Hydroxocobalamin for Initial and Long-term Therapy for Vitamin B12 Deficiency

ABSTRACT. Skouby AP (Medical Department II, Municipal Hospital, Copenhagen, Denmark). Hydroxocobalamin for initial and long-term therapy for vitamin B₁₂ deficiency. Seventeen patients were treated for vitamin B₁₂ deficiency with i.m. injection of 1 mg hydroxocobalamin every three months as maintenance therapy for eight to 20 years after an initial depot treatment of one or two series of five i.m. injections on alternate days. In three of four patients given two depot series ≤3 months apart, and with no antibody to transcobalamin II (TC II) detected previously, abnormally high values of serum cobalamins were measured at the end of injection intervals after seven to 12 years. No increase in unsaturated B₁₂ binding capacity (UB₁₂BC) was found in contrast to findings in patients given identical therapy, in whom an early increase above the normal level occurred associated with antibody to TC II. One depot series followed by i.m. injection of 1 mg hydroxocobalamin every third month secured values within the normal range for serum cobalamin, UB₁₂BC and total B₁₂ binding capacity (TB₁₂BC).     

Repeated provocation tests in asthmatic children for testing tachyphylaxis to histamine

Tachyphylaxis to histamine was investigated in 16 children, aged 7-15 years, with mild asthma. Three consecutive histamine challenges were performed at intervals of 24 hours and 1 hour, respectively. No significant differences in IVC, FEV1, and PC20-histamine values between the three measurements were observed. After a 24 hour interval there was no difference in percentage fall of FEV1, but there was a slight (not significant) decrease in fall of FEV1 after a 1 hour interval. The PC20-histamine values showed good reproducibility with a 24 hour as well as with a 1-hour period between the tests (geometric mean PC20, 2.04 mg/mL +/- 3.50 %SD, 1.96 mg/mL +/- 4.37 %SD, 2.17 mg/mL +/- 4.12 %SD; correlation coefficients for a 24 hour interval, r = 0.87 and for a one-hour interval, r = 0.94 (P less than 0.01]. We conclude that in children there is no strong evidence for tachyphylaxis to histamine. Our results differ from studies on tachyphylaxis in adult asthmatics. Possibly different mechanisms exist in children and in adults.     

细菌对利福定的耐药性与细菌包膜屏障的关系

选用大肠杆菌k-12及其耐利福定菌株,利用同位素示踪技术研究发现利福定明显抑制~3H-尿苷掺入敏感菌,而耐药菌掺入则不受抑制,加用膜通透剂EDTA后,~3H-尿苷掺入耐药菌受到明显的抑制;~3H-利福定透入耐药菌的量明显低于透入敏感菌的量,用EDTA后,透入耐药菌中的~3H-利福定显著增加。结果提示:细菌包膜屏障通透性降低使药物进入菌体减少是细菌对利福定耐药的重要机制之一。     

Protein kinase C and Gi-protein mediated modulation of cAMP production in different stages of the rat seminiferous epithelium

The modulatory role of protein kinase C (PK-C)- and G_i-protein-mediated signal transduction systems was studied in the cyclic variation of follicle-stimulating hormone (FSH)-stimulated cAMP production of rat seminiferous tubules. FSH (Metrodin, Serono, 30 mg/1) stimulated cAMP production 10-fold (p < 0.01) in a 3 h incubation of 5 mm segments of seminiferous tubules of stages II–VI of the epithelial cycle, but only 2-fold (p < 0.01) in stages VII–VIII. The PK-C activator 12-O-tetradecanoylphorbol 13-acetate (TPA, 100 nmol/1) suppressed the FSH effect on cAMP output by 50–70% (p < 0.01) in stages II–VI, but had no effect in stages VII–VIII. If the tubular segments were preincubated for 3 h in the presence of pertussis toxin (PT, 100 μg/1), the FSH-stimulated cAMP production of stages VII-VIII increased by 100–200% (p < 0.01), and now they also became responsive to the TPA suppression. Conversely, no effect of PT was observed in stages II–VI. Cholera toxin (CT, 100 μg/1) and forskolin (Fk, 100 μmol/1) nearly similarly stimulated the cAMP production in both stages studied (about 10-fold, p < 0.01), and TPA and PT potentiated the effects in a non-additive fashion. In conclusion, both G_i-protein and PK-C-mediated mechanisms modulate cAMP production of rat seminiferous tubules. A clear cyclic variation can only be demonstrated in FSH-stimulated cAMP production, but not if the G_s-protein or adenylate cyclase are directly stimulated. Upon FSH stimulation, the low cAMP production in stages VII–VIII is mainly due to the G_i-protein-mediated inhibition. In contrast, the absence (or non-function) of this inhibition mechanism explains the brisk cAMP response to FSH in stages II–VI. PK-C activation suppresses FSH-stimulated cAMP production only if it is not inhibited by the G_i-protein-mediated mechanism (stages II–VI), probably by inhibiting the FSH-receptor-G_s-protein association. It also increases CT and Fk-stimulated cAMP production, in this case inactivating the G_i-protein.     

Genomic DNA Analysis of Rat Retinal Tumor Induced by Adenovirus Type 12

To elucidate the pathogenesis of human retinoblastoma, we investigated the genomic expression in retinal tumors induced by human adenovirus type 12 in rats, using various DNA probes. Seven rats received a single intraocular inoculation of concentrated virus fluid within 24 hours after birth. Intravitreous tumors were induced in two out of seven animals (28.5%) within 30 to 64 days after the inoculation. A remarkably uniform histologic feature, i.e., neuroblastic cells in association with Homer-Wright pseudorosettes, was present in all cases. The adenovirusrelated oncoprotein gene E1A and human retinoblastoma susceptibility gene were detected in the tumors by Southern blot hybridization. In situ hybridization analysis demonstrated expression of adenovirus type 12 E1A gene in the inner granular layer of the retina. It was suggested that integration of adenovirus type 12 E1A fragment with the host genome and expression of the gene were required for induction of this tumor.     

Fas/FasL在罗哌卡因致PC12细胞凋亡中的表达

目的检测Fas、FasL在罗哌卡因诱导PC12细胞凋亡中表达的变化,探讨罗哌卡因的神经毒性机制。方法采用不同浓度罗哌卡因(0.1、0.5、1、2、4 mmol/L)处理PC12细胞24 h以建立细胞的神经毒性模型,CCK-8法测定细胞活力。最终将细胞随机分为三组:0.5 mmol/L组、2mmol/L组和正常对照组。各组细胞培养24 h后用光学显微镜观察细胞形态学变化(加上1 mmol/L组),流式细胞仪检测细胞凋亡,免疫荧光检测Fas、FasL表达。结果与正常对照组比较,0.5 mmol/L组和2 mmol/L组细胞活力明显降低(P0.05),细胞形态明显异常(包括1 mmol/L组),凋亡率明显升高(P0.05),Fas、FasL表达明显增强(P0.05);与0.5 mmol/L组比较,2 mmol/L组细胞凋亡率和Fas、FasL表达明显增加(P0.05)。结论罗哌卡因可诱导PC12细胞凋亡,其机制可能与Fas/FasL上调有关。     

Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody

Progressing tumors in man and mouse are often infiltrated by dendritic cells (DCs). Deficient antitumor immunity could be related to a lack of tumor-associated antigen (TAA) presentation by tumor-infiltrating DCs (TIDCs) or to a functional defect of TIDCs. Here we investigated the phenotype and function of TIDCs in transplantable and transgenic mouse tumor models. Although TIDCs could encompass various known DC subsets, most had an immature phenotype. We observed that TIDCs were able to present TAA in the context of major histocompatibility complex class I but that they were refractory to stimulation with the combination of lipopolysaccharide, interferon gamma, and anti-CD40 antibody. We could revert TIDC paralysis, however, by in vitro or in vivo stimulation with the combination of a CpG immunostimulatory sequence and an anti-interleukin 10 receptor (IL-10R) antibody. CpG or anti-IL-10R alone were inactive in TIDCs, whereas CpG triggered activation in normal DCs. In particular, CpG plus anti-IL-10R enhanced the TAA-specific immune response and triggered de novo IL-12 production. Subsequently, CpG plus anti-IL-10R treatment showed robust antitumor therapeutic activity exceeding by far that of CpG alone, and elicited antitumor immune memory.     

Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype

PurposeHaploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS.MethodsWe report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status.ResultsThe expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes.ConclusionWe refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature.     

甲基丙二酸血症45例综合报道

目的:探讨甲基丙二酸血症的早期诊断及治疗干预方法。方法:总结国内外45例甲基丙二酸血症患儿的临床症状和实验室检查情况,分析其诊治及转归情况。结果:对有不明原因酸中毒,意识障碍,惊厥,肌张力低下以及体格及智力发育落后甚至倒退的患儿应引起高度重视,血尿气相色谱/质谱联用分析(GC/MS)可确诊该病,该病的治疗可分为维生素B12(VB12)有效型及无效型两类,维生素B12有效型可采用VB12注射及限制饮食的方法进行干预;对维生素B12无效型患者采取饮食限制的方法加以干预,晚期肾功能衰竭行肝肾移植可改善此类患儿预后,但不确定是否能改善远期预后。结论:对疑似患儿及时进行GC/MS尿有机酸分析可早期诊断本症,对确诊本病的患儿进行早期干预可明显改善预后。