S1P1 deletion in oligodendroglial lineage cells: Effect on differentiation and myelination

Sphingosine 1‐phosphate (S1P) receptors are G protein‐coupled receptors expressed by many cell types, including cells of oligodendrocyte (OLG) lineage. We had previously shown that targeted deletion of S1P₁ in OLG lineage cells did not result in obvious clinical phenotype or altered number of OLGs at 3 months, but there were subtle abnormalities in myelin. In this study, we examined the role of S1P₁ in developmental myelination and cell survival, focusing on age 3 weeks. We found that S1P₁ deficiency led to delayed differentiation of OLG progenitors (OPCs) into OLGs that is independent of p38 phosphorylation. This was accompanied by decreased levels of myelin basic protein (MBP) but not of myelin‐OLG glycoprotein (MOG), and slight decrease in myelin thickness in the corpus callosum of S1P₁ conditional knockout (CKO) mice. S1P₁‐deficient OLGs exhibited slower process extension, which was associated with attenuated phosphorylation of extracellular signal regulated kinases (ERKs) and p21‐activated kinases (PAKs), and with upregulation of tropomodulin1. Basal levels of pAkt were not affected, though expectedly, no response to a selective S1P₁ agonist SEW2871 was observed. S1P₁‐deficient OLGs did not exhibit increased cell death in response to cuprizone, tumor necrosis factor‐α, or deprivation of nutrients and growth factors. We conclude that S1P₁ signaling regulates OLG development, morphological maturation and early myelination. GLIA 2016;64:570–582     

Sulfated polysaccharides increase plasma levels of SDF-1 in monkeys and mice: involvement in mobilization of stem/progenitor cells.

It was previously reported that treatment with the sulfated polysaccharide fucoidan or the structurally similar dextran sulfate increased circulating mature white blood cells and hematopoietic progenitor/stem cells (HPCs) in mice and nonhuman primates; however, the mechanism mediating these effects was unclear. It is reported here that plasma concentrations of the highly potent chemoattractant stromal-derived factor 1 (SDF-1) increase rapidly and dramatically after treatment with fucoidan in monkeys and in mice, coinciding with decreased levels in bone marrow. In vitro and in vivo data suggest that the SDF-1 increase is due to its competitive displacement from heparan sulfate proteoglycans that sequester the chemokine on endothelial cell surfaces or extracellular matrix in bone marrow and other tissues. Although moderately increased levels of interleukin-8, MCP1, or MMP9 were also present after fucoidan treatment, studies in gene-ablated mice (GCSFR(-/-), MCP1(-/-), or MMP9(-/-)) and the use of metalloprotease inhibitors do not support their involvement in the concurrent mobilization. Instead, SDF-1 increases, uniquely associated with sulfated glycan-mobilizing treatments and not with several other mobilizing agents tested, are likely responsible. To the authors' knowledge, this is the first published report of disrupting the SDF-1 gradient between bone marrow and peripheral blood through a physiologically relevant mechanism, resulting in mobilization with kinetics similar to other mobilizing CXC chemokines. The study further underscores the importance of the biological roles of carbohydrates.     

Rapid size dependent deletion of foreign gene sequences inserted into attenuated HIV-1 upon infection in vivo: implications for vaccine development

Live attenuated HIV vaccines offer a means to introduce exogenous sequences into the viral genome to target the virus elimination in vivo. Foreign genes inserted into the nef region of HIV-1 NL4-3 were found to be rapidly deleted following virus infection and/or replication, in a size dependent manner, in the human fetal Thymus/Liver implants of severe combined immunodeficient mouse (SCID-hu) model. When the murine heat stable antigen (HSA) of 283 bp was substituted into HIV-1 nef region, the viral loads in vivo were comparable to the negative control nef attenuated HIV-1, and the reporter HSA gene was not deleted upon infection. However, the murine Thy1.2 gene (505 bp) substituted into the nef attenuated HIV-1, upon infection and replication, deleted 441 bp in vitro and 437 bp in vivo, of the inserted Thy1.2 gene. When the enhanced green fluorescence protein (eGFP) gene (720 bp) was substituted for nef, virus replication was aborted in vivo in the Thy/Liv implants, as seen by the background levels of viral loads, comparable to mock infected implants, and the eGFP gene was deleted. When the herpes simplex virus thymidine kinase gene, HSV-TK (1.15 kbp), or HSA gene, was substituted into the viral vpr gene, TK but not HSA gene was deleted, upon infection in vitro. Moreover, NL-TKI reporter virus with both intact nef and vpr genes shows deletion of TK gene both in vitro and in vivo. Excision of foreign genes occurred within the exogenous segments but not in the viral own regions. These results suggest that larger "suicide" genes introduced via HIV-1 can be deleted upon infection. However, smaller size nucleotide sequences or genes (approximately 300 bp) inserted in place of viral nef or vpr gene may be used to target the virus or its components, for attack and elimination in vivo, and thus have implications for the development of live attenuated HIV vaccines.     

Bronchiolitis obliterans organizing pneumonia in cancer: a case series

Bronchiolitis obliterans with organizing pneumonia (BOOP) is an infrequently encountered clinical condition that can mimic a number of other pathologic lung processes. The presentation of this treatable condition in cancer patients has not been described in any large series.We conducted a retrospective study of patients with BOOP at Memorial Sloan-Kettering Cancer Center, NewYork, NY, U.S.A. from January 1992 to December 1999. The type and treatment of primary cancer, clinical and radiographic features of initial BOOP presentation, and outcome following therapy were recorded. Forty-three patients with an underlying diagnosis of cancer were found on lung biopsy to have BOOP as an isolated entity. BOOP was encountered in patients with a variety of clinical presentations, and many types of malignancies. The symptom patterns were non-specific, as were the physiological abnormalities. The only clear relationship between the underlying malignancyand the diagnosis of BOOP at presentation was in the chest radiographic findings. Patients with solid organ tumors were more likely to have nodular or mass like radiographic abnormalities (81%) than to have diffuse infiltrates (19%).We observed the opposite pattern in patients with hematologic malignancies (22% vs.67%). The vast majority of patients recovered from this condition. In conclusion, For cancer patients, BOOP represents a treatable cause of lung disease with protean manifestations. BOOP can mimic pulmonary malignancy and pulmonary infection. In cancer patients, the evaluation of new pulmonary symptoms accompanied by radiographic changes should include a consideration of this diagnosis.     

Emergence and control of methicillin-resistant Staphylococcus aureus in a children's hospital and pediatric long-term care facility.

BACKGROUND: After a 6-year quiescence, methicillin-resistant Staphylococcus aureus (MRSA) was isolated from 30 patients in a children's hospital and a pediatric long-term care facility from November 1987 through April 1989. After six nosocomial cases had occurred at the children's hospital, increased infection control measures directed at MRSA were initiated in August 1988. Because MRSA had been identified in three patients in the pediatric long-term care facility within 24 hours of their admission to the children's hospital, other patients transferred from the pediatric long-term care facility to the children's hospital were isolated and screened for MRSA. METHODS: We reviewed the medical records of these patients and evaluated their response to therapy with rifampin alone or in combination with trimethoprim-sulfamethoxazole. RESULTS: In the 8-month period after initiation of infection control measures, MRSA was identified in 10 residents of the pediatric long-term care facility; there was also one nosocomial children's hospital case. Phage typing showed that one MRSA strain predominated in patients at the pediatric long-term care facility but did not implicate this strain as the source for MRSA introduction into the children's hospital. Of 16 patients with MRSA who completed therapy and were available for follow-up, 13 (81%) had elimination of colonization. CONCLUSION: Prompt institution of MRSA surveillance, barrier isolation, and therapy to eliminate colonization should be considered in hospitals with a new introduction of MRSA.     

The interplay between metabolic alterations,diastolic strain rate and exercise capacity in mild heart failure with preserved ejection fraction: a cardiovascular magnetic resonance study

Background

Heart failure (HF) is characterized by altered myocardial substrate metabolism which can lead to myocardial triglyceride accumulation (steatosis) and lipotoxicity. However its role in mild HF with preserved ejection fraction (HFpEF) is uncertain. We measured myocardial triglyceride content (MTG) in HFpEF and assessed its relationships with diastolic function and exercise capacity.

Methods

Twenty seven HFpEF (clinical features of HF, left ventricular EF >50%, evidence of mild diastolic dysfunction and evidence of exercise limitation as assessed by cardiopulmonary exercise test) and 14 controls underwent ¹H-cardiovascular magnetic resonance spectroscopy (¹H-CMRS) to measure MTG (lipid/water, %), ³¹P-CMRS to measure myocardial energetics (phosphocreatine-to-adenosine triphosphate - PCr/ATP) and feature-tracking cardiovascular magnetic resonance (CMR) imaging for diastolic strain rate.

Results

When compared to controls, HFpEF had 2.3 fold higher in MTG (1.45?±?0.25% vs. 0.64?±?0.16%, p?=?0.009) and reduced PCr/ATP (1.60?±?0.09 vs. 2.00?±?0.10, p?=?0.005). HFpEF had significantly reduced diastolic strain rate and maximal oxygen consumption (VO₂ max), which both correlated significantly with elevated MTG and reduced PCr/ATP. On multivariate analyses, MTG was independently associated with diastolic strain rate while diastolic strain rate was independently associated with VO₂ max.

Conclusions

Myocardial steatosis is pronounced in mild HFpEF, and is independently associated with impaired diastolic strain rate which is itself related to exercise capacity. Steatosis may adversely affect exercise capacity by indirect effect occurring via impairment in diastolic function. As such, myocardial triglyceride may become a potential therapeutic target to treat the increasing number of patients with HFpEF.

     

Flibanserin toxicity in a toddler following ingestion

Introduction: Flibanserin is a medication recently approved by the FDA for treatment of generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Its mechanism of action is not fully understood but is thought to modulate serotonin receptors and increase levels of norepinephrine and dopamine. While much is known about toxicity of other drugs which affect these systems, there is little information about toxicity of flibanserin at this time.

Case: We present a case of a 2-year-old boy who ingested an estimated 600?mg of his mother’s flibanserin. Following ingestion, the child developed facial twitching and unresponsiveness to pain, concerning for seizure-like activity. In the emergency department (ED) he was found to have hypertension, mydriasis, slurred speech, and normal labs. He responded well to supportive care including administration of benzodiazepines. Shortly after admission to the hospital, his temperature increased to 38.4?°C. Toxicology testing revealed the presence of 1-(3-trifluoromethylphenyl)-piperazine (TFMPP), a flibanserin metabolite. TFMPP is a recreational drug used as an alternative to 3,4-methylenedioxymethamphetamine (more commonly known as “MDMA” or “ecstasy”).

Discussion: This case highlights potential toxicity associated with ingestion of flibanserin.