SLC4A1 复合杂合突变致遗传性球形红细胞增多症并远端肾小管酸中毒1 例报告并文献复习

目的分析SLC4A1复合杂合突变致遗传性球形红细胞增多症(HS)并远端肾小管酸中毒(dRTA)的临床表型与基因变异的关系。方法回顾分析1例确诊HS合并dRTA患儿的临床资料,以及患儿及父母外周血全外显子测序及Sanger验证结果。结果男性患儿,1岁7个月,主要临床表现为输血依赖性球形红细胞增多、代谢性酸中毒、低钾血症及生长发育迟缓。检测到患儿SLC4A1 基因2个已报道的错义变异c.2102GA p.(Gly701Asp),c.1988TC p.(Met663Thr),分别来源于父母。结论经基因检测确诊由SLC4A1复合杂合变异所致的遗传型HS合并dRTA,符合常染色体隐性遗传。     

uPAR Controls Vasculogenic Mimicry Ability Expressed by Drug-Resistant Melanoma Cells

Malignant melanoma is a highly aggressive skin cancer characterized by an elevated grade of tumor cell plasticity. Such plasticity allows adaptation of melanoma cells to different hostile conditions and guarantees tumor survival and disease progression, including aggressive features such as drug resistance. Indeed, almost 50% of melanoma rapidly develop resistance to the BRAFV600E inhibitor vemurafenib, with fast tumor dissemination, a devastating consequence for patients’ outcomes. Vasculogenic mimicry (VM), the ability of cancer cells to organize themselves in perfused vascular-like channels, might sustain tumor spread by providing vemurafenibresistant cancer cells with supplementary ways to enter into circulation and disseminate. Thus, this research aims to determine if vemurafenib resistance goes with the acquisition of VM ability by aggressive melanoma cells, and identify a driving molecule for both vemurafenib resistance and VM. We used two independent experimental models of drug-resistant melanoma cells, the first one represented by a chronic adaptation of melanoma cells to extracellular acidosis, known to drive a particularly aggressive and vemurafenib-resistant phenotype, the second one generated with chronic vemurafenib exposure. By performing in vitro tube formation assay and evaluating the expression levels of the VM markers EphA2 and VE-cadherin by Western blotting and flow cytometer analyses, we demonstrated that vemurafenib-resistant cells obtained by both models are characterized by an increased ability to perform VM. Moreover, by exploiting the CRISPR-Cas9 technique and using the urokinase plasminogen activator receptor (uPAR) inhibitor M25, we identified uPAR as a driver of VM expressed by vemurafenib-resistant melanoma cells. Thus, uPAR targeting may be successfully leveraged as a new complementary therapy to inhibit VM in drug-resistant melanoma patients, to counteract the rapid progression and dissemination of the disease.     

Intravenous ketogenic diet therapy for neonatal-onset pyruvate dehydrogenase complex deficiency

BackgroundPyruvate dehydrogenase complex (PDHC) deficiency is an inborn error of metabolism that causes lactic acidosis and neurodevelopmental changes. Five causative genes have been identified: PDHA1, PDHB, DLAT, DLD, and PDHX. Four neurological phenotypes have been reported: neonatal encephalopathy with lactic acidosis, non-progressive infantile encephalopathy, Leigh syndrome, and relapsing ataxia. Of these, neonatal encephalopathy has the worst mortality and morbidity and there is no effective treatment.Subjects and methodsWe studied two girls who were clinically diagnosed with PDHC deficiency as neonates; they were subsequently found to have PDHA1 mutations. The clinical diagnosis was based on white matter loss and a lateral ventricular septum on fetal MRI, spasticity of the lower extremities, and lactic acidosis worsening after birth. Intravenous ketogenic diets were started within 24 h after birth. The ketogenic ratio was increased until the blood lactate level was controlled, while monitoring for side effects.ResultsIn both cases, the lactic acidosis improved immediately with no apparent side effects. Both children had better developmental outcomes than previously reported cases; neither exhibited epilepsy.ConclusionsIntravenous ketogenic diet therapy is a treatment option for neonatal-onset PDHC deficiency. Further studies are needed to optimize this therapy.     

Successful treatment of linezolid-induced severe lactic acidosis with continuous venovenous hemodiafiltration: A case report

Linezolid is an oxazolidinone antibiotic. Linezolid-associated lactic acidosis has been reported in 6.8% of linezolid-treated patients. Lactic acidosis is associated with poor clinical outcomes, with high blood lactate levels resulting in organ dysfunction and mortality. This case report describes the development of lactic acidosis in a 64-year-old Chinese woman who had received 33 days of treatment with antituberculosis drugs and 28 days of treatment with oral linezolid for tuberculous meningitis. Severe lactic acidosis was reversed by withdrawing antituberculosis drugs and using continuous venovenous hemodiafiltration (CVVH). When the patient's condition was stable, she was transferred to the infectious disease department, and antituberculosis drugs, with the exception of linezolid, were reintroduced. This did not result in recurrence of lactic acidosis. The causal relationship between lactic acidosis and linezolid was categorized as ‘probable’ on the Adverse Drug Reaction Probability Scale. This case demonstrates that CVVH has potential as an alternative to discontinuation of linezolid alone for rapid reversal of linezolid-associated severe lactic acidosis.     

A comparative study of general anesthesia versus combined spinal–epidural anesthesia on the fetus in cesarean section

BackgroundObstetric anesthesia guidelines recommend regional over general anesthesia for most caesarean sections to decrease the risk for both fetus and mother.Aim of the workTo determine the effects of combined spinal epidural anesthesia and general anesthesia on the newborns and the mother undergoing elective cesarean section.SubjectsA total of 60 consecutive women with uncomplicated singleton pregnancies at term and scheduled to undergo elective cesarean section at Kasr Al-Aini obstetric hospital participated in this prospective study. The women were divided into 2 groups (each 30), a general anesthesia group (A) and combined spinal–epidural anesthesia group (B).MethodsUmbilical artery blood gas analysis and Apgar scores were assessed at 1 and 5 min after delivery in the newborn while systolic and diastolic blood pressure, heart rate, oxygen saturation and (capnography in general anesthesia) were measured preoperative and after 5, 10 and 15 min of induction of anesthesia in the mothers. In addition, the time from induction of anesthesia till delivery of the fetus and duration in operative room were measured.ResultsApgar score recorded statistically significant differences between the 2 groups at 1 min and 5 min, where with combined spinal–epidural anesthesia the Apgar score readings were higher than with general anesthesia. HCO₃ readings showed a statistically significant difference between the 2 groups after 1 and 5 min, where the newborns in general anesthesia group had a statistically significant lower HCO₃ compared to the newborns in combined spinal–epidural group. Patients in general anesthesia group were significantly more tachycardic compared to patients in combined spinal–epidural group.ConclusionCombined spinal–epidural anesthesia is safer on the newborn than general anesthesia regarding the APGAR scores and acid–base balance.