Impacto da implantação do inventário rotativo diário na acurácia do estoque de medicamentos em um hospital público de médio porte / Impact of the implementation of the daily rotating inventory on the accuracy of the medicines stock in a medium-sized public hospital

Objetivo: Avaliar o impacto da implantação do inventário rotativo diário na acurácia do estoque de medicamentos em um hospital público de médio porte. Metodologia: Trata-se de um estudo descritivo exploratório transversal que avaliou a implantação de um inventário rotativo de janeiro a julho de 2022. Foram selecionados 143 medicamentos que posteriormente foram inventariados, uma vez por mês, ao longo de sete meses. Esses medicamentos foram classificados segundo a curva ABC, XYZ e o grau de divergência em: baixo, médio e alto. Foi calculada a acurácia para cada grupo, ao longo dos meses analisados, e o Percentual de Mudança Relativa (PMR) para comparação entre o período inicial e final. Resultado: Houveum aumento de 64% na acurácia do estoque de medicamentos, sendo observada diferença entre os grupos ABC e XYZ. Em relação a curva ABC, o grupo A teve um aumento de 170%, o B de 358% e o C de 23% no mesmo período. Em relação a criticidade, o grupo Z foi o que teve maior acurácia, seguido dos grupos Y e X. Os medicamentos classificados como de alta taxa de divergência tiveram redução de 80% e o de baixa 25% após implantação do inventário. Conclusão: A implantação do inventário rotativo aumentou a acurácia do estoque de medicamentos ao longo dos meses avaliados. Essa ferramenta pode ser uma estratégia utilizada na melhoria do gerenciamento de estoque de medicamentos. (AU)

Objective: To evaluate the impact of implementing a daily rotating inventory on the accuracy of medicines stocks in a medium-sized public hospital. Methodology: This is a cross-sectional exploratory descriptive study that evaluated the implementation of a rotating inventory from January to July 2022. 143 medicines were selected and subsequently inventoried once a month over seven months. These medicines were classified according to the ABC, XYZ curve and the degree of divergence in low, medium and high. Accuracy was calculated for each group, over the analyzed months, and the Relative Percentage Change (RPC) for comparison between the initial and final period. Result: There was a 64% increase in the accuracy of medicines inventory, with a difference being observed between the ABC and XYZ groups. Regarding the ABC curve, group A had an increase of 170%, group B 358% and group C 23% in the same period. Regarding criticality, group Z had the highest accuracy, followed by groups Y and X. Medicines classified as having a high rate of divergence had a reduction of 80% and the low rate of 25% after implementation of the inventory. Conclusion: The implementation of the rotating inventory increased the accuracy of the medicines stock over the evaluated months. This tool can be a strategy used to improve medicine inventory management. (AU)

Sex-specific involvement of the Notch-JAG pathway in social recognition.

Under the hypothesis that olfactory neural epithelium gene expression profiles may be useful to look for disease-relevant neuronal signatures, we examined microarray gene expression in olfactory neuronal cells and underscored Notch-JAG pathway molecules in association with schizophrenia (SZ). The microarray profiling study underscored JAG1 as the most promising candidate. Combined with further validation with real-time PCR, downregulation of NOTCH1 was statistically significant. Accordingly, we reverse-translated the significant finding from a surrogate tissue for neurons, and studied the behavioral profile of Notch1+/- mice. We found a specific impairment in social novelty recognition, whereas other behaviors, such as sociability, novel object recognition and olfaction of social odors, were normal. This social novelty recognition deficit was male-specific and was rescued by rapamycin treatment. Based on the results from the animal model, we next tested whether patients with psychosis might have male-specific alterations in social cognition in association with the expression of NOTCH1 or JAG1. In our first episode psychosis cohort, we observed a specific correlation between the expression of JAG1 and a face processing measure only in male patients. The expression of JAG1 was not correlated with any other cognitive and symptomatic scales in all subjects. Together, although we acknowledge the pioneering and exploratory nature, the present work that combines both human and animal studies in a reciprocal manner suggests a novel role for the Notch-JAG pathway in a behavioral dimension(s) related to social cognition in psychotic disorders in a male-specific manner.

Evaluation of five different suture materials in the skin of the earthworm (Lumbricus terrestris).

The purpose of this study was to determine which suture material is the most appropriate for dermal closure of terrestrial annelids. This paper describes the tissue reactions of the earthworm, Lumbricus terrestris, to five different types of suture materials in order to determine which suture material is the most appropriate for dermal closure. Silk, monofilament nylon, polydiaxonone, polyglactin 910, and chromic gut were studied. There was mild to moderate tissue reaction to all five suture materials. In all of the biopsies wound-healing reaction consisted of aggregates of blastemal cells which appeared in various stages of dedifferentiation from the body wall. Inflammatory cells infiltrated the wound sites, reminiscent of the typical foreign body reaction in vertebrates. The results indicate polyglactin 910 would be the best suture material with regards to tissue security and reaction scores. Chromic gut occupies the next position but there were problems with suture security over time. This appears to be the first suture material performance study on a terrestrial invertebrate. The earthworm, Lumbricus terrestris, was chosen for its wide availability, size, and the extensive species knowledge base. The earthworm may prove to be a good surgical/suture model for economically important invertebrates such as mollusks, tunicates, and insect larval stages.

Detection of pituitary antibodies by immunofluorescence: approach and results in patients with pituitary diseases.

CONTEXT: Pituitary antibodies have been measured mainly to identify patients whose disease is caused or sustained by pituitary-specific autoimmunity. Although reported in over 100 publications, they have yielded variable results and are thus considered of limited clinical utility. OBJECTIVES: Our objectives were to analyze all publications reporting pituitary antibodies by immunofluorescence for detecting the major sources of variability, to experimentally test these sources and devise an optimized immunofluorescence protocol, and to assess prevalence and significance of pituitary antibodies in patients with pituitary diseases. STUDY DESIGN AND OUTCOME MEASURES: We first evaluated the effect of pituitary gland species, section fixation, autofluorescence quenching, blockade of unwanted antibody binding, and use of purified IgG on the performance of this antibody assay. We then measured cross-sectionally the prevalence of pituitary antibodies in 390 pituitary cases and 60 healthy controls, expressing results as present or absent and according to the (granular, diffuse, perinuclear, or mixed) staining pattern. RESULTS: Human pituitary was the best substrate to detect pituitary antibodies and yielded an optimal signal-to-noise ratio when treated with Sudan black B to reduce autofluorescence. Pituitary antibodies were more common in cases (95 of 390, 24%) than controls (3 of 60, 5%, P = .001) but did not discriminate among pituitary diseases when reported dichotomously. However, when expressed according to their cytosolic staining, a granular pattern was highly predictive of pituitary autoimmunity (P < .0001). CONCLUSION: We report a comprehensive study of pituitary antibodies by immunofluorescence and provide a method and an interpretation scheme that should be useful for identifying and monitoring patients with pituitary autoimmunity.

Modeling heterogeneous patients with a clinical diagnosis of schizophrenia with induced pluripotent stem cells.

Schizophrenia (SZ) is a devastating complex genetic mental condition that is heterogeneous in terms of clinical etiologies, symptoms, and outcomes. Despite decades of postmortem, neuroimaging, pharmacological, and genetic studies of patients, in addition to animal models, much of the biological mechanisms that underlie the pathology of SZ remain unknown. The ability to reprogram adult somatic cells into human induced pluripotent stem cells (hiPSCs) provides a new tool that supplies live human neurons for modeling complex genetic conditions such as SZ. The purpose of this review is to discuss the technical and clinical constraints currently limiting hiPSC-based studies. We posit that reducing the clinical heterogeneity of hiPSC-based studies, by selecting subjects with common clinical manifestations or rare genetic variants, will help our ability to draw meaningful insights from the necessarily small patient cohorts that can be studied at this time.

Deficits in microRNA-mediated Cxcr4/Cxcl12 signaling in neurodevelopmental deficits in a 22q11 deletion syndrome mouse model.

22q11 deletion syndrome (22q11DS) frequently accompanies psychiatric conditions, some of which are classified as schizophrenia and bipolar disorder in the current diagnostic categorization. However, it remains elusive how the chromosomal microdeletion leads to the mental manifestation at the mechanistic level. Here we show that a 22q11DS mouse model with a deletion of 18 orthologous genes of human 22q11 (Df1/+ mice) has deficits in migration of cortical interneurons and hippocampal dentate precursor cells. Furthermore, Df1/+ mice show functional defects in Chemokine receptor 4/Chemokine ligand 12 (Cxcr4/Cxcl12; Sdf1) signaling, which reportedly underlie interneuron migration. Notably, the defects in interneuron progenitors are rescued by ectopic expression of Dgcr8, one of the genes in 22q11 microdeletion. Furthermore, heterozygous knockout mice for Dgcr8 show similar neurodevelopmental abnormalities as Df1/+ mice. Thus, Dgcr8-mediated regulation of microRNA is likely to underlie Cxcr4/Cxcl12 signaling and associated neurodevelopmental defects. Finally, we observe that expression of CXCL12 is decreased in olfactory neurons from sporadic cases with schizophrenia compared with normal controls. Given the increased risk of 22q11DS in schizophrenia that frequently shows interneuron abnormalities, the overall study suggests that CXCR4/CXCL12 signaling may represent a common downstream mediator in the pathophysiology of schizophrenia and related mental conditions.

Hepatic encephalopathy: etiology, pathogenesis, and clinical signs.

Hepatic encephalopathy (HE) is a manifestation of clinical signs that may result from a variety of liver diseases. In small animals, HE is most commonly a result of portosystemic shunting. The pathogenesis is not completely understood, although it is likely multifactorial. Theories of pathogenesis include altered ammonia metabolism and glutamine and glutamate transmission, an increase in gamma-aminobutyric acid agonists and benzodiazepine-like substances, alterations of the serotonergic system and amino acid metabolism, elevated taurine levels, contributions from inflammatory mediators, and toxic effects of manganese. An understanding of the underlying mechanisms that result in HE may lead to new treatments in the future.

Hepatic encephalopathy: diagnosis and treatment.

Hepatic encephalopathy (HE) is a neurologic syndrome resulting from the synergistic action of multiple pathologic factors, which are discussed in a companion article. Early recognition of the clinical signs can improve treatment outcome, as well as reduce the incidence of risk factors. Multimodal treatment of HE is usually indicated. Studies on the pathogenesis and treatment of HE in people may shed new light on further treatment modalities in small animal patients.

Anatabine ameliorates experimental autoimmune thyroiditis.

Tobacco smoking favorably influences the course of Hashimoto thyroiditis, possibly through the antiinflammatory proprieties of nicotine. In this study we tested anatabine, another tobacco alkaloid, in a model of experimental autoimmune thyroiditis. Experimental autoimmune thyroiditis was induced by different doses of thyroglobulin, to produce a disease of low, moderate, or high severity, in 88 CBA/J female mice: 43 drank anatabine supplemented water and 45 regular water. Mice were bled after immunization and killed to assess thyroid histopathology, thyroglobulin antibodies, T(4), and thyroid RNA expression of 84 inflammatory genes. We also stimulated in vitro a macrophage cell line with interferon-γ or lipopolysaccharide plus or minus anatabine to quantitate inducible nitric oxide synthase and cyclooxygenase 2 protein expression. Anatabine reduced the incidence and severity of thyroiditis in the moderate disease category: only 13 of 21 mice (62%) developed thyroid infiltrates when drinking anatabine as compared with 22 of 23 (96%) controls (relative risk 0.59, P = 0.0174). The median thyroiditis severity was 0.5 and 2.0 in anatabine and controls, respectively (P = 0.0007 by Wilcoxon rank sum test). Anatabine also reduced the antibody response to thyroglobulin on d 14 (P = 0.029) and d 21 (P = 0.045) after immunization and improved the recovery of thyroid function on d 21 (P = 0.049). In the thyroid transcriptome, anatabine restored expression of IL-18 and IL-1 receptor type 2 to preimmunization levels. Finally, anatabine suppressed in a dose-dependent manner macrophage production of inducible nitric oxide synthase and cyclooxygenase 2. Anatabine ameliorates disease in a model of autoimmune thyroiditis, making the delineation of its mechanisms of action and potential clinical utility worthwhile.

A percepção dos estudantes de graduação sobre a atuação do "doutor palhaço" em um hospital universitário / Ungraduate students view on the presence of clown-doctors at the University Hospital

Objetivos: Compreender como os estudantes percebem a humanização da saúde, bem como as contribuições do Projeto Y doutores-palhaços na formação acadêmica e na rotina hospitalar, identificando a relevância do grupo neste meio na construção de novos paradigmas. Métodos: Estudo envolveu dimensão qualitativa, com participação de acadêmicos de medicina/psicologia e estagiários da enfermaria pediátrica de um Hospital Universitário, Fortaleza CE, Brasil. Foram realizadas, no período de março a julho de 2009, dez entrevistas individuais gravadas e transcritas na íntegra que foram analisadas por rede interpretativa, composta pelas categorias: conhecendo o Projeto Y: diferentes formas percebidas; atuação do Projeto Y no ambiente hospitalar: a percepção dessa estratégia na visão dos espectadores; a humanização na saúde: o olhar do futuro profissional. O referencial interpretativo contempla concepções relativas a atividades de promoção à saúde, embasadas na humanização da assistência, desempenhadas por estudantes de graduação em formação. Resultados: Os estudantes conheceram o Projeto Y a partir da observação das atividades realizadas nas enfermarias e ao perceberem os sorrisos das crianças durante a integração com os palhaços. Relatam que as visitas diminuem o estresse das crianças, dos acompanhantes e auxiliam na recuperação dos doentes, atua também na formação humanizada do profissional de saúde, considerada essencial, e contribui para a prática da multidisciplinaridade. Conclusões: Os entrevistados acreditam que o Projeto Y pode influenciar positivamente na formação do profissional de saúde, ampliando a prática interdisciplinar e proporcionando alívio à dor integral do paciente. Dessa forma, aprimora a comunicação daqueles que partilham o ambiente hospitalar e alivia o sofrimento humano.

Objectives: To understand how students perceive the humanization of health, as well as the contributions of Project Y clown doctors in academic and hospital routine, identifying the relevance of this group through the construction of new paradigms. Methods: The study involved qualitative dimension, with the participation of medical students / interns in psychology and pediatric ward from a university hospital in Fortaleza - CE, Brazil. From March to July 2009, ten interviews were performed, recorded and fully transcribed and analyzed by interpretative network, comprising the categories: knowing the Project Y: different forms cognizable; role of Project Y in the hospital environment: the perception of this strategy in view of the spectators; humanization in health: the look of the future professional. The interpretive framework includes concepts related to health promotion activities, basedin the humanization of care performed by graduate students in training. Results: Students have known Project Y from the observation of the activities performed in the infirmaries and to realize the smiles of children during the integration with the clowns. Reported that the visits, as well as diminishing the stress of children, caregivers and assist in the recovery of patients, also act in humane training of health professionals and contributes to the practice of multidisciplinarity. Conclusions: The respondents believe that Project Y can positively influence the training of health professionals, expanding interdisciplinary practice and providing complete pain relief of the patient. Thus, enhances communication of those who share the hospital environment and relieve human suffering.

Pituitary antibodies in women with Hashimoto's thyroiditis: prevalence in diagnostic and prediagnostic sera.

BACKGROUND: Pituitary antibodies have been reported with greater frequency in patients with Hashimoto's thyroiditis than in healthy controls, although there is significant variability in the strength of the association and the methodologies used. METHODS: We designed a nested case-control study to characterize the prevalence of pituitary antibodies at the time of the clinical diagnosis of Hashimoto's thyroiditis, as well as at 2, 5, and 7 years before diagnosis. Active component female service member cases (n=87) and matched female controls (n=107) were selected using the Defense Medical Surveillance System database (DMSSD) between January 1998 and December 2007. Pituitary antibodies were measured by immunofluorescence using human pituitary glands collected at autopsy as the substrate. RESULTS: At diagnosis, pituitary antibodies were present in 9% of cases with Hashimoto's (8 of 87) and 3% of controls (3 of 107). When the data were analyzed using a conditional logistic regression model, which takes into account the matching on age and work status, pituitary antibodies increased the odds of having Hashimoto's thyroiditis by sevenfold (95% confidence interval from 1.3 to 40.1, p=0.028), after adjusting for components of the DMSSD-category-termed race and for thyroperoxidase antibodies. Before diagnosis, pituitary antibodies were positive in 3 of the 11 subjects (2 cases and 1 control) at the -2-year time point, and negative in all 11 subjects at the -5- and -7-year time points. CONCLUSIONS: In summary, using a nested case-control design, we confirm that pituitary antibodies are more common in Hashimoto's thyroiditis and suggest that they appear late during its natural history.

Placenta suppresses experimental autoimmune hypophysitis through soluble TNF receptor 1.

Pregnancy modulates autoimmune diseases through diverse and still incompletely defined mechanisms, in part operating at the decidua-placenta interface. To assess the immunological contribution of placenta, we administered mouse placental proteins to a mouse model of autoimmune hypophysitis, a disease known to be strongly associated with pregnancy. Emulsified placental proteins suppressed both the cellular and humoral aspects of hypophysitis. Suppression was specific to self antigens and not seen when two foreign antigens, tetanus toxoid or tuberculin purified protein derivative, were used. Proteomic analysis revealed high levels of soluble TNF receptor 1 in placenta, suggesting that blockade of the TNF-α pathway was a mechanism of disease suppression. Placentas derived from mice deficient in TNF receptor 1 lost the ability to suppress hypophysitis. Notably, hypophysitis suppression was seen only when the TNF-α pathway was blocked locally, at the site of immunization, and not systemically. These findings provide evidence that placenta contributes to the immune tolerance of pregnancy by locally inhibiting the TNF-α pathway.

From pituitary expansion to empty sella: disease progression in a mouse model of autoimmune hypophysitis.

Lymphocytic hypophysitis has a variable clinical course, where a swelling of the pituitary gland at presentation is thought to be followed by pituitary atrophy and empty sella. Data in patients, however, are scanty and contradictory. To better define the course of hypophysitis, we used an experimental model based on the injection of pituitary proteins into SJL mice. A cohort of 33 mice was divided into three groups: 18 cases were immunized with pituitary proteins emulsified in complete Freund's adjuvant; six controls were injected with adjuvant only; and nine controls were left untreated. Mice were followed by cranial magnetic resonance imaging (MRI) for up to 300 d, for a total of 106 MRI scans, and killed at different time points to correlate radiological and pathological findings. Empty sella was defined as a reduction in pituitary volume greater than 2 sd below the mean volume. All immunized mice showed by MRI a significant expansion of pituitary volume during the early phases of the disease. The volume then decreased gradually in the majority of cases (14 of 18, 78%), reaching empty sella values by d 300 after immunization. In a minority of cases (four of 18, 22%), the decrease was so rapid and marked to induce a central area of necrosis accompanied by hemorrhages, mimicking the condition known in patients as pituitary apoplexy. No radiological or pathological changes were observed in controls. Overall, these findings indicate that the evolution of hypophysitis is complex but can lead, through different routes, to the development of empty sella.

IgG4-related hypophysitis: a new addition to the hypophysitis spectrum.

CONTEXT: Hypophysitis is a chronic inflammation of the pituitary gland that comprises an increasingly complex clinicopathological spectrum. Within this spectrum, lymphocytic and granulomatous hypophysitis are the most common forms, but newer variants have recently been reported. OBJECTIVE: The aims of the study were to describe a new patient with IgG4-related hypophysitis, review the published literature, and provide diagnostic criteria. SETTING: A 75-yr-old man presented with a 1-yr history of frontal headache. Initial studies revealed panhypopituitarism and a mass in both the sella turcica and the sphenoidal sinus. The patient underwent transphenoidal surgery, initiated high-dose prednisone followed by hormone replacement therapy, and was closely monitored for 3 yr. RESULTS: Symptoms improved after prednisone, along with shrinkage of the pituitary and sphenoidal masses, but recurred when prednisone dose was lowered. Histopathology showed a marked mononuclear infiltrate in both the pituitary and sphenoidal specimens, mainly characterized by increased numbers of plasma cells. Many of the infiltrating plasma cells (>10 per high-power field) were IgG4-positive. Review of the literature identified 11 cases of IgG4-related hypophysitis (two diagnosed based on pituitary histopathology). CONCLUSIONS: We describe the first Caucasian patient with biopsy-proven IgG4-related hypophysitis and provide classification criteria for this disease.

Pituitary and systemic autoimmunity in a case of intrasellar germinoma.

Germinomas arising in the sella turcica are difficult to differentiate from autoimmune hypophysitis because of similar clinical and pathological features. This differentiation, nevertheless, is critical for patient care due to different treatments of the two diseases. We report the case of an 11-year-old girl who presented with diabetes insipidus and growth retardation, and was found to have an intra- and supra-sellar mass. Initial examination of the pituitary biopsy showed diffuse lymphocytic infiltration of the adenohypophysis and absent placental alkaline phosphatase expression, leading to a diagnosis of hypophysitis and glucocorticoid treatment. Because of the lack of clinical and radiological response, the pituitary specimen was re-examined, revealing this time the presence of scattered c-kit and Oct4 positive germinoma cells. The revised diagnosis prompted the initiation of radiotherapy, which induced disappearance of the pituitary mass. Immunological studies showed that the patient's serum recognized antigens expressed by the patient's own germinoma cells, as well as pituitary antigens like growth hormone and systemic antigens like the Sjögren syndrome antigen B and alpha-enolase. The study first reports the presence of pituitary and systemic antibodies in a patient with intrasellar germinoma, and reminds us that diffuse lymphocytic infiltration of the pituitary gland and pituitary antibodies does not always indicate a diagnosis of autoimmune hypophysitis.

Pregnancy, postpartum autoimmune thyroiditis, and autoimmune hypophysitis: intimate relationships.

Autoimmune diseases comprise a group of about 85 heterogeneous conditions that can affect virtually any organ and tissue in the body. Many autoimmune diseases change significantly during pregnancy: some ameliorate, some worsen, and others are unaffected. Two autoimmune diseases present prominently in relation to pregnancy: postpartum autoimmune thyroiditis and autoimmune hypophysitis. This article will review the current state of knowledge of the immunological changes that occur during normal pregnancy, and will explore the striking temporal association with pregnancy observed in thyroiditis and hypophysitis.

Preparation of mouse pituitary immunogen for the induction of experimental autoimmune hypophysitis.

Autoimmune hypophysitis is a chronic inflammation of the pituitary gland caused or accompanied by autoimmunity(1). It has traditionally been considered a rare disease but reporting has increased markedly in recent years. Hypophysitis, in fact, develops not uncommonly as a "side effect" in cancer patients treated with antibodies that block inhibitory receptors expressed on T lymphocytes, such as CTLA-4(2) and PD-1 receptors. Autoimmune hypophysitis can be induced experimentally by injecting mice with pituitary proteins mixed with an adjuvant(3). In this video article we demonstrate how to extract proteins from mouse pituitary glands and how to prepare them in a form suitable for inducing autoimmune hypophysitis in SJL mice.

Induction of experimental autoimmune hypophysitis in SJL mice.

Autoimmune hypophysitis can be reproduced experimentally by the injection of pituitary proteins mixed with an adjuvant into susceptible mice(1). Mouse models allow us to study how diseases unfold, often providing a good replica of the same processes occurring in humans. For some autoimmune diseases, like type 1A diabetes, there are models (the NOD mouse) that spontaneously develop a disease similar to the human counterpart. For many other autoimmune diseases, however, the model needs to be induced experimentally. A common approach in this regard is to inject the mouse with a dominant antigen derived from the organ being studied. For example, investigators interested in autoimmune thyroiditis inject mice with thyroglobulin(2), and those interested in myasthenia gravis inject them with the acetylcholine receptor(3). If the autoantigen for a particular autoimmune disease is not known, investigators inject a crude protein extract from the organ targeted by the autoimmune reaction. For autoimmune hypophysitis, the pathogenic autoantigen(s) remain to be identified(4), and thus a crude pituitary protein preparation is used. In this video article we demonstrate how to induce experimental autoimmune hypophysitis in SJL mice.

Interleukin-12 induces salivary gland dysfunction in transgenic mice, providing a new model of Sjögren's syndrome.

OBJECTIVE: Interleukin-12 (IL-12) is a pleiotropic cytokine that is elevated in the affected organs of patients with Sjögren's syndrome (SS). We have previously reported that overexpression of IL-12 in CBA mice leads to mononuclear infiltration of salivary and lacrimal glands, as well as to expansion of bronchial lymphoid tissue and decreased mucociliary clearance. Because xerostomia is one of the most important clinical features in SS patients, our main objective in the current study was to evaluate salivary gland function in IL-12-transgenic mice. Our secondary objective was to further characterize this animal model and to determine if the changes observed in these mice are representative of those observed in patients with SS overall. METHODS: Pilocarpine-stimulated salivary flow was used to address salivary gland function in a large group of IL-12-transgenic mice bred onto the autoimmune-prone SJL background. Furthermore, salivary glands were removed to assess the formation of infiltrates in the glands and gland morphology. Serum was also collected from these animals to investigate the formation of autoantibodies. RESULTS: Pilocarpine-stimulated salivary flow was significantly lower in IL-12-transgenic mice than in wild-type controls. Salivary glands from transgenic mice exhibited an increase in both the number and the size of lymphocytic foci, versus glands from age-matched controls. Furthermore, the acini in transgenic mice were fewer in number and larger in size compared with acini in controls. An age-dependent increase in anti-SSB/La antibodies was observed in IL-12-transgenic mice and was accompanied by an increase in antinuclear antibodies. CONCLUSION: Our findings indicate that a number of conditions associated with SS are exhibited by IL-12-transgenic SJL mice and that this model might be useful in researching multiple aspects of the disease.

Immunoproteasome overexpression underlies the pathogenesis of thyroid oncocytes and primary hypothyroidism: studies in humans and mice.

BACKGROUND: Oncocytes of the thyroid gland (Hürthle cells) are found in tumors and autoimmune diseases. They have a unique appearance characterized by abundant granular eosinophilic cytoplasm and hyperchromatic nucleus. Their pathogenesis has remained, thus far, unknown. METHODOLOGY/PRINCIPAL FINDINGS: Using transgenic mice chronically expressing IFNgamma in thyroid gland, we showed changes in the thyroid follicular epithelium reminiscent of the human oncocyte. Transcriptome analysis comparing transgenic to wild type thyrocytes revealed increased levels of immunoproteasome subunits like LMP2 in transgenics, suggesting an important role of the immunoproteasome in oncocyte pathogenesis. Pharmacologic blockade of the proteasome, in fact, ameliorated the oncocytic phenotype. Genetic deletion of LMP2 subunit prevented the development of the oncocytic phenotype and primary hypothyroidism. LMP2 was also found expressed in oncocytes from patients with Hashimoto thyroiditis and Hürthle cell tumors. CONCLUSIONS/SIGNIFICANCE: In summary, we report that oncocytes are the result of an increased immunoproteasome expression secondary to a chronic inflammatory milieu, and suggest LMP2 as a novel therapeutic target for the treatment of oncocytic lesions and autoimmune hypothyroidism.