Combined exposure to maternal high-fat diet and neonatal lipopolysaccharide disrupts stress-related signaling but normalizes spatial memory in juvenile rats.

Both neonatal infections and exposure to maternal obesity are inflammatory stressors in early life linked to increased rates of psychopathologies related to mood and cognition. Epidemiological studies indicate that neonates born to mothers with obesity have a higher likelihood of developing neonatal infections, however effects on offspring physiology and behavior resulting from the combination of these stressors have yet to be investigated. The aim of this study was to explore immediate and persistent phenotypes resulting from neonatal lipopolysaccharide (nLPS) administration in rat offspring born to dams consuming a high-fat diet (HFD). Neural transcript abundance of genes involved with stress regulation and spatial memory were examined alongside related behaviors. At the juvenile age point, unlike offspring exposed to maternal HFD (mHFD) or nLPS alone, offspring with combined exposure to mHFD + nLPS displayed altered transcript abundances of stress-related genes in the ventral hippocampus (HPC) in a manner conducive to potentiating stress responses. For memory-related phenotypes, juveniles exposed to mHFD + nLPS exhibited normalized spatial memory and levels of memory-related gene expression in the dorsal HPC similar to control diet offspring, while control diet + nLPS, and mHFD offspring exhibited reduced levels of memory-related gene expression and impaired spatial memory. These findings suggest that dual exposure to unique inflammatory stressors in early life can disrupt neural stress regulation but normalize spatial memory processes.

Maternal high-fat diet induces sex-specific changes to glucocorticoid and inflammatory signaling in response to corticosterone and lipopolysaccharide challenge in adult rat offspring.

BACKGROUND: Maternal obesity as a result of high levels of saturated fat (HFD) consumption leads to significant negative health outcomes in both mother and exposed offspring. Offspring exposed to maternal HFD show sex-specific alterations in metabolic, behavioral, and endocrine function, as well as increased levels of basal neuroinflammation that persists into adulthood. There is evidence that psychosocial stress or exogenous administration of corticosterone (CORT) potentiate inflammatory gene expression; however, the response to acute CORT or immune challenge in adult offspring exposed to maternal HFD during perinatal life is unknown. We hypothesize that adult rat offspring exposed to maternal HFD would show enhanced pro-inflammatory gene expression in response to acute administration of CORT and lipopolysaccharide (LPS) compared to control animals, as a result of elevated basal pro-inflammatory gene expression. To test this, we examined the effects of acute CORT and/or LPS exposure on pro and anti-inflammatory neural gene expression in adult offspring (male and female) with perinatal exposure to a HFD or a control house-chow diet (CHD). METHODS: Rat dams consumed HFD or CHD for four weeks prior to mating, during gestation, and throughout lactation. All male and female offspring were weaned on to CHD. In adulthood, offspring were 'challenged' with administration of exogenous CORT and/or LPS, and quantitative PCR was used to measure transcript abundance of glucocorticoid receptors and downstream inflammatory markers in the amygdala, hippocampus, and prefrontal cortex. RESULTS: In response to CORT alone, male HFD offspring showed increased levels of anti-inflammatory transcripts, whereas in response to LPS alone, female HFD offspring showed increased levels of pro-inflammatory transcripts. In addition, male HFD offspring showed greater pro-inflammatory gene expression and female HFD offspring exhibited increased anti-inflammatory gene expression in response to simultaneous CORT and LPS administration. CONCLUSIONS: These findings suggest that exposure to maternal HFD leads to sex-specific changes that may alter inflammatory responses in the brain, possibly as an adaptive response to basal neuroinflammation.

Diffuse dermal angiomatosis associated with severe atherosclerosis: two cases and review of the literature.

Diffuse dermal angiomatosis (DDA) is a rare condition characterized by endothelial proliferation in the reticular dermis. Several diseases have been associated with DDA, including peripheral arterial disease (PAD). We report two cases of DDA associated with PAD. Patient 1 was a 71-year-old woman, who presented with painful necrotic ulcerations on her trunk and a medical history of PAD. Skin biopsy revealed a dermal proliferation of endothelial cells, and despite medical treatment, she died 1 month later. Patient 2 was an 81-year-old man, who presented with an erythematous, bluish plaque of the shoulder. He was a heavy smoker, with severe PAD. Biopsy showed dermal capillary hyperplasia, with a few fibrin thrombi, and follow-up only was recommended. In both cases, laboratory tests and Doppler ultrasonography ruled out other thrombotic conditions and vascularitis. DDA is a rare complication of PAD, and the optimum medical treatment remains to be clarified, especially when revascularization has failed or is not possible, as in our cases.

Long-term efficacy and safety of alemtuzumab in advanced primary cutaneous T-cell lymphomas.

BACKGROUND: Alemtuzumab has been proposed as salvage therapy for refractory cutaneous T-cell lymphomas (CTCLs). Long-term follow-up data are scarce. OBJECTIVES: To assess the efficacy and safety of alemtuzumab in the treatment of advanced CTCL. METHODS: A multicentre retrospective analysis was carried out of 39 patients with advanced CTCL treated with alemtuzumab between 2003 and 2013. RESULTS: Thirty-nine patients (median age 62 years, range 20-83) with Sézary syndrome (SS, n = 23) or advanced mycosis fungoides (MF, n = 16) received alemtuzumab 30 mg two to three times per week for a median duration of 12 weeks (range 1-35). Fifteen patients received maintenance therapy for a median duration of 24 weeks (range 6-277). Eleven patients (28%) had transformed disease (MF, n = 10; SS, n = 1). After a median follow-up of 24 months (range 0.3-124), eight patients (21%) were still alive. The overall response rate was 51% in the whole study group (partial response, n = 13; complete response, n = 7); 70% in patients with SS and 25% in patients with MF (P = 0.009). The median time to progression was 3.4 months (range 0.4-42). Six patients (15%; SS, n = 5; MF, n = 1) remained progression free for > 2 years (median 56 months, range 28-117). Five patients experienced cutaneous large T-cell transformation during alemtuzumab treatment and one patient developed primary cutaneous large B-cell lymphoma. Twenty-four patients (62%) had a grade three or higher infectious adverse event and 10 (26%) a haematological toxicity, which led to treatment discontinuation in 17 cases (44%) and death in two (5%). CONCLUSIONS: Alemtuzumab may induce long-term remission in SS but seems ineffective in MF and transformed CTCL.

Immune disease dialogue of chemokine-based cell communications as revealed by single-cell RNA sequencing meta-analysis.

Immune-mediated diseases are characterized by aberrant immune responses, posing significant challenges to global health. In both inflammatory and autoimmune diseases, dysregulated immune reactions mediated by tissue-residing immune and non-immune cells precipitate chronic inflammation and tissue damage that is amplified by peripheral immune cell extravasation into the tissue. Chemokine receptors are pivotal in orchestrating immune cell migration, yet deciphering the signaling code across cell types, diseases and tissues remains an open challenge. To delineate disease-specific cell-cell communications involved in immune cell migration, we conducted a meta-analysis of publicly available single-cell RNA sequencing (scRNA-seq) data across diverse immune diseases and tissues. Our comprehensive analysis spanned multiple immune disorders affecting major organs: atopic dermatitis and psoriasis (skin), chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (lung), ulcerative colitis (colon), IgA nephropathy and lupus nephritis (kidney). By interrogating ligand-receptor (L-R) interactions, alterations in cell proportions, and differential gene expression, we unveiled intricate disease-specific and common immune cell chemoattraction and extravasation patterns. Our findings delineate disease-specific L-R networks and shed light on shared immune responses across tissues and diseases. Insights gleaned from this analysis hold promise for the development of targeted therapeutics aimed at modulating immune cell migration to mitigate inflammation and tissue damage. This nuanced understanding of immune cell dynamics at the single-cell resolution opens avenues for precision medicine in immune disease management.

Cell-type-specific epigenetic effects of early life stress on the brain.

Early life stress (ELS) induces long-term phenotypic adaptations that contribute to increased vulnerability to a host of neuropsychiatric disorders. Epigenetic mechanisms, including DNA methylation, histone modifications and non-coding RNA, are a proposed link between environmental stressors, alterations in gene expression, and phenotypes. Epigenetic modifications play a primary role in shaping functional differences between cell types and can be modified by environmental perturbations, especially in early development. Together with contributions from genetic variation, epigenetic mechanisms orchestrate patterns of gene expression within specific cell types that contribute to phenotypic variation between individuals. To date, many studies have provided insights into epigenetic changes resulting from ELS. However, most of these studies have examined heterogenous brain tissue, despite evidence of cell-type-specific epigenetic modifications in phenotypes associated with ELS. In this review, we focus on rodent and human studies that have examined epigenetic modifications induced by ELS in select cell types isolated from the brain or associated with genes that have cell-type-restricted expression in neurons, microglia, astrocytes, and oligodendrocytes. Although significant challenges remain, future studies using these approaches can enable important mechanistic insight into the role of epigenetic variation in the effects of ELS on brain function.

Fulminant Pneumocystis carinii pneumonia in 4 patients with dermatomyositis.

Between 1989 and 1996, 4 cases of Pneumocystis carinii pneumonia (PCP) were observed in patients seronegative for the human immunodeficiency virus who were receiving corticosteroid therapy for dermatomyositis in our institution. These cases were considered unusual in light of the short delay of their onset after initiation of immunosuppressive therapy and their fulminant course: 3 of these patients died of PCP occurring during the first month of treatment with prednisone. In all 4 patients lymphopenia was observed before the initiation of corticosteroid treatment and low CD4 and CD8 cell counts were evident at the time of PCP. These observations support the view of an increase in both the severity and incidence of PCP in patients without human immunodeficiency virus infection and question the need for a primary prophylaxis in patients with connective tissue diseases receiving high-dose corticosteroid therapy.

[Infection of ascitic fluid by perforation of a sclerodermic colon]. / Infection d'ascite par perforation sur côlon sclérodermique.

In progressive systemic scleroderma, a disease of protean manifestations, involvement of the gastrointestinal tract is noted infrequently in patients who are asymptomatic, and is rarely fatal. We report the case of a 65-year-old woman who was admitted for ascitis related to a non A, non B cirrhosis. The patient presented with bacterial peritonitis due to colonic perforation by fecal impaction associated with sclerodermic involvement. Pathologic study of the resected colon showed that the true muscularis was very atrophic and fibrotic, characteristic of scleroderma. To our knowledge, this cause of ascitic fluid infection has not been previously reported.

[Urinary porphyrin excretion in human immunodeficiency virus infection]. / Excrétion des porphyrines urinaires au cours de l'infection par le virus de l'immunodéficience humaine.

OBJECTIVES: Porphyria cutanea tarda has been reported in about 60 patients with human immunodeficiency virus (HIV) since 1987. We looked for porphyrin metabolism disorders in HIV infected patients without patent porphyria cutanea tarda. METHODS: Urinary porphyrin excretion was measured in 64 patients with an HIV infection. RESULTS: Excreted levels were abnormal in 23 patients (36%) including 4 (6%) with patterns highly suggestive of porphyria cutanea tarda. One of these patients developed the disease 2 years later. In 15 patients (23%) there was a significant increase in coproporphyrinuria. Minimal alterations in uroporphyrin or its precursors were seen in the other patients. Abnormal excretion was significantly more frequent in patients with hepatopathy and in patients who had progressed to AIDS. CONCLUSION: Our findings suggest that HIV infection does not play a direct role in altered porphyrin metabolism because of the frequency of liver disorders observed in these patients.

[Aggressive cutaneous T-cell lymphoma associated with the presence of Epstein-Barr virus. 2 cases]. / Lymphome T cutané agressif associé à la présence de virus Epstein-Barr. Deux cas.

INTRODUCTION: The factors of prognosis of the cutaneous T-cell lymphomas are less well known as those of the B-cell lymphomas and the role of the Epstein-Barr virus (EBV) is not yet definitively evaluated. CASE REPORTS: Two male patients aged 62 and 82 years had a mycosis fungoides with a lethal outcome. The first patient had mutilating facial tumors; the RNA m of EBV and the genome of EBV were demonstrated in the diseased skin. The second patient had an erythrodermic course with enlarged peripheral lymph nodes and circulating Sézary's cells; the genome of EBV was demonstrated by PCR in the diseased skin. DISCUSSION: The role of the EBV has already been demonstrated in peripheral aggressive T-cell lymphomas. In the mycosis fungoides, the EBV is associated with the lesions in 0 to 32 p. cent according to the published series. EBV associated T-cell lymphomas have a poor survival rate and the EBV infection may be associated with the expression of the multidrug resistant gene-1 (MDR-1) and the risk of a terminal hemophagocytosis. In our both patients the presence of the EBV in the lymphocytes of the skin lesions is also an argument in favour of the pathogenic role of the virus.

[Adult T-cell lymphoma associated with HTLV-1: a familial form]. / Lymphome à cellules T de l'adulte associé à l'HTLV-1: une forme familiale.

BACKGROUND: Adult T-cell leukemia-lymphoma (ATL) can occur in siblings infected with HTLV-1. CASE REPORTS: Two Caribbean siblings developed ATL a few years apart. One case has been reported previously. Both individuals had peripheral lymph node T-cell lymphoma and a few atypical lymphocytes on blood smear. Lymphocytosis, bone marrow biopsy, abdominal computed tomographic scanning, and chest radiography were normal. Clonal rearrangement of T-cell receptor was present in skin lesions for both patients and in the blood for one. HTLV-1 serology was positive. Clonal integration of HTLV-1 provirus was demonstrated in skin lesions in one patient and in blood lymphocytes in the other. Chemotherapy, then interferon alpha, were unsuccessful in the first patient. Topical metchloretamine was partially effective for the second patient. DISCUSSION: ATL in siblings is explained by mother-to-child transmission of HTLV-1 infection during breastfeeding.

Cutaneous T-cell lymphoma associated with granulomatous slack skin.

Granulomatous slack skin disease (GSS) is a rare disorder characterized by bulky cutaneous lesions and epithelioid and giant cell granulomas with destruction of the dermal elastic tissue. We detail the observation of a 29-year-old man with clinical and histological features of GSS. Pendulous skin tumors were associated with typical clinical and immunohistochemical aspects of mycosis fungoides and with clonal rearrangement of the V gamma T-cell receptor gene in lesional skin. This case report supports cutaneous T-cell lymphoma as a cause of GSS.

Prenatal diagnosis of fetal varicella-zoster virus infection with polymerase chain reaction of amniotic fluid in 107 cases.

OBJECTIVE: Varicella, resulting from primary infection by varicella zoster virus, carries a risk of severe congenital varicella. Prenatal diagnosis is rarely applied because methods remain to be validated. STUDY DESIGN: From 1989 to 1994, 107 women contracted clinical varicella before 24 weeks of pregnancy. Amniocentesis was performed in all cases, with simultaneous fetal blood sampling in 82 cases. Virus was detected in amniotic fluid by cell culture inoculation and polymerase chain reaction. Fetal blood was tested for anti-varicella zoster virus immunoglobulin M. RESULTS: Of the 107 amniotic fluid samples tested, nine of 107 (8.4%) were positive by polymerase chain reaction, but only two of these (1.8%) were positive in cell culture; none of the blood samples from infected fetuses were positive for specific anti-varicella zoster virus immunoglobulin M. The outcome of 99 pregnancies was fully documented. CONCLUSION: The risk of transplacental passage before 24 weeks of pregnancy was 8.4% in our series. The risk of congenital varicella is 3 in 107 (2.8%) and that of isolated postnatal varicella zoster infection is 3 in 78 (3.8%). Polymerase chain reaction is more sensitive than cell culture for the detection of varicella zoster virus in amniotic fluid.