Outcomes of Systemic Lupus Erythematosus in Patients who Discontinue Hydroxychloroquine.

BACKGROUND: Hydroxychloroquine (HCQ) is an antimalarial drug that is recommended as a safe, daily prophylactic intervention for individuals with systemic lupus erythematosus (SLE) based on previous studies that showed an association of HCQ use with reductions in flares compared with placebo. Our study aims to determine whether the discontinuation of HCQ leads to relapse of disease and whether the duration of HCQ use impacts the success of its eventual discontinuation. METHODS: A retrospective chart review was performed on the medical records of patients diagnosed with SLE between July 1, 2006, and June 30, 2016. The data gathered included demographic factors, diagnostic symptoms, laboratory values, and SLE medications. Additionally, HCQ usage and discontinuation rates were collected as well as the timing and prevalence of flares during and after HCQ usage. Patients who were diagnosed with SLE but never used HCQ were excluded from the study. The occurrence of flares, clinical characteristics, and duration of treatment with HCQ were compared between the group that continued HCQ and the group that discontinued HCQ. RESULTS: Of the 509 patients who met inclusion criteria, 66.2% (n = 337) continued HCQ throughout the duration of their treatment (median duration of HCQ treatment was 8.0 years), whereas 33.8% (n = 172) did not (median duration of HCQ treatment was 1.9 years). Patients who received HCQ for less than 1 year before discontinuation (median duration of HCQ treatment was 2.5 months) were more likely to experience SLE flares compared with those who continued HCQ for more than 1 year (13.1% vs 5.7%, P = 0.019). Patients who experienced a flare while on HCQ were more likely to have arthritis, oral ulcers, leukopenia, and thrombocytopenia. CONCLUSION: With over 500 patient charts reviewed, this is the largest study comparing outcomes for patients on HCQ with those who discontinued it. Patients who discontinue HCQ after being on it for less than 1 year are at greater risk for flares compared with those who take HCQ for longer than 1 year. These findings should be used to guide treatment, educate patients on the role of continued treatment with HCQ, and ultimately reduce morbidity and mortality.

Hyperbaric oxygen for neurologic indications--action plan for multicenter trials in: stroke, traumatic brain injury, radiation encephalopathy & status migrainosus.

The 2008 Toronto Hyperbaric Medicine Symposium was convened to discuss research into neurologic indications for hyperbaric oxygen therapy (HBO2T). Four topics were particularly addressed: acute ischemic stroke; acute traumatic brain injury; brain radiation necrosis; and status migrainosus. Four multicenter trials were designed and proposed to evaluate the efficacy of HBO2T for these indications and are presented here in addition to brief reviews of the rationale behind each.

Activation of liver X receptor reduces global ischemic brain injury by reduction of nuclear factor-kappaB.

Recent studies have found that liver X receptors (LXRs) agonists decrease brain inflammation and exert neuroprotective effect. The aim of this study was to examine the mechanisms of action of liver X receptor agonist GW3965 against brain injury following global cerebral ischemia in the rat. The 48 male SD (Sprague-Dawley) rats were randomly partitioned into three groups: sham, global ischemia (4-vessel occlusion for 15 min; 4VO) treated with vehicle and global ischemia treated with GW3965 (20 mg/kg, via i.p. injection at 10 min after reperfusion). The functional outcome was determined by neurological evaluation at 24 h post ischemia and by testing rats in T maze at 3 and 7 days after reperfusion. The rats' daily body weight, incidence of seizures and 72 h mortality were also determined. After Nissl staining and TUNEL in coronal brain sections, the numbers of intact and damaged cells were counted in the CA1 sector of the hippocampus. The expression of phosphorylated inhibitor of kappaB (p-IkappaBalpha), nuclear factor-kappaB (NF-kappaB) subunit p65, and cyclo-oxygenase-2 (COX-2) were analyzed with Western blot at 12 h after reperfusion. GW3965 tended to reduce 72 h mortality and the incidence of post-ischemic seizures. GW3965-treated rats showed an improved neuronal survivability in CA1 and a significant increase in the percentage of spontaneous alternations detected in T-maze on day 7 after ischemia. GW3965-induced neuroprotection was associated with a significant reduction in nuclear translocation of NF-kB p65 subunit and a decrease in the hippocampal expression of NF-kB target gene, COX-2. LXR receptor agonist protects against neuronal damage following global cerebral ischemia. The mechanism of neuroprotection may include blockade of NF-kappaB activation and the subsequent suppression of COX-2 in the post ischemic brain.

Radiation exposure prior to ischemia decreases lesion volume, brain edema and cell death.

PURPOSE: To investigate the neuronal response to ischemic injury following exposure to whole brain proton irradiation. METHODS: Brain only proton irradiation (8 Gy, 250 MeV) was performed ten days prior to middle cerebral artery occlusion (MCAO) in 1 year old male Sprague Dawley rats. MCAO was induced in two animal groups: proton irradiated (MCAO + Rad) and MCAO only. Magnetic resonance imaging (MRI) and quantitative analysis were performed prior to and 2 days after irradiation, and then 2, 14 and 28 days after MCAO. After the last imaging time point animals were sacrificed and TUNEL staining was performed on 4% paraformaldehyde - fixed brain sections. RESULTS: Neuroimaging demonstrated a reduction in ischemic lesion volume in the MCAO + Rad group compared with MCAO alone. Neurological deficits did not differ between ischemia groups. Interestingly, there was a 34% decrease in the number of TUNEL-positive cells in MCAO + Rad brains compared to MCAO alone. CONCLUSION: Our results suggest that radiation treatment reduces brain edema, ischemic lesion volume and peri-ischemic apoptosis. The underlying mechanisms are currently unknown and additional studies will elucidate the significance of these results.

Effects of superoxide dismutase and catalase derivates on intracerebral hemorrhage-induced brain injury in rats.

The use of exogenous superoxide dismutase (SOD) and catalase (CAT) has been previously evaluated against various reactive oxygen species-mediated brain injuries, especially those associated with ischemia/ reperfusion. In this study, we investigated effects of these enzymatic antioxidants on intracerebral hemorrhage (ICH)-induced brain injury. A total of 65 male Sprague-Dawley rats (300-380 g) were divided into a sham group, an untreated ICH group, 3 groups of ICH rats treated with lecithinized SOD (PC-SOD) at doses of 0.1, 0.3, and 1 mg/kg, and a group treated with polyethylene glycol conjugated CAT (PEG-CAT) at a dose of 10,000 U/kg. An additional group of ICH rats received a combination of PC-SOD (1 mg/kg) and PEG-CAT (10,000 U/kg). ICH was induced by collagenase injection. All drugs were administered intravenously immediately after ICH induction. Brain injury was evaluated by scoring neurological function and measuring brain edema at 24 h after ICH induction. Our results demonstrated that ICH caused significant neurological deficit associated with remarkable brain edema. Treatment with PC-SOD, PEG-CAT, or PC-SOD in combination with PEG-CAT did not reduce brain edema or neurological deficit after ICH. We conclude that intravenously administered PC-SOD and/or PEG-CAT do not reduce brain injury in the collagenase-induced ICH rat model.

Deficiency of CD18 gene reduces brain edema in experimental intracerebral hemorrhage in mice.

Experimental studies of intracerebral hemorrhage (ICH) point toward leukocytes as a major contributor to ICH-induced brain injury. Leukocyte and endothelial cell adhesion molecules are responsible for injurious neutrophil-endothelial cell interactions in vasculature. Since deficiency of leukocyte-expressed CD18 protects against ischemia-reperfusion injury, we hypothesized that such deficiency may have similar effect in ICH-induced injury. Our aim was to investigate whether CD18 deficiency affords neuroprotection by decreasing ICH-induced brain injury, thereby improving neurological function and reducing mortality. A total of 20 males wild-type CDI8+/+ mice and 12 CD18-/- knockout mice were used in our study. ICH was induced by collagenase injection. Mortality, neurological function, and brain edema were measured at 24h after ICH. Data were analyzed by ANOVA, Chi-square, and Student t-test. Differences of p < 0.05 were considered statistically significant. Our study showed that the increase in brain water content caused by ICH was significantly smaller in CD18 knockout mice compared with wild-type mice (p < 0.05, Student t-test). This result correlated with a tendency toward improvement of neurological function and a decrease in mortality. We conclude that CD18 deficiency significantly reduces brain edema after ICH, which corresponds with a trend toward reduction in neurological deficit and mortality.

Effect of amantadine sulphate on intracerebral hemorrhage-induced brain injury in rats.

Recent studies have shown that amantadine, an uncompetitive N-methyl-d-aspartate receptor antagonist and dopamine agonist, is effective for the treatment of various cerebral disorders and causes relatively mild side effects. In this study, we investigated whether administration of amantadine will provide a neuroprotective effect in the intracerebral hemorrhage (ICH) rat model. A total of 15 male Sprague Dawley rats (300-380 g) were divided into sham, ICH-untreated, and ICH-treated with amantadine sulphate groups. ICH was induced by collagenase injection. Total dose 6 mg/kg of amantadine sulphate was divided into 3 injections and administered intraperitoneally at 1, 8, and 16 h after ICH. Brain injury was evaluated by investigating neurological function and brain edema at 24 h after ICH. Our data demonstrates that ICH caused significant neurological deficit associated with marked brain edema. Amantadine did not reduce brain injury after ICH; neurological function and brain edema in the treated group were not different from those of the untreated group. We conclude that amantadine sulphate does not offer neuroprotection in acute stage of experimental ICH-induced brain injury.

Dynamic production of hypoxia-inducible factor-1alpha in early transplanted islets.

More than half of transplanted beta-cells undergo apoptotic cell death triggered by nonimmunological factors within a few days after transplantation. To investigate the dynamic hypoxic responses in early transplanted islets, syngeneic islets were transplanted under the kidney capsule of balb/c mice. Hypoxia-inducible factor-1alpha (HIF-1alpha) was strongly expressed at post-transplant day (POD) 1, increased on POD 3, and gradually diminished on POD 14. Insulin secretion decreased on POD 3 in association with a significant increase of HIF-1alpha-related beta-cell death, which can be suppressed by short-term hyperbaric oxygen therapy. On POD 7, apoptosis was not further activated by continually produced HIF-1alpha. In contrast, improvement of nerve growth factor and duodenal homeobox factor-1 (PDx-1) production resulted in islet graft recovery and remodeling. In addition, significant activation of vascular endothelial growth factor in islet grafts on POD 7 correlated with development of massive newly formed microvessels, whose maturation is advanced on POD 14 with gradual diminution of HIF-1alpha. We conclude that (1) transplanted islets strongly express HIF-1alpha in association with beta-cell death and decreased insulin production until adequate revascularization is established and (2) early suppression of HIF-1alpha results in less beta-cell death thereby minimizing early graft failure.

Neuroprotective effect of hyperbaric oxygen in a rat model of subarachnoid hemorrhage.

Acute brain ischemia after subarachnoid hemorrhage (SAH) induces oxidative stress in brain tissues. Up-regulated NADPH oxidase (NOX), a major enzymatic source of superoxide anion in the brain, may contribute to early brain injury after SAH. We evaluated the effects of hyperbaric oxygen (HBO) on protein expression of gp91(phox) catalytic subunit of NOX, lipid peroxidation as a marker of oxidative stress, and on neurological and neuropathological outcomes after SAH. Twenty-nine male Sprague-Dawley rats (300 to 350 g) were randomly allocated to control (sham operation), SAH (endovascular perforation), and SAH treated with HBO groups (2.8 ATA for 2 hours, at 1 hour after SAH). Cerebral blood flow was measured using laser Doppler flowmetry. Rats were sacrificed after 24 hours and brain tissues collected for histology (Nissl staining and gp91 (phox) immunohistochemistry) and biochemistry. Mortality and neurological scores were evaluated. Neuronal injury associated with enhanced gp91 (phox) immunostaining was observed in the cerebral cortex after SAH. The lipid peroxidation product, malondialdehyde, accumulated in the ipsilateral cerebral cortex. HBO treatment reduced expression of NOX, diminished lipid peroxidation, and reduced neuronal damage. HBO caused a drop in mortality and ameliorated functional deficits. HBO-induced neuroprotection after SAH may involve down-regulation of NOX and a subsequent reduction in oxidative stress.

A novel method to determine lean body water using localized skin biopsies: correlation between lean skin water and lean body water in an overhydration model.

To determine the relationship between total body water (TBW) fraction and local water content measured in the skin (SW) this study assessed eight anesthetized piglets in an overhydration model. TBW was assessed by deuterium oxide dilution and body mass measurements taken throughout the experiments, and by whole body carcass analysis at the end of each experiment. Additionally, extracellular water and plasma volume were assessed using bromide dilution and Evan's blue dilution, respectively. SW was assessed by tissue biopsies taken at 60-min intervals throughout the experiment. Lean body water (LBW) fraction and lean skin water (LSW) fraction were assessed by extracting the fat from the carcass and biopsy samples. A correlation does exist between TBW fraction and SW fraction with r2=0.58 (P<0.05); however, the strongest correlation occurred between the LBW fraction and LSW fraction with r2=0.87 (P<0.05) and an SE of prediction of 0.77%. These data demonstrate that LSW gives an accurate and precise estimate of LBW and could therefore be used to determine the hydration index in appropriate research settings.

Exposure to airborne fungi, MVOC and mycotoxins in biowaste-handling facilities.

Health impacts due to fungi in indoor air can only be estimated reliably, if both fungal propagules and fungal secondary metabolites are qualified and quantified. In the present study, the fungal species composition in a compost facility is compared to the spectrum of microbial metabolites in the air with regard to the physiological properties of different fungal species. A number of relevant fungi was tested for the production of both volatile and non-volatile metabolites on different substrata. The profiles of mycotoxins and microbial volatile organic compounds (MVOC) turned out to be specific for certain species in pure culture. Consequently, the fungi may have different toxicological health impacts, though information on the relevance of microbial volatiles is still limited.

Species-specific profiles of mycotoxins produced in cultures and associated with conidia of airborne fungi derived from biowaste.

The potential to produce mycotoxins and non-volatile secondary metabolites was investigated for approximately 250 freshly isolated fungal strains. Among the eleven most relevant species, viz. Aspergillus flavus, A. fumigatus, A. niger, A. parasiticus, A. versicolor, Emericella nidulans, Paecilomyces variotii, Penicillium brevicompactum, P. clavigerum, P. crustosum, and P. polonicum, a wide range of metabolites partly of toxicological relevance was identified. Several unknown metabolites were found for the less frequent species, which were primarily investigated for chemotaxonomic delimitation from closely related species. The spectra of metabolites in conidial extracts and culture extracts (containing also mycelium and medium) were compared for a limited number of relevant fungi. Some mycotoxins, such as sterigmatocystin in Emericella nidulans, were not present in the conidial extracts, though produced by most strains. Fumigaclavine C, tryptoquivaline, and trypacidin, characteristic for A. fumigatus, were found in conidial extracts, but highly toxic compounds such as gliotoxin and fumitremorgens were not present. Finally, compounds such as cyclopenol, cyclopenin, and penitrem A being characteristic for certain penicillia, were found in conidial extracts and are therefore assumed to occur in native bioaerosols.

Novel ring chromosome composed of X- and Y-derived material in a girl with manifestations of Ullrich-Turner syndrome.

We present a female infant who has a novel genetic variant of Ullrich-Turner syndrome. Chromosome analysis on amniotic fluid cells obtained because of ultrasound observation of nuchal thickening showed 45,X in all cells. The infant was born with a low posterior hairline and moderate edema over hands and feet. Postnatal chromosome analysis demonstrated two cell lines-47% of the metaphases were 45,X, but 53% had a ring chromosome in addition to the normal X. FISH studies using alpha satellite probes, an X-whole-chromosome-paint (WCP) probe, and a Y-cocktail probe determined that the ring was composed of both X and Y sequences. FISH studies also determined that the KAL locus was present on the ring, but that XIST was absent. PCR-based analysis of lymphocyte DNA documented that the ring contained sequences from both the short and the long arm of the Y chromosome. X-chromosome analysis using a panel of highly polymorphic markers indicated that the ring contained material derived only from Xp22.1 to Xp21.3. No Xq material was identified on the ring, and androgen receptor-based X-inactivation studies suggested that the intact X chromosome was not subject to random X inactivation.

Effect of coenzyme Q(10) on biochemical and morphological changes in experimental ischemia in the rat brain.

The aim of the work was to evaluate an influence of CoQ(10) on lactate acidosis, adenosine-5'-triphosphate (ATP) concentrations, oxidized to reduced glutathione ratio and on superoxide dismutase activity in endothelin model of cerebral ischemia in the rat. Light microscopic studies in the central nervous system and morphometric analysis of pyramidal cells in the hippocampus were also performed. Endothelins (ET-1 or ET-3; 20 pmoles) were injected into the right lateral cerebral ventricle (intracerebroventricularly). CoQ(10) was given intraperitoneally (i.p.) just before the operation (i.p. 10 mgkg b. wt.). More severe changes of investigated biochemical parameters were observed in the animals treated with ET-1 in comparison with ET-3. Recovery was noted earlier in the group subjected to ET-3 and CoQ(10) administration, than in the animals subjected to ET-1 and CoQ(10) treatment. Histopathological observations showed sparse foci of a neuronal loss in the cerebral cortex and in the hippocampus only in the ET-1 model of ischemia. Additionally more numerous dark neurons were present in above brain structures following ET-1 administration comparing with ET-3 one. Morphometrical studies demonstrated that CoQ(10) diminished neuronal injury in the hippocampal CA1, CA2 and CA3 zones. Above data indicate on neuroprotective effect of CoQ(10) as a potent antioxidant and oxygen derived free radicals scavenger in the cerebral ischemia.

Species-specific production of microbial volatile organic compounds (MVOC) by airborne fungi from a compost facility.

Thirteen airborne fungal species frequently isolated in composting plants were screened for microbial volatile organic compounds (MVOC), i.e., Aspergillus candidus, A. fumigatus, A. versicolor, Emericella nidulans, Paecilomyces variotii, Penicillium brevicompactum, Penicillium clavigerum, Penicillium crustosum, Penicillium cyclopium, Penicillium expansum, Penicillium glabrum, Penicillium verruculosum, and Tritirachium oryzae. Air samples from pure cultures were sorbed on Tenax GR and analyzed by thermal desorption in combination with GC/MS. Various hydrocarbons of different chemical groups and a large number of terpenes were identified. Some compounds such as 3-methyl-1-butanol and 1-octen-3-ol were produced by a number of species, whereas some volatiles were specific for single species. An inventory of microbial metabolites will allow identification of potential health hazards due to an exposure to fungal propagules and metabolites in the workplace. Moreover, species-specific volatiles may serve as marker compounds for the selective detection of fungal species in indoor domestic and working environments.

Mycotoxins of Aspergillus fumigatus in pure culture and in native bioaerosols from compost facilities.

Exposure to secondary metabolites of airborne fungi in waste handling facilities is discussed in regard to potential toxic impacts on human health. The relevance of mycotoxins has been intensely studied in connection with contamination of food and feed. Toxic secondary metabolites are expected to be present in airborne spores, but exposure to mycotoxins in bioaerosols has not been studied sufficiently. Aspergillus fumigatus is one of the most frequent species in the air of compost plants. A wide range of secondary metabolites was found in pure cultures of freshly isolated strains of A. fumigatus. Tryptoquivaline, a compound with tremorgenic properties, and trypacidin, for which no toxic properties are described, were found in native bioaerosols in a compost facility. The highly toxic metabolites gliotoxin and verruculogen were not found in the bioaerosols.

The experimental squalene encephaloneuropathy in the rat.

Accumulation of squalene in the CNS is observed after administration of tellurium and squalene has been proposed to be a mediator of tellurium encephaloneuropathy. The aim of this study was to investigate the effects of squalene on the central and peripheral nervous systems in rat at the ultrastructural level. Squalene was administered at a dose of 20 g/kg body weight, once daily for 4 days, and the animals were sacrificed 7 days and 30 days after the initiation of the experiment. After 7 days a mild swelling of mitochondria and dilation of the Golgi complex cisterns in few neurons in the cerebral cortex and hippocampus were observed. The swelling of astrocytes and their processes was also seen. Some myelin sheaths in the cerebral white matter were disintegrated. In the peripheral nervous system (the sciatic nerve), a damage of the Schwann cells, a destruction of the myelin sheaths, and lipid-like deposits between myelin lamellae causing a secondary compression of axons were present. Squalene administration caused a stimulation of fibroblast to synthesize collagen and an activation of macrophages in the perineurium. After 30 days, the lipid-like material was present in some neurons as well as in the myelin sheaths in the central nervous system. Endothelial cells were hypertrophic and a few demonstrated features of apoptosis. Endothelial cell hypertrophy caused a narrowing of vessel lumen associated with an aggregation of blood morphological elements. Disturbances in myelination and swelling of astrocytic processes persisted in the central nervous system. In the peripheral nervous system, lipid-like deposits were localized in some fibroblasts and extracellularly between the collagen fibers in the perineurium. In conclusion, our electron microscopic studies indicate that squalene produces characteristic pathological changes both in the central and peripheral nervous systems. However, these alterations differ in some aspects (changes in endothelia, accumulation of lipid-like material) from the known features of tellurium encephaloneuropathy.

Effect of coenzyme Q10 (CoQ10) on superoxide dismutase activity in ET-1 and ET-3 experimental models of cerebral ischemia in the rat.

The aim of the work was to evaluate the influence of CoQ10 on superoxide dismutase (SOD) activity levels in the rat model of cerebral ischemia induced by endothelins (ET-1 or ET-3). ETs (20 pmol) were injected into the right lateral cerebral ventricle and immediately CoQ10 was given intraperitoneally (10 mg/kg b.w.). In the brains of experimental animals subjected both to ET-1 and ET-2 administration there was observed a decrease of SOD activity in the brain stem, in the cerebrallum and in the cerebral cortex at all time intervals. ET-1, as compared to ET-3 evoked longer lasting disturbances in SOD activity. In the cerebellum and in the cerebral cortex positive effect of CoQ10 and recovery to the control values was noted after 4 hours in the group subjected to ET-3 injection and after 24 hours in the ET-1 treated animal. Investigated brain areas showed different sensitivity to ETs. Above data may indicate on beneficial effect CoQ10 in the cerebral ischemia via decrease of free radicals concentration.

[Mycotoxins as exposure parameters in bioaerosols of composting sites]. / Mykotoxine als Expositionsparameter in Bioaerosolen von Kompostierungsanlagen.

The potential to produce mycotoxins was investigated for freshly isolated strains of airborne fungi. The spectra of metabolites in conidial extracts and culture extracts were compared for some relevant species. Furthermore, their potential to produce mycotoxins on semi-natural media (compost extract agar) supplemented with sucrose, yeast extract, and carboxymethylcellulose in different combinations was investigated. In native bioaerosols in a compost facility (plant 2), tryptoquivaline, a compound with tremorgenic properties, and trypacidin, for which no toxic properties are described, were found. The highly toxic metabolites gliotoxin and verruculogen were not found in the bioaerosols, although they were produced by some strains in pure culture. An inventory of microbial metabolites in addition of fungal propagules has led to a more detailed identification of potential health hazards at the working place. In addition to the pathogenic and allergological relevance, airborne fungi are thus of toxicological concern.