Myelodysplastic syndrome-like response after voriconazole treatment of systemic lupus erythematosus complicated with fungal infection: a case report.

Background: Voriconazole is mainly used to treat progressive and potentially life-threatening infections in immunocompromised patients. The adverse drug reactions related to voriconazole are varied. In some rare cases, the use of voriconazole can result in myelodysplastic syndrome (MDS)-like adverse reactions. Case presentation: Here, we present a rare case of systemic lupus erythematosus patient with a fungal infection that developed MDS-like adverse reactions after treatment with voriconazole. The patient was admitted to the hospital because of 3 days of chest tightness and dyspnea. After the admission, the patient's sputum culture showed Candida albicans infection, and voriconazole was prescribed to be taken orally. After using voriconazole, drug-related adverse reactions such as visual impairment, nausea, vomiting, hiccup, middle and lower abdominal pain, disorders of consciousness, delirium, hallucination, slow response, and subcutaneous ecchymosis appeared, as well as the gradually increased serum creatinine, oliguria, and aggravated lower limb edema. In addition, there was a decrease in peripheral blood cells, and MDS-like changes in bone marrow were indicated by bone marrow biopsy. After discontinuing voriconazole, drug-related adverse symptoms disappeared, and hematocytopenia and the changes in MDS were significantly improved, which was confirmed by a subsequent bone marrow puncture at a 6 months interval. Conclusion: This case reminded us that when using voriconazole for treatment, individual differences in patients should be considered, and the blood concentration of voriconazole should be closely monitored. Otherwise, potential drugs that affect voriconazole metabolism should be noted, and related adverse symptoms of patients should be closely observed during medication to reduce the occurrence of adverse drug events.

Apoptosis in human myelodysplastic syndrome CD34+ cells is modulated by the upregulation of TLRs and histone H4 acetylation via a ß-arrestin 1 dependent mechanism.

Excessive apoptosis of hematopoietic precursors in the bone marrow underlies the ineffective hematopoiesis characteristic of myelodysplastic syndrome (MDS). Toll-like receptor (TLR) signaling is abnormally activated in MDS and may be involved in excessive programmed cell death in the pathogenesis of MDS. TLRs expression and global histone H3/H4 acetylation were analyzed in bone marrow (BM) CD34+ cells from 20 lower-risk and 20 higher-risk MDS patients and 10 healthy controls. Apoptosis of BM CD34+ cells was examined by flow cytometry, and its correlation to histone acetylation and the expression of TLR2 and ß-arrestin1 (ß-arr1), measured by enzyme-linked immunosorbent assay and qRT-PCR, was assessed. TLR1, TLR2 and TLR6 expression and H4 acetylation levels were higher in lower-risk MDS patients than in higher-risk MDS patients or controls, and TLR2 expression and H4 acetylation levels were positively correlated with an increased rate of apoptosis. Lower-risk MDS was associated with increased ß-arr1 expression and histone acetyltransferase p300 activity. In in vitro-cultured primary normal and lower-risk MDS CD34+ cells, TLR2 activation-induced apoptosis was mediated by the upregulation of ß-arr1 leading to the recruitment of p300 and increased histone H4 acetylation. The nuclear accumulation of ßarr1 following TLR2 activation promote H4 acetylation at specific target gene promoters and may thus affect transcription of target genes in BM CD34+ cells. The mechanisms underlying the deregulation of TLR2 and increased apoptosis in MDS may involve the ß-arr1 mediated recruitment of p300 leading to increased levels of histone H4 acetylation.

Two compound frame-shift mutations in succinate dehydrogenase gene of a Chinese boy with encephalopathy.

OBJECTIVE: To investigate respiratory chain complex II deficiency resulted from mutation in succinate dehydrogenase gene (SDH) encoding complex II subunits in China. METHODS: An 11-year-old boy was admitted to our hospital. He had a history of progressive psychomotor regression and weakness since the age of 4years. His cranial magnetic resonance imaging revealed focal, bilaterally symmetrical lesions in the basal ganglia and thalamus, indicating mitochondrial encephalopathy. The activities of mitochondrial respiratory chain enzymes I-V in peripheral leukocytes were determined via spectrophotometry. Mitochondrial DNA and the succinate dehydrogenase A (SDHA) gene were analyzed by direct sequencing. RESULTS: Complex II activity in the leukocytes had decreased to 33.07nmol/min/mg mitochondrial protein (normal control 71.8±12.9); the activities of complexes I, III, IV and V were normal. The entire sequence of the mitochondrial DNA was normal. The SDHA gene showed two heterozygous frame-shift mutations: c.G117G/del in exon 2 and c.T220T/insT in exon 3, which resulted in stop codons at residues 56 and 81, respectively. CONCLUSIONS: We have described the first Chinese case of mitochondrial respiratory chain complex II deficiency, which was diagnosed using enzyme assays and gene analysis. Two novel, compound, frame-shift mutations, c.G117G/del in exon 2 and c.T220T/insT in exon 3 of the SDHA gene, were found in our patient.

Heterogeneity of six children and their mothers with mitochondrial DNA 3243 A>G mutation.

To study the clinical, biochemical, and genetic heterogeneity of six Chinese patients and their mothers with the 3243 A>G mutation, six patients (ranging from 5 to 11 years) were hospitalized. All the mothers were healthy. Mitochondrial respiratory chain enzyme activities were determined by spectrophotometry. Mitochondrial gene was analyzed in all patients. Six core pedigrees were investigated. Two patients had mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome and one had Leigh syndrome. The common initial symptoms were headache, vomiting, blurred vision, and epilepsy. m.3243A>G mutation was detected in all patients and their mothers. The mutation loads ranged from 43.6% to 58% and those of their mothers ranged from 14.1% to 28.6%. Varied respiratory chain deficiencies were observed in all patients and two mothers. m.3243A>G mutation can result in a wide spectrum of respiratory chain complex deficiencies. Mitochondrial DNA mutation detected in blood may be likely to transmit to offspring, and the mutation load may increase.

Expression of integrin beta1 in squamous cell carcinoma / 中国医学科学院学报

<p><b>OBJECTIVE</b>To study the expression of integrin beta1 in squamous cell carcinoma (SCC) and explore the relationship between stem cell marker and SCC.</p><p><b>METHODS</b>The expressions of integrin beta1 in SCC tissues and SCC cell strain A431 were detected with immunohistochemical methods and cell staining method. The differentiation of SCC cells were induced with all-trans-retinoic acid (ATRA). The changes of integrin beta1 levels before and after induction were detected with RT-PCR.</p><p><b>RESULTS</b>In highly differentiated SCC tissues, integrin beta1 was constantly expressed in the basal-like cells in the edge of tumor; some cells inside arranged as island also showed positive integrin beta1 expression. In poorly differentiated SCC tissues, island-like integrin beta1-positive cells remarkably increased and distributed in a diffuse way. In SCC A431 cells, integrin beta1 was expressed unevenly in tumor cells. After treatment by ATRA, level of integrin beta1 mRNA in A431 cells significantly decreased compared with untreated control (P < 0.05), and the ratios between the intensity values of integrin beta1 to beta-actin were 0.071 +/- 0.025 and 0.029 +/- 0.018 at 24 h and 48 h, respectively, whereas in controls were 0.148 +/- 0.027 and 0.136 +/- 0.011 (P < 0.05).</p><p><b>CONCLUSIONS</b>Integrin beta1 is heterogeneously expressed in both SCC tissues and SCC A431 cells. The expression of Integrin beta1 decreases when the differentiation level of tumor cells increase, indicating that integrin beta1 is closely related with the initiation of SCC and potential cancer stem cells in SCC.</p>

Inhibition of promyelocytic leukemia gene by tazarotene in hyperproliferative epidermis of psoriasis / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the mechanism of tazarotene against active psoriasis vulgaris.</p><p><b>METHODS</b>A randomized, controlled trial was conducted in 43 patients with active psoriasis vulgaris, who were divided into tazarotene and control groups. Promyelocytic leukemia (PML) mRNA in active psoriatic lesions before and 14 days after tazarotene treatment was detected by in situ hybridization.</p><p><b>RESULTS</b>PML mRNA expression was detected not only in the basal layer (86.96%), but also in the suprabasal layers of the epidermis in the manner of focal expression (78.26%). After tazarotene treatment, virtually no PML mRNA expression could be detected in the psoriatic lesions (8.69% in the basal layer and 4.35% in the suprabasal layers). PML mRNA expression in the control group underwent no obvious changes during the observation.</p><p><b>CONCLUSIONS</b>Tazarotene may inhibit abnormal proliferation of keratinocytes through down-regulating PML gene expression in active psoriatic epidermis.</p>