Psychosocial burden of autoimmune blistering diseases: A comprehensive survey study.

BACKGROUND: Autoimmune blistering diseases (AIBDs) are severe dermatologic disorders known for their debilitating physical impact. Recent research has reported that AIBDs lead to psychosocial impairment, including depression and anxiety. Missing from the extant literature is an examination of the impact of AIBDs on body image and related psychological constructs. OBJECTIVES: The current study seeks to characterize the psychological and social consequences of AIBD diagnosis, with particular attention to body image dissatisfaction. METHODS: We conducted a survey study of adults with AIBDs. The survey was open from February 2023 to March 2023. Validated self-report questionnaires assessed depressive symptomatology, body image disturbance and quality of life. Demographic information and self-reported psychiatric history before and after AIBD diagnosis were collected via self-report. Participants were 451 adults with AIBDs, recruited through the International Pemphigus and Pemphigoid Foundation newsletters, email distribution lists and social media. RESULTS: Participants reported increased incidence of psychiatric disorders following AIBD diagnosis. Participants reported high levels of depressive symptomatology and impairments to quality of life compared to other patient groups. The sample reported extremely high levels of body image disturbance, more so than other patients with disfiguring diseases or injury. Correlation analyses revealed significant relationships between body image variables and quality of life, even after controlling for depression. CONCLUSIONS: Current treatment guidelines for AIBDs focus primarily on the management of disease flares and the consequences of immunosuppression, without consideration of the psychosocial consequences of the disease. The current study underscores the need for mental health support for patients with AIBDs.

Sunscreen use and affordability attitudes based on ethnicity, socioeconomic status, and Fitzpatrick skin type.

IMPORTANCE: One in five Americans will develop skin cancer during their lifetime. While use of sunscreen can help prevent the development cutaneous cancer, regular use remains low nationwide. OBJECTIVE: To assess and better understand health care consumer preferences for sun protection products and perceived product accessibility and availability based on socioeconomic factors, race, and ethnicity. DESIGN: This quantitative survey study was conducted March through June of 2023. SETTING: Participants were recruited from two university family medicine clinical sites in the Buffalo, New York area, one located in a low and one located in a middle-to-upper socioeconomic neighborhood. PARTICIPANTS: Eligible participants were 18 years or older, fluent in English, and residents of the Buffalo, New York area. Surveys and consent forms were distributed by scripted verbal invitation, inviting all clinic patients who met eligibility criteria to participate. Participants were asked to self-report their racial/ethnic group as well as other demographic information including age, gender identification, household income, and household size. Information regarding sun exposure behaviors, and affordability/access was obtained using a combination of multiple choice and yes/no questions. A total of 405 participants were recruited. After excluding 235 incomplete responses, 170 surveys were available for analysis. INTERVENTIONS: None. MAIN OUTCOMES AND MEASURES: Our study aim was to expose health care consumer preferences as well as barriers to access based on socioeconomic factors, race, and ethnicity. RESULTS: Using a 25-question anonymous survey, 405 participants from two university family medicine clinical sites representing low- and middle-to-high-income neighborhoods, participated in the survey. 170 participants completed the survey questions and were included for analysis. Of those, 61.8% identified as female, 37.6% as male, and 0.6% as other. 51.2% of participants identified as lower income, 38.2% as middle-income, and 10.6% as upper income. The results of the survey revealed disparities in sunscreen use and affordability perceptions across demographic groups. Compared with Hispanics, Caucasians exhibited higher rates of sunscreen use (85 Caucasians, 7 Hispanics; p = 0.0073), prioritized SPF (95 Caucasians, 10 Hispanics; p = 0.0178), and were more likely to perceive sunscreen as unaffordable (6 Caucasians, 4 Hispanics; p = 0.0269). Analysis by Fitzpatrick Skin Type demonstrated differences in sunscreen utilization, with Types I-III using more compared to Types IV-VI (70 Types I-III, 51 Types IV-VI; p = 0.0173); additionally, Type I-III individuals were significantly more likely to cite cost as barrier to sunscreen purchase (40 Type I-III, 65 Types IV-VI; p < 0.0001). Moreover, lower-income individuals were significantly more likely to perceive sunscreen as unaffordable (12 lower-income, 1 middle & upper income; p = 0.0025) and cited cost as a barrier to purchase (46 lower-income, 59 middle & upper income; p = 0.0146) compared to middle-to-upper income counterparts. Though statistical significance was not established, respondents from middle & upper income groups reported higher sunscreen usage rates compared with their lower-income peers. CONCLUSIONS AND RELEVANCE: These findings highlight the importance of socioeconomic factors and ethnicity on accessibility to sunscreen and the impact of disparities in utilization among different ethnic and socioeconomic groups.

Low-Level Parasite Persistence Drives Vasculitis and Myositis in Skeletal Muscle of Mice Chronically Infected with Trypanosoma cruzi.

In chronic Trypanosoma cruzi infection, the cause of Chagas disease, life-threatening inflammatory diseases develop over time in the heart, esophagus, and colon of some patients. C57BL/6 mice infected with the myotropic Colombiana strain of T. cruzi model many of the immunological and parasitological features of human infection but succumb to chronic paralyzing myositis and skeletal muscle vasculitis, not cardiomyopathy or gastrointestinal disease. Here we show that T cell depletion in the chronic phase of this model increased tissue parasitism to acute-phase levels and induced neutrophilic skeletal muscle inflammation. Conversely, after daily treatment with the trypanocide benznidazole for 8 weeks during the chronic phase, viable parasites were no longer detectable, myositis completely resolved, vasculitis was ∼80% reduced, fibrosis was reduced, and myofiber morphology normalized. After the drug was discontinued, parasitism rebounded, and immunopathology recurred. The parasite load was statistically strongly correlated with the severity of inflammation. Thus, both T cell immunity and trypanocidal pharmacotherapy suppress to very low levels, but do not cure, T. cruzi infection, which is necessary and possibly sufficient to induce crippling chronic skeletal muscle myositis and vasculitis in the model.

Self-management of stress urinary incontinence via a mobile app: two-year follow-up of a randomized controlled trial.

INTRODUCTION: We investigated the long-term effects of using a mobile app to treat stress urinary incontinence with a focus on pelvic floor muscle training. MATERIAL AND METHODS: A previous randomized controlled trial of 123 women aged 27-72 years found that three months of self-managing stress urinary incontinence with support from the Tät® app was effective. We followed up the women in the app group (n = 62) two years after the initial trial with the same primary outcomes for symptom severity (International Consultation on Incontinence Questionnaire Short Form) and condition-specific quality of life (ICIQ-Lower Urinary Tract Symptom Quality of Life) and compared the scores with those at baseline. RESULTS: Of the 62 women, 61 and 46 (75.4%), respectively, participated in three-month and two-year follow-ups. Baseline data did not differ between responders and non-responders at follow-up. The mean decreases in International Consultation on Incontinence Questionnaire Short Form and ICIQ-Lower Urinary Tract Symptom Quality of Life scores after two years were 3.1 (95% confidence interval 2.0-4.2) and 4.0 (95% confidence interval 2.1-5.9), respectively. Of the 46 women, four (8.7%) rated themselves as very much better, nine (19.6%) as much better, and 16 (34.8%) as a little better. The use of incontinence protection products decreased significantly (p = 0.04), and the proportion of women who felt they could contract their pelvic muscles correctly increased from 14/46 (30.4%) at baseline to 31/46 (67.4%) at follow-up (p < 0.001). CONCLUSIONS: Self-management of stress urinary incontinence with support from the Tät® app had significant and clinically relevant long-term effects and may serve as first-line treatment.

Orai1-Mediated Antimicrobial Secretion from Pancreatic Acini Shapes the Gut Microbiome and Regulates Gut Innate Immunity.

The gut microbiome participates in numerous physiologic functions and communicates intimately with the host immune system. Antimicrobial peptides are critical components of intestinal innate immunity. We report a prominent role for antimicrobials secreted by pancreatic acini in shaping the gut microbiome that is essential for intestinal innate immunity, barrier function, and survival. Deletion of the Ca2+ channel Orai1 in pancreatic acini of adult mice resulted in 60%-70% mortality within 3 weeks. Despite robust activation of the intestinal innate immune response, mice lacking acinar Orai1 exhibited intestinal bacterial outgrowth and dysbiosis, ultimately causing systemic translocation, inflammation, and death. While digestive enzyme supplementation was ineffective, treatments constraining bacterial outgrowth (purified liquid diet, broad-spectrum antibiotics) rescued survival, feeding, and weight gain. Pancreatic levels of cathelicidin-related antimicrobial peptide (CRAMP) were reduced, and supplement of synthetic CRAMP prevented intestinal disease. These findings reveal a critical role for antimicrobial pancreatic secretion in gut innate immunity.

Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice.

Infectious agents are often considered potential triggers of chronic inflammatory disease, including autoimmunity; however, direct evidence is usually lacking. Here we show that following control of acute infection of mice with the myotropic Colombiana strain of Trypanosoma cruzi, parasites persisted in tissue at low levels associated with development of systemic necrotizing vasculitis. Lesions occurred in many but not all organs and tissues, with skeletal muscle arteries being the most severely affected, and were associated with myositis, atrophy, paresis/paralysis, and death. Histopathology showed fibrinoid vascular necrosis, rare amastigote nests within skeletal muscle myocytes, and massive leukocyte infiltrates composed mainly of inflammatory monocytes, F4/80(+)macrophages, and T. cruzi tetramer-specific CD8(+) T lymphocytes capable of producing gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) but not interleukin-17 (IL-17). T. cruzi-specific IgG was detected in sera from infected mice, but antibody deposits and neutrophilic inflammation were not features of the lesions. Thus,T. cruzi infection of mice may be a specific infectious trigger of paralyzing systemic necrotizing vasculitis most severely affecting skeletal muscle, driven by pathogen-specific type I immune responses.

Immunoglobulin E plays an immunoregulatory role in lupus.

The (patho)physiological role of IgE in nonallergic inflammatory diseases is not well understood. Here, we explored the effect of IgE deficiency on the inflammatory response in FcγRIIB-deficient mice as well as in mice carrying both a deletion of FcγRIIB and the chromosomal translocation of Y-linked autoimmune acceleration (Yaa) that hastens and results in a more aggressive lupuslike disease in these mice. The findings show that deficiency of IgE delays disease development and severity as demonstrated by reduced autoantibody production and amelioration of organ pathologies. This was associated with decreased numbers of plasma cells and reduced levels of IgG2b and IgG3. Unexpectedly, the loss of IgE also caused a striking decrease of immune cell infiltration in secondary lymphoid organs with a marked effect on the presence of dendritic cells, monocytes, neutrophils, and eosinophils in these organs and decreased activation of basophils. The presence of autoreactive IgE in human systemic lupus erythematosus subjects was also associated with increased basophil activation and enhanced disease activity. These findings argue that IgE facilitates the amplification of autoimmune inflammation.

Investigation and identification of etiologies involved in the development of acquired hydronephrosis in aged laboratory mice with the use of high-frequency ultrasound imaging.

Laboratory mice develop naturally occurring lesions that affect biomedical research. Hydronephrosis is a recognized pathologic abnormality of the mouse kidney. Acquired hydronephrosis can affect any mouse, as it is caused by any naturally occurring disease that impairs free urine flow. Many etiologies leading to this condition are of particular significance to aging mice. Non-invasive ultrasound imaging detects renal pelvic dilation, renal enlargement, and parenchymal loss for pre-mortem identification of this condition. High-frequency ultrasound transducers produce high-resolution images of small structures, ideal for detecting organ pathology in mice. Using a 40 MHz linear array transducer, we obtained high-resolution images of a diversity of pathologic lesions occurring within the abdomen of seven geriatric mice with acquired hydronephrosis that enabled a determination of the underlying etiology. Etiologies diagnosed from the imaging results include pyelonephritis, neoplasia, urolithiasis, mouse urologic syndrome, and spontaneous hydronephrosis, and were confirmed at necropsy. A retrospective review of abdominal scans from an additional 149 aging mice shows that the most common etiologies associated with acquired hydronephrosis are mouse urologic syndrome and abdominal neoplasia. This report highlights the utility of high-frequency ultrasound for surveying research mice for age-related pathology, and is the first comprehensive report of multiple cases of acquired hydronephrosis in mice.

Mutation of inhibitory helix-loop-helix protein Id3 causes γδ T-cell lymphoma in mice.

Human γδ T-cell lymphoma is a rare clinicopathologic entity with aggressive course and poor prognosis. The etiology and pathogenesis of γδ T-cell lymphoma is unknown. We show here that mice with deficiency in inhibitory helix-loop-helix protein Id3 (Id3(-/-)) developed γδ T-cell lymphoma that resembled human γδ T-cell lymphoma. The Id3(-/-) mice with lymphoma showed splenomegaly, hepatomegaly, and lymphadenopathy with involvement of bone marrow, thymus, kidney, and lungs between 6 and 15 months of age. Phenotypic analysis revealed that lymphomatous cells were cluster of differentiation (CD)3(+), γδ T-cell receptor (TCR)(+), and αß TCR(-), and expressed CD8(+)CD4(-), CD4(+)CD8(-), or a mixture of the two. Id3(-/-) γδ T-cell lymphoma used predominantly Vγ1.1, some Vγ3, yet no Vγ2 TCR, and some showed increased levels of the oncogene c-Myc. Strikingly, adoptive transfer of the γδ T-cell lymphoma into syngeneic Rag1(-/-) mice resulted in aggressive γδ T-cell lymphoma, identical to the Id3(-/-) donor. Thus, our data demonstrate that Id3 regulates the development of γδ T-cell lymphoma in mice, raising a possibility of Id3 gene mutation in human γδ T-cell lymphoma. Our model will provide a tool for studying the molecular mechanisms and development of human γδ T-cell lymphoma.

Generation of the pathogenic R5-tropic simian/human immunodeficiency virus SHIVAD8 by serial passaging in rhesus macaques.

A new pathogenic R5-tropic simian/human immunodeficiency virus (SHIV) was generated following serial passaging in rhesus macaques. All 13 animals inoculated with SHIV(AD8) passaged lineages experienced marked depletions of CD4(+) T cells. Ten of these infected monkeys became normal progressors (NPs) and had gradual losses of both memory and naïve CD4(+) T lymphocytes, generated antiviral CD4(+) and CD8(+) T cell responses, and sustained chronic immune activation while maintaining variable levels of plasma viremia (10(2) to 10(5) RNA copies/ml for up to 3 years postinfection [p.i.]). To date, five NPs developed AIDS associated with opportunistic infections caused by Pneumocystis carinii, Mycobacterium avium, and Campylobacter coli that required euthanasia between weeks 100 and 199 p.i. Three other NPs have experienced marked depletions of circulating CD4(+) T lymphocytes (92 to 154 cells/microl) following 1 to 2 years of infection. When tested for coreceptor usage, the viruses isolated from four NPs at the time of their euthanasia remained R5 tropic. Three of the 13 SHIV(AD8)-inoculated macaques experienced a rapid-progressor syndrome characterized by sustained plasma viremia of >1 x 10(7) RNA copies/ml and rapid irreversible loss of memory CD4(+) T cells that required euthanasia between weeks 19 and 23 postinfection. The sustained viremia, associated depletion of CD4(+) T lymphocytes, and induction of AIDS make the SHIV(AD8) lineage of viruses a potentially valuable reagent for vaccine studies.

Effects of endogenous ascorbate on oxidation, oxygenation, and toxicokinetics of cell-free modified hemoglobin after exchange transfusion in rat and guinea pig.

Chemically modified hemoglobin (Hb) solutions are promising oxygen therapeutics; however, these agents are prone to intravascular oxidation. Using a 50% exchange transfusion (ET) model with bovine polymerized hemoglobin (PolyHbBv), we examined heme oxidation, oxygenation markers, and toxicokinetics in rats, an ascorbic acid (AA)-producing species, and in guinea pigs, a non-AA-producing species. Plasma AA decreased by 50% in guinea pigs after ET, but it was unchanged in rats for the first 20 h post-ET. Both species cleared PolyHbBv from the circulation at similar rates. However, exposure to ferric PolyHbBv over time was 5-fold greater in the guinea pig. Mass spectrometry analysis of plasma revealed oxidative modifications within the tetrameric fraction of PolyHbBv in guinea pig. Oxygen equilibrium curves of PolyHbBv measured in plasma after ET were more left-shifted in guinea pigs compared with rats, consistent with increased ferric PolyHbBv formation. Renal hypoxia-inducible factor (HIF)-1alpha, whose activity strictly depends on the partial pressure of oxygen increased over time, and it correlated inversely with circulating ferrous PolyHbBv in both species. Interestingly, HIF-1alpha activity was greater in guinea pigs compared with rats at 72 h post-ET. Mean arterial pressure increases were also greater in guinea pigs; however, minimal differences in cardiac and renal pathology were observed in either species. The present findings suggest the importance of plasma AA in maintaining the stability of acellular Hb susceptible to oxidation, and they may be relevant to humans, which display a similar plasma/tissue antioxidant status to guinea pig.

Demodex spp. in the hair follicles of rhesus macaques (Macaca mulatta).

The perineal or perineal and facial skin were evaluated on 53 rhesus macaques as part of a necropsy protocol. Microscopic evaluation of H & E stained skin sections revealed 19 animals positive for Demodex spp. Mites were seen within all portions of the hair follicles. Infestation varied from minimal to severe. Mites were found in macaques of all ages and in both sexes. Reaction to the mites ranged from no reaction, to minimal follicular epidermal hyperplasia to furunculosis. Immune status of the animal did not determine infestation but immune compromised macaques had more severe lesions. This is the first known report of Demodex spp. in rhesus macaques.

Use of a hemoglobin-based oxygen-carrying solution in cats: 72 cases (1998-2000).

OBJECTIVE: To determine clinical features and outcome associated with use of a hemoglobin-based oxygen-carrying (HBOC) solution in cats. DESIGN: Retrospective study. ANIMALS: 72 cats. PROCEDURE: Medical records of cats that received an HBOC solution were reviewed. RESULTS: The most common clinical signs and physical examination findings prior to infusion of the HBOC solution were associated with anemia; vomiting, neurologic signs, and respiratory abnormalities were also detected. The HBOC solution was given as a supportive measure in treatment of anemia in 70 cats, most often because compatible blood was not readily available. There were 80 separate HBOC solution infusion events (mean dose, 14.6 ml/kg [6.6 mg/lb]; mean rate of infusion, 4.8 ml/kg [2.2 ml/lb] per hour). Improvements in 37 of 43 of the more closely monitored cats included increased rectal temperature, blood hemoglobin concentration, blood pressure, appetite, and activity. Adverse events in 44 cats included pulmonary edema (n = 8), pleural effusion (21), mucous membrane discoloration (21), pigmenturia (11), vomiting (4), and neurologic abnormalities (4). Twenty-three cats were discharged from the hospital, and 49 cats died or were euthanatized. Necropsy examination of 23 cats did not reveal evidence of renal or hepatic toxicosis associated with HBOC administration. CONCLUSIONS AND CLINICAL RELEVANCE: Although administration of an HBOC solution may provide temporary support to anemic cats, the development of pulmonary edema or pleural effusion potentially associated with rapid infusion rate and large volume of infusion of the HBOC solution should be investigated further before use of the solution can be recommended in cats.