Imperfect Space Clamp Permits Electrotonic Interactions between Inhibitory and Excitatory Synaptic Conductances, Distorting Voltage Clamp Recordings

The voltage clamp technique is frequently used to examine the strength and composition of synaptic input to neurons. Even accounting for imperfect voltage control of the entire cell membrane (“space clamp”), it is often assumed that currents measured at the soma are a proportional indicator of the postsynaptic conductance. Here, using NEURON simulation software to model somatic recordings from morphologically realistic neurons, we show that excitatory conductances recorded in voltage clamp mode are distorted significantly by neighboring inhibitory conductances, even when the postsynaptic membrane potential starts at the reversal potential of the inhibitory conductance. Analogous effects are observed when inhibitory postsynaptic currents are recorded at the reversal potential of the excitatory conductance. Escape potentials in poorly clamped dendrites reduce the amplitude of excitatory or inhibitory postsynaptic currents recorded at the reversal potential of the other conductance. In addition, unclamped postsynaptic inhibitory conductances linearize the recorded current-voltage relationship of excitatory inputs comprising AMPAR and NMDAR-mediated components, leading to significant underestimation of the relative contribution by NMDARs, which are particularly sensitive to small perturbations in membrane potential. Voltage clamp accuracy varies substantially between neurons and dendritic arbors of different morphology; as expected, more reliable recordings are obtained from dendrites near the soma, but up to 80% of the synaptic signal on thin, distant dendrites may be lost when postsynaptic interactions are present. These limitations of the voltage clamp technique may explain how postsynaptic effects on synaptic transmission could, in some cases, be attributed incorrectly to presynaptic mechanisms

Near/Far Matching: A Study Design Approach to Instrumental Variables

Classic instrumental variable techniques involve the use of structural equation modeling or other forms of parameterized modeling. In this paper we use a nonparametric, matching-based instrumental variable methodology that is based on a study design approach. Similar to propensity score matching, though unlike classic instrumental variable approaches, near/far matching is capable of estimating causal effects when the outcome is not continuous. Unlike propensity score matching, though similar to instrumental variable techniques, near/far matching is also capable of estimating causal effects even when unmeasured covariates produce selection bias. We illustrate near/far matching by using Medicare data to compare the effectiveness of carotid arterial stents with cerebral protection versus carotid endarterectomy for the treatment of carotid stenosis

Clinical significance of BRAF mutations in metastatic melanoma

Forty to eighty percent of melanoma tumors have activating mutations in BRAF although the clinical importance of these mutations is not clear. We previously reported an analysis of BRAF mutations in metastatic melanoma samples from 68 patients. In this study, we correlated patient baseline characteristics, prognostic factors, and/or clinical outcomes with the presence of BRAF mutations. No significant differences were observed in age, gender, location of primary melanoma, stage at the diagnosis, and depth of primary tumor between patients with and without BRAF mutations. Melanomas harboring BRAF mutations were more likely to metastasize to liver (P = 0.02) and to metastasize to multiple organs (P = 0.048). Neither time to progression to stage IV nor overall survival were associated with BRAF mutations. In conclusion, we observed no significant differences in clinical characteristics or outcomes between melanomas with or without BRAF mutations. Although there was an increased frequency of liver metastasis and tendency to metastasize to multiple organs in tumors with BRAF mutations, there was no detectable effect on survival. Future prospective studies should include analysis of whether BRAF mutations in melanoma tumors correlate with an increased tendency to metastasize to liver or to multiple organs

A Patient Registry for the Management of Uterine Fibroids in Canada: Protocol for a Multicenter, Prospective, Noninterventional Study

Background: Uterine fibroids are the most common benign tumor in women. Among those with fibroids, approximately 30% become symptomatic, with abnormal uterine bleeding, pelvic pain, and bulk symptoms. Despite the high prevalence of fibroids, little information is available regarding symptoms, treatment choices, and outcomes for patients. Objective: A Canada-wide patient registry was established to understand the real-world practice. This registry included patient presentation and treatment preferences, health care provider attitudes, and clinical outcomes in the management of symptomatic uterine fibroids. Methods: This study is a prospective, noninterventional, observational patient registry. It will include women diagnosed with uterine fibroids and being managed for symptoms. Participant inclusion criteria were (1) at least 18 years of age, (2) premenopausal with a confirmed diagnosis of uterine fibroids, and associated symptoms, and (3) initiating treatment (drug intervention, procedure intervention, or a combination of both) or watchful waiting. Patients (or legal representative) must understand the nature of the project and provide written informed consent before enrollment. Participant exclusion criteria were (1) they have known or suspected clinically significant pelvic pathology not associated with uterine fibroids, and (2) they are undergoing an emergency hysterectomy at the initial visit. Outcomes will be evaluated in the context of routine clinical practice. Results: Participant recruitment of this registry began in July 2015. This study currently has a total sample of 1500 patients. Conclusions: This registry, a first in Canada, will accumulate evidence on the risks and benefits of watchful waiting, and medical and procedural interventions. It will contribute to enhancing access to treatment options for patients

Incident hyperglycaemia among older adults with or at-risk for HIV infection

HIV infection has been associated with development of prediabetes and diabetes. Optimum screening practices for these disorders in HIV-infected populations remain unclear

Convergent Surface Water Distributions in U.S. Cities

Earth's surface is rapidly urbanizing, resulting in dramatic changes in the abundance, distribution and character of surface water features in urban landscapes. However, the scope and consequences of surface water redistribution at broad spatial scales are not well understood. We hypothesized that urbanization would lead to convergent surface water abundance and distribution: in other words, cities will gain or lose water such that they become more similar to each other than are their surrounding natural landscapes. Using a database of more than 1 million water bodies and 1 million km of streams, we compared the surface water of 100 US cities with their surrounding undeveloped land. We evaluated differences in areal (A WB) and numeric densities (N WB) of water bodies (lakes, wetlands, and so on), the morphological characteristics of water bodies (size), and the density (D C) of surface flow channels (that is, streams and rivers). The variance of urban A WB, N WB, and D C across the 100 MSAs decreased, by 89, 25, and 71%, respectively, compared to undeveloped land. These data show that many cities are surface water poor relative to undeveloped land; however, in drier landscapes urbanization increases the occurrence of surface water. This convergence pattern strengthened with development intensity, such that high intensity urban development had an areal water body density 98% less than undeveloped lands. Urbanization appears to drive the convergence of hydrological features across the US, such that surface water distributions of cities are more similar to each other than to their surrounding landscapes. © 2014 The Author(s)

Assessing the clinical utility of measuring Insulin-like Growth Factor Binding Proteins in tissues and sera of melanoma patients

<p>Abstract</p> <p>Background</p> <p>Different Insulin-like Growth Factor Binding Proteins (IGFBPs) have been investigated as potential biomarkers in several types of tumors. In this study, we examined both IGFBP-3 and -4 levels in tissues and sera of melanoma patients representing different stages of melanoma progression.</p> <p>Methods</p> <p>The study cohort consisted of 132 melanoma patients (primary, n = 72; metastatic, n = 60; 64 Male, 68 Female; Median Age = 56) prospectively enrolled in the New York University School of Medicine Interdisciplinary Melanoma Cooperative Group (NYU IMCG) between August 2002 and December 2006. We assessed tumor-expression and circulating sera levels of IGFBP-3 and -4 using immunohistochemistry and ELISA assays. Correlations with clinicopathologic parameters were examined using Wilcoxon rank-sum tests and Spearman-rank correlation coefficients.</p> <p>Results</p> <p>Median IGFBP-4 tumor expression was significantly greater in primary versus metastatic patients (70% versus 10%, p = 0.01) A trend for greater median IGFBP-3 sera concentration was observed in metastatic versus primary patients (4.9 μg/ml vs. 3.4 μg/ml, respectively, p = 0.09). However, sera levels fell within a normal range for IGFBP-3. Neither IGFBP-3 nor -4 correlated with survival in this subset of patients.</p> <p>Conclusion</p> <p>Decreased IGFBP-4 tumor expression might be a step in the progression from primary to metastatic melanoma. Our data lend support to a recently-described novel tumor suppressor role of secreting IGFBPs in melanoma. However, data do not support the clinical utility of measuring levels of IGFBP-3 and -4 in sera of melanoma patients.</p

Adverse clinical sequelae after skin branding: a case series

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Labelling, Deviance and Media

Labelling theory is a perspective that emerged as a distinctive approach to criminology during the 1960s, and was a major seedbed of the radical and critical perspectives that became prominent in the 1970s. It represented the highpoint of an epistemological shift within the social sciences away from positivism – which had dominated criminological enquiry since the late-1800s – and toward an altogether more relativistic stance on the categories and concepts of crime and control. It inspired a huge amount of work throughout the 1960s and 1970s, and still resonates powerfully today. This short chapter maps out some of the ways in which labelling, deviance, media and justice interact at the levels of definition and process. It presents an overview and analysis of key mediatised labelling processes, such as the highly influential concept of moral panics. It discusses how the interconnections between labelling, crime and criminal justice are changing in a context of technological development, cultural change and media proliferation. The conclusion offers an assessment and evaluation of labelling theory’s long-term impact on criminology