Behavioral Insights into Nociceptor Function: A Systematic Approach to Understanding Postsurgical and Neuropathic Pain Mechanisms in Rats

Postsurgical and neuropathic pain are each clinically common, and often associated with ongoing pain. Ongoing pain has been linked to ongoing activity (OA) in human C-fiber nociceptors. Preclinical studies using rodent neuropathic models have concentrated on allodynia driven by OA generated in non-nociceptive Aβ fibers, but little attention has been paid to postsurgical pain in sham controls or to C-fiber nociceptor OA promoting ongoing pain. Operant assays that reveal negative motivational and cognitive aspects of voluntary pain-related behavior may be particularly sensitive to pain-related alterations. In the mechanical conflict (MC) test, rodents can freely choose to escape from a brightly lit chamber by crossing sharp probes. Most studies employing the MC test habituate rodents to the device and measure the latency to escape the bright light. We found reducing habituation caused rats to repeatedly return to the light chamber when probes were absent, presumably as part of their exploratory behavior. We asked whether combining motivations to avoid the bright light and to explore the device would reveal a conflicting, pain-related reluctance of rats to cross noxious probes. Rats with a thoracic spinal cord injury (SCI), lumbar spinal nerve transection, or chronic constriction injury of the sciatic nerve, as well as their sham controls, exhibited heightened pain-avoidance behavior compared to uninjured controls. These findings have important implications for investigations into behavioral and neuronal alterations contributing to postsurgical and neuropathic pain. Many C-fiber nociceptors generate OA in vivo in rats with SCI and ongoing pain. Probable nociceptors continue to generate OA in vitro after dissociation. We used whole-cell recordings from isolated dorsal root ganglion neurons and novel algorithms that analyze irregular changes in membrane potential (MP) to define neurophysiological alterations underlying SCI-induced nociceptor OA. In a distinct type of probable nociceptor, SCI caused 3 chronic alterations that promote OA: 1) depolarization of resting MP, 2) reduction in the voltage threshold for action potential generation, and 3) enhancement of depolarizing spontaneous fluctuations (DSFs) in MP. In vitro modeling of acute inflammation by combining serotonin with artificial depolarization also potentiated DSFs and OA. These findings reveal nociceptor specializations for generating OA during ongoing pain

Economic Issues in the Management of Plants Invading Natural Environments: Scotch Broom in Barrington Tops National Park

Scotch broom (Cytisus scoparius, L.), is an exotic leguminous shrub, native to Europe, which invades pastoral and woodland ecosystems and adjoining river systems in cool, high rainfall regions of southeastern Australia. Broom has invaded 10,000 hectares of eucalypt woodland at Barrington Tops National Park in New South Wales, and is having a major impact on the natural ecology of the sub-alpine environment. It is extremely competitive with the native flora, retarding their growth and in many areas blanketing the ground and preventing growth of many understorey species in open forest areas. An active program to manage this invasion is being implemented by the National Parks and Wildlife Service. The management issues include whether eradication or containment is economically desirable, and when biological control is economically desirable. Management choices depend on the marginal costs of increments of government intervention, effects of uncertain budgets on the control of broom, choice of control measures and effects of uncertain values of biodiversity. These issues are addressed through the application of a detailed bioeconomic model of broom management.Scotch broom, economic issues, management issues, natural environments, bioeconomic model, Environmental Economics and Policy,

Papillary thyroid carcinoma arising from a mature teratoma in a cryptorchid testis : a case report

Struma testis is a rare entity, and malignant transformation of a testicular teratoma to papillary thyroid carcinoma (PTC) has only once been previously described. Furthermore, sold tumor metastases to the testis are rare, with a less than 1% rate of testicular metastases from solid tumors, and there are no reports of primary thyroid carcinomas metastasizing to the testis. We report the case of a 56 year old man who was found to have a cryptorchid testis containing a mature teratoma with malignant somatic component in the form of a 1.6 centimeter PTC

An Examination of Prevalent Twenty-First Century Models of Community Engagement by the Black Churches

An Examination of Prevalent Twenty-First Century Models of Community Engagement by the Black Churches Brian Odem Bellamy (ABSTRACT) This thesis examines three prevalent models of community engagement in the black churches in the United States of America since the year 2000. It will contribute to existing scholarship by identifying theological motivations for community engagement by the black churches, and assessing the extent to which the black churches address and fulfill criteria for advancing liberation delineated from three generations of scholarship in Black Theology. This shall provide theological insight into the continued social relevance of the black churches. Existing scholarship has shown that the black churches historically have engaged the oppressed communities they have served by addressing their secular and social needs in addition to their spiritual ones, with a sense of mission to affirm human dignity and advance social justice. This praxis of liberation through community engagement was necessitated by the oppressive contexts in which the black churches were founded, and has continued in varied ways in tandem with shifts in social location of black people in America. Black church community initiatives have also been marked among three generations of scholars in Black Theology, who have delineated imperatives for which the black churches might engage their communities to fully continue the praxis of liberation in the present. The interrelated aims of this thesis are to discover the theological motivations of black church community engagement agents, and, to consider the extent to which the community engagement initiatives of the black churches of the twenty-first century address critical theological criteria from Black Theology for advancing liberation; each of which will help to illuminate theological implications for the continued social relevance of the black churches. This project requires an examination of contemporary models of black church community engagement in their own social reality. The models of community engagement that are researched are grass-roots movements where black churchpersons use non-violent direct action to advance particular social justice causes, community development corporations where churches filter grant money from the government to create economic opportunities for their local communities, and megachurch initiatives where congregations use the revenue of their large memberships to effect positive change in their communities. Local examples of each model are examined from a grounded theory approach through interviews with clergy and community workers, observations of worship and program activities, and textual analysis of bulletins, websites, and brochures

A retrospective cross-sectional study: Fresh cycle endometrial thickness is a sensitive predictor of inadequate endometrial thickness in frozen embryo transfer cycles

BACKGROUND: The purpose of this study is to assess predictors of inadequate endometrial cavity thickness (ECT), defined as < 8 mm, in frozen embryo transfer (FET) cycles. METHODS: This is a retrospective cross-sectional study at an academic fertility center including 274 women who underwent their first endometrial preparation with estradiol for autologous FET in our center from 2001-2009. Multivariable logistic regression was performed to determine predictors of inadequate endometrial development in FET cycles. RESULTS: Neither age nor duration of estrogen supplementation were associated with FET endometrial thickness. Lower body mass index, nulliparity, previous operative hysteroscopy and thinner fresh cycle endometrial lining were associated with inadequate endometrial thickness in FET cycles. A maximum thickness of 11.5 mm in a fresh cycle was 80% sensitive and 70% specific for inadequate frozen cycle thickness. CONCLUSIONS: Previous fresh cycle endometrial cavity thickness is associated with subsequent FET cycle endometrial cavity thickness. Women with a fresh cycle thickness of 11.5 mm or less may require additional intervention to achieve adequate endometrial thickness in preparation for a frozen cycle

Chronic BDNF simultaneously inhibits and unmasks superficial dorsal horn neuronal activity.

Funder: Department of Anesthesiology and Critical Care Medicine, University of New Mexico Health Sciences CenterFunder: Canadian Institutes of Health Research; doi: http://dx.doi.org/10.13039/501100000024Brain-derived neurotrophic factor (BDNF) is critically involved in the pathophysiology of chronic pain. However, the mechanisms of BDNF action on specific neuronal populations in the spinal superficial dorsal horn (SDH) requires further study. We used chronic BDNF treatment (200 ng/ml, 5-6 days) of defined-medium, serum-free spinal organotypic cultures to study intracellular calcium ([Ca2+]i) fluctuations. A detailed quantitative analysis of these fluctuations using the Frequency-independent biological signal identification (FIBSI) program revealed that BDNF simultaneously depressed activity in some SDH neurons while it unmasked a particular subpopulation of 'silent' neurons causing them to become spontaneously active. Blockade of gap junctions disinhibited a subpopulation of SDH neurons and reduced BDNF-induced synchrony in BDNF-treated cultures. BDNF reduced neuronal excitability assessed by measuring spontaneous excitatory postsynaptic currents. This was similar to the depressive effect of BDNF on the [Ca2+]i fluctuations. This study reveals novel regulatory mechanisms of SDH neuronal excitability in response to BDNF

HIV-1 Superinfection in Women Broadens and Strengthens the Neutralizing Antibody Response

Identifying naturally-occurring neutralizing antibodies (NAb) that are cross-reactive against all global subtypes of HIV-1 is an important step toward the development of a vaccine. Establishing the host and viral determinants for eliciting such broadly NAbs is also critical for immunogen design. NAb breadth has previously been shown to be positively associated with viral diversity. Therefore, we hypothesized that superinfected individuals develop a broad NAb response as a result of increased antigenic stimulation by two distinct viruses. To test this hypothesis, plasma samples from 12 superinfected women each assigned to three singly infected women were tested against a panel of eight viruses representing four different HIV-1 subtypes at matched time points post-superinfection (∼5 years post-initial infection). Here we show superinfected individuals develop significantly broader NAb responses post-superinfection when compared to singly infected individuals (RR = 1.68, CI: 1.23–2.30, p = 0.001). This was true even after controlling for NAb breadth developed prior to superinfection, contemporaneous CD4+ T cell count and viral load. Similarly, both unadjusted and adjusted analyses showed significantly greater potency in superinfected cases compared to controls. Notably, two superinfected individuals were able to neutralize variants from four different subtypes at plasma dilutions >1∶300, suggesting that their NAbs exhibit elite activity. Cross-subtype breadth was detected within a year of superinfection in both of these individuals, which was within 1.5 years of their initial infection. These data suggest that sequential infections lead to augmentation of the NAb response, a process that may provide insight into potential mechanisms that contribute to the development of antibody breadth. Therefore, a successful vaccination strategy that mimics superinfection may lead to the development of broad NAbs in immunized individuals

HIV-Specific Antibodies Capable of ADCC Are Common in Breastmilk and Are Associated with Reduced Risk of Transmission in Women with High Viral Loads

There are limited data describing the functional characteristics of HIV-1 specific antibodies in breast milk (BM) and their role in breastfeeding transmission. The ability of BM antibodies to bind HIV-1 envelope, neutralize heterologous and autologous viruses and direct antibody-dependent cell cytotoxicity (ADCC) were analyzed in BM and plasma obtained soon after delivery from 10 non-transmitting and 9 transmitting women with high systemic viral loads and plasma neutralizing antibodies (NAbs). Because subtype A is the dominant subtype in this cohort, a subtype A envelope variant that was sensitive to plasma NAbs was used to assess the different antibody activities. We found that NAbs against the subtype A heterologous virus and/or the woman's autologous viruses were rare in IgG and IgA purified from breast milk supernatant (BMS) – only 4 of 19 women had any detectable NAb activity against either virus. Detected NAbs were of low potency (median IC50 value of 10 versus 647 for the corresponding plasma) and were not associated with infant infection (p = 0.58). The low NAb activity in BMS versus plasma was reflected in binding antibody levels: HIV-1 envelope specific IgG titers were 2.2 log10 lower (compared to 0.59 log10 lower for IgA) in BMS versus plasma. In contrast, antibodies capable of ADCC were common and could be detected in the BMS from all 19 women. BMS envelope-specific IgG titers were associated with both detection of IgG NAbs (p = 0.0001)and BMS ADCC activity (p = 0.014). Importantly, BMS ADCC capacity was inversely associated with infant infection risk (p = 0.039). Our findings indicate that BMS has low levels of envelope specific IgG and IgA with limited neutralizing activity. However, this small study of women with high plasma viral loads suggests that breastmilk ADCC activity is a correlate of transmission that may impact infant infection risk