Dehydroepiandrosterone attenuates LPS-induced inflammatory responses via activation of Nrf2 in RAW264.7 macrophages.

Dehydroepiandrosterone (DHEA) is the major steroid hormone in humans and animals, which can regulate the body's inflammatory responses. However, the detail mechanism of this beneficial function is still poorly understood. The present study aimed to explore the anti-inflammation effect of DHEA and its underlying molecular mechanism in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. The findings showed that DHEA significantly inhibited the inflammation-related mediators production and pro-inflammatory cytokines expression level. Further research found that DHEA obviously blocked the LPS-stimulated PI3K/AKT, MAPK and NF-κB activation in RAW 264.7 cells. Meanwhile, DHEA enhanced the autophagy-dependent Keap1 protein degradation, subsequently activated the Nrf2 pathway to alleviate the redox imbalance and inflammatory responses. In conclusion, our data demonstrated that DHEA suppresses inflammatory responses through the activation of Nrf2 and inhibition of NF-κB in LPS-stimulated macrophages.

Topical 11ß-Hydroxysteroid Dehydrogenase Type 1 Inhibition Corrects Cutaneous Features of Systemic Glucocorticoid Excess in Female Mice.

Glucocorticoid (GC) excess drives multiple cutaneous adverse effects, including skin thinning and poor wound healing. The ubiquitously expressed enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activates mouse corticosterone from 11-dehydrocorticosterone (and human cortisol from cortisone). We previously demonstrated elevated 11ß-HSD1 activity during mouse wound healing, but the interplay between cutaneous 11ß-HSD1 and systemic GC excess is unexplored. Here, we examined effects of 11ß-HSD1 inhibition by carbenoxolone (CBX) in mice treated with corticosterone (CORT) or vehicle for 6 weeks. Mice were treated bidaily with topical CBX or vehicle (VEH) 7 days before wounding and during wound healing. CORT mice displayed skin thinning and impaired wound healing but also increased epidermal integrity. 11ß-HSD1 activity was elevated in unwounded CORT skin and was inhibited by CBX. CORT mice treated with CBX displayed 51%, 59%, and 100% normalization of wound healing, epidermal thickness, and epidermal integrity, respectively. Gene expression studies revealed normalization of interleukin 6, keratinocyte growth factor, collagen 1, collagen 3, matrix metalloproteinase 9, and tissue inhibitor of matrix metalloproteinase 4 by CBX during wound healing. Importantly, proinflammatory cytokine expression and resolution of inflammation were unaffected by 11ß-HSD1 inhibition. CBX did not regulate skin function or wound healing in the absence of CORT. Our findings demonstrate that 11ß-HSD1 inhibition can limit the cutaneous effects of GC excess, which may improve the safety profile of systemic steroids and the prognosis of chronic wounds.

Prenatal exposure to dexamethasone disturbs sex-determining gene expression and fetal testosterone production in male embryos.

Prenatal stress is known to cause intrauterine fetal growth retardation, and is also associated with various long-term effects in the form of metabolic and neurodevelopmental diseases in adults. Many of the diseases associated with prenatal stress exhibit a sex bias. Perturbations and vulnerability to prenatal stress are often more profound in males, but the mechanisms responsible for this relationship are not clear. We have previously shown that administration of the synthetic glucocorticoid, dexamethasone (Dex), at embryonic days 7.5, 8.5, and 9.5, induces embryonic growth restriction in a sex-dependent manner in a mouse model. Here we examined the effect of prenatal exposure to Dex on gonadal development. During male gonadal development, sex-determining genes, such as Sry, Sox9, and other downstream genes, were found to be dysregulated in response to prenatal Dex, whereas the genes for the ovarian pathway were affected to a lesser degree in females. In addition, fetal testosterone concentrations were decreased by prenatal exposure to Dex, in parallel with reduced numbers of 3ß-hydroxysteroid dehydrogenase (3ß-HSD)-positive cells in the embryonic testis. These results show that prenatal exposure to Dex differentially influences male versus female on the gene expression and hormone production during sex determination. We believe these studies provide valuable insights into possible mechanisms responsible for sex-specific responses to prenatal stress.

Multi-drug intoxication fatality involving atorvastatin: A case report.

Mixed antihypertensive drug intoxication poses a significant risk for patient mortality. In tandem to antihypertensives, hypolipidemic medicines (especially statins) are often prescribed. Among their well-known adverse effects belongs rhabdomyolysis. We report a case of fatal multi-drug overdose in a 65-year-old female alcoholic. The patient was unconscious at admission. Empty blister packs indicated the abuse of 250 tablets of urapidil, 42 tablets of verapamil/trandolapril, 50 tablets of moxonidin, 80 tablets of atorvastatin and 80 tablets of diacerein. Standard measures (gastric lavage, activated charcoal, mechanical ventilation, massive doses of vasopressors, volume expansion, diuretics and alkalinization) failed to provide sufficient drug elimination and hemodynamic support and the sufferer deceased on the fourth day. Dramatic elevations of serum myoglobin (34,020 µg/L) and creatine kinase (219 µkat/L) were accompanied by rise in cardiac troponin I and creatinine. Gas chromatography revealed ethanol 1.17 g/kg (blood) and 2.81 g/kg (urine). Thin layer chromatography and gas chromatography of gastric content and urine verified verapamil, moxonidin and urapidil fragment (diacerein method was unavailable). Atorvastatin and trandolapril concentrations (LC-MS(n)) equaled 277.7 µg/L and 57.5 µg/L, resp. (serum) and 8.15 µg/L and 602.3 µg/L, resp. (urine). Histology confirmed precipitates of myoglobin with acute necrosis of proximal renal tubules in association with striated muscle rhabdomyolysis and myocardial dystrophy. Cardiogenic-distributive shock in conjunction with acute renal failure due to the combined self-poisoning with vasoactive agents and atorvastatin were determined to be this decedent's immediate cause of death. The manner of death was assigned to be suicidal.

[Misuse of substances theoretically without abuse potential--case series]. / Naduzywanie substancji teoretycznie bez znanego potencjalu uzalezniajacego--przeglad przypadków.

The aim of our study was to present cases of misuse of different substances theoretically without abuse potential. In the last few years such behavior became an increasing problem in toxicological and emergency units. Lack of typical signs of intoxication with psychoactive substances, and negative results of standard toxicological tests may be a challenge for toxicologists and emergency medicine practitioners.

Cushing syndrome from percutaneous absorption of 1% hydrocortisone ointment in Netherton syndrome.

Netherton syndrome is a congenital skin disease associated with decreased skin barrier function and increased percutaneous absorption. We report an 11-year-old boy with Netherton syndrome who developed Cushing syndrome after application of 1% hydrocortisone ointment to his entire body for more than 1 year. This presentation illustrates that even low-potency steroid ointments should be used with caution in Netherton syndrome and warns about the use of long-term topical medications with potential systemic side effects when used in large quantities in any chronic skin disease.

[Retrospective analysis of toxicity of eardrops, topical nasal and oropharyngeal medicines, documented in São Paulo, Brazil]. / Análise retrospectiva da toxicidade de gotas otológicas, medicamentos tópicos nasais e orofaríngeos registrada na Grande São Paulo.

BACKGROUND: Retrospective analysis of human toxicity files involving topical medicines for treatment of upper airways diseases (eardrops, topical nasal medicines, lozenges, drops and sprays for oropharyngeal affections). METHODS: Thirty-four brands of eardrops, 48 of topical nasal medicines and 22 of tablets, lozenges and sprays for oropharyngeal affections were selected, from a total of 104 products available in Brazil. We analyzed the registries in the electronic database from the Poison Control Centre of São Paulo (CCI-Jabaquara), Brazil, for the period from January 1996 through December 2000. The cases related to selected pharmaceuticals were collected. RESULTS: 10,823 cases of human toxicity caused by medicines were voluntarily reported to CCI-Jabaquara. Topical medicines for treatment of upper airways diseases accounted for 291 cases (2.68%), from which 240 (82.5%) represented poisoning; 12 (4.1%) involved ear drops, 268 (92%), topical nasal medicines and 11 (3.9%), topical medicines for oropharyngeal affections. Among topical nasal medicines, vasoconstrictors predominated (233 cases), and among medicines for oropharyngeal affections, it was tetracaine (four cases). Considering age distribution, toxicity predominated significantly in children aged from 1 to 4 years (p=0.0003). The main causes of toxicity were: accidental intake of medicines (43%) and error in drug administration (14.8%). Hypereflexia and vomiting were the most frequent symptoms related to toxicity. CONCLUSIONS: There was significant incidence of systemic toxicity due to eardrops, topical nasal and oropharyngeal medicines in children 1 to 4 years-old, whose main cause was accidental intake of these medicines.

Massive sulfasalazine and paracetamol ingestion causing acidosis, hyperglycemia, coagulopathy, and methemoglobinemia.

CASE REPORTS: Reports of acute toxicity following sulfasalazine ingestion are rare. A case of an acute ingestion of sulfasalazine 50 g and paracetamol 50 g resulting in severe lactic acidosis, seizures, coagulopathy, hyperglycemia, ketosis, and methemoglobinemia is reported. Despite the ingestion of a large amount of paracetamol with serum paracetamol 5486 nmol/L (844 mg/L), significant hepatotoxicity did not occur. The patient recovered fully following administration of intravenous N-acetylcysteine, methylene blue, sodium bicarbonate, and supportive therapy.

A confused man with rapid respiration.

A 71-year-old man presented with incoherent, slurred speech, auditory hallucinations, and tachypnea. According to the neighbor who called for emergency medical service, the man had appeared to be in good health the day before. On admission, his blood pressure was normal.

Fatal self-poisoning with benoxaprofen.

A report of the first fatal self-poisoning due to primary toxicity of benoxaprofen. Benoxaprofen is toxic in acute overdosage to the central nervous system, myocardium and kidneys, but appears to spare the liver.

Piroxicam poisoning in a 2-year-old child. A case report.

This report describes the severe multisystem toxicity which followed ingestion of 5 piroxicam capsules (100 mg) by a 2-year-old child. Gastro-intestinal symptoms developed within 2 hours, resulting in severe fluid and electrolyte imbalance, mental confusion and a generalized seizure. Evidence of liver and renal dysfunction developed within 3 days. Haemopoietic toxicity was manifested by progressive peripheral pancytopenia, bone marrow aplasia and coagulopathy. Pseudomonas septicaemia developed during the period of neutropenia. Clinical, biochemical and haematological abnormalities slowly resolved over 3-4 weeks. In view of the increasing use of piroxicam as an anti-inflammatory agent it seemed important to draw attention to the potentially serious effects of accidental overdosage.

Overdosage of piroxicam.

A 54-year-old woman took an overdose of 1 800 mg piroxicam. She complained of nausea and abdominal pain. Endoscopy revealed multiple superficial ulcerations in the pyloric antrum and the first part of duodenum. There were no symptoms or signs from other organ system and recovery was uneventful. The highest serum concentration was 241.6 mg/l, which is about 30 times the usual therapeutic level of 5-10 mg/l.