Retinoic Acid Signalling in the Pineal Gland Is Conserved across Mammalian Species and Its Transcriptional Activity Is Inhibited by Melatonin.

The pineal gland is integral to the circadian timing system due to its role in nightly melatonin production. Retinoic acid (RA) is a potent regulator of gene transcription and has previously been found to exhibit diurnal changes in synthesis and signalling in the rat pineal gland. This study investigated the potential for the interaction of these two systems. PCR was used to study gene expression in mouse and human pineal glands, ex-vivo organotypic cultured rat pineal gland and cell lines. The mouse and human pineal glands were both found to express the necessary components required for RA signalling. RA influences the circadian clock in the brain, therefore the short-term effect of RA on clock gene expression was determined in ex vivo rat pineal glands but was not found to rapidly regulate Per1, Per2, Bmal1, or Cry1. The interaction between RA and melatonin was also investigated and, unexpectedly, melatonin was found to suppress the induction of gene transcription by RA. This study demonstrates that pineal expression of the RA signalling system is conserved across mammalian species. There is no short-term regulation of the circadian clock but an inhibitory effect of melatonin on RA transcriptional activity was demonstrated, suggesting that there may be functional cross-talk between these systems.

Triple-negative mammary carcinoma in two male dogs.

Triple-negative tumors are characterized immunohistochemically by the absence of positivity to sex hormone receptors and to human epidermal growth factor receptor 2. Additionally, they are differentiated into basal-like and non-basal (or null) subtypes, based on the presence of basal cytokeratin expression (CK5/6, 14, and17). Triple-negative subtypes are yet to be characterized in male dogs, to our knowledge. We report herein the clinical and pathologic findings and molecular characterization of carcinoma in the mammary glands of 2 male dogs. Case 1 was diagnosed as a grade II tubulopapillary carcinoma; case 2 was diagnosed as a grade II carcinoma in a mixed tumor. The tumors were characterized phenotypically as triple-negative basal and triple-negative non-basal, respectively.

A rare case of gastric mucormycosis in an immunocompetent patient.

We report the case of a 23-year-old immunocompetent patient who presented at the emergency department of a Brazilian hospital with epigastric pain and fever. After an investigation that included a computed tomography scan and upper gastrointestinal endoscopy with biopsy, a diagnosis of mucormycosis was established. The patient exhibited favorable progress after surgery and antifungal therapy. Mucormycosis is a rare condition that usually affects immunocompromised patients, with a high mortality rate of up to 85%. Correct diagnosis and fast initiation of therapy are required to ensure improved patient prognosis.

A rare case of gastric mucormycosis in an immunocompetent patient

Abstract We report the case of a 23-year-old immunocompetent patient who presented at the emergency department of a Brazilian hospital with epigastric pain and fever. After an investigation that included a computed tomography scan and upper gastrointestinal endoscopy with biopsy, a diagnosis of mucormycosis was established. The patient exhibited favorable progress after surgery and antifungal therapy. Mucormycosis is a rare condition that usually affects immunocompromised patients, with a high mortality rate of up to 85%. Correct diagnosis and fast initiation of therapy are required to ensure improved patient prognosis.

Correction to: Chronic Granulomatous Disease in a Brazilian Patient Mimetizing Sarcoidosis.

The original version of abstract PO-162 "Chronic Granulomatous Disease in a Brazilian Patient Mimetizing Sarcoidosis" incorrectly listed the name of the second author as Micheli Barsioti. The correct spelling of the author's name is Michele Baziotti Man.

Expression of the retinoic acid catabolic enzyme CYP26B1 in the human brain to maintain signaling homeostasis.

Retinoic acid (RA) is a potent regulator of gene transcription via its activation of a set of nuclear receptors controlling transcriptional activation. Precise maintenance of where and when RA is generated is essential and achieved by local expression of synthetic and catabolic enzymes. The catabolic enzymes Cyp26a1 and Cyp26b1 have been studied in detail in the embryo, where they limit gradients of RA that form patterns of gene expression, crucial for morphogenesis. This paracrine role of RA has been assumed to occur in most tissues and that the RA synthetic enzymes release RA at a site distant from the catabolic enzymes. In contrast to the embryonic CNS, relatively little is known about RA metabolism in the adult brain. This study investigated the distribution of Cyp26a1 and Cyp26b1 transcripts in the rat brain, identifying several novel regions of expression, including the cerebral cortex for both enzymes and striatum for Cyp26b1. In vivo use of a new and potent inhibitor of the Cyp26 enzymes, ser 2-7, demonstrated a function for endogenous Cyp26 in the brain and that hippocampal RA levels can be raised by ser 2-7, altering the effect of RA on differential patterning of cell proliferation in the hippocampal region of neurogenesis, the subgranular zone. The expression of CYP26A1 and CYP26B1 was also investigated in the adult human brain and colocalization of CYP26A1 and the RA synthetic enzyme RALDH2 indicated a different, autocrine role for RA in human hippocampal neurons. Studies with the SH-SY5Y human neuroblastoma cell line implied that the co-expression of RA synthetic and catabolic enzymes maintains retinoid homeostasis within neurons. This presents a novel view of RA in human neurons as part of an autocrine, intracellular signaling system.

Atypical presentation of histoplasmosis in an immunocompromised patient.

We present a case of disseminated cutaneous histoplasmosis in a male patient, rural worker, HIV positive for 20 years, with a history of irregular use of antiretroviral therapy, T cell counts below 50 cells/mm3 and with good response to treatment with Itraconazole. We highlight importance of skin lesions in clarifying early diagnosis, since this co-infection often leads patients to death.

Wolf's isotopic response, presenting as lichen planus.

The term "Wolf's isotopic response" describes the occurrence of a new skin disorder at the site of another unrelated and already healed skin disease. In most cases, herpes zoster is the inicial disease. Different disorders may develop on the same site, most commonly granulomatous and lichenoid reactions, infiltration of hematologic diseases, skin tumors and infections. There are few related cases of lichen planus presenting as isotopic response. We report a case of a 74 year-old woman, with multiple itchy, rose-colored and shiny papules that developed at site of previously healed herpes zoster, on the right arm and shoulder. The pathogenesis of this phenomenon is still unknown and further studies are needed.

Medullary nephritis in the diagnosis of acute cellular rejection.

BACKGROUND: The purpose of this study was to understand the role of lymphomononuclear inflammation (nephritis) in the renal allograft medulla of transplant recipients with acute dysfunction, by comparing the immunophenotype of inflammatory cells present in the medulla and cortex of kidney graft biopsies. METHOD: This is a retrospective study of 113 renal allograft needle biopsies, presenting with medullary nephritis, divided into two groups according to the main location of nephritis: in cortical and medullary regions (corticomedullary nephritis) or exclusively in the medullary region (medullary nephritis). We performed immunohistochemistry (IHC) of the cells composing the inflammatory foci, using anti-CD4, CD8, CD20, CD68, and CD138 antibodies, respectively for T-helper cells, cytotoxic T cells, B lymphocytes, macrophages and plasmocytes. The clinical follow-up of the patients was correlated with the morphological findings. RESULTS: The nephritis was corticomedullary in 66 of the 113 cases (58.4%) and exclusively medullary in the remaining 47 cases (41.6%). The immunophenotype of the inflammatory cells was similar in the cortical and medullary compartments and were mainly: cytotoxic T lymphocytes (CD8) and macrophages CD68. The immunosuppressive therapeutic response to acute cellular rejection (ACR), based on decreasing of serum creatinine values, was 81.8% in the patients of the corticomedullary nephritis group and 63.6% in those of the medullary nephritis group. CONCLUSION: Medullary nephritis in renal allograft biopsies may indicate ACR, as could be noted by the immunophenotype, which presented the same cellular mediators of rejection seen in the allograft cortex, and by the positive immunosuppressive therapeutic response observed in most patients.

Wolf's isotopic response, presenting as lichen planus

The term "Wolf's isotopic response" describes the occurrence of a new skin disorder at the site of another unrelated and already healed skin disease. In most cases, herpes zoster is the inicial disease. Different disorders may develop on the same site, most commonly granulomatous and lichenoid reactions, infiltration of hematologic diseases, skin tumors and infections. There are few related cases of lichen planus presenting as isotopic response. We report a case of a 74 year-old woman, with multiple itchy, rose-colored and shiny papules that developed at site of previously healed herpes zoster, on the right arm and shoulder. The pathogenesis of this phenomenon is still unknown and further studies are needed.

Atypical presentation of histoplasmosis in an immunocompromised patient

We present a case of disseminated cutaneous histoplasmosis in a male patient, rural worker, HIV positive for 20 years, with a history of irregular use of antiretroviral therapy, T cell counts below 50 cells/mm3 and with good response to treatment with Itraconazole. We highlight importance of skin lesions in clarifying early diagnosis, since this co-infection often leads patients to death.

Expression in the human brain of retinoic acid induced 1, a protein associated with neurobehavioural disorders.

Retinoic acid induced 1 (RAI1) is a protein of uncertain mechanism of action which nevertheless has been the focus of attention because it is a major contributing factor in several human developmental disorders including Smith-Magenis and Potocki-Lupski syndromes. Further, RAI1 may be linked to adult neural disorders with developmental origins such as schizophrenia and autism. The protein has been extensively examined in the rodent but very little is known about its distribution in the human central nervous system. This study demonstrated the presence of RAI1 transcript in multiple regions of the human brain. The cellular expression of RAI1 protein in the human brain was found to be similar to that described in the mouse, with high levels in neurons, but not glia, of the dentate gyrus and cornus ammonis of the hippocampus. In the cerebellum, a second region of high expression, RAI1 was present in Purkinje cells, but not granule cells. RAI1 was also found in neurons of the occipital cortex. The expression of this retinoic acid-induced protein matched well in the hippocampus with expression of the retinoic acid receptors. The subcellular distribution of human neuronal RAI1 indicated its presence in both cytoplasm and nucleus. Overall, human RAI1 protein was found to be a highly expressed neuronal protein whose distribution matches well with its role in cognitive and motor skills.

Lichen planus pigmentosus inversus.

Twenty-five year old male patient presenting with asymptomatic brown spots, on cervical, axillary, inguinal and popliteal regions, for the last nine months. Pathological examination showed hydropic degeneration of the basal layer, pigmentary incontinence and moderate inflammatory lymphocytic infiltrate in the dermis. Lichen planus pigmentosus inversus is a rare subtype of lichen planus characterized by hyperchromic, asymptomatic or mildly pruritic macules, measuring from millimeters to centimeters in diameter, with defined borders, affecting intertriginous areas, most commonly in the axillae and groin of Caucasian patients. It presents unique lichenoid histology. We report a case with typical clinical features, histology and evolution.

Lichen planus pigmentosus inversus / Liquen plano pigmentoso invertido

Twenty-five year old male patient presenting with asymptomatic brown spots, on cervical, axillary, inguinal and popliteal regions, for the last nine months. Pathological examination showed hydropic degeneration of the basal layer, pigmentary incontinence and moderate inflammatory lymphocytic infiltrate in the dermis. Lichen planus pigmentosus inversus is a rare subtype of lichen planus characterized by hyperchromic, asymptomatic or mildly pruritic macules, measuring from millimeters to centimeters in diameter, with defined borders, affecting intertriginous areas, most commonly in the axillae and groin of Caucasian patients. It presents unique lichenoid histology. We report a case with typical clinical features, histology and evolution.

Homem, 25 anos, com manchas acastanhadas, assintomáticas, nas regiões cervicais, axilares, inguinais e poplíteas há nove meses. Anatomopatológico com degeneração hidrópica da basal, incontinência pigmentar e infiltrado inflamatório linfocitário moderado na derme. O líquen plano pigmentoso invertido é um subtipo raro de líquen plano, caracterizado por máculas hipercrômicas, assintomáticas ou discretamente pruriginosas, de milímetros a centímetros de diâmetro, com limites nítidos, nas áreas intertriginosas, sendo mais comum nas flexuras axilares e inguinais de indivíduos de pele clara. Apresenta histologia liquenóide peculiar. Relata-se um caso com clínica, histologia e evolução típicas.

Experimental diabetes exacerbates skin transplant rejection in rats.

PURPOSE: To investigate the effect of chronic experimental diabetes on skin allografts in rats as a simple model that could clarify some basic aspects and mechanisms involved in transplant rejection in diabetes compared to normal animals. METHODS: Skin grafting was performed with fragments of tail skin from sex matched non diabetic Wistar rats engrafted onto the thoracic area of diabetic and non diabetic recipients. Grafts were scored for rejection every other day and were removed on day 14. Skin grafts were graded according to the following itens: no rejection; or rejection including: acute, chronic and humoral and/or cellular rejection. Statistical analysis was performed using JMP 5.1 software with ANOVA test. Diabetes was induced with IV injection of alloxan 40 mg/kg. RESULTS: Inflammatory vascular infiltrate compromising the endothelium with areas of fibrinoid necrosis and thrombosis characteristics of acute humoral rejection and subendothelial lymphocyte infiltrate typical of acute cellular rejection were significantly (p<0.003) higher in diabetic than in non diabetic recipients as the inflammatory infiltrate in the epidermis (p<0.002). CONCLUSION: Skin transplant acute rejection from chronic alloxan diabetic rats to normal tissue was significantly more intense than the acute rejection between normal rats.

Experimental diabetes exacerbates skin transplant rejection in rats

PURPOSE: To investigate the effect of chronic experimental diabetes on skin allografts in rats as a simple model that could clarify some basic aspects and mechanisms involved in transplant rejection in diabetes compared to normal animals. METHODS: Skin grafting was performed with fragments of tail skin from sex matched non diabetic Wistar rats engrafted onto the thoracic area of diabetic and non diabetic recipients. Grafts were scored for rejection every other day and were removed on day 14. Skin grafts were graded according to the following itens: no rejection; or rejection including: acute, chronic and humoral and/or cellular rejection. Statistical analysis was performed using JMP 5.1 software with ANOVA test. Diabetes was induced with IV injection of alloxan 40 mg/kg. RESULTS: Inflammatory vascular infiltrate compromising the endothelium with areas of fibrinoid necrosis and thrombosis characteristics of acute humoral rejection and subendothelial lymphocyte infiltrate typical of acute cellular rejection were significantly (p<0.003) higher in diabetic than in non diabetic recipients as the inflammatory infiltrate in the epidermis (p<0.002). CONCLUSION: Skin transplant acute rejection from chronic alloxan diabetic rats to normal tissue was significantly more intense than the acute rejection between normal rats.

Histological reaction of the subcutaneous tissue of rats following implantation of bone morphogenetic protein (rhBMP-2) in inorganic bone scaffold and stimulation using low-power laser light / Reação histológica do tecido subcutâneo de rato após implante de proteína morfogenética óssea(rhBMP-2) em arcabouço de osso inorgânico e estimulado com luz laser de baixa potência

The aim of this study was to assess the histological reaction of the subcutaneous tissue of rats after the implantation of natural inorganic mineral scaffold from a calf femur containing recombinant human bone morphogenetic protein (rhBMP-2) and irradiated with low-power laser light. Material and methods: Sixteen Wistar rats were incised in the torso in a medial-longitudinal orientation, and the subcutaneous tissue of the left and right sides of the incision was pulled apart for implantation of the inorganic bone scaffold containing rhBMP-2. Diode laser light was applied to the right side implant at a dose of 8 J/cm2 for 3 minutes, forming two groups: G1 (control) and G2 (irradiated with laser). Implants and surrounding tissuewere removed from four animals on days 7, 21, 40 and 112 for microscopic study. The histological resultswere assessed by means of grading (0 = absence, 1 = slight presence, 2 = representative and 3 = very representative),considering the following events: formation of osteoid structure, acute inflammation, chronicinflammation, fibrin deposition, neovascularization, foreign body granuloma and fibrosis. Results: The resultsshowed no statistically significant differences in each of the four periods when the two groups werecompared (p>0.05 – Mann-Whitney’s test). Conclusion: The natural inorganic scaffold from a calf femurwith rhBMP-2 was a biocompatible combination. Under these conditions, the inductive capacity of rhBMP-2for cell differentiation was inhibited. A slight hastening of tissue healing was shown in the group that wasirradiated with low-power laser light...

O objetivo deste estudo foi avaliar a reação histológica do tecido subcutâneo de rato após o implante de matriz de osso inorgânico mineral natural de fêmur de vitelo com proteína morfogenética do osso recombinante humana (rhBMP-2) e irradiado com luz laser de baixa potência. Material e métodos: Dezesseis ratos (Wistar) foram incisados no dorso no sentido medio-longitudinal. O tecido subcutâneo do lado direito e esquerdo da incisão foram divulsionados para o implante da matriz de osso inorgânico com rhBMP-2. Na direção do implante do lado direito foi aplicada luz laser, diodo em dose única de 8 J/cm2, por 3 minutos, formando dois grupos: G1 (controle) e G2 (irradiado com laser). Foram removidos implantes com o tecido circundante de quatro animais nos períodos de 7, 21, 40 e 112 dias para estudo microscópico. Os resultados histológicos foram avaliados através de postos (0 = ausência, 1 = discreta presença, 2 = representativo e 3 = muito representativo),considerando os seguintes eventos: formação de estrutura osteoide, inflamação aguda, inflamação crônica, depósito de fibrina, neovascularização, granuloma de corpo estranho e fibrose. Resultados: Os resultados não mostraram diferenças estatísticas significativas nos eventos em cada um dos períodos quando comparados os dois grupos (p>0,05 – teste Mann-Whitney). Conclusão: A matriz de osso inorgânico natural de fêmur de vitelo com rhBMP-2 é um conjunto biocompatível. Nestas condições, a capacidade indutora de diferenciação celular da rhBMP-2 foi inibida. Ficou evidenciado discreto aceleramento na cicatrização tecidual no grupo que foi irradiado com luz laser de baixa potência...

High expression of retinoic acid receptors and synthetic enzymes in the human hippocampus.

Retinoic acid, the active form of the nutrient vitamin A, regulates several facets of neuronal plasticity in the hippocampus, including neurogenesis and synaptic strength, acting via specific retinoic acid receptors (RARs). Essential for conversion of vitamin A to retinoic acid is the enzyme retinaldehyde dehydrogenase (RALDH) and in the rodent hippocampus this is only present in the adjacent meninges where it must act as a locally released paracrine hormone. Little is known though about the expression of RALDHs and RARs in the human hippocampus. This study confirms that RALDH levels are very low in mouse neurons but, surprisingly, strong expression of RALDH protein is detected by immunohistochemistry in hippocampal neurons. The receptors RARα, ß and γ were also detected, each receptor exhibiting differing subcellular locations implying their potential regulation of both transcription and non-genomic actions. These results imply an essential function of retinoic acid in the human hippocampus likely to include regulation of neuronal plasticity.