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ABSTRACT: We review developments in conducting inference for model parameters in the presence of intertemporal and cross‐sectional dependence with an emphasis on panel data applications. We review the use of heteroskedasticity and autocorrelation consistent (HAC) standard error estimators, which include the standard clustered and multiway clustered estimators, and discuss alternative sample‐splitting inference procedures, such as the Fama–Macbeth procedure, within this context. We outline pros and cons of the different procedures. We then illustrate the properties of the discussed procedures within a simulation experiment designed to mimic the type of firm‐level panel data that might be encountered in accounting and finance applications. Our conclusion, based on theoretical properties and simulation performance, is that sample‐splitting procedures with suitably chosen splits are the most likely to deliver robust inferential statements with approximately correct coverage properties in the types of large, heterogeneous panels many researchers are likely to face. [ABSTRACT FROM AUTHOR]

An abstract of the article "Reducing the impact of penetrating trauma in the UK: a project by young doctors to teach first responder skills to young offenders," by N. Rhead and colleagues is presented.

A letter to the editor is presented in response to the article "Why I Am a Skeptic about Religious Claims," by Paul Kurtz in the June and July 2006 issue.

The article highlights the major tax developments in Indiana that occurred through the calendar year of 2009. The 116th Indiana General Assembly has passed several pieces of legislation affecting various areas of the state and local taxation including property taxes, sales and use taxes, state income taxes, and local taxes. Also investigated is the enactment of some changes to property tax legislation that must be included on a sales disclosure form.

Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer's disease (AD), with recent proteomic studies highlighting disrupted glial metabolism in AD. We report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN), rescues hippocampal memory function in mouse preclinical models of AD by restoring astrocyte metabolism. Activation of astrocytic IDO1 by amyloid β and tau oligomers increases KYN and suppresses glycolysis in an aryl hydrocarbon receptor-dependent manner. In amyloid and tau models, IDO1 inhibition improves hippocampal glucose metabolism and rescues hippocampal long-term potentiation in a monocarboxylate transporter-dependent manner. In astrocytic and neuronal cocultures from AD subjects, IDO1 inhibition improved astrocytic production of lactate and uptake by neurons. Thus, IDO1 inhibitors presently developed for cancer might be repurposed for treatment of AD.

In our article titled, "How WEIRD and androcentric is sex research? Global inequities in study populations," we showed that the published sex research is dominated by male and WEIRD (Western, Educated, Industrialized, Rich, and Democratic) samples. The commentary on our article by Sakaluk and Daniel critiqued the dichotomous coding of WEIRD and non-WEIRD contexts. After acknowledging how the androcentric bias finding was disregarded in the whole discussion, we used this critique as an opportunity to expand our argument about the epistemic exclusion and invisibility of researchers and samples from the majority of the world in sex research. We think having this debate between two groups of researchers located at Western universities is at odds with our intention. Thus, we invited researchers from Global South countries to join the debate via a short survey, and expanded our recommendations from the original paper with the help of these voices.

Background and Aims: Intestinal failure [IF] is a recognised complication of Crohn's disease [CD]. The aim of this study was to identify factors predicting the development and recurrence of CD in patients with IF [CD-IF], and their long-term outcomes., Methods: This was a cohort study of adults with CD-IF admitted to a national UK IF reference centre between 2000 and 2021. Patients were followed from discharge with home parenteral nutrition [HPN] until death or February 28, 2021., Results: In all, 124 patients were included; 47 [37.9%] changed disease location and 55 [44.4%] changed disease behaviour between CD and CD-IF diagnosis, with increased upper gastrointestinal involvement [4.0% vs 22.6% patients], p <0.001. Following IF diagnosis, 29/124 [23.4%] patients commenced CD prophylactic medical therapy; 18 [62.1%] had a history of stricturing or penetrating small bowel disease; and nine [31.0%] had ileocolonic phenotype brought back into continuity. The cumulative incidence of disease recurrence was 2.4% at 1 year, 16.3% at 5 years and 27.2% at 10 years; colon-in-continuity and prophylactic treatment were associated with an increased likelihood of disease recurrence. Catheter-related bloodstream infection [CRBSI] rate was 0.32 episodes/1000 catheter days, with no association between medical therapy and CRBSI rate., Conclusions: This is the largest series reporting disease behaviour and long-term outcomes in CD-IF and the first describing prophylactic therapy use. The incidence of disease recurrence was low. Immunosuppressive therapy appears to be safe in HPN-dependent patients with no increased risk of CRBSI. The management of CD-IF needs to be tailored to the patient's surgical disease history alongside disease phenotype., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Haglund's deformity is clinically defined by the presence of retrocalcaneal tenderness, with previous radiographic parameters relying on calcaneal anatomic parameters that did not considering the influence of ankle motion on posterior calcaneal-Achilles impingement METHODS: Standing foot radiographs from 55 patients with clinically defined Haglund's deformity were compared to 50 control patients using previously described measurements and 2 new angular measurements based on the linkage between ankle rotation and posterior calcaneal-Achilles impingement. The ability of each measure to distinguish between Haglund's and control patients was assessed., Results: The combination of the angles to account for both increased calcaneal tubercle height and increased posterior calcaneal prominence could distinguish between the two patient groups (p = .018, Area under the curve = 63.2%). None of the previously published radiographic criteria were different between the two patient groups., Conclusions: The proposed radiographic criteria were more predictive than previous criteria that did not address the role of ankle motion., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8 + T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.

Background: A fungal-related catheter-related bloodstream infection (CRBSI) is less frequent than those induced by bacteria. In the past, a single episode of fungal CRBSI has been used as a marker of home parenteral nutrition (HPN) failure and thus a possible indication for intestinal transplantation., Methods: Survival outcomes were assessed from a prospectively maintained database of patients initiated on HPN for underlying chronic intestinal failure between 1993 and 2018, with a censoring date of December 31, 2020. Cox regression was performed to assess predictors of mortality with univariable and multivariable analysis., Results: A total of 1008 patients were included in the study, with a total of 1 364 595 catheter days. There were 513 CRBSI events recorded in 262 patients, equating to a CRBSI rate of 0.38/1000 catheter days. A total of 38/262 (14.5%) patients had at least one episode of fungal CRBSI, whereas 216/262 (82.4%) had at least one bacterial but no fungal CRBSI. The median time between HPN initiation and the first CRBSI episode was 20.6 months (95% confidence interval, 16.5-24.1). Episodes of fungal or bacterial CRBSI and the number of CRBSI episodes were not associated with increased mortality. Overall, 15 CRBSI-related deaths were observed in the observation period (0.01 CRBSI deaths/1000 catheter days), two of these were fungal in origin., Conclusion: The occurrence of a fungal CRBSI does not increase the risk of death compared with patients who have bacterial CRBSI or those without a CRBSI event., (© 2022 American Society for Parenteral and Enteral Nutrition.)

Introduction: Catheter-related bloodstream infections (CRBSIs) remain the commonest complication associated with home parenteral nutrition (HPN). Although the management outcomes of CRBSIs have been extensively reported by specialized intestinal failure (IF) centers, there are minimal data reporting CRBSI outcomes for HPN-dependent patients admitted to nonspecialized hospitals., Method: This was an observational study from a prospectively maintained database of CRBSIs in HPN-dependent patients managed outside of a specialized IF center., Results: Three hundred and six patients from a total cohort of 1066 HPN-dependent patients suffered from 489 CRBSI events from 2003 to 2021; after 2017, 71 of these events were managed at the patient's local, nonspecialized hospital and the remainder at the specialized IF center. From 2017 to 2021, salvage of the central venous catheter (CVC) with antimicrobial therapy was attempted in 32 out of 71 (45.1%) patients admitted to the nonspecialized hospital, with successful salvage recorded in 23 (71.8%) cases. Notably, CVC salvage was attempted more commonly (77 out of 103 [74.8%]; P = 0.004 vs nonspecialized hospital), with a better salvage success rate (64 out of 77 [83.1%] P = 0.01 vs nonspecialized hospital) in patients who were admitted to the specialized IF center., Conclusion: In some instances, CRBSIs can be effectively managed when patients presenting to a nonspecialized hospital; however, overall salvage is more likely to be successful in the specialized setting. Further development of clinical and educational networks between IF centers and patients' local hospitals aimed at standardizing care may lead to improved CRBSI outcomes., (© 2022 American Society for Parenteral and Enteral Nutrition.)

There is little data on what influences posttraumatic growth for women who experienced non-consensual sexual contact (NCSC) as an undergraduate college student. The purpose of this study is to garner a better understanding of posttraumatic growth among women-identifying survivors of undergraduate NCSC by addressing the following aims: 1) evaluate the mediating role of NCSC-related shame on the relationship between perceived peer rape myth acceptance and posttraumatic growth ( n = 174); and 2) evaluate the shared and independent variance contributions of mental health symptoms and trauma history clusters on posttraumatic growth ( n = 151).NCSC-related shame did not mediate the relationship between perceived peer rape myth acceptance and posttraumatic growth. Mental health symptoms and trauma history significantly contributed to 35.27% of posttraumatic growth variance, with the trauma history cluster significantly influencing posttraumatic growth scores beyond mental health symptoms. Based on these findings, it is important that clinicians assess for a history of trauma and the impact of that trauma in addition to mental health symptoms when trying to understand posttraumatic growth after campus sexual violence., (© Copyright 2022 Springer Publishing Company, LLC.)

African Americans (AAs) are 20% more likely to develop serious psychological distress compared to Whites but are less likely to use mental health services. The study objective was to evaluate the effectiveness of recruitment strategies to engage AA fathers in a mental health intervention.Using the community-based participatory research (CBPR) approach, a community-academic partnership (CAP) developed and implemented direct and indirect referral strategies to engage AA fathers in a mental health intervention. Direct referral strategies focused on community partner identification of potentially eligible participants, providing information about the study (i.e., study flyer), and referring potential participants to the study. Indirect referrals included posting flyers in local businesses frequented by AA men, radio advertisements, and social media posts from community organizations.From January to October 2019, 50 direct and 1388 indirect referrals were documented, yielding 24 participants screened and 15 enrolled. Of all participants screened, 58% were referred through indirect referral, 38% were referred directly by community partners, and 4% of the participants were referred through both direct and indirect referrals. Twenty percent of those exposed to the direct referral methods and 1% of those exposed to the indirect referral methods were enrolled. The indirect referrals accounted for 60% of enrollment, whereas the direct referrals accounted for 33.3% of enrollment.Collaborating with the community partners to engage hard-to-reach populations in mental health studies allowed for broad dissemination of recruitment methods, but still resulted in low participant accrual. Additional focus on increasing direct referral methods appears to be a fruitful area of CBPR.

Therapies that utilize immune checkpoint inhibition work by leveraging mutation-derived neoantigens and have shown greater clinical efficacy in tumors with higher mutational burden. Whether tumors with a low mutational burden are susceptible to neoantigen-targeted therapy has not been fully addressed. To examine the feasibility of neoantigen-specific adoptive T-cell therapy, the authors studied the T-cell response against somatic variants in five patients with myelodysplastic syndrome (MDS), a malignancy with a very low tumor mutational burden. DNA and RNA from tumor (CD34 + ) and normal (CD3 + ) cells isolated from the patients' blood were sequenced to predict patient-specific MDS neopeptides. Neopeptides representing the somatic variants were used to induce and expand autologous T cells ex vivo, and these were systematically tested in killing assays to determine the proportion of neopeptides yielding neoantigen-specific T cells. The authors identified a total of 32 somatic variants (four to eight per patient) and found that 21 (66%) induced a peptide-specific T-cell response and 19 (59%) induced a T-cell response capable of killing autologous tumor cells. Of the 32 somatic variants, 11 (34%) induced a CD4 + response and 11 (34%) induced a CD8 + response that killed the tumor. These results indicate that in vitro induction of neoantigen-specific T cells is feasible for tumors with very low mutational burden and that this approach warrants investigation as a therapeutic option for such patients., (Copyright © 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Pregnant women with opioid use disorder (OUD) are at risk of overdose, infectious diseases, and inadequate prenatal care. Additional risks include adverse pregnancy and infant outcomes, such as preterm birth and neonatal abstinence syndrome. Management and treatment of OUD during pregnancy are associated with improved maternal and infant outcomes. Professional organizations, including the American College of Obstetricians and Gynecologists, recommend offering opioid agonist pharmacotherapy ( i.e. , methadone or buprenorphine) combined with behavioral therapy as standard treatment for pregnant women with OUD. Other medications and herbal supplements have also been used by pregnant women for OUD. Determining which OUD treatments optimize maternal and infant outcomes is challenging given the host of potential factors that affect these outcomes. The Centers for Disease Control and Prevention initiated the MATernaL and Infant NetworK to Understand Outcomes Associated with Treatment of Opioid Use Disorder during Pregnancy (MAT-LINK) to monitor more than 2000 mothers and their infants, using data collected from geographically diverse clinical sites. Information learned from MAT-LINK will inform the future management and treatment of pregnant women with OUD.

Acute severe colitis is a medical emergency and requires prompt treatment with intravenous steroids. Infliximab is typically used as rescue therapy in those who fail to respond to corticosteroids. This article outlines the altered pharmacokinetics of infliximab in acute severe UC and summarised the latest published data surrounding accelerated infliximab dosing., Competing Interests: Competing interests: SrS has received speaker fee from Abbvie, Dr Falk Pharma, Shire, Takeda, Janssen and received educational grant from Abbvie, Actavis, Janssen, Takeda, Dr Falk Pharma and is an advisory board member for Abbvie, Dr Falk Pharma and Vifor Pharma., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The purpose of this study was to describe the day-to-day healing processes of women who experienced undergraduate sexual violence. We engaged 19 women in a photo-elicitation experience with follow-up individual interviews to identify themes of both healing and darker moments in survivors' everyday lives. Healing was found to function on a continuum influenced by darker moments (i.e., moments that elicited fear, anxiety, loneliness, guilt, anger, and worthlessness) and healing moments (i.e., rebuilding moments of self-care, self-love, connection, hope, peace, and freedom). Responses to darker moments included feeling overwhelmed, disconnected, and intentional vulnerability. Healing moments were influenced by self-reflection, authentic interactions, and resource utilization. The photographs taken in this study shed light on the impact of sexual violence in women's daily lives long after these traumatic and unjust experiences. This knowledge can be used to foster a sense of universality in survivors who are currently struggling and growing after their experiences as well as give service providers greater insight into what survivors' day-to-day needs may be., (© 2019 Wiley Periodicals, Inc.)

Introduction: Adults living in bateyes (i.e., sugarcane plantation villages) in the Dominican Republic have minimal access to health care services. Hypertension (HTN) is a serious and often unrecognized health problem among batey residents. The Jonas Batey Hypertension Program was built on existing social networks to address the detection and treatment of HTN., Methods: An ongoing community-based participatory research endeavor involves a partnership among three organizations and collaboration with promotoras who engage their batey communities in a mobile HTN screening and treatment program. Adults are screened and, if indicated, are treated with antihypertensive medications. Data collection includes project documentation, participant observation, demographic data, blood pressure (BP) measurements, and pill counts., Results: To date, 243 adults have received HTN treatment in four batey communities. A within-group, as-treated, repeated-measures, pre-/postanalysis showed that among participants who had been receiving antihypertensive treatment for 12 months ( n = 70), there was a significant decrease in BP ( p < .005)., Conclusion: Results of an interim data analysis indicate that the program model has been implemented successfully and is making a positive impact on BP control. Evaluation is ongoing with regard to the long-term HTN-related health outcomes of batey residents. Ensuring program sustainability is an important consideration for the future.

Background: Many prisoners rationalise criminal behaviour, and this type of thinking has been linked to recidivism. Correctional programmes for modifying criminal thinking can reshape how offenders view themselves and their circumstances., Aim: Our aim was to test whether participation in a cognitive-based curriculum called Steps to Economic and Personal Success (STEPS) was associated with changes in criminal thinking., Methods: The STEPS curriculum is delivered in 15 video-based facilitated classes. A pre-intervention/post-intervention survey design was applied to 128 adult male prisoners who completed the programme. Criminal thinking was measured by the Texas Christian University Criminal Thinking Scale, a self-report instrument with the six domains: entitlement, justification, power orientation, cold heartedness, criminal rationalisation and personal irresponsibility., Results: Participants had lower scores in most of the criminal thinking domains after the intervention than before, with largest reductions in justification and power orientation., Conclusion: Findings provide evidence that attitudes to crime can be changed in a correctional setting, and the programme under study shows promise as an effective intervention for changing these attitudes among prisoners. Future research should build on these findings to examine whether and how such changes are related to desistance from offending behaviours. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

We proposed that the premise that monogamy is the exemplary form of romantic partnership underlies much theory and research on relationship quality, and we addressed how this bias has prompted methodological issues that make it difficult to effectively address the quality of nonmonogamous relationships. Because the idea that consensually nonmonogamous (CNM) relationships are functional (i.e., satisfying and of high quality) is controversial, we included a basic study to assess, in a variety of ways, the quality of these relationships. In that study, we found few differences in relationship functioning between individuals engaged in monogamy and those in CNM relationships. We then considered how existing theories could help researchers to understand CNM relationships and how CNM relationships could shed light on relationship processes, and we proposed a model of how CNM and monogamous relationships differ. Finally, in a second study, we determined that even researchers who present data about CNM are affected by the stigma surrounding such relationships. That is, researchers presenting findings favoring polyamory were perceived as more biased than researchers presenting findings favoring monogamy.

Objectives: To determine whether patient sex makes a difference to in-hospital mortality and survival in patients undergoing isolated coronary artery bypass graft surgery (CABG) receiving a radial artery graft., Methods: Analysis of consecutive patients on a validated prospective cardiac surgery database was performed for patients undergoing isolated CABG. Uni- and multivariate analyses were performed for in-hospital mortality and long-term survival. A propensity analysis was also performed., Results: Overall mortality was 2.1% (n = 284) for all cases, n = 13 369. Median follow-up was 7.0 (interquartile range 4.1-10.1) years. Of the cases 28.2% of males (n = 384) and 29.7% of females (n = 764) had a radial artery utilized. Univariate analysis demonstrated that in-hospital mortality was significantly lower in male patients, P < 0.001, and radial artery use was associated with increased survival in males, P < 0.0001, but not in females, P = 0.82. In male patients, multivariate analysis failed to identify the radial artery as a risk factor for in-hospital death. The radial artery was identified as a significant prognostic factor, associated with improved long-term survival (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.69-0.88, P = 0.0001). Propensity analysis confirmed this finding (HR 0.76, 95% CI 0.67-0.86, P < 0.0001). In female patients, multivariate analysis failed to identify the radial artery as a significant factor determining in-hospital mortality or long-term survival. Propensity analysis confirmed these findings., Conclusion: Males derive a significant survival advantage if they receive a radial artery graft when undergoing isolated CABG. The radial artery makes no difference to long-term survival in female patients. Radial artery use does not affect in-hospital mortality regardless of patient sex., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: To determine if on- or off-pump coronary artery bypass grafting (CABG) makes a difference to in-hospital mortality and long-term survival in obese patients., Methods: Analysis of consecutive patients on a validated prospective cardiac surgery database was performed for patients undergoing isolated CABG. Obesity was defined as a body mass index (BMI) >30 kg/m(2). Uni- and multivariate analyses were performed for in-hospital mortality and long-term survival. A propensity analysis was also performed., Results: The overall mortality rate was 2.1% (N = 284) for all cases, N = 13 369. The mortality rate for obese patients (N = 4289) was 2.3%, and for non-obese patients (N = 9080) it was 2.0%; P = 0.4. The median follow-up was 7.0 (interquartile range 4.1-10.1) years. Univariate analysis identified that in-hospital mortality was significantly lower in obese patients undergoing off-pump CABG; P = 0.01. No significant difference existed with regard to non-obese patients; P = 0.55. Kaplan-Meier survival analysis identified that off-pump CABG was associated with improved survival in obese patients; P = 0.01. Multivariate analysis of non-obese patients did not identify on- or off-pump CABG as a significant factor determining in-hospital mortality or long-term survival. Multivariate analysis of obese patients identified off-pump CABG as being associated with significantly reduced in-hospital mortality (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.34-0.93, P = 0.03), and significantly improved long-term survival (hazard ratio 0.81, 95% CI 0.67-0.98, P = 0.03). In-hospital mortality and long-term survival were significantly affected by the era of surgery, regardless of patients' BMI. Propensity matching of non-obese patients (N = 6088, 1:1 matching) did not identify on- or off-pump CABG as a significant factor determining in-hospital mortality or long-term survival. Propensity matching of obese patients (N = 2980, 1:1 matching) identified on-pump CABG as a significant factor determining in-hospital mortality (OR 0.50, 95% CI 0.26-0.98, P = 0.04), but having no effect on long-term survival., Conclusions: Univariate, multivariate and propensity matching suggest that obese patients undergoing CABG have reduced in-hospital mortality if they undergo revascularization with the off-pump technique., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

We examined the distribution of neurons immunoreactive for neuropeptide Y (NPY) in the posterior part of the superior temporal cortex (Brodmann's area 22 or area Tpt) of humans and nonhuman haplorrhine primates. NPY has been implicated in learning and memory and the density of NPY-expressing cortical neurons and axons is reduced in depression, bipolar disorder, schizophrenia, and Alzheimer's disease. Due to the role that NPY plays in both cognition and neurodegenerative diseases, we tested the hypothesis that the density of cortical and interstitial neurons expressing NPY was increased in humans relative to other primate species. The study sample included great apes (chimpanzee and gorilla), Old World monkeys (pigtailed macaque, moor macaque, and baboon) and New World monkeys (squirrel monkey and capuchin). Stereologic methods were used to estimate the density of NPY-immunoreactive (-ir) neurons in layers I-VI of area Tpt and the subjacent white matter. Adjacent Nissl-stained sections were used to calculate local densities of all neurons. The ratio of NPY-ir neurons to total neurons within area Tpt and the total density of NPY-ir neurons within the white matter were compared among species. Overall, NPY-ir neurons represented only an average of 0.006% of the total neuron population. While there were significant differences among species, phylogenetic trends in NPY-ir neuron distributions were not observed and humans did not differ from other primates. However, variation among species warrants further investigation into the distribution of this neuromodulator system., (© 2012 Wiley Periodicals, Inc.)

Objective: To investigate the hypothesis that proteasome inhibition may have potential in the treatment of SLE, by targeting plasmacytoid dendritic cells (PDCs) and plasma cells, both of which are critical in disease pathogenesis., Methods: Lupus-prone mice were treated with the nonselective proteasome inhibitors carfilzomib and bortezomib, the immunoproteasome inhibitor ONX 0914, or vehicle control. Tissue was harvested and analyzed by flow cytometry using standard markers. Nephritis was monitored by evaluation for proteinuria and by histologic analysis of kidneys. Serum anti-double-stranded DNA (anti-dsDNA) levels were measured by enzyme-linked immunosorbent assay (ELISA), and total IgG and dsDNA antibody-secreting cells (ASCs) by enzyme-linked immunospot assay. Human peripheral blood mononuclear cells or mouse bone marrow cells were incubated with Toll-like receptor (TLR) agonists and proteasome inhibitors, and interferon-α (IFNα) levels were measured by ELISA and flow cytometry., Results: Early treatment of lupus-prone mice with the dual-targeting proteasome inhibitors carfilzomib or bortezomib or the immunoproteasome-specific inhibitor ONX 0914 prevented disease progression, and treatment of mice with established disease dramatically abrogated nephritis. Treatment had profound effects on plasma cells, with greater reductions in autoreactive than in total IgG ASCs, an effect that became more pronounced with prolonged treatment and was reflected in decreasing serum autoantibody levels. Notably, proteasome inhibition efficiently suppressed production of IFNα by TLR-activated PDCs in vitro and in vivo, an effect mediated by inhibition of both PDC survival and PDC function., Conclusion: Inhibition of the immunoproteasome is equally efficacious as dual targeting agents in preventing lupus disease progression by targeting 2 critical pathways in disease pathogenesis, type I IFN activation and autoantibody production by plasma cells., (Copyright © 2012 by the American College of Rheumatology.)

Background: Various structural components of human skin biopsy specimens are difficult to visualize using conventional histologic approaches., Methods: We used two-photon microscopy and advanced imaging software to render three-dimensional (3D) images of in situ nerves, blood vessels, and hair follicles labeled with various fluorescent markers. Archived frozen human skin biopsy specimens were cryosectioned up to 150 micro m in thickness and fluorescently stained with rhodamine- or fluorescein-labeled antibodies or lectins. Optical sections were collected by two-photon microscopy and the resulting data sets were analyzed in three dimensions using Voxx software., Results: Reconstructed image volumes demonstrated the complex 3D morphology of nerves, blood vessels and adnexal structures in normal mucocutaneous tissue., Conclusion: Two-photon microscopy and Voxx rendering software allow for detailed 3D visualization of structures within human mucocutaneous biopsy specimens, as they appear in situ, and facilitate objective interpretation of variations in their morphology. These techniques may be used to investigate disorders involving cutaneous structures that are difficult to visualize by means of traditional microscopy.