Agreement between CBNAAT,liquid culture and line probe assay for detection of Mycobacterium tuberculosis and anti-tubercular drug resistance in extrapulmonary samples

PurposeCartridge based nucleic acid amplification test (CBNAAT) has been endorsed by the WHO as the screening test for diagnosing extrapulmonary tuberculosis (EPTB). In the present study we report the agreement between CBNAAT (Xpert MTB/RIF), liquid culture (LC) and line probe assay (LPA) for diagnosis of Mycobacterium tuberculosis and detection of drug resistance among EPTB cases.MethodsThe EP samples were subjected to CBNAAT (Xpert MTB/RIF, Cepheid, USA) and wherever possible, to LC (MGIT 960, Becton Dickinson, USA) followed sequentially by first line and second line-LPA (FL-LPA, SL-LPA, Hain Lifescience, Germany) on the isolates.ResultsTotal 566/4080 (13.9%) EP samples were detected positive for M. tuberculosis on CBNAAT. Aspirates from lymph nodes were most often positive (11/30; 36.6%), followed by pus (240/873; 27.5%) and CSF samples (166/104; 15.8%). The detection of M. tuberculosis was more in adults than children except in tissue biopsy samples. Rifampicin resistance was also higher among adults except CSF in which resistance was more in children. Total 185 of 566 (32.7%) CBNAAT positive and 770 of 3510 (21.9%) CBNAAT negative samples could be cultured of which 110/185 (59.4%) and 33/770 (4.3%) respectively turned positive. FL-LPA and SL-LPA of 143 culture isolates showed that 27 isolates had drug resistance, of which 3 (2.1%) were XDR, 11 (7.7%) were Pre-XDR (FQ) and 13 (9.1%) were MDR. Of these 27 resistant isolates, 12 were negative by CBNAAT and two were mislabeled as Rifampicin sensitive or indeterminate based on the unique RpoB gene mutation patterns on LPA. The positive and negative agreements between LC and CBNAAT for detection of M. tuberculosis were 67.1% and 92.7% respectively and between LPA and CBNAAT for rifampicin resistance detection were 98.9% and 92.9% respectively.ConclusionsFor EPTB, CBNAAT should be accompanied with LC wherever possible irrespective of the CBNAAT result.     

An inhibitor of cytotoxic functions produced by CD8+CD57+ T lymphocytes from patients suffering from AIDS and immunosuppressed bone marrow recipients

An inhibitor of the cytotoxic functions (ICF) mediated by human immunodeficiency virus (HIV)- or HLA-specific cytotoxic T lymphocytes, natural killer and lymphokine-activated killer (LAK) cells is secreted by CD8⁺CD57^? T lymphocytes, a subset expanded during infection with HIV and after bone marrow transplantation. We previously showed an apparent molecular mass of 20–30 kDa for this soluble glycosylated concanavalin A-binding inhibitor which is distinct from known cytokines. Here, we report a characterization of the mechanism of action of this CD8⁺CD57⁺ ICF. We show that the ICF-induced inhibition of LAK cell cytolytic activity is transient, with a spontaneous recovery of cytolytic potential after 18 h. When testing interactions of ICF with a large set of cytokines we found that the ICF-mediated inhibition of cytotoxic functions is antagonized by two cytokines: recombinant interleukin (rIL)-4 and recombinant interferon (rIFN)-γ. Finally, we show that ICF acts at the level of cytolytic effector cells, where it induces a significant increase of cyclic AMP (cAMP) level. In contrast, no modification of either cell surface antigen expression or of target/effector cell conjugate formation could be evidenced. Addition of rIL-4 and rIFN-γ reverses such an increase of cAMP levels and in parallel restores the cytolytic activity. Altogether, these data demonstrate that the glycoprotein ICF produced by CD8⁺CD57⁺ cells (1) inhibits cell-mediated cytotoxicity by sensitizing cytolytic effector cells to the cAMP pathway, and (2) is part of a cytokine network controlling cell-mediated cytotoxic functions.     

Rapid hydroxylation of methtryptoline (1-methyltetrahydro-β-carboline) in rat: Identification of metabolites by chiral gas chromatography-mass spectrometry

Summary Racemic methtryptoline (1-methyltetrahydro--carboline) and 5-hydroxymethtryptoline-9-carboxylic acid (6-hydroxy-1-methyltetrahydro--carboline-1-carboxylic acid) were administered intraperitoneally to rats and the components of their urine was subsequently investigated by chiral gas chromatography-mass spectrometry. Methtryptoline rapidly became hydroxylated in the 5- and 6-position and excreted in urine. There was about a ninefold predominance of the S(–) enantiomer over the other in the 5-hydroxylated species, while the 6-hydroxylation produced a small excess of the R(+) enantiomer. About 75% of the injected dose of methtryptoline was recovered in the urine as 5- and 6-hydroxylated compounds during the first 24 h period, demonstrating that hydroxylation represents the major metabolic pathway. Treatment with 6-hydroxymethtryptoline-9-carboxylic acid led to a fivefold increase in the urinary excretion of 5-hydroxymethtryptoline during the first 24 h period with a predominance of the S(–)-enantiomer, indicating a much smaller conversion rate than from methtryptoline. It was concluded that hydroxylation of methtryptoline is a likely pathway for the natural formation of 5-hydroxymethtryptoline.     

Species differences in the relative analgesic potencies of some classical opiates and opioid peptides

The analgesic ED₅₀ values of some classical morphine congeners (morphine, methadone, fentanyl, azidomorphine) in the rat and mouse tail-flick tests were found to be similar. However, several synthetic derivatives of the natural enkephalins were more potent in mice than in rats. (These analogs contain d-amino acid in position 2 and d- or l-sulfonic (or phosphonic) acid residue in position 5). -Endorpin, d-Met², Pro⁵-enkephalinamide and two partial agonists showed intermediate interspecies relative potencies. According to the data obtained, similar opiate receptors might mediate the analgesic action of classical opiates in rats and in mice. However, the opiate receptors responsible for the antinociceptive effects of the above mentioned enkephalin analogues must be dissimilar in the two species examined. The results are discussed in terms of the role of - and -receptors in mediation of the analgesic effect induced by different types of opioids.     

Effect of destruction of central noradrenergic and serotonergic nerve terminals by systemic neurotoxins on the long-term effects of antidepressants onβ-adrenoceptors and 5-HT2 binding sites in the rat cerebral cortex

Summary The dependence of intact noradrenergic and serotonergic nerve terminals for the decrease in the number of-adrenoceptors and 5-HT₂ binding sites in the cerebral cortex produced by long-term treatment of rats with antidepressant drugs was examined. Noradrenergic nerve terminals were destroyed with the selective noradrenaline neurotoxin DSP4, and serotonergic nerve terminals were destroyed with p-chloroamphetamine (PCA). It was found that lesioning of the noradrenergic nerve terminals abolished the decrease in-adrenoceptors produced by desipramine, mianserin and zimeldine and partially antagonized that of the-adrenoceptor agonist clenbuterol. PCA pretreatment did not antagonize the long-term effects on the-adrenoceptor produced by these compounds.Lesioning of serotonergic nerve terminals affected the down-regulation of 5-HT₂ binding sites produced by long-term treatment with mianserin, desipramine and amiflamine. DSP4 pretreatment partially abolished the down-regulation of 5-HT₂ binding sites produced by long-term treatment with desipramine, while the effects of mianserin and amiflamine were unaffected by pretreatment with DSP4.     

TUBB8基因突变致早期胚胎发育停滞一例

青岛大学附属烟台毓璜顶医院生殖医学中心对1例反复体外受精/卵细胞质内单精子注射（IVF/ICSI）助孕后早期胚胎发育停滞的患者进行了全外显子基因检测,发现了一种新的TUBB8基因突变型（c.208C>T/p.Pro70Ser）,并进一步探讨了TUBB8基因突变与早期胚胎发育停滞之间的联系,为反复种植失败的诊断与治疗提供更多可能性。     

Highly Pathogenic Avian Influenza A(H5N8) Virus Spread by Short- and Long-Range Transmission,France, 2016–17

We detected 3 genotypes of highly pathogenic avian influenza A(H5N8) virus in France during winter 2016–17. Genotype A viruses caused dramatic economic losses in the domestic duck farm industry in southwestern France. Our phylogenetic analysis suggests that genotype A viruses formed 5 distinct geographic clusters in southwestern France. In some clusters, local secondary transmission might have been started by a single introduction. The intensity of the viral spread seems to correspond to the density of duck holdings in each production area. To avoid the introduction of disease into an unaffected area, it is crucial that authorities limit the movements of potentially infected birds.     

SARS-CoV-2 neutralizing antibodies after first vaccination dose in breast cancer patients receiving CDK4/6 inhibitors

Undoubtedly, the development of COVID-19 vaccines displays a critical step towards ending this devastating pandemic, considering their protective benefits in the general population. Yet, data regarding their efficacy and safety in cancer patients are limited. Herein we provide the initial analysis of immune responses after the first dose of vaccination in 21 breast cancer patients receiving cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors. The levels of neutralizing antibodies post vaccination were similar to the matched healthy controls, whereas no safety issues have been raised. Further exploration is needed to reduce the uncertainty of SARS-CoV-2 immunity among cancer patients under treatment.     

Safety of cyclin-dependent kinase4/6 inhibitor combined with palliative radiotherapy in patients with metastatic breast cancer

IntroductionCyclin-dependent kinase (CDK)4/6 inhibitor is a first-line therapy for metastatic ER+/HER2-breast cancer. However, there are limited data on safety of combined radiotherapy (RT) and CDK4/6 inhibition.MethodsWe conducted a retrospective study of women with metastatic breast cancer who received palliative RT within 14 days of CDK4/6 inhibitor use. The primary endpoint was toxicity per Common Terminology Criteria for Adverse Events v5. Secondary endpoints were pain response and local control based on clinical assessment and imaging.ResultsThirty patients underwent 36 RT courses with palbociclib (n = 34 courses, 94.4%) or abemaciclib (n = 2, 5.6%). RT was delivered before, concurrently or after CDK4/6 inhibitors in 7 (19.4%), 8 (22.2%), and 21 (58.3%) of cases with median 3.5 days from RT to closest CDK4/6 inhibitor administration. Median RT dose was 30Gy (range 8–40.05Gy). Treated sites included brain (n = 5, 11.6%), spine (n = 19, 44.2%), pelvis (n = 9, 20.9%), other bony sites (n = 6, 14.0%) and others (n = 4, 9.3%). No acute grade ≥3 non-hematologic toxicity occurred. No increased hematologic toxicity was attributable to RT with grade 3 hematologic toxicities rates 16.7%, 0%, and 6.7% before, during, and 2 weeks after RT completion. All but one patient (29/30) achieved symptom relief. Local control rates were 94.4%, 91.7% at 6 and 12 months.ConclusionsThe use of RT within 2 weeks of CDK4/6 inhibitors had low acceptable toxicity and high efficacy, suggesting that it is safe for palliation of metastatic breast cancer.     

改良关节镜下弹性固定 Latarjet 手术中移植骨块偏外放置对肩关节退变影响的影像学研究

目的探讨改良关节镜下弹性固定 Latarjet 手术治疗伴有明显肩胛盂前缘骨缺损的肩关节复发性前脱位时，移植骨块偏外放置在术后中期对肩关节退变的影响。方法回顾分析 2015 年 1 月—2016 年 11 月收治且符合选择标准的 18 例肩关节复发性前脱位伴肩胛盂前缘骨缺损患者临床资料，均接受改良关节镜下弹性固定 Latarjet 手术。男 12 例，女 6 例；年龄 19～37 岁，平均 26.2 岁。肩关节脱位 4～30 次，平均 8.8 次。病程 8～49 个月，平均 23.8 个月。肩胛盂前缘骨缺损为 20%～29%，平均 25.2%。肩关节不稳定严重指数评分（ISIS）为 7～10 分，平均 7.6 分。肩关节退变 Samilson-Prieto 分级：0 级 13 例，Ⅰ级 3 例，Ⅱ级 2 例。手术前后采用疼痛视觉模拟评分（VAS）、美国肩肘外科协会评分（ASES）、Walch-Duplay 评分、Rowe 评分和肩关节活动度评价临床疗效。影像学观察肩关节退变情况以及移植骨块位置、肩胛盂塑形情况。结果术后患者均获随访，随访时间 55～62 个月，平均 59.6 个月。无血管神经损伤、感染、固定物和移植骨块相关并发症发生，随访期间无肩关节脱位复发和翻修患者。患者均恢复正常生活，17 例重返运动。末次随访时，VAS 评分较术前明显降低，ASES 评分、Walch-Duplay 评分、Rowe 评分明显提高，差异均有统计学意义（P<0.05）；肩关节前屈、外展、外展 90° 外旋、0° 外旋和外展 90° 内旋活动度与术前比较，差异均无统计学意义（P>0.05）。术后即刻三维 CT 显示所有移植骨块中心在肩胛盂 En-face 面上位于 3∶30～4∶30（右肩）或 7∶40～8∶20（左肩）位置，无移植骨块过高或过低；在 CT 横断面上相对于肩胛盂偏外 2.3～4.6 mm，平均 3.5 mm。患者术后 36、48 个月及末次随访时的肩关节退变 Samilson-Prieto 分级与术前一致，均未进展。所有移植骨块在术后 24 个月内塑形达稳定，在三维 CT 肩胛盂 En-face 面显示塑形后的肩胛盂外形为与正常肩胛盂相近的正梨形，在 CT 横断面上为与肩胛盂齐平并形成与肱骨头圆形近似的弧形。末次随访时肩胛盂外形与术后 24 个月比较无明显变化。 结论改良关节镜下弹性固定 Latarjet 手术中移植骨块偏外放置，术后中期未出现肩关节退变进展的影像学改变。