutamatergic synaptic transmission in the BLA. We found that slices prepared from CIE and WD animals had significantly increased contributions by synaptic NMDA receptors. In addition, CIE increased the amplitude of AMPA-receptor-mediated spontaneous excitatory postsynaptic currents (sEPSCs), whereas only WD altered the amplitude and kinetics of tetrodotoxin-resistant spontaneous events (mEPSCs). Similarly, the frequency of sEPSCs was increased in both CIE and WD neurons, although only WD increased the frequency of mEPSCs. These data suggest that CIE and WD differentially alter both pre- and postsynaptic properties of BLA glutamatergic synapses. Finally, we show that microinjection of the AMPA-receptor antagonist, DNQX, can attenuate withdrawal-related anxiety-like behavior. Together, our results suggest that increased glutamatergic function may contribute to anxiety expressed during withdrawal from chronic ethanol.     

Motor cortical representation of position and velocity during reaching

This study examines motor cortical representation of hand position and its relationship to the representation of hand velocity during reaching movements. In all, 978 motor cortical neurons were recorded from the proximal arm area of rostral motor cortex. The results demonstrate that position and velocity are simultaneously encoded by single motor cortical neurons in an additive fashion and that the relative weights of the position and velocity signals change dynamically during reaching. The two variables--hand position and hand velocity--are highly correlated in the standard center-out reaching task. A new reaching task (standard reaching) is introduced to minimize these correlations. Likewise, a new decoding method (indirect OLE) was developed to analyze the data by simultaneously decoding both three-dimensional (3D) hand position and 3D hand velocity from correlated neural activity. This method shows that, on average, the reconstructed velocity led the actual hand velocity by 122 ms, whereas the reconstructed position signal led the actual hand position by 81 ms.     

Subgroup analysis based on prognostic and predictive gene signatures for adjuvant chemotherapy in early-stage non-small-cell lung cancer patients

In treating patients diagnosed with early Stage I non-small-cell lung cancer (NSCLC), doctors must choose surgery alone, Adjuvant Cisplatin-Based Chemotherapy (ACT) alone or both. For patients with resected stages IB to IIIA, clinical trials have shown a survival advantage from 4–15% with the adoption of ACT. However, due to the inherent toxicity of chemotherapy, it is necessary for doctors to identify patients whose chance of success with ACT is sufficient to justify the risks. This research seeks to use gene expression profiling in the development of a statistical decision-making algorithm to identify patients whose survival rates will improve from ACT treatment. Using the data from the National Cancer Institute, the lasso method in the Cox-Proportional-Hazards regression model is used as the main method to determine a feasible number of genes that are strongly associated with the treatment-related patient survival. Considering treatment groups separately, the patients are assigned a risk category based on the estimation of survival times. These risk categories are used to develop a Random Forests classification model to identify patients who are likely to benefit from chemotherapy treatment. This model allows the prediction of a new patient’s prognosis and the likelihood of survival benefit from ACT treatment based on a feasible number of genomic biomarkers. The proposed methods are evaluated using a simulation study.     

Improvements in Back and Leg Pain After Minimally Invasive Lumbar Decompression

HSS Journal ® - Few studies have quantified clinical improvement following minimally invasive lumbar decompression based on predominant back pain or leg pain. To quantify improvement in...     

The State of Surgical Task Sharing for Inguinal Hernia Repair in Limited-Resource Countries

Background

In limited-resource countries, the morbidity and mortality related to inguinal hernias is unacceptably high. This review addresses the issue by identifying capacity-building education of non-surgeons performing inguinal hernia repairs in developing countries and analyzing the outcomes.

Methods

PubMed was searched and included are studies that reported on task sharing and surgical outcomes for inguinal hernia surgery. Educational methods with quantitative and qualitative effects of the capacity-building methods have been recorded. Excluded were papers without records of outcome data.

Results

Seven studies from African countries reported 14,108 elective inguinal hernia repairs performed by 230 non-surgeons with a mortality rate of 0.36%. Complications were reported in 4 of the 7 studies with a morbidity rate of 14.2%. Two studies reported on follow-up: one with no recurrences in 408 patients at 7.4 months and the other one with 0.9% recurrences in 119 patients at 12 months. Direct comparison of outcomes from trained non-surgeons to surgeons or surgically trained medical doctors is limited but suggests no difference in outcomes. Quantitative capacity-building effects include increase in surgical workforce, case volume, elective procedures, mesh utilization, and decreased referrals to higher level of care institutions. Qualitative capacity-building effects include feasibility of prospective research in limited-resource settings, improved access to surgical care, and change in practice pattern of local physicians after training for mesh repair.

Conclusion

Systematic training of non-surgeons in inguinal hernia repair is potentially a high-impact capacity-building strategy. High-risk patients should be referred to a fully trained surgeon whenever possible. Randomized study designs and long-term outcomes beyond 1 year are needed.

     

Tumor Size Predicts Vascular Invasion and Histologic Grade Among Patients Undergoing Resection of Intrahepatic Cholangiocarcinoma

The association between tumor size and survival in patients with intrahepatic cholangiocarcinoma (ICC) undergoing surgical resection is controversial. We sought to define the incidence of major and microscopic vascular invasion relative to ICC tumor size, and identify predictors of microscopic vascular invasion in patients with ICC ≥5 cm. A total of 443 patients undergoing surgical resection for ICC between 1973 and 2011 at one of 11 participating institutions were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses. As tumor sized increased, the incidence of microscopic vascular invasion increased: <3 cm, 3.6 %; 3–5 cm, 24.7 %; 5–7 cm, 38.3 %; 7–15 cm, 32.9 %, ≥15 cm, 55.6 %; (p?<?0.001). Increasing tumor size was also found to be associated with worsening tumor grade. The incidence of poorly differentiated tumors increased with increasing ICC tumor size: <3 cm, 9.7 %; 3–5 cm, 19.8 %; 5–7 cm, 24.2 %; 7–15 cm, 21.1 %; >15 cm, 31.6 % (p?=?0.04). The presence of perineural invasion (odds ratio [OR]?=?2.98) and regional lymph node metastasis (OR?=?4.43) were independently associated with an increased risk of microscopic vascular invasion in tumors ≥5 cm (both p?<?0.05). Risk of microscopic vascular invasion and worse tumor grade increased with tumor size. Large tumors likely harbor worse pathologic features; this information should be considered when determining therapy and prognosis of patients with large ICC.