Does estrogen deficiency cause lacrimal gland inflammation and aqueous-deficient dry eye in mice?

Researchers have proposed that estrogen deficiency will lead to a Sjögren's syndrome (SjS)-like lacrimal gland inflammation, aqueous tear deficiency and dry eye. The purpose of this study was to determine whether this proposal is correct. Lacrimal glands were obtained from adult, age-matched wild type (WT) and aromatase knockout (ArKO) mice, in which estrogen synthesis is completely eliminated. Tissues were also obtained from autoimmune MRL/Mp-lpr/lpr (MRL/lpr) mice as inflammation controls. Tear volumes in WT and ArKO mice were measured and glands were processed for molecular biological and histological evaluation. Our results demonstrate that estrogen absence does not lead to a SjS-like inflammation in lacrimal tissue or to an aqueous-deficient dry eye. There was no upregulation of genes associated with inflammatory pathways in lacrimal glands of male or female ArKO mice. Such inflammatory activity was prominent in autoimmune MRL/lpr tissues. We also found no evidence of inflammation in lacrimal gland tissue sections of estrogen-deficient mice, and tear volumes of ArKO males were actually increased as compared to those WT controls. Interestingly, our study did show that estrogen absence influences the expression of thousands of lacrimal gland genes, and that this impact is sex- and genotype-specific. Our findings demonstrate that estrogen absence is not a risk factor for the development of SjS-like lacrimal gland inflammation or for aqueous-deficient dry eye in mice.

Targeted Drug Delivery for the Treatment of Abdominal Pain in Chronic Pancreatitis: A Retrospective Case Series.

Abdominal pain secondary to chronic pancreatitis (CP) is difficult to manage and often requires chronic oral opioid therapy (OOT). Targeted drug delivery (TDD) allows for a diminished dose of opioid intake and improved pain levels. TDD has been used in different pain syndromes with only limited reports in CP. OBJECTIVE: The objective of this article is to perform a retrospective review of CP patients treated with TDD versus OOT to compare chronic pain control and consumed morphine-equivalent doses. METHODS: Patients receiving TDD between September 2011 and August 2018 were included. All patients were weaned off oral opioids one week before intrathecal trial and pump implantation. Patients with intrathecal trials providing at least 50% pain relief underwent pump implantation. Data were collected while on OOT and at two weeks, three months, and nine months post-implant. Data were analyzed with Microsoft Excel 365 MSO using means and standard deviations. P-values were calculated using a two-tailed student's t-test with paired two-sample means. RESULTS: Twenty-three patients were analyzed. Pre-trial average pain score was 6.5/10 with a mean improvement with trials greater than 71%. The mean chronic baseline oral morphine milligram equivalents (MME) was 188. The mean MME on TDD at two weeks (0.36), three months (1.39), and nine months (2.47) were significantly lower than OOT. Mean pain scores were 6, 4.9, and 5.6 at two weeks, three months, and nine months, respectively, compared to 6.5 on OOT. DISCUSSION: The results of this study indicate that TDD provides improved pain control with significantly lower opioid doses.

Peripheral Nerve Stimulation in Chronic Knee Pain: A Case Series.

Introduction Chronic knee pain is increasing in prevalence and is associated with substantial limitations in functional mobility. Peripheral nerve stimulation (PNS) has been increasingly used to treat various chronic pain conditions. However, there is a paucity of research exploring the potential therapeutic benefit of PNS for chronic knee pain. Methods This research is a retrospective case series of all patients who received PNS for the treatment of chronic knee pain performed at a single-center academic medical institution between March 2021 and June 2022. The primary outcome was percent pain reduction six months after implantation. Outcome data was obtained via chart review and phone calls to patients. Secondary outcomes included percent pain reduction two weeks and two months after implantation and adverse medical events related to the procedure and nerve stimulation. Results Fourteen individual patients received PNS for chronic knee pain during the study period. Three of these patients received bilateral PNS for a total of 17 cases. The mean percent pain reduction six months after implantation was 52% (SD=28.2) (N=12). A total of 75.0% of participants (9/12) reported ≥50% reductions in pain six months after implantation. No adverse events were reported relating to the implantation procedure and/or nerve stimulation. Conclusion PNS is a safe and efficacious treatment modality for chronic knee pain with demonstrated long-term benefit. Further research should clarify patient factors associated with improved treatment response.

Corticosteroid regimens for treatment of acute and chronic graft versus host disease (GvHD) after allogenic stem cell transplantation.

BACKGROUND: Corticosteroids are commonly used in treatment of acute and chronic graft-versus-host disease (GvHD). Nevertheless, there has been no systematic analysis of effects of their use on the patients' survival and quality of life. OBJECTIVES: To compare the effect of corticosteroids in treatment of patients with GvHD and to compare the effect of different regimens of corticosteroids. SEARCH STRATEGY: We searched MEDLINE (up to July 2008), EMBASE (up to July 2008) and the Cochrane Controlled Trials Register (up to July 2008) to identify relevant studies. All of the references were assessed in order to identify additional trials. SELECTION CRITERIA: Randomized controlled trials of any language were included in the study as long as they met any of the predefined comparisons of interest. The primary outcome in question was the overall survival of the patients. Due to lack of evidence, inclusion criteria was revised during the process of the review to include studies comparing different dosage of corticosteroids. DATA COLLECTION AND ANALYSIS: All derived citations and abstracts were screened by two independent review authors for relevance. For the potentially relevant trials, the full text was obtained and reviewed by two review authors independently. Two review authors completed data extraction independently. After revising the inclusion criteria, this process was retried to ensure all relevant evidence is included in the review. MAIN RESULTS: No studies met the original inclusion criteria but two studies (four articles) met the revised inclusion criteria. As they addressed different clinical questions, meta-analysis was not performed. The outcomes of one study were in favor of efficacy of corticosteroids in inducing an earlier remission of acute GvHD, while the other study reported that early corticosteroid therapy of acute GvHD could not prevent progression of the disease to higher grades, although it was accompanied by a slightly better prognosis in the patients who responded by the fifth day of treatment. AUTHORS' CONCLUSIONS: There is no certain study regarding appropriate use, dose and length of therapy for acute GvHD. Further studies are needed to define the appropriate use of steroids and whether other agents are appropriate as frontline therapy.

Testosterone Influence on Gene Expression in Lacrimal Glands of Mouse Models of Sjögren Syndrome.

Purpose: Sjögren syndrome is an autoimmune disorder that occurs almost exclusively in women and is associated with extensive inflammation in lacrimal tissue, an immune-mediated destruction and/or dysfunction of glandular epithelial cells, and a significant decrease in aqueous tear secretion. We discovered that androgens suppress the inflammation in, and enhance the function of, lacrimal glands in female mouse models (e.g., MRL/MpJ-Tnfrsf6lpr [MRL/lpr]) of Sjögren syndrome. In contrast, others have reported that androgens induce an anomalous immunopathology in lacrimal glands of nonobese diabetic/LtJ (NOD) mice. We tested our hypothesis that these hormone actions reflect unique, strain- and tissue-specific effects, which involve significant changes in the expression of immune-related glandular genes. Methods: Lacrimal glands were obtained from age-matched, adult, female MRL/lpr and NOD mice after treatment with vehicle or testosterone for up to 3 weeks. Tissues were processed for analysis of differentially expressed mRNAs using CodeLink Bioarrays and Affymetrix GeneChips. Data were analyzed with bioinformatics and statistical software. Results: Testosterone significantly influenced the expression of numerous immune-related genes, ontologies, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in lacrimal glands of MRL/lpr and NOD mice. The nature of this hormone-induced immune response was dependent upon the autoimmune strain, and was not duplicated within lacrimal tissues of nonautoimmune BALB/c mice. The majority of immune-response genes regulated by testosterone were of the inflammatory type. Conclusions: Our findings support our hypothesis and indicate a major role for the lacrimal gland microenvironment in mediating androgen effects on immune gene expression.

Sex Effects on Gene Expression in Lacrimal Glands of Mouse Models of Sjögren Syndrome.

Purpose: Sjögren syndrome is an autoimmune disease that occurs primarily in women, and is associated with lacrimal gland inflammation and aqueous-deficient dry eye. We hypothesize that sex-associated differences in lacrimal gland gene expression are very important in promoting lymphocyte accumulation in this tissue and contribute to the onset, progression, and/or severity of the inflammatory disease process. To test our hypothesis, we explored the nature and extent of sex-related differences in gene expression in autoimmune lacrimal glands. Methods: Lacrimal glands were collected from age-matched, adult, male and female MRL/MpJ-Tnfrsf6lpr (MRL/lpr) and nonobese diabetic/LtJ (NOD) mice. Glands were processed for the analysis of differentially expressed mRNAs by using CodeLink Bioarrays and Affymetrix GeneChips. Data were evaluated with bioinformatics and statistical software. Results: Our results show that sex significantly influences the expression of thousands of genes in lacrimal glands of MRL/lpr and NOD mice. The immune nature of this glandular response is very dependent on the Sjögren syndrome model. Lacrimal glands of female, as compared with male, MRL/lpr mice contain a significant increase in the expression of genes related to inflammatory responses, antigen processing, and chemokine pathways. In contrast, it is the lacrimal tissue of NOD males, and not females, that presents with a significantly greater expression of immune-related genes. Conclusions: These data support our hypothesis that sex-related differences in gene expression contribute to lacrimal gland disease in Sjögren syndrome. Our findings also suggest that factors in the lacrimal gland microenvironment are critically important in mediating these sex-associated immune effects.

Corneal Epithelial Immune Dendritic Cell Alterations in Subtypes of Dry Eye Disease: A Pilot In Vivo Confocal Microscopic Study.

PURPOSE: To evaluate density and morphology of corneal epithelial immune dendritic cells (DCs) in different subtypes of dry eye disease (DED) using in vivo confocal microscopy (IVCM). METHODS: This retrospective study included 59 eyes of 37 patients with DED and 40 eyes of 20 age-matched healthy controls. Based on clinical tests, eyes with DED were categorized into two subtypes: aqueous-deficient (n = 35) and evaporative (n = 24). For all subjects, images of laser scanning in vivo confocal microscopy (IVCM) of the central cornea were analyzed for DC density and DC morphology (DC size, number of dendrites, and DC field). These DC parameters were compared among all dry eye and control groups. RESULTS: Compared with the controls, patients with DED had significantly higher DC density, larger DC size, higher number of dendrites, and larger DC field (all P < 0.001). Comparison between aqueous-deficient and evaporative subtypes demonstrated that DC density was significantly higher in aqueous-deficient subtype (189.8 ± 36.9 vs. 58.9 ± 9.4 cells/mm2, P = 0.001). However, there were no significant differences in morphologic parameters between DED subtypes. When aqueous-deficient DED with underlying systemic immune disease (Sjögren's syndrome and graft versus host disease) were compared with nonimmune conditions, the immunologic subgroup showed significantly higher DC density, DC size, and number of dendrites (all P < 0.05). CONCLUSIONS: Corneal IVCM demonstrated differential changes in DC density and morphologic DC parameters between subtypes of DED. These changes, which reflect the degree of immune activation and inflammation in DED, can be used for clinical practice and endpoints in clinical trials.