The role of the HLA allelic repertoire on the clinical severity of COVID-19 in Canadians,living in the Saskatchewan province

AimsThe HLA system has been implicated as an underlying determinant for modulating the immune response to SARS-CoV-2. In this study, we aimed to determine the association of patients’ HLA genetic profiles with the disease severity of COVID-19 infection.MethodsProspective study was conducted on COVID-19 patients (n = 40) admitted to hospitals in Saskatoon, Canada, between March and December 2020. Next-generation sequencing was performed on the patient samples to obtain high-resolution HLA typing profiles. The statistical association between HLA allelic frequency and disease severity was examined. The disease severity was categorized based on the length of hospital stay and intensive care needs or demise during the hospital stay.ResultsHLA allelic frequencies of the high and low-severity cohorts were normalized against corresponding background allelic frequencies. In the high-severity cohort, A*02:06 (11.8-fold), B*51:01 (2.4-fold), B*15:01(3.1-fold), C*01:02 (3.3-fold), DRB1*08:02 (31.2-fold), DQ*06:09 (11-fold), and DPB1*04:02(4-fold) were significantly overrepresented (p < 0.05) making these deleterious alleles. In the low-severity cohort, A*24:02 (2.8-fold), B*35:01 (2.8-fold), DRB1*04:07 (5.3-fold), and DRB1*08:11 (22-fold) were found to be significantly overrepresented (p < 0.05) making these protective alleles. These above alleles interact with NK cell antiviral activity via the killer immunoglobulin-like receptors (KIR). The high-severity cohort had a higher predilection for HLA alleles associated with KIR subgroups; Bw4-80I (1.1-fold), and C1 (1.6-fold) which promotes NK cell inhibition, while the low-severity cohort had a higher predilection for Bw4-80T (1.6-fold), and C2 (1.6-fold) which promote NK cell activation.ConclusionIn this study, the HLA allelic repository with the distribution of deleterious and protective alleles was found to correlate with the severity of the clinical course in COVID-19. Moreover, the interaction of specific HLA alleles with the KIR-associated subfamily modulates the NK cell-mediated surveillance of SARS-CoV-2. Both deleterious HLA alleles and inhibitory KIR appear prominently in the severe COVID-19 group focusing on the importance of NK cells in the convalescence of COVID-19.     

Immunological changes among workers occupationally exposed to styrene

The functional status of the immune system was investigated in a group of 71 workers exposed to styrene and in 65 control subjects, recruited according to the same selection criteria and comparable as to sex, age, and confounding variables. Air and biological monitoring were used to characterize styrene exposure (median of the main urinary metabolites in the next-morning spot samples: 106 mg/g creatinine). Phenotypic analysis of peripheral blood lymphocytes (PBL) by automated flow cytometry revealed a reduced proportion of T lymphocyte subsets (CD3⁺, CD4⁺ and CD4⁺45⁺), with no changes in CD8⁺, and a higher proportion of B lymphocytes (CD19⁺) among styrene-exposed workers. The exposed workers showed a higher proportion of activation markers, namely DR and interleukin-2 receptors (CD25). Immunoglobulin subclasses were comparable in the two groups. An increased prevalence of abnormally low values was apparent for CD2⁺, CD3⁺, CD4⁺, CD4⁺45⁺ and CD11b subsets among workers exposed to styrene, whereas CD19⁺, DR⁺ and CD25⁺ showed an increased prevalence of abnormally high values. Natural killer-related phenotypes (CD56⁺, CD56+16⁺, and CD56⁺16^–) were more expressed among styrene workers, with average increase of 30%. However, the frequency distribution of the lytic activity of natural killer cells against K-562 target cells was shifted towards lower values in the exposed workers as compared to control subjects. Dose-response relationships between indices of internal dose and prevalence of abnormal values were detectable for T lymphocyte subsets, NK phenotypes, and activation markers. These findings suggest that moderate exposure to styrene is associated with an altered distribution of lymphocyte subsets. The decreased proportion of T lymphocytes, mainly of T helper-inducer cells, could hamper regulatory functions, thus suggesting a negative modulation by styrene exposure. Since a proper balance between immunocycte subsets is important for immunological responses, such changes should be regarded as adverse effects.     

A decade of spontaneous long-term course of psychogenic impairment in a community population sample

Background: Our epidemiological study demonstrates the spontaneous long-term course of predominantly psychosocially influenced (“psychogenic”) disorders (neurotic spectrum disorders, personality disorders, stress reactions and somatoform disorders) in a representative community sample of the normal adult population of Mannheim, an industrial and university town in Germany. The natural spontaneous course of these disorders in a population sample over a long period remains largely unknown. Method: Beginning in 1979 (n _t1 = 600) a random population sample was investigated three times over a mean period of approximately 11 years. The last follow-up study ended in 1994 (n _t3 = 301). The follow-up sample was representative of the t1 sample. Psychodynamically trained and clinically experienced interviewers used a semi-structured interview and standardized clinical and psychometric instruments. Psychogenic impairment was assessed using a standardized expert rating (Impairment Score, IS). Results: The mean sum-score of psychogenic impairment after 11 years exceeded the value at t1. The case rate (point prevalence, ICD diagnosis + clinical cut-off/IS) increased from 21.6% at t1 to 26.2% at t3 in the investigated follow-up sample. Intra-individual correlation of psychogenic impairment between t1 and t3 was high (r = 0.55). We found strong evidence for an unfavorable long-term course of psychogenic impairment and only a weak tendency (23.1%) for spontaneous remission of clinically relevant psychogenic impairment. Within a regression model clinical variables, childhood development conditions and personality traits at t1 predicted psychogenic impairment at t3. Conclusion: All clinical variables conclusively indicate an unfavorable spontaneous long-term course of psychogenic impairment. Together with the well-known high prevalence of psychogenic disorders in the normal population, this underlines the need for early therapeutic and preventive intervention. Accepted: 20 August 1999     

Bioprosthetic heart valves--replacing order with chaos: electron microscopic study

Rheumatic heart disease is a significant clinical entity in young children, especially in the developing world. One of the major long-term effects of ill managed rheumatic fever is irreversible damage to the cardiac valve leaflets, primarily on the left side. With the limited success of currently available mechanical and bioprosthetic valves, there is an urgent need for new directions in bioprosthetic valves, both in material, including source, degree of fixation, surface, bulk modifications, etc., and design. In the present paper, new proposals in the material selection and fabrication of bioprosthetic valves are proposed based on electron microscopic studies of natural valve leaflets and the pericardial surface. Current approaches for bioprosthetic valve fabrications include the wide use of the pericardium as a leaflet material. The present study indicates a need for nondestructive surface examination of pericardial sheets for the elimination of areas of surface voids resulting from gross fiber disorientation. Also, there seems to be a need for incorporation of an in situ fiber renewal mechanism in bioprosthetic leaflets to emulate the natural valve more closely. Apparently natural leaflets have built-in fiber renewal mechanism(s).     

Einfluß des operationstraumas auf die NK-zell-aktivität beim ösophaguskarizinom nach transmediastinaler dissektion vs. transthorakaler en-bloc-resektion

Zusammenfassung Um den Einfluß des chirurgischen Traumas beim Ösophaguskarzinom auf das zelluläre Immunsystem zu erfassen, wurden perioperativ in einer prospektiven Studie die Aktivität der natürlichen Killerzellen sowie die Serumkonzentrationen von Interleukin-2, Interleukin-6 un TNF- bei transmediastinaler Dissektion (n=12) vs. transthorakaler En-bloc-Resektion (n=10) der Speiserörhre im Vergleich zu einer Kontrollgruppe mit thorakoabdominalen chirurgischen Eingriffen bei nicht maligner Grunderkrankung erfaßt. Die Bestimmung der NK-Zell-Aktivität erfolgte präoperativ sowie am 4. und 10. Tag postoperativ durch einen standardisierten Europiumchlorid-release-Assay unter Verwendung von K-562-Targetzellen, die Lymphokine Interleukin-2, Interleukin-6 und TNF- wurden zusätzlich am 1. und 7. Tag postoperativ mit stadardisierten ELISA-Assays bestimmt.In unserem Patientengut sank die NK-Zellaktivität am 4. postoperrativen Tag sowohl in der Kontrollgrupe al auch bei beiden Operations verfahren zur Speiseröhrenresektion signifikant (p<0,05) zum Ausgangswert: in der Kontrollgruppe durchschnittlich um 45%, nach transmediastinaler Speriseröhrendissektion (1-Höhlen-Eingriff) durchschnittlich um 34%, nauch transthorakaler En-bloc-Resektion (2-Höhlen-Eingriff) im Mittel um 63% zum präoperativen Wert. Die transthorakale En-bloc-Resektion der Speiseröhre führte durch das größere chirurgische Trauma zu einer stäkeren Abnahme der zytotoxischen Aktivität der natürlichen Killerzellen. Eine Suppression der immunologischen Tumorabwehr insbesondere in der vulnerablen perioperativen Phase kann damit indirekt das Risiko der Manifestation von hämatogene Metastasen auf dem Boden einer intraoperativen Tumorzelldissemination u. a. bedingt durch Tumormanipulation begünstigen und damit prognostisch relevant werden.

---

Influence of surgical trauma on natural killer cell activity in esophageal carcinoma following transmediastinal dissection compareed with transthoracic en bloc resection

In order to assess the impact of surgical trauma involved in the therapy of esophageal carcinoma on the cellular immune system, a perspective study was performed involving perioperative hematological parameters. The activity of natural killer cells and the serum concentrations of interleuin-2, interleukin-6 and TNF- were measured in 12 cases of transmediastinal dissection and 10 cases of transthioracic en bloc esophageal resection and compared to values of a control group of thoracic and abdominal surgical patients with non-malignant maladies. Natural killer cells assume a central role in the non-specific immunological response in tumor patients. Their main function is the destruction of tumor cells via cytotoxic activities amplified by the release of interleukin-2 and TNF-. Natural killer cell activity was measured prior to surgery and on postoperative days 4 and 10 using a standardized europium chloride release assay, utilizing K 562 target cells. Lymphokines interleukin-2, interleukin-6, and THF- were also measured on postoperative days 1 and 7 using standardized ELISA assays. The activity of natural killer cells in our patient group sank significantly (P<0.05) on postoperative day 4 and likewise in the control group and both study groups, activity sank to the original values. In the control groups, natural killer cell activity averaged 45% of preoperative values, in comparison with an average of 63% following transmediastinal esophageal carcinoma resection (one cavity procedure), and transthoracic en bloc resection patients only reached 61% of preoperative values, transmediastinal dissection patients assumed 75%, and 77% was achieved by control group members. Transthoracic en bloc resection of the esophagus led to a more extreme reduction in cytotoxic cellular activity owing to the greater surgical trauma. Suppression of the immunological tumor resistance, especially in the vulnerable perisurgical pahse, can have an indirect negative effect on the manifestation risk of hematogenic metastases owing to intraoperative tumor cell dissemination resulting from tumor manipulation and may thus be prognostically relevant.

     

生地黄中环烯醚萜苷类的纯化分离工艺

目的:寻找有效纯化分离生地黄中环烯醚萜苷类的方法.方法:生地黄水提物用高效液相色谱法,以梓醇为其环烯醚萜苷类的测定指标,比较101 果汁澄清剂和科阳1＋1天然澄清剂的纯化效果,以及乙醇和非极性大孔吸附树脂的分离效果.结果:生地黄水提物以科阳1＋1天然澄清剂纯化,用非极性大孔吸附树脂分离,可使其中的环烯醚萜苷类有效分离出来.结论:在工业生产中可用科阳1＋1天然澄清剂与非极性大孔吸附树脂联合应用来纯化分离生地黄中的环烯醚萜苷类.     

体外培育牛黄与天然牛黄指纹图谱的比较研究

目的：研究、比较体外培育牛黄与天然牛黄的指纹图谱。方法：利用TOFMS、HPIEJMS技术研究、比较体外培育牛黄与天然牛黄中肽类、胆汁酸类和胆红素类3类成分的指纹图谱。结果：体外培育牛黄与天然牛黄3类成分的指纹基本一致，但各成分间的相对含量有差异。结论：10批体外培育牛黄的指纹图谱有较好的一致性，说明体外培育牛黄的质量稳定。4批天然牛黄的指纹图谱，尤其是胆汁酸类成分的指纹图谱差异明显，说明天然牛黄由于来源不同，导致质量不够稳定.     

国家自然科学基金资助基础研究项目评述(1)中药化学

中药化学是中药学基础研究中的分支学科，主要对中草药(植物、矿物、动物药物)单味或复方进行提取、分离和成分测定，并对其中具有明确治疗作用的单一化学成分或多组化学成分做进一步研究。本文简要介绍和分析了中药化学的研究情况及国家自然科学基金委员会(NSFC)生命科学部中医学和中药学学科近五年(1998～2002)间对中药化学研究项目的资助情况以及目前国内中药化学的研究概况。     

Depressed natural killer cell activity due to decreased natural killer cell population in a vitamin E-deficient patient with Shwachman syndrome: reversible natural killer cell abnormality by α-tocopherol supplementation

Natural Killer (NK) cell activity was examined in a 16-month-old Japanese boy with Shwachman syndrome associated with severe vitamin E deficiency. As evaluated by ⁵¹Cr-release assay from K562 cells, NK cell activity was constantly decreased. After 8 weeks of oral α-tocopherol (α-Toc) supplementation (100 mg/day), NK cell activity had normalised. When α-Toc supplementation was interrupted for 16 weeks, NK cell activity again decreased. Flow cytometry of peripheral lymphocytes revealed a lowered number of CD16⁺ CD 56⁻ fraction, which has the most potent NK cell activity. Single cell-in-agarose assay, to investigate the binding and cytolytic activity of NK cell at the single cell level, revealed that the number of NK cells which bind to K562 cell was decreased, but that the cytolytic activity of the individual binding cell was relatively unaffected. A second supplementation of α-Toc for 8 weeks successfully restored NK cell activity, the number of cells expressing NK cell markers and the number of K562-binding cells as compared to the age-matched normal range. Conclusion These results indicate that severe vitamin E deficiency caused impaired NK cell activity due to a decrease in the number of CD16⁺ CD56⁻ NK cells and that this abnormality is reversible with α-Toc supple‐mentation. Received: 30 January 1996 and in revised form: 19 November 1996 / Accepted: 22 November 1996     

头颈部肿瘤患者自然杀伤细胞活性及计数分析

本文对25例头颈部肿瘤患者的外周血NK细胞杀伤活性及NK细胞计数进行测定，其中有15例患者手术治疗切除肿瘤，于术后三周复查NK活性及NK计数，并与正常人组对照。实验结果显示：头颈部肿瘤患者NK活性及NK计数均低于正常人，两组比较均有极显著性差异（P＜0．01）；术后患者的NK活性比术前有明显提高，配对t检验P＜0．01，NK计数比术前也有所提高，配对t检验P＜0．05，有显著性差异；NK活性的水平与肿瘤的分期有相关性，晚期（T4期）癌症患者NK活性明显低于早期（T1、T2）患者，可以看出NK活性随着肿瘤的发展而降低，肿瘤对宿主有免疫抑制作用；NK活性与NK数量之间无显著的相关性，二者之间的相关系数r＝0．344。